Download see p. 2750 - Viktor`s Notes for the Neurosurgery Resident

DIABETES MELLITUS
2750 (1)
Diabetes Mellitus
Last updated: May 2, 2017
CLASSIFICATION ................................................................................................................................................... 3
ETIOPATHOGENESIS............................................................................................................................................. 5
PATHOLOGY ......................................................................................................................................................... 9
PATHOPHYSIOLOGY ........................................................................................................................................... 13
EPIDEMIOLOGY .................................................................................................................................................. 15
SIGNS & SYMPTOMS .......................................................................................................................................... 16
DIAGNOSIS ......................................................................................................................................................... 18
SCREENING......................................................................................................................................................... 19
TREATMENT .............................................................................................................................................. 19
Non-pharmacologic Measures...................................................................................................................... 20
I. Diet ................................................................................................................................................. 21
II. Exercises........................................................................................................................................ 22
PREDIABETES ......................................................................................................................................................... 23
TYPE 1 DIABETES .................................................................................................................................................... 23
Insulin Preparations ...................................................................................................................................... 23
Insulin Regimens ........................................................................................................................................... 26
A. CONVENTIONAL INSULIN THERAPY .............................................................................................. 26
B. INTENSIVE INSULIN THERAPY ....................................................................................................... 28
Complications of insulin treatment .............................................................................................................. 31
Lifestyle Changes .......................................................................................................................................... 32
Pancreas/Islet Transplantation ..................................................................................................................... 33
TYPE 2 DIABETES .................................................................................................................................................... 33
Pharmacologic Intervention ......................................................................................................................... 34
ORAL GLUCOSE-LOWERING AGENTS ................................................................................................ 34
INSULIN THERAPY ............................................................................................................................. 41
Treatment Strategies for Type 2 Diabetes.................................................................................................... 41
MONITORING ........................................................................................................................................................ 42
TREATMENT IN SPECIAL CIRCUMSTANCES ................................................................................................................... 45
During sick days ............................................................................................................................................ 45
During hospitalizations ................................................................................................................................. 46
Type 1 diabetics ................................................................................................................................ 46
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Type 2 diabetics ................................................................................................................................ 46
During surgical procedures ........................................................................................................................... 46
Type 1 diabetics ................................................................................................................................ 46
Type 2 diabetics ................................................................................................................................ 47
During pregnancy ......................................................................................................................................... 47
Obstetric complications of diabetes ................................................................................................. 48
During labor and delivery ............................................................................................................................. 48
ACUTE METABOLIC COMPLICATIONS.......................................................................................................... 49
DIABETIC KETOACIDOSIS (DKA) .......................................................................................................................... 49
HYPERGLYCEMIC HYPEROSMOLAR SYNDROME (HHS) ...................................................................................... 52
ALCOHOLIC KETOACIDOSIS ................................................................................................................................ 58
NEONATAL HYPERGLYCEMIA ............................................................................................................................. 59
HYPOGLYCEMIA ................................................................................................................................................. 59
Pathophysiology ........................................................................................................................................... 60
Signs & symptoms......................................................................................................................................... 60
Diagnosis ....................................................................................................................................................... 61
Treatment ..................................................................................................................................................... 61
Classification of hypoglycemias .................................................................................................................... 62
NEONATAL HYPOGLYCEMIA .............................................................................................................................. 64
Physiology ......................................................................................................................................... 64
Etiology ............................................................................................................................................. 64
Symptoms, Signs ............................................................................................................................... 65
Prophylaxis ........................................................................................................................................ 65
Treatment ......................................................................................................................................... 65
CHRONIC DIABETIC COMPLICATIONS.......................................................................................................... 66
Pathogenesis................................................................................................................................................. 66
Screening ...................................................................................................................................................... 66
DIABETIC MICROANGIOPATHY .................................................................................................................................. 67
DIABETIC RETINOPATHY........................................................................................................................................... 67
epidemiology .................................................................................................................................... 67
pathology .......................................................................................................................................... 67
treatment .......................................................................................................................................... 69
Screening .......................................................................................................................................... 69
DIABETIC NEPHROPATHY ......................................................................................................................................... 69
DIABETES MELLITUS
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epidemiology .................................................................................................................................... 69
pathophysiology................................................................................................................................ 70
klinika & diagnosis ............................................................................................................................ 76
Treatment ......................................................................................................................................... 76
Screening .......................................................................................................................................... 77
DIABETIC FOOT ...................................................................................................................................................... 78
klinika ................................................................................................................................................ 78
prevention......................................................................................................................................... 78
Treatment ......................................................................................................................................... 79
HYPERTENSION ...................................................................................................................................................... 79
ATHEROSCLEROSIS .................................................................................................................................................. 80
Metabolic syndrome (s. syndrome X, syndrome of insulin resistance)........................................................ 82
CANCER ................................................................................................................................................................ 82
DERMATOLOGICAL MANIFESTATIONS OF DIABETES ...................................................................................................... 83
Necrobiosis Lipoidica ........................................................................................................................ 83
Acanthosis Nigricans ......................................................................................................................... 83
Erythrasma ........................................................................................................................................ 84
GESTATIONAL DIABETES ............................................................................................................................ 85
DIABETIC NEUROPATHY – see 2751 p.
DIABETES MELLITUS - group of chronic disorders characterized by impaired metabolism of glucose and other
energy-yielding fuels (hyperglycemia is common denominator in all these disorders).

pagrindinis mechanizmas - INSULIN DEFICIENCY (total, partial, relative) - plays primary role in metabolic
derangements;
Hyperglycemia plays key role in complications!

normal fasting glycemia is 70-110 mg/dL.

acute severe illnesses may provoke stress hyperglycemia (result of insulin antagonistic hormones
hypersecretion), but it is self-limited.
CLASSIFICATION
Risk categories (Prediabetes)
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I. Impaired fasting glucose
II. Impaired glucose tolerance
III. Hemoglobin A1C 5.7-6.4%
Clinical Diabetes
I. Type 1 diabetes
(formerly called insulin-dependent diabetes mellitus (IDDM) or "juvenile-onset diabetes")
A. Immune mediated (type 1A diabetes)
B. Idiopathic (type 1B diabetes)
II. Type 2 diabetes
(formerly called non-insulin-dependent diabetes (NIDDM) or "adult-onset diabetes")
III. Other specific types
A. Genetic defects of β-cell function
(e.g. maturity-onset diabetes of young [MODY], mutations in mitochondrial DNA)
B. Genetic defects in insulin action
(e.g. leprechaunism, Rabson-Mendenhall syndrome, acanthosis nigricans, lipoatrophic diabetes)
C. Disease of exocrine pancreas
(e.g. pancreatitis, trauma, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis,
fibrocalculous pancreatopathy)
D. Endocrinopathies
(e.g. acromegaly, Cushing's syndrome, hyperthyroidism, pheochromocytoma, glucagonoma,
somatostatinoma, aldosteronoma) ≈ type 2 diabetes
E. Drug or chemical induced
(e.g. glucocorticoids, thiazides, diazoxide, pentamidine, rodenticide Vacor, thyroid hormone,
phenytoin, β-agonists, oral contraceptives)
F. Infections
(e.g. congenital rubella, cytomegalovirus)
G. Uncommon forms of immune-mediated diabetes
(e.g. "stiff-man" syndrome, anti-insulin receptor antibodies)
H. Other genetic syndromes
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(e.g. Down, Klinefelter's, Turner's syndrome, Huntington's disease, myotonic dystrophy,
lipodystrophy, ataxia-telangiectasia)
IV. Gestational diabetes
N.B. any form of diabetes may require insulin treatment - previously used terms INSULIN-DEPENDENT and
NON-INSULIN-DEPENDENT have been eliminated.
ETIOPATHOGENESIS
TYPE 1 DIABETES
interplay of factors (genetic, environmental, autoimmune) → selective β-cell destruction → absolute insulin
deficiency with secondary insulin resistance.
I. GENETIC FACTORS – predisposing factors.
see also 3776 p. (GENETICS)

concordance 30-50% in identical twins (because concordance is not 100%, environmental factors must be
important).

risk in first-degree relative ≈ 10%.

genetic susceptibility is polygenic.
Genes linked to disease:
1) gene within insulin promoter region (chromosome 11) - influences insulin gene expression in
thymus (thymic selection of insulin-reactive T cells).
2) gene in or near HLA region (chromosome 6p) - dominant role; risk of diabetes in non-affected
siblings:
–
if they are HLA identical – 15-20%
–
if they share one HLA gene - 5%
–
if they are HLA non-identical - < 1%.

specific HLA-D haplotypes linked to type 1 diabetes: 90-95% express DR3 and/or DR4 class II HLA
molecules (vs. only 50-60% in general population), and 60% express both alleles (<6% in general
population).

HLA-DR2 has negative association with disease.
N.B. no single class II HLA gene accounts for HLA-associated susceptibility (significant genetic
heterogeneity exists).

association with specific class II HLA genes implies CD4+ T cells involvement in autoimmunity process.

certain genetic syndromes (Down, Klinefelter, Turner) increase risk for diabetes.
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II. ENVIRONMENTAL FACTORS – initiating (triggering) factors:
a) directly damage β-cells and unclose hidden β-cell antigens
b) molecular mimicry between β-cell antigens and initiating factor
1. Diet

exposure to cow's milk rather than maternal milk in infancy (specific cow's milk albumin sequence
may cross-react with islet protein).
2. Toxins
3. Viruses (mumps, coxsackievirus, congenital rubella) – most likely initiating factor.

viruses (that contain epitope that resembles β-cell protein – molecular mimicry) trigger
autoimmune response;
e.g. sequence homology has been identified between coxsackievirus B protein and β-cell
enzyme glutamic acid decarboxylase (important autoantigen in type 1 diabetes).
III. AUTOIMMUNE FACTORS – executive factors.
Humoral immunity

80% of patients have islet cell autoantibodies (against insulin, glutamic acid decarboxylase isoforms [GAD
65, GAD 67], secretory granule protein ICA 512, etc.).
N.B. antibodies are markers rather than cause of β-cell injury!
-

GAD autoantibodies can be detected long before onset of clinical symptoms –
naudojami prospektyvinėse preventyvinėse studijose.
diabetui progresuojant, autoantibodies become undetectable.
Cellular immunity – primary mechanism of β-cell destruction (apoptotic and cytotoxic mechanisms):
1) cytokines released by T cells and macrophages
2) direct actions of T cells.
o
at disease onset there are monocytic (CD8+ and CD4+ T cells, macrophages) infiltrates
restricted to islets (INSULITIS);
o
at time of clinical diagnosis, about 5-10% of β-cell mass remains;
o
as disease progresses, islets become completely devoid of β-cells and inflammatory infiltrates,
with α, δ, and PP cells left intact.

specific antigens recognized by diabetogenic T cells remain uncertain.

monozygotic twins with diabetes who receive pancreas grafts from their non-diabetic, genetically identical
sibling require little or no immunosuppression for graft acceptance, but islets are soon selectively invaded
with mononuclear cells → recurrence of diabetes.

immunosuppressive drugs (e.g. cyclosporine) slow or prevent progression of recent-onset diabetes, but
must be administrated continuously to maintain effect.

CHRONIC SMOLDERING disease nature suggests also presence of protective (regulatory) populations of T cells.
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TYPE 2 DIABETES
Insulin resistance → insulin levels are too low relative to magnitude of insulin resistance and ambient glucose
levels → relative insulin deficiency.
Vicious cycle in which hyperglycemia begets more severe hyperglycemia:
1) undefined genetic defect leads to hyperglycemia
 concordance in identical twins is ≈ 100%, risk in first-degree relative 20%.
N.B. no HLA association!
2) hyperglycemia itself impairs insulin secretion and action ("glucose toxicity" phenomenon).

spėjamas “glucotoxicity” mechanizmas: glucosamine (product of glucose metabolism via
hexosamine pathway) impairs insulin-induced GLUT 4 translocation to cell membrane.
3) galiausiai all patients exhibit both insulin resistance and defective insulin secretion.
 jei gydant pavyksta sunormalizuoti glikemiją → insulin resistance↓ (reversal of glucotoxicity).
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INSULIN RESISTANCE

type 2 diabetes is characterized by marked impairment in insulin action (nukenčia ne tik glucose uptake in
peripheral tissues, bet ir kiti metaboliniai insulino efektai - inhibition of hepatic glucose production and
lipolysis, etc.).

mechanisms for insulin resistance remain poorly understood:
a) defects in "post-receptor" events play predominant role - variety of genetic abnormalities
produce identical clinical phenotype.
b) ↓number of insulin receptors
c) defects in insulin binding to receptors – various rare syndromes (e.g. leprechaunism).


mechanisms of insulin resistance in obese and non-obese patients do not differ, but coexistence of OBESITY
accentuates severity of resistant state;
–
abdominal (vs. lower body) obesity is associated with ↑insulin resistance - visceral (intraabdominal) fat has higher lipolytic rate (delivers free fatty acids to liver) and is more
resistant to modulating effects of insulin than is peripheral (subcutaneous) fat.
–
fat distribution priklauso nuo hereditary factors and/or cortisol hypersecretion.
longstanding insulin resistance is associated with dyslipidemia, central obesity, hypertension, and
hyperglycemia (common coexistence of cardiovascular disease and diabetes).
INSULIN SECRETION

fasting insulin levels are normal (or increased), but relatively low for coexisting hyperglycemia.

insulin secretory defects start ≈ 10 years before diagnosis.

in mildest form, β-cell defect is subtle – only loss of acute (1st phase) insulin response to glucose (taigi,
nukenčia sekrecija, o ne insulino sintezė).

defect worsens as disease progresses → lose capacity to respond to [glucose]↑; in established diabetes
glucose-stimulated insulin secretion is clearly decreased.

cause of β-cell failure is unknown:
a) decreased expression of GLUT 2.
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b) amyloid-like deposits between cells within islets (composed of "amylin" - peptide synthesized in βcell and co-secreted with insulin).
c) impaired insulin receptor signaling within β-cell.
RESUME

insulin resistance is initial predisposing defect.

for diabetes to become manifested, additional factor of impaired insulin secretion is required;
it is unclear whether secretory defect is secondary phenomenon (e.g., "β-cell exhaustion" or islet
amyloid polypeptide hypersecretion) or independent defect.
N.B. it is unlikely that single pathogenetic mechanism is responsible for type 2 diabetes.
MATURITY-ONSET DIABETES OF YOUNG (MODY)

formerly was included as form of type 2 diabetes.

inherited in autosomal dominant pattern (monogenic defects with high penetrance).

early onset, usually before age 25.

accounts for < 5% diabetes cases.

normal weight, lack of GAD antibodies, lack of insulin resistance syndrome.
Several genetic defects of β-cell function:
1. MODY type 1 - mutation of HNF-4α (hepatocyte nuclear factor-4alpha), chromosome 20.
2. MODY type 2 - mutation of glucokinase, chromosome 7 → interference with transduction of glucose
signal to β-cell.
3. MODY type 3 (most common form) - mutation of HNF-1α, chromosome 12.
4. MODY type 4 - mutation of IPF-1, chromosome 13.
5. MODY type 5 - mutation of HNF-1β, chromosome 17.
6. MODY type 6 - mutation of NeuroD1, chromosome 2.
PANCREATIC PATHOLOGY

patients lose both INSULIN-secreting and GLUCAGON-secreting islets → only mild hyperglycemia.

lack of effective counterregulation (glucagon) - sensitive to low doses of exogenous insulin - frequently
suffer from rapid onset of hypoglycemia.
PATHOLOGY
DIABETES MELLITUS
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PANCREAS lesions are inconstant and rarely of diagnostic value.
Type 1 diabetes:
1) ↓number and ↓size of islets (esp. in rapidly advancing disease) – selektyviai nyksta β-cells; kitų tipų
ląstelės nenukenčia!
2) leukocytic infiltration of islets (INSULITIS).
3) β -cell degranulation - depletion of stored insulin in already damaged β-cells.
Type 2 diabetes:
1) subtle reduction in islet cell mass (demonstrated only by special morphometric studies).
2) amyloid replacement of islets - pink, amorphous material in and around capillaries and between cells;
in advanced stages islets may be virtually obliterated; fibrosis may also be observed.
CAPILLARIES – pathognomonic basement membrane thickening.
Normal islets of Langerhans:
Normal islets of Langerhans (RIGHT - staining for insulin to identify beta cells; LEFT - staining for glucagon to
identify alpha cells):
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Diabetes mellitus type 1 (acute stage) - islet of Langerhans demonstrates insulitis (lymphocytic infiltrates in
edematous islet):
Diabetes mellitus type 1 (chronic stage) - islet cells entirely replaced by amyloid:
DIABETES MELLITUS
Diabetes mellitus type 2 - islet of Langerhans demonstrates amorphous pink deposition (amyloid):
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DIABETES MELLITUS
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PATHOPHYSIOLOGY
Body metabolically responds as if it is starving even though food is available (“starvation in the midst of
plenty”).
GLUCOSE CONSUMPTION IN PERIPHERAL TISSUES↓ + HEPATIC GLUCOSE OUTPUT↑ →
→ intracellular glucose deficiency + extracellular glucose excess

CNS and RBCs glucose uptake, intestinal and renal glucose (re)absorption are unaffected by diabetes.

diabetikų organizmas energiją pagrinde gauna iš fats & proteins.

metaboliniai profiliai abiejų diabeto tipų atvejais vienodi, išsk. type 2 atveju esti [insulin]↑
Liver plays crucial role in determining fasting HYPERGLYCEMIA:

peripheral glucose consumption↓ svarba ne tokia didelė - because basal glucose uptake occurs largely in
non-insulin-sensitive tissues, total-body glucose uptake is even increased (mass action of hyperglycemia).

portal insulin deficiency → hepatic gluconeogenesis↑.

insulin deficiency → excessive release of counterregulatory hormones:
1) glucagon (insulinas nebeslopina α-cells; glucagon excess esti net po
pankreatektomijos, nes gliukagoną gamina ir GI mucosa)
2) GH

counterregulatory hormones increase gluconeogenesis further and block compensatory increases in
glucose utilization.
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Lack of insulin leads to:
1) mobilization of substrates (for gluconeogenesis and ketogenesis) from muscle and adipose tissue.
2) accelerated production of glucose and ketones by liver.
3) impaired removal of fuels (endogenously produced and exogenous) by insulin-responsive tissues.
4) net result is HYPERGLYCEMIA and HYPERKETONEMIA that overwhelm renal removal mechanisms.
Hypoinsulinemia + counterregulatory hormones↑:

lipolysis↑ + lipogenesis↓ → fasting levels of free fatty acids↑
[free fatty acids]↑ parallel [glucose]↑;
in some ways [free fatty acids]↑ is better indicator of diabetes severity than [glucose]↑.

although FFA are not directly converted to glucose, they promote hyperglycemia by:
1) providing liver with energy to support gluconeogenesis
increase in substrate delivery may become so pronounced that it saturates oxidative
pathway and leads to fatty liver and severe HYPERTRIGLYCERIDEMIA.
2) interfering with glucose uptake in muscle (by reducing glucose utilization).

pronounced acetyl-CoA excess (from FFA) → ketogenesis↑ in liver;
–
in type 2 diabetes, endogenous insulin in portal blood suppresses ketogenesis.
–
in type 1 diabetes, mobilized FFA are readily converted to ketone bodies.

hypoinsulinemia decreases ketone turnover → ketosis↑.

protein synthesis↓ + protein conversion to glucose↑ → NEGATIVE NITROGEN BALANCE.

protein depletion → resistance to infections↓.
D:\Viktoro\Neuroscience\USMLE 2\Endocrine system, metabolism (2701-2800)\ViktoroUSMLE 2Endocrine
DIABETES MELLITUS
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system, metabolism - NESPAUSDINTA01. vadovėlių tekstaiDiabetes mellitus (2)I598.fig - topDiabetes is
characterized by marked postprandial HYPERGLYCEMIA after carbohydrate ingestion.

in liver - impaired suppression of glucose production and ability to store glucose as glycogen.

in muscle - reduced capacity to remove glucose excess and store it as glycogen.

hyperglycemia is partially compensated by renal glycosuria;
–
su kiekvienu šlapimo gliukozės gramu kūnas netenka 4.1 kcal.
–
dėl osmotinės diurezės netenkama daug K+ ir Na+.

most marked and prolonged elevations in blood glucose are in type 1 patients (low portal insulin levels are
not reversed by subcutaneous insulin therapy).

type 1 patients also exhibit protein and fat intolerance - HYPERAMINOACIDEMIA (failure to uptake amino acids
in muscle) and HYPERTRIGLYCERIDEMIA (↓activity of lipoprotein lipase).
EPIDEMIOLOGY

serga ≈3% pasaulio žmonių, ≈ 8% USA populiacijos (esp. American Indians and Alaska Natives - 16.5%,
blacks - 11.8%, Hispanics - 10.4%).

4th most common reason for patient contact with physician, major cause of premature disability - 15% of
health care costs in USA.

leading cause of blindness, end-stage renal disease, non-traumatic limb amputations.

7th leading cause of death in USA.

major factor in neonatal morbidity and mortality.
TYPE 1 DIABETES

5-10% of diabetes in USA.

females = males
PREVALENCE in USA is 0,3-0,5% (it is accurate number because patients invariably become symptomatic).
–
more prevalent in Scandinavia, Scotland, Sardinia.
–
uncommon in Asian countries.
–
prevalence rates are strikingly different among different ethnic groups (living in the same
geographic environment) - explained by genetic differences.
INCIDENCE have risen in last half century (due to introduction of unidentified environmental factor).

age-specific incidence rises progressively from infancy to puberty (peak 10-15 years) and then declines
(but continues at low level for many decades).

30% pacientų suserga > 20 m. amžiuje (jiems dažnai klaidingai diagnozuojamas type 2 diabetes mellitus).
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TYPE 2 DIABETES

90-95% of diabetic patient population.

females > males.
PREVALENCE rates are imprecise (dažniausiai diagnozuojama skrininguojant asimptomiškus pacientus), but at
least 6% in USA (10-15% in persons > 50 years).
–
age at onset is usually > 40 years.
–
there may be 1 undiagnosed case for every 2 diagnosed cases.
–
more common (and occurs at earlier age) in Native Americans, Mexican descendants, and
blacks.
Risk factors:
1) obesity!!! (also ↑severity and duration of obesity, higher waist-hip ratios)
2) increasing age
3) reduced physical activity
4) diabetic parents
SUMARY: abiejų tipų diabetu galima susirgti bet kokiame amžiuje!
SIGNS & SYMPTOMS
apie diabetikų infekcijas → see 217 (1) p. (INFECTION)
TYPE 1 DIABETES

long asymptomatic pre-clinical stage (often lasting years) – β-cells are gradually destroyed.

commonly (but not always), clinical stage appears abruptly (over days ÷ weeks) in previously healthy nonobese child or young adult.
 manifestuoja kai būna prarasta >90% β-cells.
 acute illness may speed transition from pre-clinical to clinical stage;

at initial evaluation appears ill with marked classic symptoms (POLYURIA, POLYDIPSIA, POLYPHAGIA, WEIGHT LOSS),
and may demonstrate ketoacidosis.
–
normal glycemia does not exceed renal threshold (≈ 180 mg/dL).

glucose intolerance is of unstable (brittle) type – glycemia is quite sensitive to exogenous insulin,
deviations from normal diet, unusual physical activity, infection, or other forms of stress.

inadequate fluid intake, vomiting may rapidly lead to significant dehydration and electrolyte dysbalance.
TYPE 2 DIABETES

typically appears after age of 40 years.
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
high rate of genetic penetrance (unrelated to HLA genes!).

associated with obesity.

clinical features are much more insidious - classic symptoms may be mild (fatigue, weakness, dizziness,
blurred vision, other non-specific complaints may dominate picture) and may be tolerated for many years;
sometimes disease manifests only with complications.
½ patients with newly diagnosed T2DM have established chronic complications!

skin infections and oral and vaginal thrush are common.

metabolic derangements are easier to control and less severe.
D:\Viktoro\Neuroscience\USMLE 2\Endocrine system, metabolism (2701-2800)\ViktoroUSMLE 2Endocrine
system, metabolism - NESPAUSDINTA01. vadovėlių tekstaiDiabetes mellitus (2)I597.fig - top
IMPAIRED GLUCOSE TOLERANCE AND IMPAIRED FASTING GLUCOSE
- intermediate metabolic states between normal glucose homeostasis and overt diabetes - glucose levels are
higher than normal but lower than accepted as diagnostic for diabetes mellitus.

increase risk for cardiovascular disease, but do not produce classic microvascular and neuropathic
complications.

significantly increased (25-30%) later risk of type 2 diabetes mellitus (part of diabetes natural history?).
Distinction between diabetes types is usually made on clinical grounds;

small subgroup of patients are difficult to classify - they display features common to both type 1 and 2
diabetes (some have slowly evolving type 1, whereas others defy easy categorization).
–
more Americans become overweight - although T1DM patients are traditionally lean, many
now are overweight and some have metabolic syndrome characteristics.
–
80-90% T2DM patients are overweight / have metabolic syndrome, but some are leaner and
more active and do not have metabolic syndrome.
What suggest insulin deficiency (T1DM) (but not be definitive):
1) high titers of three antibodies - IA-2 (islet cell antigen 512), anti-GAD65 (glutamic acid
decarboxylase), anti-insulin - latent autoimmune diabetes.
2) C-peptide measurements
3) age at onset
4) body habitus
5) severe loss of glycemic control with or without ketonemia
6) weight loss
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DIAGNOSIS
Most diabetes is diagnosed by RANDOM or FASTING glucose!
Rarely, by oral glucose tolerance test.
Hemoglobin A1C can also be used.
Random
≥ 200 mg/dL Plus classic symptoms
Fasting (8 hrs)
≥ 126 mg/dL Needs confirmation*
At 2 h post-glucose load ≥ 200 mg/dL Needs confirmation*
Hemoglobin A1C
≥ 6.5%
Needs confirmation*
*with repeated testing
RANDOM venous plasma glucose ≥ 200 mg/dL - further diagnostic testing is unwarranted and delays treatment
(nors kai kas siūlo tai verifikuoti pakartotiniu tyrimu).
N.B. classic symptoms (polyuria, polydipsia, unexplained weight loss) should be present if
random glucose criteria are used, but surprisingly, many people with diabetes are relatively
asymptomatic.
N.B. sveikiems žmonėms jokiais atvejais glikemija negali būti ≥ 200 mg/dL.

glycosuria strongly suggests diabetes, but low renal glucose threshold can also produce glycosuria.
If diabetes is suspected but not confirmed by random glucose determination → OVERNIGHT (8 HRS) FASTING
plasma glucose (varies less from day to day and is more resistant to factors that non-specifically alter glucose
metabolism):
a) < 100 mg/dL (5.55 mmol/L) = NORMA.
b) ≥ 126 mg/dL (6.99 mmol/L) on at least two separate occasions = DIABETES*
N.B. previously used value was 140 mg/dL; it is now appreciated that 126 mg/dL more closely reflects
diagnostic level and level at which diabetic complications appear.
c) 100-125 mg/dL = IMPAIRED FASTING GLUCOSE (decreased insulin secretion) → oral glucose tolerance test
(OGTT):
75 g** glucose per os → measure plasma glucose at 2 hours:
–
if < 140 mg/dL (7.77 mmol/L) = NORMA
–
if ≥ 200 mg/dL (11.1 mmol/L) = DIABETES*
–
if 140-199 mg/dL = IMPAIRED GLUCOSE TOLERANCE (increased insulin
resistance)
*needs confirmation on second day if patient is asymptomatic
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**or 1.75 g/kg if weight < 43 kg
PREDIABETES:
A) IMPAIRED GLUCOSE TOLERANCE (IGT)
B) IMPAIRED FASTING GLUCOSE (IFG)
Labai svarbu žinoti faktorius, kurie gali iškreipti OGTT rezultatus:
1) carbohydrate restriction (< 150 g for 3 days)
2) bed rest (days) or severe inactivity (weeks)
3) medical or surgical stress
4) drugs (e.g. thiazides, β-blockers, glucocorticoids, phenytoin)
5) smoking during test
6) anxiety from repeated needlesticks.
2010 ADA recommendations - hemoglobin A1C can also be used (single nonfasting blood sample):
< 5% = norma 5.7-6.4% = prediabetes ≥ 6.5% = diabetes
N.B. no diagnostic markers can distinguish individuals with IMPAIRED FASTING GLUCOSE / IMPAIRED GLUCOSE
TOLERANCE who will become diabetic – all these individuals should be tested annually with fasting glucose
measurement!

such patients (like those with diabetes) have higher risk of premature cardiovascular disease - it is prudent
to prescribe same lifestyle changes as offered to overtly diabetic patients.
SCREENING
Many type 2 diabetics have long asymptomatic course - it is important to screen (fasting glucose
measurement) high-risk individuals.
further see 4800 p.
TREATMENT
DIABETES MELLITUS
2750 (20)
TREATMENT GOALS:
Short term
1. Improve sense of well-being
2. Restore metabolism to as close to normal as possible:
1) control hyperglycemic symptoms (polyuria, infections, blurred vision, etc.)
2) prevent acute metabolic complications
Long term - prevent chronic diabetic complications.
TREATMENT STRATEGIES:
TYPE 1 DIABETES - primary focus is to replace insulin secretion;
lifestyle changes only facilitate insulin therapy and optimize health.
TYPE 2 DIABETES - lifestyle changes are cornerstone of treatment (esp. in early stages);
pharmacologic intervention is secondary treatment strategy.
RELATIONSHIP BETWEEN DIABETES CONTROL AND ITS COMPLICATIONS
National Institutes of Health initiated Diabetes Control and Complications Trial (DCCT) - 9-year multicenter
study involving 1441 type 1 patients aged 13-39 years:

there is no threshold level at which complications occur - any degree of glycemia improvement has benefit
- normalization is not required to slow progression of complications.

very intensive control has negativities:
1) hypoglycemia episodes
2) weight gain
3) greater immediate costs (although long-term cost savings are obvious)
N.B. in some patients risks of intensive therapy may outweigh benefits!
If patient is willing and able to actively participate in management, goal should be the best level of glycemic
control possible (without placing at undue risk) – secondary prevention is fully possible (vs. primary diabetes
prevention – gal tik in type 2 - avoidance of obesity).

when to avoid hypoglycemia:
a) hypoglycemia is unacceptable (e.g. short life expectancy, cerebrovascular or cardiac disease).
b) increased risk of hypoglycemia (e.g. unreliable patients, autonomic neuropathy).
NON-PHARMACOLOGIC MEASURES
Behavior modification objectives should be firm:
DIABETES MELLITUS
2750 (21)
few (1-3 at a time is plenty)
individualized to patient's specific behavioral challenges
realistic (beware big strides quickly)
measurable (patient should be given tracking form to record daily progress on each objective).
N.B. start ASPIRIN if 10-year risk for c/v event exceeds 10% (i.e. diabetic men > 50 yrs or
women > 60 yrs if they have 1 additional c/v risk factor: hypertension, dyslipidemia, smoking,
albuminuria, or family Hx of c/v disease).
I. DIET
– goals:
1. Weight loss (for obese patients)
2. Cardiovascular risk ↓

individuals with prediabetes / diabetes should receive individualized medical nutrition therapy (MNT) as
needed to achieve treatment goals, ideally by registered dietitian who is knowledgeable about diabetes.
I. WEIGHT LOSS (for obese patients).

even modest weight reduction (e.g. 5 kg), irrespective of starting weight, leads to rapid decline in blood
glucose levels:
1) insulin resistance diminishes
2) glucose production declines
3) hyperglycemia↓ → improved insulin secretion.

in sedentary diabetic patients, daily caloric requirements are as low as 25-30 kcal/kg/d (classic 1800-kcal
diet is generally ineffective).

siūloma pradėti nuo dietos su caloric deficit 500 kcal/day (3500 kcal caloric deficit is required to lose 1 lb
of body fat - weight loss can be expected to be ≈ 1 lb/week).

jeigu nesiseka, very low calorie diets (600-800 kcal/day) can be done under medical supervision.

svorio metimas type 2 diabetikams ypatingai sunkus dėl metabolizmo ypatumų:
- normal decrease in basal metabolic rate during weight loss is accentuated;
- dieting reduces glycosuria (urinary caloric loss↓).
II. REDUCE RISK OF CARDIOVASCULAR DISEASE
saturated & trans fat↓ + moderate consistent carbohydrate + monounsaturated fat↑
DIABETES MELLITUS
2750 (22)
Eating must be regular - do not skip meals!!!
Anksčiau buvo manoma, kad reikia RIBOTI ANGLIAVANDENIUS.
Low-carbohydrate diets (< 130 g/day) are even not recommended for weight loss!

diet higher in carbohydrates (50-60% of total calories) improves insulin action and glycemic control!

reduced carbohydrates (45% of total calories) and greater reliance on monounsaturated fats
rekomenduojama, kai yra:
1) severe fasting hyperglycemia
2) triglycerides↑.
Anksčiau buvo manoma, kad reikia vartoti tik COMPLEX CARBOHYDRATES (starches).

simple sugars raise glucose levels to about the same extent as complex carbohydrates.
N.B. total amount of carbohydrate rather than source of carbohydrate should be primary
consideration!
Carbohydrates should be included as important part of healthy diet; limiting
carbohydrate consumption is based on controlling postprandial blood glucose (< 180
mg/dL 1-2 hours after beginning meal).

optimal source - foods containing water-soluble fibers (e.g. oats, gums, legumes, fruit pectin – i.e. whole
grains, fruits, vegetables)
1) blunt meal-induced rise in blood glucose (by delaying gastric emptying).
2) lower triglyceride and LDL.

anksčiau buvo manoma, kad sucrose leads to excessive glycemic excursions.
N.B. modest amounts of sucrose are harmless within context of mixed meals (proteins
and fats delay absorption) - it is unnecessary to forbid sucrose - such restrictions could lead to
poor adherence to meal plan!
Key component of meal plan is to reduce / change composition of DIETARY FAT.

saturated fat promotes atherosclerosis.

siūloma vietoj saturated fats naudoti monounsaturated fatty acids (olive, canola, peanut oil).
II. EXERCISES
– goals:
1. Weight loss (for obese patients)
2. Cardiovascular risk ↓
3. Improved insulin action

at least 150 min / week of moderate activity with 50-70% of maximum heart rate (such as walking).
DIABETES MELLITUS

2750 (23)
type 2 diabetics should also perform resistance training 3 times per week.
PREDIABETES
- treatment is directed at diabetes prevention:
1. Reduce body mass (lose 5-10%).
2. Increase physical activity - at least 150 min / week of moderate activity with 50-70% of maximum
heart rate (such as walking).

METFORMIN is considered in patients with very high risk for diabetes (combined IFG and IGT + other risk
factors + obese + < 60 yrs).

monitor every year for development of diabetes.
TYPE 1 DIABETES

patients depend on exogenous insulin to prevent metabolic decompensation and death.

endogenous insulin secretory capacity is gradually lost (over several years).

iki atrandant insuliną (Banting and Best, 1921), vienintelis gydymas buvo starvation (Allen regimen) →
glikemija↓, fat depots↓↓↓ (nėra iš ko vystytis ketonemijai).
INSULIN PREPARATIONS
Nearly all insulin preparations contain 100 U/mL (U-100).
N.B. more concentrated regular insulin (500 U/mL or U-500) with more prolonged action can
be obtained for resistant patients.
effect after subcutaneous injection*
CLASS
Short-acting
Meal insulins
Rapid-acting
analogues
Intermediateacting
Basal insulins
PREPARATION
onset
peak (hr)
duration (hr)
Regular
15-30 min
2-4
5-8
Lispro, Aspart,
Glulisine
5-15 min
45-75 min
2-4
Inhaled
10-15 min
1-2
6-8
Semilente
90-120 min
4-9
10-16
NPH, Lente
0.5-3 hr
4-10
16-24
Glargine
1.1-4 hr
none**
≥ 24
Detemir
2-3 hr
6-14
< 24
Long-acting
DIABETES MELLITUS
PZI, Ultralente
2750 (24)
4-6 hr
8-20
24-28
*extreme variability among patients!
**glargine is the only insulin that may be used × 1 / d (dose may be used any time of
the day as long as it is reasonably consistent)
Insulin effects on HbA1c – see oral hypoglycemic drugs (table in Type 2 DM treatment)
HUMAN INSULIN is now the only form sold in North America and other industrialized countries.

less antigenic than porcine and much less antigenic than bovine insulin (detectable insulin antibody levels,
usually very low, develop even with human insulin preparations!).

because generates lower titers of insulin antibodies, it acts more rapidly and effects persist for shorter time
- better synchrony between insulin peaks and meal absorption.

insulin should be refrigerated but never frozen (most insulins are stable at room temperature for months).

the same insulin preparation may produce variable responses in given patient - peak and duration depend
on (1) route of administration, (2) dose, (3) treatment duration.
I. MEAL insulin preparations
Indications:
1) blunting glucose elevations following meals.
2) rapid adjustments based on glycemia measurements by patient (e.g. during illness, large meals).
3) intensive care.
Side effects: hypoglycemia, weight gain.
INHALED INSULIN (EXUBERA®, AFREZZA®) – inhaled powder.

always dosed only at mealtimes.

rapid onset similar to that of rapid analogues, but because it is regular insulin, its duration of action is 6 to
8 hours

additional side effects: cough, altered PFTs, possibly ↑risk of primary lung cancer.

contraindication - less than 70% of predicted of any:
1) FEV1
2) dissociation of pulmonary diffusing capacity (DLCO)
REGULAR INSULIN - only preparation that can be given i/v.

is in hexameric form - must dissociate into monomers - delay in absorption from subcutaneous injection
sites.
DIABETES MELLITUS

2750 (25)
begins to act in 30 minutes - should be given 20-30 minutes before meal.
INSULIN LISPRO (Humalog®) - reversed order of amino acids in positions B28 [lysine] and B29 [proline].

more easily dissociates into monomers - absorbed more rapidly - can be given just before or immediately
after eating (more convenient than REGULAR insulin - simplifies meal planning).

effects wane more rapidly - ↓risk of hypoglycemia if next meal is delayed.
INSULIN ASPART (NovoLog®) - homologous with human insulin with exception of single substitution of
proline by aspartic acid in position B28.

kinetics as LISPRO.
INSULIN GLULISINE (Apidra®) – differs from human insulin in that amino acid asparagine at position B3 is
replaced by lysine and lysine in position B29 is replaced by glutamic acid;

kinetics as LISPRO.
SEMILENTE INSULIN (zinc insulin microcrystals in acetate buffer) - slightly slower rapid-acting insulin.
II. BASAL (INTERMEDIATE-ACTING and LONG-ACTING) insulin preparations

delayed absorption → prolonged action.

kaip tai pasiekiama:
b) protamine is added
c) size of zinc-insulin crystal is enlarged.
Prolongation method
protamine added
INTERMEDIATE-ACTING
LONG-ACTING
NPH (neutral protamine Hagedorn), s.
PZI (protamine zinc insulin) negatively charged insulin, combined
with positively charged excess
protamine
ISOPHANE INSULIN
enlarged size of zinc-insulin
crystal

LENTE (tai 30% Semilente ir 70%
Ultralente mišinys)
ULTRALENTE
Intermediate-acting insulins - some degree of meals coverage (coinciding with peak actions) + basal levels
of insulin (when given twice per day).
DIABETES MELLITUS
2750 (26)
Longer-acting insulins have less evident "peaks” - basal insulin replacement (generally still require twicedaily dosing).
INSULIN GLARGINE (Lantus)
INSULIN DETEMIR (Levemir)
LENTE INSULIN vs. NPH INSULIN:
o
LENTE does not contain foreign protein (protamine) - negligible clinical significance.
o
NPH is preferred in pre-mixed preparations (excess zinc in Lente may cause regular insulin to
precipitate out of solution and delay absorption).
Mixtures of insulin preparations - doses of two preparations in the same syringe.

manufacturers recommend that SEMILENTE be mixed only with LENTE or ULTRALENTE (to maintain the same
buffer solution).

Novolin 70/30 or Humulin 70/30 - mixture of 70% NPH and 30% REGULAR insulin.

Humalog - 75% neutral protamine lispro and 25% LISPRO insulin.

Novolog - 70% neutral protamine aspart and 30% ASPART insulin.

PZI must always be injected separately, because it contains protamine excess.
INSULIN REGIMENS
A. Conventional
B. Intensive (multiple subcutaneous injections, continuous subcutaneous insulin infusion)
N.B. no universal algorithm can be uniformly applied to all patients.
A. CONVENTIONAL INSULIN THERAPY

most patients start with two daily injections (before breakfast and dinner) of mixture of intermediateacting and rapid-acting insulin.

total dose ≈ 40 U/d; 2/3 dozės skiriama ryte, 1/3 – vakare.

inject in same region (but at different locations) at same time each day:
–
in abdomen in morning - to optimize insulin delivery;
–
in leg or buttock at night - to slow absorption.
DIABETES MELLITUS
2750 (27)
Dosage
Variant A

initially intermediate-acting (basal) insulin is adjusted to optimize glucose levels (twice daily NPH or once
daily GLARGINE or DETEMIR) - 10 U once near bedtime → weekly increases by 2-8 U to achieve
preprandial plasma glucose 80-130 mg/dL).

adjustments in insulin dose are restricted to 10-20% at time; effects are assessed over 3-7 days before any
further increment is made (more rapid adjustments of regular insulin are indicated if hypoglycemia
threatens!).
–

optional snacks require insulin coverage based on INSULIN-TO-CARBOHYDRATE RATIO. see
below
eventually HbA1c rises > 8% - signals need for rapid-acting (meal) insulin optimized for postprandial, prelunch and bedtime glucose values.
N.B. didelė pagunda naudoti mixture preparations, bet geriau naudoti atskirą gerą basal insulin (e.g.
glargine or detemir) ir atskirai injekuoti rapid-acting analogue (lispro, aspart, glulisine).
Variant B

establish total daily dose (0.2-0.4 U/kg/d) → increase to optimize glucose levels (eventually many require
dose 0.6-0.7 U/kg/d).

total daily dose is divided:
½ as basal insulin (once daily GLARGINE or DETEMIR or twice daily NPH [2/3 in morning, 1/3 at
bedtime])
½ as meal insulin divided before meals (each dose is determined by meal carbohydrate content and
premeal glycemia)

some patients may experience brief initial “HONEYMOON period” - partial recovery of β-cells and reversal of
insulin resistance caused by acute illness - smaller doses of insulin are required.

in first few years some degree of β-cell function persists - patients can achieve glycemic control with less
intensive (conventional) therapy.
Examples of regimens:
BREAKFAST
LUNCH
DINNER
BEDTIME
Insulin mixture
Insulin mixture
NPH + rapid/short
NPH + rapid/short
NPH + rapid/short
rapid/short
NPH or glargine
NPH + rapid/short
rapid/short
rapid/short
NPH + rapid/short
rapid/short
rapid/short
rapid/short
NPH or glargine
NPH + rapid/short
NPH + rapid/short
rapid/short
NPH
DIABETES MELLITUS
glargine + rapid/short
rapid/short
2750 (28)
glargine* + rapid/short
* ≈ 20% patients need glargine × 2 / d

INTENSIVE INSULIN THERAPY (≥ 3 injections / day) – standard of modern therapy.

for patients on basal-bolus regimen, optional snacks require adjustable insulin coverage determined on:
INSULIN-TO-CARBOHYDRATE RATIO - grams of carbohydrate covered by 1 U of insulin (≈ 450 divided by total
daily dose)
CORRECTION FACTOR or SENSITIVITY INDEX (CF/SI) - expected decrement in glucose following 1 U of rapid-
acting insulin (≈ 1650 divided by total daily dose); CF/SI is applied no more than every 2-3 hours to
lower elevated blood glucose toward target range to avoid so-called stacking of insulin action and
subsequent hypoglycemia.
Initiation of insulin therapy in children:
Establish total daily dose:
a) no ketonuria or acidosis - 0.25-0.5 U/kg/d.
b) ketonuria without acidosis or dehydration - 0.5-0.75 U/kg/d.
N.B. these doses are for prepubertal children; for pubertal children, doses are 0.25 U/kg/d higher!
Divide total dose between individual injections:
B. INTENSIVE INSULIN THERAPY
Absolute indication is pregnancy (ideally, intensive insulin therapy should be instituted before conception).
I. MULTIPLE SUBCUTANEOUS INJECTIONS

several years after type 1 diabetes onset, residual insulin secretion ceases and twice-daily insulin injections
no longer suffice.
DIABETES MELLITUS
2750 (29)

optimal control requires close simulation of normal insulin secretion pattern - continuous "basal" insulin
secretion (throughout day and night) + brief increases coinciding with meals.

Pen injectors (containing cartridges filled with insulin) make multidose insulin regimens more convenient.
Major problem with twice-daily regimens:
1) pre-dinner intermediate-acting insulin effect is greatest when requirements are lowest (2:00
to 3:00 A. M.) → NOCTURNAL HYPOGLYCEMIA
2) when requirements are increasing in early morning (5:00 to 8:00 A. M.), insulin levels decline +
sleep-associated GH secretion↑ → FASTING HYPERGLYCEMIA (“dawn” phenomenon).
H: intermediate insulin↑ at bedtime.
3) if bedtime insulin dose is too large → nocturnal hypoglycemia → rebound morning FASTING
HYPERGLYCEMIA with ketonemia (SOMOGYI phenomenon).
H: intermediate insulin↓ at bedtime.
N.B. fasting hyperglycemias ypatingai sunkiai susireguliuoja (once hepatic gluconeogenesis has
been activated, it is not readily suppressed by subcutaneous injections of insulin, and
hyperglycemia persists after breakfast).
Sprendimo būdas - insulin regimens when effects do not peak in middle of night but become dissipated in
morning:
a) 3-doses regimen – mixture (intermediate- + short-acting) before breakfast, short-acting before dinner, and
intermediate-acting at bedtime.

total daily dose division - 1/2 before breakfast, 1/4 before dinner, and 1/4 at bedtime.
b) short-acting before each meal and intermediate-acting at bedtime (4-doses regimen)
c) Ultralente (twice daily) to replace basal insulin secretion and short-acting before each meal.
DIABETES MELLITUS
2750 (30)
II. CONTINUOUS SUBCUTANEOUS INSULIN INFUSION
- provides greater flexibility in insulin dosing; mimic natural insulin secretion; most convenient method for
pediatric patients!!!


rapid-acting insulin is administered continuously around the clock via externally worn, computercontrolled infusion pump;
–
needle is inserted subcutaneously, preferably in abdomen, to optimize absorption.
–
delivers basal rates continuously and varies flow rate automatically for set periods (↓
at 1:00 to 4:00 A. M. and ↑ early in 5:00 to 8:00 A. M.).
boluses (determined by blood glucose self-monitoring) are given before meals by manually activating
pump (after patient determines his glycemia by finger prick).
PARADIGM SYSTEM - FDA approved device that integrates glucose meter and insulin pump with
dose calculator into one device - automatically calculates how much insulin is needed;
patients still prick fingers, but pager-sized monitor uses wireless technology to beam glucose
reading straight to implanted insulin pump to send out right dose.

disadvantages:
1) any interruption in flow (džn. insulin precipitation within catheter) → rapid deterioration in
control.
2) local infections
3) sophistication.
III. INSULIN IV DRIP
1. Check BG q1hr; if BG level is in target range for 4 hours in a row, may check BG every 2 hours
DIABETES MELLITUS
2750 (31)
2. Use the following formula: (BG - 60) × 0.02 = units of insulin/h.
BG is current blood glucose level, and 0.02 is the multiplier.

adjust to current multiplier in drip from previous multiplier according to the following directions:
When BG level is greater than HIGH target, increase multiplier by 0.01.
When BG level is less than LOW target, decrease multiplier by 0.01.
When BG level is within target range, do not change multiplier, and adjust drip rate according
to formula.
If hypoglycemia (BG <80 mg/dL), decrease the multiplier by 0.01 and continue the insulin drip.

do not stop IV insulin drip if insulin rate is >0.5 U/h until subcutaneous insulin therapy is initiated. (BG
values should be within target range for > 4 hours before IV insulin infusion is discontinued.)

if glucose intake is abruptly stopped, immediately discontinue the insulin drip until glucose intake is
resumed.
COMPLICATIONS OF INSULIN TREATMENT
1. Hypoglycemia (žr. žemiau).
2. Local allergic reactions: immediate pain and burning → local erythema, pruritus, induration (may persist
for days).

spontaneously disappear after weeks of continued insulin injection - require no specific treatment
(antihistamines are sometimes mixed with insulin).
3. Generalized insulin allergy

may occur with any type of insulin (incl. human biosynthetic insulin).

shortly after injection - urticaria, angioedema, pruritus, bronchospasm, … circulatory collapse.

H: antihistamines, epinephrine, i/v glucocorticoids.

if continued insulin treatment is required → skin testing and desensitization.
4. Immunologic insulin resistance (insulin requirement ≥ 200 U/day) – due to circulating insulin-binding IgG
antibodies.

remission may be spontaneous or induced if insulin treatment can be stopped for 1-3 mo.

PREDNISONE may decrease insulin requirements within 2 wk.
5. Local fat atrophy or hypertrophy (at injection sites)

improves by switching to human insulin and injecting it directly into affected area.

no specific treatment is required, but injection sites should be rotated.
6. Weight gain.
7. Accelerated atherosclerosis (syndrome X)?
DIABETES MELLITUS
2750 (32)
D:\Viktoro\Neuroscience\USMLE 2\Endocrine system, metabolism (2701-2800)\ViktoroUSMLE 2Endocrine
system, metabolism - NESPAUSDINTA01. vadovėlių tekstaiDiabetes mellitus (2)I602.fig - top
LIFESTYLE CHANGES
- careful balance between calorie intake (diet) and energy expenditure (exercise) while taking into account
availability of injected insulin.

introduction of intensive insulin regimens has permitted opportunity for more normal lifestyle, thus
minimizing compliance problems.
DIET (best if directed by trained dietician; patient and family should also be instructed on carbohydrate
counting)
1) sufficient calories (1800-kcal diet commonly used in type 2 patients is grossly insufficient).
carbohydrates: 45-65% (depending on diabetes severity and triglyceride levels)
protein: 15%
fat: 30%

weight reduction, gain, or maintenance (as appropriate); body mass index (BMI) should be
monitored at every visit.

potential for weight gain requires special emphasis on portion control and appropriate (but not
excessive) food intake for hypoglycemia treatment.

avoid long delays between meals; frequent small snacks may be needed at times of peak insulin
action to avoid hypoglycemia.

most patients require bedtime snack to reduce nocturnal hypoglycemia.
In general, children require 3 meals ± up to 3 snacks to match anticipated peaks of insulin
action.
Unexpected snacks require insulin coverage based on insulin-to-carbohydrate ratios.
2) minimizing long-term cardiovascular risk.

↓ saturated fat (< 10% of calories), ↓ cholesterol (< 200 mg/d), ↑ monounsaturated fat
(depending on need to limit carbohydrate)

concentrated sweets↓, complex carbohydrates↑, dietary fibers↑

Na restriction (if prone to hypertension)
Diet management aims to restrict variations in meals (timing, size, composition).

all insulin-treated patients require detailed diet management - professional dietitian can tailor diet plan
and education to meet patient's individual needs.

American Diabetes Association have exchange lists - translate dietary prescription into diet plan.
DIABETES MELLITUS
2750 (33)
EXERCISE promotes well-being and reduces vascular complications.
1. Aerobic strongly preferred.
2. Intensity: increase pulse to at least 120-140 (depending on age and cardiovascular state)
3. Frequency: 3-4 /week
4. Duration: 20-30 min, preceded and followed by stretching - flexibility exercises.

iš esmės, jokios sporto šakos nedraustinos.

jei jau yra c/v komplikacijų, krūvį gali tekti mažinti.

avoid Valsalva maneuvers (heavy lifting, straining) that raise blood pressure.

glycemia < 60 mg/dL or > 400 mg/dL are contraindications to exercise.

exercise accelerates insulin absorption from injection site – do not use extremities as site for injection
before exercise!

exercise didina non-insulin-dependent peripheral glucose uptake by muscle:
–
jei krūvis didelis, reikia papildomai užvalgyti: child take 5-15 g of carbohydrates before
exercise if blood sugar is below target, and repeat 5-15 g carbohydrate for every 30 minutes of
sustained activity;
–
vartok mažesnė insulino dozę prieš exercise!!!
N.B. hypoglycemia may be complication if patient is unable to appropriately adjust diet and insulin.

check blood glucose before activity, every hour during sustained activity, and at completion of activity.
–
for first several days of increased activity, also check blood sugar frequently during 12-hour
postexercise period - often delayed drop following exercise (i.e. lag effect).
PANCREAS/ISLET TRANSPLANTATION

because of need for long-term immunosuppression, pancreas transplantation is used only for type 1
diabetics with renal allografts (pancreas transplantation prevents nephropathy in grafted kidney).

islet transplantation is difficult (problems with obtaining sufficient numbers of viable islets);
islet transplantation is more successful in total pancreatectomy with intraportal injection of patient’s own
islets.
TYPE 2 DIABETES

in most patients, diet and exercise are key or only therapeutic intervention required to restore metabolic
control (use pharmacologic agents only if hyperglycemia is severe).
Cardiovascular risk reduction therapy is very high priority!
DIABETES MELLITUS
2750 (34)

patients are not dependent on exogenous insulin for immediate survival and ketosis rarely develops (except
under great physical stress).

nevertheless, patients may require insulin to control hyperglycemia.
PHARMACOLOGIC INTERVENTION
General rule with all therapies is add, don't switch.
ORAL GLUCOSE-LOWERING AGENTS
Indikacijos:
1) if diet and exercise fail to achieve treatment goals.
2) mild hyperglycemia
3) older patient
4) obesity.
Contraindications:
1) severe insulin deficiency
2) allergy
3) pregnancy
N.B. patients with severe hyperglycemia initially require insulin (to eliminate "toxic" effects of severe
hyperglycemia on β-cell function), then many such patients become responsive to oral agents.
oral HYPOGLYCEMIC drugs (stimulate insulin secretion - hipoglikemijos rizika!):
1) sulfonylureas
2) glinides s. benzoic acid derivatives (rapid secretagogues)
3) incretins
oral ANTIHYPERGLYCEMIC drugs (reduce insulin resistance):
1) biguanides (first choice drugs!!!)
2) thiazolidinediones
3) α-glucosidase inhibitors (least potent drugs)
4) amylin agonists
5) bile acid sequestrants
 kombinacijose vartojami skirtingų tipų vaistai (HYPOGLYCEMIC + ANTIHYPERGLYCEMIC)
DIABETES MELLITUS
2750 (35)
N.B. add (don't switch) drug (unless side effects require it).
AGENT
DOSES PER DAY
METABOLISM, EXCRETION
ACTION DURATION (h)
Sulfonylureas
1st generation
CHLORPROPAMIDE
1
60 (longest action)
kidney > liver
ACETOHEXAMIDE
Up to 24
TOLAZAMIDE
1-2
liver > kidney
TOLBUTAMIDE
2-3
6-12 (shortest action)
2nd generation - 100 times more potent, rapidly absorbed
GLIMEPIRIDE
1
GLYBURIDE
liver >> kidney
Up to 24
before each
meal
liver > kidney
short (T1/2 ≈ 1)
2-3
kidney
6-10 (up to 24)
liver
Up to 24
small fraction which is absorbed
in GI is eliminated via kidneys
N/A (2-10?)
1-2
GLIPIZIDE
Glinides (benzoic acid derivatives)
REPAGLINIDE
NATEGLINIDE
Biguanides
METFORMIN (Glucophage)
Thiazolidinediones (“glitazones”)
TROGLITAZONE
1
PIOGLITAZONE (Actos)
ROSIGLITAZONE (Avandia)
1-2
α -Glucosidase inhibitors
ACARBOSE
MIGLITOL
at beginning of
each meal
Incretins (GLP-1* receptor agonists)
DIABETES MELLITUS
AGENT
DOSES PER DAY
EXENATIDE
2750 (36)
METABOLISM, EXCRETION
ACTION DURATION (h)
2
Sodium-glucose co-transporter 2 (SGLT2) inhibitors
DAPAGLIFLOZIN
Incretins (DPP-4** inhibitors)
SITAGLIPTIN
VIDAGLIPTIN
LINAGLIPTIN
Amylin agonists
PRAMLINTIDE
at each meal
Bile acid sequestrants
COLESEVELAM (WelChol)
not absorbed systemically
*GLP-1 - glucagon-like peptide-1
**DPP-4 - dipeptidyl peptidase-4
Mechanism of action:
Class
HbA1c
lowering
(% points)
Effect on
Glycemia
Mechanism of Action
Side Effects
DIABETES MELLITUS
2750 (37)
(Pre- / Postprandial)
Secretagogues
1.5-2
++ / +
Insulin secretion↑
Hypoglycemia,
weight gain
Biguanides
1.5-2
+++ / 0
Hepatic glucose output↓
GI, lactic acidosis
0.7-1.5
+++ / 0
Peripheral glucose
utilization↑
Hepatotoxicity,
CHF
Thiazolidinediones
α -Glucosidase
inhibitors
Intestinal absorption of
complex carbohydrates↓
GLP-1 receptor
agonists
0.9-1.1
+ / ++
Strong GLP-1 effects (insulin
secretion, glucagon
suppression)
DPP-4 inhibitors
0.6-0.8
+ / ++
Moderate GLP-1 effects
Amylin agonists
0.5-0.7
≈ 0 / ++
Bile acid
sequestrants
0.5
Basal insulin
1.5.-2.5
+++ / 0
Meal insulin
1.0-2.0
0 / ++
Inhaled insulin
1.5.-2.5
++ / ++
Nausea,
vomiting, weight
loss
Amylin effects (glucagon↓)
Nausea, vomiting
↓ hepatic glucose output,
muscle glucose disposal↑
Hypoglycemia,
weight gain
I. SULFONYLUREAS

the only class available in USA before 1995.

inexpensive.

act on pancreas: bind to sulfonylurea receptors (on β-cell surface) associated with ATP-dependent K
channels → closure of K+ channels and opening of Ca2+ channels → cellular depolarization → insulin
secretion↑

totally ineffective in type 1 diabetes.

side effects:
1) HYPOGLYCEMIA – main side effect!
o
hipoglikemija esti sunki ir gali trukti / recidyvuoti kelias dienas net nutraukus vaisto
vartojimą – pacientą būtina stacionarizuoti sekimui 2-3 dienoms (mortality ≈ 4.3%)!
o
each drug has similar hypoglycemic effects when used in maximal doses;
–
shorter-acting drugs have problems with compliance;
–
longer-acting drugs require only once-per-day dosing but enhance risk of
hypoglycemia in patients who omit meals.
DIABETES MELLITUS
–
2750 (38)
intermediate-duration drugs offer compromise (but still have risk of severe
hypoglycemia!).
2) weight gain
3) allergic reactions (acetohexamide may be used in allergy to other sulfonylureas).
4) other (e.g. cholestatic jaundice) - relatively uncommon.
chlorpropamide should not be used in elderly patients - can potentiate ADH →
hyponatremia with mental status↓ (in elderly may not be recognized as drug-induced
effect).

treatment is initiated with short-acting drug at low doses → dosage increased every 1-2 weeks until
treatment goals or maximally effective doses are reached.

15-20% of patients do not respond (PRIMARY FAILURE).
SECONDARY FAILURE occurs at rate of 5-10% per year:
a) failure to sustain enthusiasm for diet and exercise
b) progression of β-cell failure
c) superimposition of other medical problems or drugs
d) drug tolerance.
H: enforce diet, increase drug dosage; hyperglycemia despite maximal drug doses → add another
class of oral agent or insulin.
II. GLINIDES (s. BENZOIC ACID DERIVATIVES)
- interact with different portion of sulfonylurea receptor → insulin secretion↑

second-line alternative to sulfonylureas.

indications - patients who are sulfonylurea allergic, extremely erratic in eating, or at high risk for
hypoglycemia.

rapid secretagogues - used as monotherapy (15 min before each meal).

major advantage - rapid and short duration of action (↓risk of hypoglycemia).
III. BIGUANIDES (first choice drugs!!! – reduce risk of MI and death)
METFORMIN (the only biguanide approved in USA; has been used as primary therapy in type
2 diabetes for > 30 years in most of world; the only drug FDA approved for children)
- reduce hepatic glucose production (mechanism is uncertain) ± increases peripheral glucose utilization.

may induce mild weight loss (unlike other oral agents) - particularly suitable for obese patients!!!

reduces hyperlipidemia!

eliminated unmetabolized exclusively by kidney – contraindicated in renal dysfunction (measure
creatinine clearance for patients > 80 yrs before administering metformin).
DIABETES MELLITUS
2750 (39)
Old FDA label: contraindicated for patients with serum creatinine levels ≥ 1.5 mg/dL for men
and 1.4 mg/dL for women.
Revised FDA label: contraindicated if eGFR is below 30 mL/minute/1.73 m2; drug is not
recommended in patients with eGFR 30-45.

side effects:
1) GI - anorexia and nausea (contribute to weight loss).
2) rarely can produce lactic acidosis (tai dažnesnė problema su PHENFORMIN, kuris dėl to ir išimtas iš
apyvartos) - 50% MORTALITY.
– avoid in renal insufficiency, liver disease, congestive heart failure, chronic hypoxia, alcohol
abuse (iš esmės, acute hospitalizations metu metformino rekomenduojama nevartoti)
N.B. does not produce hypoglycemia when used as monotherapy!

synergistic in combination with sulfonylurea.
IV. THIAZOLIDINEDIONES (“GLITAZONES”) – most expensive drugs!
- insulin sensitizers (reduce insulin resistance): (stimulate peripheral [muscle & fat; not hepatic]
glucose metabolism) - activate peroxisome proliferator-activated receptor gamma (nuclear receptor
for transcription of several insulin-responsive genes) → plasma glucose↓ and insulin↓.

need insulin presence - used only* in combination with insulin or oral secretagogue agent (e.g.
sulfonylurea).
*but also FDA-approved for monotherapy

little effect on hepatic glucose production.

max effect is achieved in 4-6 weeks.
Adverse effects:
1) idiosyncratic hepatotoxicity (transaminases↑ in 2% of patients, rarely severe liver failure) measure liver enzymes at baseline every month for 1st year and on regular basis thereafter
(stop drug if transaminases↑).

new thiazolidinediones (rosiglitazone, pioglitazone) have much lower
hepatotoxicity.
2) weight gain
3) congestive heart failure!!! (observe patients carefully after starting drug therapy for rapid
weight gain, shortness of breath, edema); risk of heart failure is increased when combined
with insulin; NYHA Class III-IV heart failure is contraindication for glitazones.
4) ROSIGLITAZONE (vs. PIOGLITAZONE) rises LDL and increases coronary ischemic events by
43%.
FDA announced that manufacturer of Avandia (rosiglitazone) has agreed to add new
information to existing boxed warning (FDA's strongest form of warning) in drug's
labeling about potential increased risk for heart attacks!
5) hypoglycemia is rare when used as monotherapy.
V. α-GLUCOSIDASE INHIBITORS
DIABETES MELLITUS
2750 (40)
- reversible inhibitors of intestinal α-glucosidases (intestinal brush border enzymes that break down
complex carbohydrates into monosaccharides) → delayed absorption of complex carbohydrates →
postprandial hyperglycemia peak↓
N.B. does not affect absorption of monosaccharides!

must be taken at beginning of each meal.

major advantage - do not have significant toxicity (most commonly - abdominal bloating,
flatulence, sometimes diarrhea – due to shifting carbohydrate digestion more distally; H: dozė
didinama pamažu).

can be used in combinations with any other drugs.
VI. INCRETINS
Incretins - gut hormones that enhance food-induced (glucose-dependent) insulin secretion,
slow stomach emptying, and suppress appetite (→ weight loss!!!)
–
most important incretins - glucagon-like peptide-1 (GLP-1),
gastrointestinal insulinotropic polypeptide (GIP);
–
dipeptidyl peptidase-4 (DPP-4) - peptidase that normally rapidly
degrades GLP-1 and GIP.
Incretin drugs:
A) GLP-1 receptor agonists (injectable EXENATIDE);
–
works immediately on injection.
–
substantial GI side effects (nausea, vomiting, and diarrhea) generally wane within
weeks; hemorrhagic and necrotizing pancreatitis cases have been described.
–
little tendency for hypoglycemia (because insulin secretion is glucose-dependent).
B) Inhibitors of DPP-4 (oral SITAGLIPTIN, VIDAGLIPTIN) - enhance endogenous levels for GLP-1 and
GIP.
–
SITAGLIPTIN is excreted by kidney largely unchanged.
–
relatively minor side effects (little nausea, vomiting, diarrhea).
VII. AMYLIN AGONISTS
Amylin - beta cell hormone, cosecreted with insulin; effects of amylin - lower glycemia, reduce
excess glucagon levels, curb appetite, slow gastric emptying.
PRAMLINTIDE - injectable synthetic analogue of amylin.
–
nausea and vomiting can occur.
VIII. BILE ACID SEQUESTRANTS
DIABETES MELLITUS
2750 (41)
COLESEVELAM – has FDA approved dual action: lowers LDL cholesterol + decreases HbA1c.
–
also FDA approved (alone or in combination with statins) for reduction of LDL
cholesterol in primary hypercholesterolemia (Fredrickson Type IIa).
INSULIN THERAPY
Indications:
1. Goals not met on dual oral agent therapy (dažniausia klaida - insulinas pridedamas per vėlai).
2. Temporarily initial therapy for severely hyperglycemic patients.
3. Temporarily required during severe stress (e.g. infection, surgery) or in pregnancy.
Contraindications:
1) poorly compliant patients (who are unwilling to self-monitor glucose levels)
2) high risk of hypoglycemia.

start with single dose of basal insulin (NPH, glargine, or detemir) 10 U in evening near bedtime
–
follow by weekly increases 2-8 units to achieve fasting glucose (3F rule) 90-130 mg/dL.

at some point, basal insulin therapy alone may become insufficient (e.g. fasting hyperglycemia; or fasting
goal is met but HbA1c remains elevated; or postprandial glycemia ≥ 180 mg/dL) → add meal insulin.

reikalingos didesnės insulino dozės (dėl insulin resistance) negu type I diabetikams.
TREATMENT STRATEGIES FOR TYPE 2 DIABETES
UKPDS (United Kingdom Prospective Diabetes Study) demonstrated that therapy with each pharmacologic
agent is beneficial and no specific therapy is superior (insulin vs. oral agents vs. combinations) - goals of
therapy should be the same - to lower blood glucose as close to normal as possible.

for most patients, glycemic control deteriorates over time.

failure to meet glycemic goals (HbA1c < 7%) within 3 months → treatment modification: patients who
were initially well controlled with only one drug will with time require dual drug combination therapy and
may ultimately use basal insulin (in addition to drugs) → additional meal insulin.
N.B. if glycemic targets are not met with oral agents, insulin is effective addition!
DIABETES MELLITUS
2750 (42)
Algorithm or T2DM treatment steps:
1. Behavioral self-management
2. Biguanide (METFORMIN) - titrate to maximally effective dose at 1-2 months.
3. Add second medication:
a) sulfonylurea (GLIMEPIRIDE or extended-release GLIPIZIDE)
b) basal insulin (NPH or GLARGINE) - preferred if HbA1c > 8.5% or symptoms secondary to
hyperglycemia are present.
c) thiazolidinedione - dual insulin-resistance strategy.
4. Add meal insulin

insulin secretagogues (sulfonylurea or glinides) should be discontinued (or tapered and then discontinued)
once insulin injections are started.

in patients with hazardous jobs (hypoglycemia is particularly dangerous) - adding EXENATIDE* or
PIOGLITAZONE may be considered (ROSIGLITAZONE is not recommended).
*esp. patients who need to lose weight (and HbA1c is < 8.0%)
MONITORING
Most precise marker of endogenous insulin secretion is C peptide – it escapes hepatic metabolism (unlike
insulin).
I. SELF-MONITORING (and communication of these results with diabetes team at frequent intervals):
Blood GLUCOSE
1) allows rapid treatment adjustments
2) actively involves patients in treatment process
3) reinforces diet therapy
DIABETES MELLITUS

record results along with amount of carbohydrate intake and amount of insulin administered.

especially useful during periods of stress and if susceptible to hypoglycemia.
2750 (43)
Targets:
–
before each meal: 90-130 mg/dL (< 110 ideally)*; vaikams < 13 m. leidžiama iki < 180.
3F rule: Fix Fasting glucose First
–
90-120 minutes after meals (to control postprandial hyperglycemia): < 180 minimal (< 140
ideally)*
–
at bedtime: 90-150; vaikams < 13 m. leidžiama iki < 180 (< 6 m. – iki < 200).
–
occasionally, in middle of night (e.g., 3 A. M.) to avoid nocturnal hypoglycemia.
*t.y. siekti, jog hiperglikemija nepatektų į diabetes diagnostines ribas
Monitoring frequency (tests should be performed on regular basis):
a) if maintained by diet – should learn self-monitoring so can better appreciate how
individual foods adversely affect glycemia.
b) if taking oral agents – no clear guidelines; more frequently at treatment beginning and
any time when metabolic control deterioration is suspected.
c) if treated with insulin – self-monitoring daily (before breakfast and dinner and at
bedtime), for children ≥ 4 times / day (if using insulin pump, ≥ 6 times / day).
Indications for monitoring of Blood* / Urine** for KETONES:
* β-hydroxybutyric acid
** acetoacetate and acetone
a) periods of illness ("sick days"), esp. with nausea, vomiting, or abdominal pain
b) blood glucose ≥ 250-300 mg/dL
II. GLYCOHEMOGLOBIN (HbA1c)

2-4 times per year.

glycohemoglobin is formed when glucose non-enzymatically covalently reacts with hemoglobin A
molecule

glycohemoglobin is composed of several fractions, major one being Hb A1c (expressed as % of total
hemoglobin).

Hb A1c reflects average glucose level over RBC lifespan.
N.B. glycohemoglobin provides the most accurate (“gold standard”) estimate of overall glycemic
control during preceding 6-12 weeks, but is not valuable in determining what specific changes in
therapy are indicated (use blood glucose measurements instead)!
Advantages – test results are not influenced by:
DIABETES MELLITUS
2750 (44)
1) patient's ability to monitor blood glucose
2) acute changes in blood glucose
3) interval since last meal.
False-lows:
1) increased RBC turnover (e.g. pregnancy, hemolytic anemia)
2) hemoglobinopathies (sickle cell disease or trait, hemoglobin C or D)
False-highs:
1) hemoglobin F↑ (e.g. thalassemia, myeloproliferative disorders)
2) large doses of aspirin.

in most laboratories, normal HbA1c level is < 6%.

minimum goal for most diabetics is < 7%; for children, patients with history of severe hypoglycemia,
limited life expectancies, comorbid conditions, long duration of diabetes and minimal or stable
microvascular complications, less stringent A1C goals may be appropriate
vaikams < 13 m. leidžiamos didesnės normos < 8% (< 6 m. – net iki < 8.5%).
in poorly controlled diabetics, level ranges 9-12%.
Hb A1c < 8% is threshold below which most complications can be prevented
FRUCTOSAMINE (formed by chemical reaction of glucose with plasma protein) - reflects glucose control in
previous 1 to 3 weeks - helpful in intensive treatment regimens.
III. OTHER EXAMINATIONS
At each visit:
1) seek for early signs and symptoms of retinal, vascular, neurologic, foot complications (pulses &
sensations in feet and legs)
2) reinforce diet and exercise prescription.
Annually:
1) complete ophthalmologic examination
2) cardiovascular risk factors (lipid profile)
3) urine collection for albumin; serum - BUN and creatinine.
DIABETES MELLITUS
2750 (45)
THERAPEUTIC TARGETS FOR NON-PREGNANT DIABETIC PATIENTS
NORMAL
TARGET
(for general population)
(for diabetics)
Premeal glucose (mg/dL)
< 110
90-130 (< 110 ideally)
Postprandial (90-120 min after
meal) glucose (mg/dL)
< 140
< 180
Bedtime glucose (mg/dL)
< 120
100-140
<6
<7
LDL (mg/dL)
< 130
< 100
HDL (mg/dL)
> 35
> 40 (men) > 50 (women)
Fasting triglycerides (mg/dL)
< 150
< 150
< 140/90
< 130/80
PARAMETERS
Hb A1c (%)
Blood pressure (mmHg)
TREATMENT IN SPECIAL CIRCUMSTANCES
During SICK DAYS
- principles:
1. Acute illness increases insulin requirement (due to catecholamines↑) - never omit insulin!*
–
supplemental rapid- / short-acting insulin doses (5-20% of TDD) depending on degree of
hyperglycemia and ketosis.
*although it is more common to require more insulin during illnesses, some patients
require reduction of basal / meal insulin dose if unable to eat and glycemia is < 200
mg/dL
2. Prevent dehydration
3. Monitor blood glucose frequently (q 2-4 hours)
4. Monitor for ketosis
5. Frequent contact with diabetes team.
Educate about symptoms that warrant immediate medical attention:
1) dehydration (dry mouth, sunken eyes, cracked lips, weight loss, dry skin)
DIABETES MELLITUS
2750 (46)
2) persistent vomiting for > 2-4 hours
3) persistent glycemia > 300 mg/dL or ketones for > 12 hours
4) symptoms of DKA (nausea, abdominal pain, chest pain, vomiting, ketotic breath, hyperventilation,
altered consciousness).
During HOSPITALIZATIONS
1) coexisting illnesses, bed rest, regular diet can aggravate hyperglycemia.
2) anorexia, vomits, ↓food intake may cause hypoglycemia in continuation of drugs.
TYPE 1 DIABETICS
1) continue intermediate-acting insulin at 50-70% dose divided bid or tid.
2) supplemental regular insulin on sliding scale.

blood glucose should be measured qid before meals.

if receiving parenteral nutrition – insulin i/v/i.
TYPE 2 DIABETICS
- often do well without any change in drugs.

if food intake↓ - hypoglycemic drugs may be discontinued (add insulin if plasma glucose remains high).
During SURGICAL PROCEDURES

elective cases are scheduled for first case in morning.

fast at least 12 hours before surgery (due to gastroparesis).

increased risk of infections (use monofilament sutures), delayed healing of wounds.
TYPE 1 DIABETICS

surgical procedures can markedly increase plasma glucose and induce DKA! – ypač vengti emergency
procedures!

substitute shorter-acting for longer-acting insulin.

provide reduced insulin dose on surgery morning.

when fasting diabetic is given insulin, provide glucose in intravenous fluids!

anesthesiologist monitors plasma glucose during surgery and gives additional insulin or dextrose as
needed.
DIABETES MELLITUS
2750 (47)
A. Subcutaneous regimen: give s/c 1/3-1/2 of usual insulin morning dose in morning before operation → 5%
glucose 1 L IVI over 6-8 h.

after operation, plasma glucose and ketones are checked at 2-4 h intervals.

preoperative insulin dose is repeated when patient has recovered from anesthesia and glucose infusion is
continued.

regular insulin is given q 4-6 h as needed to maintain glycemia 100-250 mg/dL.
Use short-acting insulin with IVI glucose!

this is continued until can be switched to oral feedings and normal insulin schedule.
B. Intravenous regimen: in morning add 6-10 U of regular insulin to 1 L of 5% glucose and infuse 150 mL/h.

continue this through recovery, with insulin adjusted on glycemia obtained at 2-4 h intervals.
TYPE 2 DIABETICS

those who take oral drugs are given 1⁄2 of their usual dose.

long-acting sulfonylurea drugs should be stopped 2-4 days before operation (shorter-acting agents should
be substituted).

METFORMIN should always be stopped (slight risk for perioperative lactic acidosis)!

measure glycemia pre- and postoperatively and q 6 h while on i/v fluids – add insulin if necessary.
During PREGNANCY

prenatal care clinic visits each week.

3 meals + 3 snacks / day (with constant timing!), moderate exercise after meals; for obese patients,
daytime snacks should be discouraged.
Visais atvejais gydoma tik INSULINU
 in type II diabetics oral drugs should be discontinued (risk of malformations)!
 human insulin is recommended (to minimize antibody formation; insulin antibodies cross placenta, but
effect (if any) on fetus is unknown).

insulino režimai individualizuojami.
 overinsulinization is risk of tight metabolic control (sometimes hypoglycemic coma may occur with no
premonitory symptoms!) - all patients should be instructed (as should their families) in giving s/c GLUCAGON
for severe hypoglycemia (unconsciousness, confusion, plasma glucose < 40 mg/dL [< 2.2 mmol/L]).
 good diabetic control:
1) fasting glycemia < 90-105, postprandial glycemia < 120, absence of wide glucose fluctuations.
2) HbA1c < 8%
DIABETES MELLITUS
2750 (48)
3) urinary glucose loss < 1 g/day (< 5.5 mmol/day).
 during 3rd trimester, care (in addition to routine prenatal care) consists mainly of:
1) controlling MATERNAL glycemia
2) periodically assessing FETAL well-being (from 28-32 wk to term): fetal kick counts during 30min period daily, nonstress tests (fetal heart rate monitoring), biophysical profiles.
3) ultrasound (20–22 wk) - to evaluate for fetal cardiac anomalies.
Admit at 32–36 weeks if maternal DM has been poorly controlled or
fetal parameters are concern!
Diabetic retinopathy and nephropathy are not contraindications for conception or reasons for terminating
pregnancy.
 monthly ophthalmologic examinations are recommended - if proliferative retinopathy is noted →
photocoagulation as soon as possible to prevent progressive deterioration.
 rekomenduojama susilaikyti nuo nėštumo bent 2 metus po renal transplantation.
OBSTETRIC COMPLICATIONS OF DIABETES
1. Congenital malformations - positively correlated with Hb A1c↑ at conception and during embryogenesis
(first 8 wk) - PRECONCEPTION counseling and diabetes control are important!
 at conception Hb A1c should be ≤ 8% (check every 4-6 weeks thereafter).
N.B. hipoglikemija irgi veikia teratogeniškai!
 diabetas padidina congenital malformations riziką 2-3 kartus (esp. cardiac, neural tube, caudal
regression) - major cause of neonatal mortality!
 fetal echocardiography at 20-22 wk should be performed if Hb A1c↑ at 1st prenatal visit or in 1st
trimester.
2. Macrosomia > 90th percentile (→ cephalopelvic disproportion → birth trauma)
 dėl maternal vascular disease galimas ir intrauterine growth restriction.
3. Polyhydramnios
4. Spontaneous abortion, preterm labor, stillbirth.
During LABOR and DELIVERY
 if pregnancy goes beyond 42 wk, fetus is at risk of death in utero - labor should be induced (many
obstetricians suggest induction at 39-40 wk);
DIABETES MELLITUS
2750 (49)
prieš tai patikrinama fetal lung maturation su amniocentesis (if labor induction is considered
at < 39 weeks).
N.B. in diabetics lecithin/sphingomyelin ratio may not be truly reflective and
phosphatidylglycerol should also be measured!
 even if glycemia was normal throughout pregnancy, macrosomia is risk - CESAREAN SECTION may be
necessary (strong indication – numatomas vaisiaus svoris > 4000 g).
 IVI infusion during labor - INSULIN with 5% DEXTROSE in 0.5% sodium chloride;
glycemia is checked q1–2 hrs → insulin dose adjusted to maintain:
70-120 mg/dL [3.8-6.6 mmol/L]

after delivery - immediate decrease in insulin requirement (abrupt loss of placenta, which
synthesized high levels of diabetogenic hormones, insulinase).

NEWBORNS have ↑number and ↑size of islets (hyperplasia in response to maternal hyperglycemia) - they
are at risk of hypoglycemia, respiratory distress, hypocalcemia, hyperbilirubinemia, polycythemia.

BREASTFEEDING is not contraindicated;
–
may be associated with hypoglycemia in type I diabetics.
–
oral hypoglycemic drugs are not recommended.
ACUTE METABOLIC COMPLICATIONS
METABOLIC DECOMPENSATION in diabetes is manifested as severe hyperglycemia ± ketoacidosis.
a) DIABETIC KETOACIDOSIS - generally seen in type 1 patients.
b) NON-KETOTIC HYPEROSMOLAR SYNDROME - generally seen in type 2 patients.
N.B. mortality is usually due to associated catastrophic illness (e.g. MI, stroke, sepsis) or acute complications
(e.g. aspiration, arrhythmias, cerebral edema) – successful treatment depends on detection of precipitating
illnesses (not just simple reversal of metabolic abnormalities with insulin).

acute metabolic complications are rare causes of death today.
DIABETIC KETOACIDOSIS (DKA)

occurs in established type 1 diabetic patients as result of:
a) insulin requirements↑ (e.g. intercurrent illness).
b) insulin availability↓ (e.g. inappropriate insulin reduction or missed injections, esp. in adolescents).
[most common scenario - failure to increase insulin and consume extra fluid during illness].
pvz. vemiantis pacientas pagalvoja, kad reikia nutraukti insuliną
DIABETES MELLITUS
2750 (50)
Most common PRECIPITATING FACTORS: infection (50%), MI, GI bleeding, noncompliance with insulin regimen.
PATHOGENESIS - transition from glucose to lipid oxidation and metabolism.

severe insulin deficiency + excessive counterregulatory hormones:
- mobilize substrates from muscle (amino acids, lactate, pyruvate) and adipose tissue (free fatty acids,
glycerol) → in liver substrates are converted to GLUCOSE and KETONE BODIES.

osmotic diuresis leads to marked DEHYDRATION.

hyperketonemia induces metabolic acidosis with respiratory compensation, and marked urinary excretion
of acetoacetic acid and β-hydroxybutyric acid (with obligate K+, Na+ losses).
KLINIKA - deterioration over days:
1) increasing hyperglycemia → polyuria, polydipsia.
2) sweet, sickly odor of acetone on patient's breath (due to ketosis)
3) abdominal pain (25%) - periumbilical and constant (can mimic surgical emergencies!).
4) anorexia & nausea ± paralytic ileus
vomiting is threatening symptom (precludes oral replacement) → quick severe volume
depletion.
5) dehydration & acidosis signs: dry skin and mucous membranes, tachycardia, orthostatic hypotension,
jugular venous pressure↓, deep & rapid Kussmaul respirations (“air hunger” – respiratory compensation
of acidosis), depressed mental function & delirium (if untreated, may progress to coma).

nors besikaupiantis acetonas (šalinasi tik per plaučius) yra CNS anestetikas, bet komos
priežastis nėra aiški.
N.B. kliniką labiau lemia acidozė negu hiperglikemija!
Fever is unusual - indicates infection!
DIAGNOSIS
Cardinal biochemical features (pakanka diagnozei patvirtinti):
1.
HYPERGLYCEMIA > 300 mg/dL
2.
HYPERKETONEMIA
3.
METABOLIC ACIDOSIS pH < 7.35 (gali būti net 6.8 - depends on respiratory compensation)
Diagnostikos eiga: clinical picture + severe hyperglycemia → test serum ketones + arterial pH.

quantitative measurements of ketones are not readily available - rapid diagnosis requires qualitative
assessment of serum ketones (e.g. reagent strips [Ketostix] or tablets [Acetest]).
N.B. these methods depend on nitroprusside reaction with acetoacetate;
DIABETES MELLITUS
2750 (51)
acetone reacts weakly;
β-hydroxybutyrate reacts not at all.
–
testai gali būti falsely-negative (in DKA esti β-hydroxybutyrate >> acetoacetate; concomitant lactic
acidosis farther reduces acetoacetate).
–
gydant insulinu β-hydroxybutyrate is converted to acetoacetate - nitroprusside reaction remains
"positive" (false impression of sustained ketosis).
N.B. reagent strips may significantly underestimate amount of ketone bodies present.
Other laboratory findings:
1) bicarbonates↓
2) serum anion gap↑ (pagrinde dėl bicarbonates↓).

anion gap = Na+ – (Cl- + bicarbonate)

occasionally, superimposed metabolic alkalosis (e.g. vomiting, diuretic use) may obscure
ketoacidosis (anion gap increase out of proportion to level of bicarbonate suggests this possibility).
3) hyponatremia (because of hyperosmolarity - water shifts to intravascular space); efektyviai gydant, gali
pereiti į hipernatremiją.

final serum sodium concentration that occurs after hyperglycemia correction can be calculated by
using CORRECTION FACTOR 1.6-2.4 (serum sodium increases by 1.6-2.4 mEq/L for each 100 mg/dL
decrease in glucose).
4) prerenal azotemia (BUN > creatinine).

if patient maintains glomerular filtration rate and is able to exchange keto acid for chloride →
hyperchloremia.
5) osmotic diuresis → potassium, phosphate, magnesium↓ (kartais tai išryškėja tik gydymo metu atstatant
hidrataciją).
6) hyperamylasemia (non-pancreatic origin) - can lead to erroneous diagnosis of pancreatitis.
7) leukocytosis (gali padėti klaidingai įtarti acute abdomen) – due to metabolic stress.
MANAGEMENT – žr. žemiau.
N.B. always seek for infection!
MORTALITY 5-10%.

dažniausiai miršta elderly patients (> 65 years) in whom ketoacidosis is initiated or complicated by serious
underlying illness.

ketoacidosis is major cause of death in type 1 diabetic children (for them DKA may be complicated by
cerebral edema).
PREVENTION - education in "sick day" management. see above
DIABETES MELLITUS
2750 (52)
Ketoacidosis predisposes to NASOPHARYNGEAL MUCORMYCOSIS (soft tissue infiltrated by broad, non-septate
hyphae of Mucor):
HYPERGLYCEMIC HYPEROSMOLAR SYNDROME (HHS)
PATHOPHYSIOLOGY - patients cannot drink enough fluid to keep pace with osmotic diuresis caused by
hyperglycemia (prisideda ir renal dysfunction with glucose loss↓) →
→ HYPEROSMOLARITY (> 320 mOsm/L) + HYPERGLYCEMIA (> 600 mg/dL) + DEHYDRATION
 endogenous insulin in type 2 diabetics suppresses ketogenesis.
KLINIKA - deterioration over weeks.

džn. elderly patients with mild / undiagnosed type 2 diabetes:
a) taking medications that contribute to diuresis and impairment in insulin secretion (e.g. thiazide
diuretics)
b) demented or institutionalized - unable to recognize thirst or have access to fluids.

profound DEHYDRATION.

↓LEVEL OF CONSCIOUSNESS (correlates with hyperosmolarity): 10% are initially seen in coma (coma is
unusual), 10% show no signs of mental obtundation.

other neurologic abnormalities (often reversible) may exist; e.g. grand mal or focal (!!!) seizures (vs. in
DKA - traukulių nebūna!), extensor plantar reflexes, aphasia, hemisensory or motor deficits, delirium,
exacerbation of pre-existing organic mental syndrome.

GI symptoms are less frequent than in diabetic ketoacidosis.
N.B. severe acidosis and ketosis are absent!
DIABETES MELLITUS
2750 (53)
Complications - thromboembolia, aspiration, rhabdomyolysis.
DIAGNOSIS – laboratoric!
1) severe hyperglycemia (gali būti net > 1000 - much higher than in most cases of DKA!).
2) severe dehydration (Hb↑) with renal dysfunction
3) hyperosmolar state:
effective osmolarity [mOsm/L] = 2 (Na+ + K+) + glucose / 18
šiuo atveju į formulę nereikia įtraukti urea,
because urea is distributed in total body water and
does not contribute to osmotic gradient.

severe hyperosmolarity → kompensatoriškai serume Na+↓ (dėl sunkios dehidratacijos [Na+] neretai esti
"normal" or even elevated).

severe K+ depletion.

BUN and serum creatinine levels are markedly increased.
No ketosis! (galima lengva acidozė ir nedaug ketonų↑)
MORTALITY 10-70% (much higher than in DKA).

acute circulatory collapse is common terminal event.

widespread in situ thrombosis is frequent (bleeding ascribed to DIC or gangrenous-appearing digits has
been observed).
Severity of hyperglycemia and ketoacidosis in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar
syndrome (HHS) - classic metabolic profiles are expressed at extreme left and right of diagram; continuum of
combinations of hyperglycemia and ketoacidosis is possible (33% patients with decompensated diabetes
mellitus have features of both syndromes):
DIABETES MELLITUS
2750 (54)
Diagnostic Features of DKA and HHS:
Measurement
DKA
HHS
Glucose (mg/dL)
≥ 300
≥ 600
Effective osmolality (mOsm/kg) < 320
≥ 320
pH
HCO3- (mEq/L)
≤ 7.30 ≥ 7.30
< 18
≥ 15
Ketones
2+ / 3+ - / 1+
Dehydration
1+ / 2+ 2+ / 3+
MANAGEMENT
(for both diabetic ketoacidosis and non-ketotic hyperosmolar syndrome)

urinary catheter to monitor hourly urine output if patient is unable to void or is obtunded.

nasogastric tube if abdomen is distended or bowel sounds are abnormal.
I. Restore vascular volume (to correct hypoperfusion)
–
total-body deficits: water (5-12 L), sodium (5-10 mEq/kg), i.e. water deficit > sodium deficit.
N.B. deficits are more profound in non-ketotic hyperosmolar syndrome!
DIABETES MELLITUS

start with NORMAL SALINE (0.9% NaCl) 1-1.5 L/hour for 2-3 hours.

kai volemija atstatyta, pereik prie normal / half-normal saline (with K+ added) at 0.25-0.5 L/hour.
2750 (55)
–
normal saline and half-normal saline are alternated for diabetic ketoacidosis (vien tik hypotonic
solutions may cause cerebral edema; vien tik normal saline - hipernatremijos pavojus↑).
–
in non-ketotic hyperosmolar syndrome hypotonic solutions are more commonly used (nes
hipernatremijos pavojus).

oral fluids can be given when tolerated.

½ of estimated fluid deficit is replaced in first 8-24 hours; remainder ½ - over remaining day ÷ next few
days.
II. Hyperglycemia correction


start with RAPID-ACTING (REGULAR) INSULIN i/v bolus 0.1 U/kg (10 U) → i/v/i 0.1 U/kg/hour.
–
kai kas siūlo netaikyti bolus, bet iš karto pradėti nuo i/v/i.
–
i/v is the most predictable delivering way to target tissues (esp.in severely hypovolemic patients);
alternative – i/m; s/c predisposes to unpredictable absorption.
būtina monitoruoti glikemiją; tikslas - blood glucose fall at steady rate (50-100 mg/dL/hour); if glycemia
falls < 50 mg/dL/hr → double insulin dose (risk of hypokalemia↑).
N.B too rapid fall may cause cerebral edema (esp. in young children)!

once glycemia falls to 250-300 mg/d:
1) intravenous fluids should be adjusted to incorporate 5% dextrose - to avoid
hypoglycemia and cerebral edema;
2) insulin dose should not be reduced until pH ≥ 7.3 or HCO3- ≥ 18 mEq/L (after that, SC
insulin* is started)
t.y. insulinas skiriamas acidozės korekcijai, o kad nesigautų hipoglikemija, tai
pridedama gliukozė.
3) begin clear liquid diet
*doses determined from prior insulin doses in patients with preexisting
diabetes; dose in new diabetics:
a) 0.4-0.5 U/kg (½ as basal insulin once or twice daily and ½ as rapidacting insulin before meals and snacks).
b) multiply final insulin infusion rate by 24 hours; 2/3 give in morning
(2/3 as NPH, 1/3 as regular), 1/3 give before supper (½ as NPH, ½ as
regular)

causes of failure:
1) severe insulin resistance → increase insulin dose.
2) inadequate replacement of intravascular volume or renal failure.
N.B. in early stages primary mechanism for lowering glycemia is glucose disposal via
urine rather than insulin-stimulated glucose consumption!
DIABETES MELLITUS

2750 (56)
(if insulin is used, low-dose regimen should be given).
III. Electrolyte replacement
1. Potassium (as KCl) – indicated for all patients at beginning of fluid therapy (contraindications: no urine
output, [K+] > 6.00 mmol/L)
N.B. patients have severe total-body potassium deficit (≈ 5 mEq/kg), yet serum [K+] may be low,
normal, or high (esp. if acidosis or renal failure is present).
Most common preventable cause of death in DKA is hypokalemia!

pradėjus gydymą (fluids + insulin), serum [K+] falls quickly:
1) insulin-mediated K shift into cells.
2) extracellular dilution.
3) improved renal perfusion → ↑ potassium renal excretion.


hipokalemijos reikia išvengti su potassium replacement based on serum levels:
–
low potassium level (≤ 4.5 mmol/L) → 30-40 mEq/hour despite existing metabolic acidosis;
–
normal potassium level → ensure adequate urine output → 20 mEq/hour.
ECG is direct assessment of intracellular K+:
–
flat or inverted T waves suggest low intracellular potassium;
–
peaked T waves suggest high intracellular potassium.
2. Phosphate (as K phosphate)
- substantial phosphate depletion exists in both DKA and HHS; check serum [phosphate] after 4 hours
of treatment.
No replacement of phosphorus is necessary unless [phosphate] is < 1.0 mg/dL.

in diabetic ketoacidosis - prophylactic use of phosphate has failed to show any significant benefit.

non-ketotic hyperosmolar syndrome has longer prodromal period - more severe phosphate losses →
replace with potassium phosphate + magnesium (be magnio gali ištikti hypocalcemic tetany).
3. Occasionally, patients require replacement of magnesium and calcium if tetany occurs.
IV. Acidosis correction (in diabetic ketoacidosis)
N.B. acidosis disappears with standard therapeutic measures (artificial correction with alkali
is unnecessary!); bikarbonatų rezervas atsistato per 24 val.
i.e. insulin suppresses lipolysis → free fatty acid flux to liver↓ → ketogenesis↓.
In severe acidosis (pH < 7.0), bicarbonate administration is indicated:

use with caution:
1) may provoke hypokalemia.
DIABETES MELLITUS
2750 (57)
2) may impair oxygen delivery to tissues (due to sudden left shift of oxyhemoglobin dissociation
curve).

bicarbonate is given in small amounts, slowly (50 mEq every 1-2 hours).

therapy is discontinued when pH reaches 7.1.
V. Other measures

seizures → benzodiazepines (PHENYTOIN should not be administered - ineffective + inhibits release of
endogenous insulin).

some clinicians routinely administer:
1) broad-spectrum antibiotics (to control suspected infection).
2) subcutaneous heparin (to avoid venous thrombosis and DIC).
PARAMETER
Volume
INITIAL MANAGEMENT
CONTINUING MANAGEMENT
i/v normal saline at 1 L/hr iki 5 half normal saline or normal saline at 250-500
L
mL/hr;
adjust rate of IV fluids on cardiovascular parameters
(heart rate, blood pressure), urine output
Insulin
regular insulin i/v bolus
regular insulin i/v/i 0.1 U/kg/hr;
0.1 U/kg
monitor blood glucose
Expected rate of fall - 100 mg/dL/hr
Initial goal: 250-300 mg/dL
blood glucose still elevated or falls slowly:
Increase insulin dose by 50-100% per hr
Glucose
Blood glucose < 250 mg/dL
Start i/v dextrose
Start s/c regular insulin and discontinue i/v insulin 2
hr after giving s/c insulin
Begin clear liquid diet
Electrolytes
Hyperkalemia may be initially
present
Hypokalemia during therapy should be anticipated
Monitor:
1) K, Ca, Mg, phosphate - replace as needed
2) ECG
DIABETES MELLITUS
PARAMETER
INITIAL MANAGEMENT
2750 (58)
CONTINUING MANAGEMENT
3) urine output (should be at least >30 mL/hr)
Acidosis
Use bicarbonate if pH < 7.1,
Monitor
shock, coma, severe
ABGs (if pH > 7.1, stop bicarbonate)
hyperkalemia is present:
Bicarbonate
1 ampule of NaHCO3 (44 mEq) Anion gap
every 1-2 hours
Monitoring during therapy:
1. Serum bicarbonates & anion gap – effectiveness of insulin therapy.
2. Glycemia, electrolytes q2h.
3. Fluid and cardiovascular status: CVP ± PCWP (in cardiac dysfunction or adult respiratory distress
syndrome), urinary catheterization.
4. Mental status (esp. in children) - risk of cerebral edema!!!
5. Leukocytosis often accompanies diabetic ketoacidosis or non-ketotic hyperosmolar syndrome and should
not be taken as rationale for antibiotic prophylaxis.
6. Gastric decompression - risk of aspiration↓.
7. Careful search for possible coexisting illness (serious medical illness may easily be overlooked for several
hours during early phases of therapy).
ALCOHOLIC KETOACIDOSIS
Etiology: abrupt withdrawal after large amounts of alcohol + prolonged starvation (nausea and vomiting
prolong starvation).
Pathophysiology: stress of illness, volume depletion, sympathetic activation following alcohol withdrawal,
prolonged starvation → fall in insulin and rise in glucagon levels → ketogenesis↑↑↑.
Klinika:
 typically chronic alcoholic young women who increase their ethanol consumption for days or weeks →
recent abrupt alcohol withdrawal due to nausea, vomiting, diffuse abdominal pain (various causes pancreatitis, gastritis, pneumonia, etc.)
 dehydration, ketoacidosis (žr. DKA).
 symptoms of alcohol withdrawal. see Psy21 p.
Diagnosis:
1) severe ketoacidosis (with anion gap↑↑↑* - due to β-hydroxybutyrate, lactate)
DIABETES MELLITUS
2750 (59)
 prie alcoholic ketoacidosis vyrauja β-hydroxybutyrate susidarymas – jo nerodo nitroprusside test
(“Acetest”).
*exclude other causes of large anion gap (e.g. methanol or ethylene glycol poisoning)
2) dehydration
3) hyperglycemia is inconsistent:
a) mild in non-diabetic subjects (hepatic alcohol metabolism inhibits gluconeogenesis despite
insulin deficiency).
b) prominent in association with underlying diabetes (or pancreatitis).
Alcoholic ketoacidosis may be confused with diabetic ketoacidosis!
Treatment - condition is rapidly reversed with i/v fluids + glucose + water-soluble vitamins + magnesium,
potassium, phosphate;
 insulin is usually not needed!
 bicarbonates i/v – only if pH < 7.1
NEONATAL HYPERGLYCEMIA
> 120 mg/dL (6.7 mmol/L) in newborns.
Etiology
a) very low birth weight (VLBW) newborns (< 1.5 kg) after rapid glucose i/v infusions during first
few days of life.
b) small-for-gestational-age newborns (transient neonatal diabetes mellitus).
c) severely stressed or septic newborns (esp. fungal sepsis).
Signs & Symptoms
 glycosuria with osmotic diuresis → dehydration, serum hyperosmolarity → neurologic damage.
Treatment
 replace fluid and electrolyte losses.
 for persisting hyperglycemia – add human insulin 0.01-0.1 U/kg/h to 10% glucose.
 response to insulin is unpredictable - monitor blood glucose and titrate insulin carefully.
 transient neonatal diabetes mellitus resolves spontaneously within few weeks.
HYPOGLYCEMIA
DIABETES MELLITUS
2750 (60)
- glycemia < 50 mg/dL.
- most frequent acute complication in type 1 diabetes (affects 10-25% patients at least once a year):
a) error in insulin dosage
b) small / missed meal
c) unplanned exercise (patients are instructed to reduce insulin or to increase carbohydrate intake
before planned exercise) – 1muscle glucose uptake↑, 2more rapid insulin absorption.
d) without apparent cause.

galima ir type 2 diabetikams (induced by oral glucose-lowering agents):
–
esp. in elderly with impaired renal function.
–
esp. longer-acting sulfonylureas (hypoglycemia may recur for 24-48 hours after drug
withdrawal).
PATHOPHYSIOLOGY


brain cannot synthesize or store more than few minutes' supply of glucose and, in short term, is wholly
dependent on constant supply of glucose.
–
blood-brain barrier excludes albumin-bound free fatty acids.
–
ketone transport into brain is too slow to meet energy requirements unless normal
plasma ketone levels are markedly increased.
insulin does not regulate glucose activity in CNS.
Hypoglycemia provokes responses that return blood glucose to normal:
1) insulin secretion↓ → peripheral glucose uptake↓
2) counterregulatory hormone secretion (glucagon, epinephrine) → hepatic glucose production↑
–
GH and cortisol secretion is delayed and less critical in acute cases (GH and cortisol
decrease peripheral glucose utilization)
3) subjective awareness of hypoglycemia → carbohydrate ingestion.
Type 1 diabetic patients are much more prone to hypoglycemia:
1) insulin enters from non-physiologic source (e.g., subcutaneous depot) that is unaffected by regulatory
responses.
2) attenuated / absent glucagon secretion during hypoglycemia (develops in most patients after 2-5 years)
3) diminuted epinephrine response to hypoglycemia (develops in half of patients after >10 years).
4) patients ability to recognize hypoglycemia may be impaired.
SIGNS & SYMPTOMS
 plasma glucose levels at which symptoms develop vary markedly among individual patients.
DIABETES MELLITUS
2750 (61)
I. Adrenergic warning symptoms (earliest subjective warning of hypoglycemia): sweating (vs. dehydration in
DKA!), tremor, faintness, palpitations, hunger.

these symptoms serve as warning to ingest sugar.

β-adrenoblockers mask warning symptoms (except of sweating)!

some patients lose autonomic warning symptoms (hypoglycemia unawareness):
a) if switched to intensive insulin regimens - iatrogenic hypoglycemia episodes suppress
counterregulatory hormone responses during subsequent episodes (laimei, tai reversible, jei
ilgesnį laiką pavyksta išvengti hipoglikemijų).
b) in long disease duration - impaired sympathoadrenal response.
II. Neuroglycopenia (glucose deficiency in CNS) symptoms occur later: weakness, double vision, oral
paresthesias, speech slurring, apraxia, behavioral disturbances (can be mistaken for inebriation), delirium
→ seizures and coma with low body temperature.
N.B. irritability and confusion may prevent patient's awareness of their cause.
 coma ištinka kai glikemija ≤ 30 mg/dL (1.7 mmol/l).
 prolonged very severe hypoglycemia can cause irreversible brain damage.
 milder recurrent episodes of hypoglycemia cause no evidence of neuropsychological impairment.
N.B. hypoglycemia may provoke seizures, accidental injury, arrhythmias or cardiac ischemia (due to
catecholamine response) - hypoglycemia accounts for 3-4% deaths in insulin-treated patients.
Hypoglycemia can become greatest fear and lead to less than optimal glycemic control!
DIAGNOSIS
 WHIPPLE’s triad: 1unexplained CNS manifestations / unexplained adrenergic symptoms + evidence that
symptoms 2occur in association with low plasma glucose and are 3corrected by raising plasma glucose.
 abnormally low plasma glucose level:
< 50 mg/dL (< 2.78 mmol/L) in men
< 45 mg/dL (< 2.5 mmol/L) in women
< 40 mg/dL (< 2.22 mmol/L) in children.
 portion of initial blood sample should be saved as frozen plasma - to determine insulin, proinsulin, Cpeptide, lactate, pH, ketones levels, to perform drug scan.
N.B. serum electrolytes are normal!
TREATMENT
 all diabetics should carry candy, lumps of sugar, or glucose tablets – hypoglycemia responds rapidly to
glucose/sucrose ingestion; glass of fruit juice or milk also works well.
DIABETES MELLITUS
2750 (62)
example: 10-15 g of rapid-acting carbohydrate → recheck blood glucose in 15 minutes →
repeat 10-15 g if blood sugar remains below target → protein-containing snack if meal will not
follow within 1-2 hours.
 family members should be instructed to administer GLUCAGON;
–
mainly useful in emergencies away from medical settings.
–
usual dose is 0.5-1 U s/c, i/m or i/v.
–
efficacy is critically dependent on hepatic glycogen stores (glucagon has little effect in
prolonged fasting or prolonged hypoglycemia).
–
if patient does not respond within 25 min, further injections are unlikely to be effective.
–
side effects are nausea and vomiting.
 identification card, bracelet, necklace (“insulin-treated diabetic”) aid in recognizing hypoglycemia in
emergencies.
In ED:
 confirm hypoglycemia with glucostick → bolus of 25-100 mL 50% glucose i/v → i/v/i of 10-30% glucose
(i/v/i tęsiama tol, kiek tikimasi “kaltininko” preparato veikimo; pvz. perdozavus chlorpropamide – several
days).
N.B. pediatricians do not recommend i/v 50% glucose bolus or i/v > 10% glucose in infants and
children - can have pronounced osmotic effects and induce marked hyperglycemia → marked
stimulation of insulin secretion.
 if i/v access is unavailable → GLUCAGON.
 alcoholics should receive 100 mg thiamine i/v prior to glucose (Wernicke-Korsakoff syndrome prophylaxis).
CLASSIFICATION OF HYPOGLYCEMIAS
A. Drug-induced hypoglycemias (most common)
1. Insulin
 C-peptide levels are low.
2. Sulfonylureas
 C-peptide levels are high → screen blood/urine for sulfonylureas.
3. Alcoholic hypoglycemia
 occurs in people who ingest alcohol after fasting long enough;
–
exhausted glycogen stores due to fasting - hepatic glucose output dependent on
gluconeogenesis;
–
hepatic alcohol oxidation increases cytosolic ratio NADH/NAD+ - inhibits hepatic
gluconeogenesis.
DIABETES MELLITUS
2750 (63)
 can be induced by blood alcohol levels well below common legal driving limit (100 mg/dL or 22
nmol/L)!
 “MORNING-AFTER SEIZURE” - hypoglycemic seizures unique to children - drinking leftover alcohol left
unsupervised after party in household.
 frequently associated with plasma lactate↑ + ketones↑ and metabolic acidosis.
 treatment with glucose i/v → prompt improvement in level of consciousness and resolution of
metabolic acidosis; close observation - blood glucose may fall again!
 mortality > 10%.
4. Other drugs: salicylates (most often in children), propranolol, pentamidine, disopyramide, hypoglycin A
(found in unripened akee fruit → Jamaican vomiting sickness).
B. Nondrug-induced hypoglycemias
I. FASTING HYPOGLYCEMIAS - CNS manifestations during fasting or exercising.
1. Inherited enzyme deficiencies:
a) defects in hepatic glucose release (deficiencies of glucose-6-phosphatase, fructose-1,6diphosphatase, phosphorylase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase,
glycogen synthetase).
b) defects in fatty acid oxidation (incl. systemic carnitine deficiency), defects in ketogenesis (3hydroxy-3-methylglutaryl-CoA lyase deficiency) - restrict energy derivation from plasma FFA
and ketones → abnormally high glucose uptake by non-neural tissues during fasting or
exercise.
c)
KETOTIC HYPOGLYCEMIA (most common cause of hypoglycemia in 1-4 yrs. children!!!) - defect in
substrate mobilization for hepatic gluconeogenesis → fasting hypoglycemia with plasma
FFA↑ and ketones↑ (ketonuria!), normal lactate, and low alanine levels (alanine infusion
restores normoglycemia – gluconeogenesis per se is intact);
–
classically first manifestation – seizures preceded by vomiting and lethargy; normal
between attacks.
–
common complication - cataracts (secondary to recurrent osmotic lens swelling) - all
patients should be referred for ophthalmologic examination.
–
diagnosis - development of symptomatic hypoglycemia in response to provocation with
ketogenic diet.
–
H: only dietary management (avoid fasting); džn. savaime pagyjama 6-8 m. amžiuje.
2. Insulinoma - uncontrolled insulin secretion. see 2752 p.
3. Nesidioblastosis - diffuse budding of insulin-secreting cells from pancreatic duct epithelium and
pancreatic microadenomas of such cells.
4. IGF-II-secreting tumors - IGF-II exerts hypoglycemia through IGF-I or insulin receptors.
5. Extensive acute liver disease can cause fasting hypoglycemia.
6. Autoimmune hypoglycemia (insulin-receptor antibodies that mimic insulin effects).
DIABETES MELLITUS
2750 (64)
7. Hypopituitarism (GH↓ + cortisol↓).
8. Addison's disease causes hypoglycemia during starvation.
II. REACTIVE HYPOGLYCEMIAS - adrenergic symptoms provoked by meal.
–
less marked and briefer than fasting hypoglycemia.
1. Hereditary fructose intolerance, galactosemia - acute inhibition of hepatic glucose output when
fructose or galactose is ingested.
2. Leucine sensitivity of childhood – ingested leucine provokes exaggerated insulin secretory
response.
3. Alimentary hypoglycemia occurs after upper GI surgical procedures (gastrectomy,
gastrojejunostomy, vagotomy, pyloroplasty) that allow rapid glucose entry and absorption →
excessive insulin response → adrenergic symptoms that are selectively corrected by ingesting
carbohydrates.
NEONATAL HYPOGLYCEMIA
< 40 mg/dL (< 2.2 mmol/L) in full-term newborn
< 30 mg/dL (< 1.7 mmol/L) in preterm newborn
 kai kas teigia jog tai per žemos “normos”, atspindinčios pasenusią tendenciją nemaitinti naujagimio
pirmas 12 valandų; rekomenduojama riba – 50 mg/dL.
PHYSIOLOGY


fetus depends completely on glucose supply via placenta and does not contribute to glucose production fetus begins to build hepatic glycogen early in gestation, accumulating most glycogen stores during second
half of 3rd trimester.
birth: glucose supply terminates, levels of epinephrine, norepinephrine, glucagon surge, while insulin
levels decline → gluconeogenesis and mobilization of hepatic glycogen stores.
in healthy, term neonates, glucose levels reach nadir* 30-360 min after birth → normal glucose
homeostasis.
*50-60 mg/dL
ETIOLOGY
a) deficient glycogen stores at birth:
1) common condition in very low birth weight (VLBW) or preterm newborns!
2) placental insufficiency.
 hypoglycemia may manifest at any time in first few days (e.g. prolonged interval between feedings
or poor nutritional intake).
b) increased glucose catabolism - perinatal asphyxia (any glycogen stores rapidly consumed in anaerobic
glycolysis).
c) hyperinsulinism:
DIABETES MELLITUS
2750 (65)
1) newborns of diabetic mothers → temporary fetal hyperinsulinemia (inversely related to degree of
diabetic control).
2) severe erythroblastosis fetalis
3) BECKWITH-WIEDEMANN syndrome (visceromegaly, macroglossia, omphalocele, hypoglycemia due to
pancreatic islet hyperplasia)
 hypoglycemia manifests in first 1-2 h (continuous glucose supply from placenta is interrupted).
SYMPTOMS, SIGNS
 many newborns remain asymptomatic.
 hypotonia or jitteriness, apneic spells or tachypnea, seizures – nonspecific signs (also may occur in
asphyxia, sepsis, hypocalcemia, narcotic withdrawal, etc).
 correlations between symptoms, hypoglycemia, and subsequent neurologic damage are inexact.
PROPHYLAXIS
Can lead to neurologic damage - should be prevented / treated promptly!!!
 start 10% glucose i/v/i at birth – indications: 1newborns of insulin-dependent diabetic women, 2extremely
prematures, 3 with respiratory distress.
 other newborns at risk who are not sick - start early, frequent formula feedings.
 all newborns - check blood glucose regularly at bedside (using glucose test strips); if levels are marginally
low – check true blood glucose.
TREATMENT
 immediately 10% glucose in water i/v/i, 5 mL/kg over 10 min.
 continue 4-8 mg glucose /kg/min (i.e. 10% glucose 60-120 mL/kg/day).
 if starting i/v infusion promptly is difficult → GLUCAGON 100-300 µg/kg i/m (effect lasts 2-3 h, except in
depleted glycogen stores).
 enteral feedings can gradually replace i/v infusion.
N.B. i/v glucose should always be tapered - sudden discontinuation may result in
hypoglycemia!
 refractory hypoglycemia:
1) HYDROCORTISONE 5 mg/kg/day i/m in 2 divided doses.
2) seek other causes (e.g. sepsis) + endocrine evaluation.
3) pancreatectomy (for Beckwith-Wiedemann syndrome, nesidioblastosis)
DIABETES MELLITUS
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CHRONIC DIABETIC COMPLICATIONS
PATHOGENESIS
I. Protein glycosylation (into advanced glycosylation end products)

proteins are readily glycosylated in vivo in direct proportion to levels of glucose.

glycosylation is non-enzymatic and non-specific - involves not only Hb but also serum and membrane
proteins, LDLs, peripheral nerve protein (tubulin), and structural proteins.

proteins become cross-linked and resistant to proteolytic digestion.

widespread modifications in cellular and structural proteins → long-term complications.
II. Other potential biochemical mechanisms:
1) polyol pathway (non-phosphorylated glucose is reduced to SORBITOL by aldose reductase) →
intracellular redox state changes, intracellular osmolarity↑.
2) diacylglycerol production↑ → activation of specific protein kinase C isoforms.
III. Microcirculatory hydrostatic pressure↑ → generalized capillary leakage of macromolecules.
see diabetic nephropathy (blow).
IV. Hyperinsulinemia per se (in insulin therapy or insulin resistance) causes atherosclerosis (syndrome X – see
below).
SCREENING
1) retinopathy – yearly ophthalmoscopy. see below
2) nephropathy – screen for microalbuminuria yearly. see below
3) hypertension – measure BP at every visit (at least every 3 mo).
4) dyslipidemia – measure LDL every 5 years (if target < 100 mg/dL is met) starting at age 2 years if there is
positive family history of cardiovascular disease or if family history is unknown (if family history is negative,
start at puberty).
5) neuropathy & angiopathy – foot testing for sensation, pulses, sores.
Type 1 patients should also be screened for AUTOIMMUNE DISEASES:
Autoimmune thyroid disease (present in 15% patients) – TSH ± thyroid autoantibodies; start at time of
diabetes diagnosis → repeat yearly.
Celiac disease (present in 6% patients) - circulating IgA autoantibody to tissue transglutaminase.
DIABETES MELLITUS
2750 (67)
–
quantitative serum IgA level should be drawn at the same time to rule out IgA deficiency (as cause for
falsely low IgA tissue transglutaminase levels).
–
positive antibodies should be confirmed with second measurement → small bowel biopsy
DIABETIC MICROANGIOPATHY
- diffuse marked thickening of basement membranes (concentric layers of hyaline material composed
predominantly of type IV collagen).

clearly related to hyperglycemia.

most evident in capillaries of skin, skeletal muscle, retina, renal glomeruli, and renal medulla.

microangiopathy underlies development of :
1) diabetic nephropathy
2) diabetic retinopathy
3) some forms of neuropathy.

indistinguishable microangiopathy can be found in aged nondiabetics, but rarely to such extent.
N.B. despite ↑thickness of basement membranes, diabetic capillaries are more leaky than normal to
plasma proteins.
DIABETIC RETINOPATHY
EPIDEMIOLOGY
Diabetes is the leading cause of blindness in persons aged 20-74 years!

diabetikams aklumas 20 k. dažnesnis (ypač kai cukraligė > 15 m. trukmės) – 10-15% of type 1 diabetic
patients become legally blind (visual acuity of 20/200 or worse in better eye).

type 2 diabetikams rizika perpus mažesnė.

primary cause of visual loss is RETINOPATHY.

severity of retinopathy increases with ↑ duration of disease (exception is early childhood diabetes - before
puberty, retinopathy is less common regardless of disease duration); po 15 sirgimo metų, retinopatija
randama > 95% type 1 diabetikų.
PATHOLOGY
for descriptions & examples – see Eye60 p.
Early NON-PROLIFERATIVE (s. background) retinopathy - does not affect vision!; capillary occlusion leads to:
DIABETES MELLITUS
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1. Microaneurysms (small red dots) - the first sign.

occur in areas of capillary occlusion.

develop after 3-5 years of diabetes in most conventionally treated patients.

can be demonstrated by fluorescein angiography.
2. Extravasations of:
blood → retinal blot hemorrhages (round with blurred edges).
lipoproteins → hard exudates (yellow, variable size, sharply defined).
3. Infarctions of nerve fiber layer → “cotton-wool spots” or “soft exudates”.
BACKGROUND = microaneurysm “dots” + microhemorrhage “blots”
Advanced NON-PROLIFERATIVE (s. pre-proliferative) retinopathy

intraretinal microvascular abnormalities, very permeable dilated capillaries, venous irregularities.

proliferative retinopathy develops within 1-2 years.
PROLIFERATIVE retinopathy
arterial / venous occlusion → ischemia → proliferation of fine tufts of new blood vessels
(neovascularization) and fibrous tissue.

vessels and fibrous tissue begin on retinal surface and later grow into vitreous → VITREOUS HEMORRHAGE →
sudden blindness or clot retraction with RETINAL DETACHMENT and blindness.

maculopathy (dažnesnė type 2 diabetikams): vascular leakage (macular edema!!!), vascular occlusion in
macula.

proliferative retinopathy esti 50% type 1 diabetikų after 20 years (vs. only 10-15% type 2 diabetikų).
DIABETES MELLITUS
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NON-RETINOPATHIC CHANGES

new vessels may invade anterior chamber angle (RUBEOSIS IRIDIS – neovessels on iris) → intractable
neovascular glaucoma → blindness.

cataracts resulting from osmotic swelling* secondary to hyperglycemia (N.B. can be reversed by improved
glycemic control).
*lęšiuko ALDOLASE REDUCTASE konvertuoja glucose → sorbitol; sorbitol negali pasišalinti iš lęšiuko
→ osmotic swelling → lens fiber rupture (cataract)

CN3, 4, 6 mononeuritis.

dėl lens dehidracijos esti relative myopia; pradėjus hiperglikemijos gydymą → hypermetropia.
N.B. koreguok refractive errors tik kai gydymas stabilizuosis!
TREATMENT
Medical therapy

optimization of glycemic control - slows progression of non-proliferative retinopathy.

hypertension must be treated aggressively.

AFLIBERCEPT (Eylea) – FDA approved injection for diabetic macular edema.
Surgical therapy

panretinal photocoagulation - treatment of choice in progressive retinopathy (at non-proliferative stage
has no detectable value!) – obliteration of neovessels.

in advanced proliferative retinopathy - vitrectomy - to remove vitreous hemorrhage or to cut extensive
fibrous bands causing retinal detachment.
SCREENING
– yearly ophthalmoscopy; start at age 10 years when has diabetes for > 3-5 years.
N.B. diabetics should have annual ophthalmologic examinations:
in type 1 diabetes - begin within 3-5 years after diabetes diagnosis;
in type 2 diabetes - begin from disease onset (dalis jau turi retinopatiją
cukraligės diagnozės nustatymo metu!).
during pregnancy – every trimester.
DIABETIC NEPHROPATHY
EPIDEMIOLOGY
DIABETES MELLITUS
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Diabetes is leading cause of end-stage renal disease (ESRD) in USA - accounts for 1/3 ESRD cases.

renal failure yra 2-a pagal dažnį diabetikų mirties priežastis.

affects 30-35% type 1 diabetics, vs. only 20% type 2 diabetics (because of their shorter life expectancy).
–
in blacks, Latinos, and Native Americans with type 2 diabetes risk is much higher and reaches that
seen in type 1 diabetes.
PATHOPHYSIOLOGY
Transglomerular pressure gradient↑ (mechanizmas neaiškus – turbūt dėl compensatory atrial natriuretic
peptide↑) → passage of proteins and glycosylation end products with accumulation in mesangium →
proliferation of mesangial cells and matrix production → Kimmelstiel-Wilson syndrome, s. intercapillary
glomerulosclerosis (vienuose glomeruluose - nodular, kituose – diffuse).
Kimmelstiel-Wilson lesion (s. nodular glomerulosclerosis) – homogenous hyaline sclerotic nodules of
mesangium at periphery of glomerular capillary loops. GSP-568
N.B. nodular glomerulosclerosis [esti ≈ 50% atvejų] implicates diabetes.
vs. diffuse form [esti 100% diabetinės nefropatijos atvejų] - may also be seen in old
age and hypertension.

histology: mesangial matrix↑, glomerular basement membrane width↑ (incl. IgG and albumin deposits),
hyaline arteriosclerosis (in afferent and efferent arterioles).
see 2750 (38a) p.
Nodular glomerulosclerosis – acellular ovoid nodules in periphery of glomerulus:
DIABETES MELLITUS
2750 (71)
Hyaline arteriosclerosis (masses of hyaline material in glomerular afferent and efferent arterioles and
in glomerulus):
Nodular glomerulosclerosis along with hyaline arteriolosclerosis (small arteriole to lower right):
DIABETES MELLITUS
Early mesangial nodule and thickened basement membrane:
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DIABETES MELLITUS
2750 (73)
DIABETES MELLITUS
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DIABETES MELLITUS
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Compensatory hyperfiltration would develop in less affected glomeruli, but they would ultimately succumb.
N.B. once glomerular injury causes compensatory hyperfiltration, progressive injury may
continue in remaining glomeruli, regardless of metabolic state!

tai patvirtina clinical data:
1) unilateral renal artery stenosis diminishes diabetic lesions in affected kidney.
2) ACE inhibitors (reduce intraglomerular pressure) slow progression of diabetic nephropathy.
 diabetic kidneys tend to be large (even in end stages).
DIABETES MELLITUS
2750 (76)
KLINIKA & DIAGNOSIS
In early stages – microalbuminuria (< 300 mg/d) - first sign of diabetic nephropathy!

glomerular capillary basement membranes are thickened*, but GFR is increased (result of renal
hypertrophy, increase in glomerular volume and capillary surface area) - serum creatinine remains normal!
*esti praktiškai visiems diabetikams (ankstyviausia mikroangiopatijos forma)

routine urinalysis test strips show no evidence of proteinuria (detection of microalbuminuria requires
sensitive assays!).

appearance of HYPERTENSION increases risk of microalbuminuria → nephropathy.

importance of detecting microalbuminuria - progression to nephropathy can be prevented / delayed by
1
glycemic control, 2ACE inhibitors, and 3hypertension control.
N.B. microalbuminuria can be only transient - induced by non-specific factors (e.g. severe
hyperglycemia or heavy exercise).
In later stages diffuse mesangial matrix deposits encroach on glomerular filtering capacity.

both diffuse and nodular forms of glomerulosclerosis induce sufficient ischemia to cause fine scarring of
kidneys (finely granular cortical surface).

gross proteinuria (>0.3 g of albumin / day) begins, renal function remains normal, but hypertension is
generally present.

after about 3 years, GFR diminishes (serum creatinine↑), nephrotic syndrome is common.

ESRD develops within ≈ 10 years.
–
in type 2 diabetes moderate proteinuria may persist for many years without substantive
deterioration in renal function.
N.B. azotemic patients are at higher risk for acute renal failure after diagnostic contrast injection.
H: ensure adequate hydration around procedure.
OTHER TYPES OF RENAL DISEASE (also more prevalent in diabetes).
1. Asymptomatic bacteriuria and pyelonephritis.

bacterial growth is enhanced by: 1autonomic bladder dysfunction, 2impaired perfusion, 3glycosuria.
2. Papillary necrosis (>50% cases).
3. Renal artery stenosis.

although renal arteries are subject to severe atherosclerosis, most damaging effect on kidneys is
exerted at level of glomeruli and microcirculation.
TREATMENT
- varies depending on stage:
DIABETES MELLITUS
2750 (77)
NO MICROALBUMINURIA
1) optimize glycemic control
2) aggressive treatment of hypertension (even mild BP↑ accelerates renal injury!)
3) routine screening for asymptomatic urinary tract infections and bladder dysfunction.
MICROALBUMINURIA
1) strict glycemic control.
2) ACE inhibitors (retard proteinuria independent of blood pressure-lowering effect).
CLINICAL NEPHROPATHY
Reducing hypertension and intraglomerular pressure with ACE inhibitors (± other antihypertensive agents)
remains the only proven means of slowing progression!

dietary protein restriction (i.e. 0.8 g/kg) – keičia glomerulo hemodinamiką - may add limited
benefit (bet ankstyvesnėse stadijose naudinga).
N.B. aggressive glycemic control have marginal value!
ESRD (therapy should be instituted earlier – diabetics tolerate uremia poorly).
A. Renal transplantation - treatment of choice for young patients.

survival rates for recipients are only 10% less than those for non-diabetic graft recipients.

cardiovascular disease is the major cause of morbidity and mortality following transplantation!
B. Most older type 2 patients are offered dialysis (continuous ambulatory peritoneal dialysis or hemodialysis).
SCREENING
DIABETES MELLITUS
2750 (78)
- yearly (at 10 y or after ≥ 5 yrs duration of diabetes):
1) urine - microalbumin-to-creatinine ratio or albumin excretion ratio
2) serum - creatinine and BUN

once ACE inhibitor is started, microalbumin excretion should be monitored q3–6 mo.
DIABETIC FOOT
Results from complex interplay of factors:
1) chronic sensorimotor neuropathy:
a) prevents detection of traumatic events (no signaling pain)
b) abnormal motor function + abnormal proprioception → altered weight distribution on
sole.
2) autonomic neuropathy → disturbed autoregulation of microcirculation
3) poor peripheral circulation (small-vessel disease may play major role!)
ischemic foot with normal pedal pulse is typical in diabetes.
4) visual loss may also contribute.
N.B. major predisposing cause is polyneuropathy (i.e. neuropathic ulcers are more common than ischemic
ulcers).
KLINIKA
1. Apparently insignificant trauma → plantar ulcers that heal slowly.

mycotic infection may be initial process, leading to wet interdigital lesions, cracks, fissures, and ulcerations
→ secondary bacterial invasion.

patients feel no pain because of neuropathy and have no systemic symptoms until late in neglected
course.

in severe cases → gangrene → amputation.
N.B. diabetes accounts for ≈50% of non-traumatic limb amputations!
2. Unnatural weight bearing → callus on metatarsal heads (may erode softer underlying tissues).

in severe cases → repeated painless fractures, displacement of normal joint surfaces (Charcot joint).
Jeigu magistralinė kraujotaka nesutrikusi, pėdos oda esti šilta ir sausa (increased skin blood flow and reduced
sweating - features of impaired autonomic regulation).
PREVENTION
DIABETES MELLITUS
2750 (79)
(education, regular checkings during routine visits and by foot care specialists).
FOOT CARE PRESCRIPTION FOR HIGH-RISK PATIENTS (those with neuropathy and/or vascular insufficiency):
1. Never walk barefooted
2. Do not apply hot water or heating pads to feet
3. Inspect feet daily (use mirror for plantar surfaces)
4. Keep feet clean, dry between toes
5. Lubricate dry skin with non-greasy lotion / cream (to avoid cracking)
6. Wear properly fitting soft shoes; break in new shoes slowly; use 2nd pair of shoes at night (larger size for
edema)
7. Cut toenails straight across
8. Visit foot care specialist regularly
9. Stop smoking
N.B. preventive care can reduce rate of amputations by 50%.
TREATMENT

for deformed feet – orthotics, orthopedically fitted shoes.

for ulcers - treat immediately with broad-spectrum antibiotics, dead tissue debridement, and appropriate
dressings;
–
local application of growth factors may be useful.
BECAPLERMIN (Regranex) Gel 0.01% - recombinant human platelet-derived growth
factor - applied directly to diabetic foot / leg ulcers that are not healing; may increase
risk of cancer! (not recommended for patients with known malignancies!)
–
cast immobilization can redistribute weight away from ulcerated area.
–
most patients have no macrovascular occlusive disease – debridement and antibiotics are enough;
if poor circulation is dominant feature, try vascular surgery or angioplasty.
Osteomyelitis should be suspected in any diabetic ulcer that does not heal within 6 weeks of appropriate care!
–
a/b treatment without debridement is unlikely to result in complete cure of osteomyelitis;
therefore, refractory cases require surgical removal of metatarsal head (source of pressure) +
amputation of involved toe.
–
in extensive cases, foot or even leg amputation may be necessary (compromised peripheral
circulation makes this outcome more likely).
N.B. diabetikams naudoti tik monofilamentinius siūlus!
HYPERTENSION
DIABETES MELLITUS

2750 (80)
prevalence is increased at least 2-fold in type 2 diabetics (partly because of obesity) – hyperinsulinemia
causes syndrome X (see below).
N.B. hypertension is not associated with type 1 diabetes in absence of nephropathy.
TREATMENT
Hypertension accelerates not only atherosclerosis but also nephropathy and retinopathy - even BP minimal
elevations should be treated!
a) ACE inhibitors - offer special advantages (esp. when renal disease and hyperkalemia are not
present).
b) β-blockers are just as effective as ACE inhibitors in reducing cardiovascular and microvascular
outcomes; moreover, β-blockers are cardioprotective.
β-blockers should be avoided, in patients who are predisposed to hypoglycemia – βblockers mask symptoms and impair normal counterregulatory response.

angiotensin II receptor blockers, α-blockers, vasodilators have no adverse metabolic effects and are
therefore good therapeutic alternatives.

diuretics may be helpful as adjuncts (if thiazides are used, they should be given in small doses to minimize
their adverse effects on glucose and lipid control).
N.B. Ca-channel blockers are less effective in reducing cardiovascular risk in diabetic subjects!
ATHEROSCLEROSIS
Atherosclerosis is the major cause of death from diabetes!
MI yra dažniausia diabetikų mirties priežastis!

atherosclerotic process is indistinguishable from non-diabetic population but begins earlier and may be
more severe.
–
diabetes is independent risk factor for accelerated atherosclerosis!
–
disparity between diabetic and normal subjects is more pronounced in women (priežastis
neaiški) – sumoje diabetikų vyrų ir moterų rizikos suvienodėję!

atherosclerosis↑ is observed over entire spectrum of diabetes (even mild hyperglycemia not necessitating
insulin).

vessels of all sizes are affected - from aorta down to smallest arterioles and capillaries.

MI risk increases in diabetes: 2-3-fold; 8-fold in presence of hypertension; 20-fold if hypercholesterolemia
coexists.
N.B. diabetes diagnosis should prompt careful search for other risk factors and initiation of
aggressive preventive measures!!!
N.B. visi suaugę diabetikai turi vartoti STATINUS nepriklausomai nuo jų [cholesterol]
DIABETES MELLITUS
2750 (81)
PATHOGENESIS
1) dyslipidemia (small denser atherogenic LDL, oxidized or glycosylated LDL, HDL↓, VLDL↑)
N.B. LDL levels are commonly not higher in diabetes – svarbą vaidina dislipidemija!
2) increased platelet aggregation, increased clotting factors and fibrinogen, hyperviscosity
3) endothelial cell dysfunction
N.B. clinical studies support hypothesis that hyperinsulinemia per se may contribute to macrovascular
disease;

impaired glucose tolerance or impaired fasting glucose → COMPENSATORY HYPERINSULINEMIA → adverse
effects on systems affected by insulin:
1) renal sodium reabsorption↑, sympathetic nervous system activity↑ → BP↑
2) hepatic triglyceride synthesis↑
3) arterial smooth muscle proliferation↑
TREATMENT - įprastinis aterosklerozės ir jos komplikacijų gydymas.

gydymui nenaudotina NICOTINIC ACID - increases insulin resistance and hyperglycemia.

low-dose ASPIRIN should be routinely recommended.

large vessel disease is treated surgically as well as in non-diabetics.
DIABETES MELLITUS
2750 (82)
pagrindinis skirtumas - angioplasty results for multiple coronary artery occlusions are significantly
worse in diabetic patients!!! – jiems rekomenduotina CABG!!!
METABOLIC SYNDROME (s. syndrome X, syndrome of insulin resistance)
- clustering of dangerous risk factors within same person; at least 3 of the following 5 components:
1. FASTING HYPERGLYCEMIA (≥ 100 mg/dL)* , i.e. diabetes mellitus, impaired glucose tolerance,
impaired fasting glucose or insulin resistance.
2. OBESITY ≥ 95th percentile, sex and age adjusted;
–
esp. abdominal (central) obesity: waist circumference ≥ 94-102 cm (male), ≥ 80-88 cm (female)
3. TRIGLYCERIDES↑ (≥ 1.695 mmol/L or 110 mg/dL)*
4. HDL↓ ≤ 0.9 mmol/L or 40 mg/dL
5. HYPERTENSION ≥ 90th percentile, adjusted for age and height (for adults, ≥ 130/85 mmHg)*
*or use of medication (antihypertensive, antihyperlipidemic,
antihyperglycemic)
N.B. LDL levels are not part of criteria used to diagnose metabolic syndrome!

no well-accepted criteria for diagnosis (different organizations (WHO, NCEP, AHA, IDF) require different
combinations of components).

PREVALENCE – 20-25% of adults worldwide; prevalence increases with age.

particularly atherogenic dyslipidemia + proinflammatory state (CRP↑) + prothrombotic state (high
fibrinogen or plasminogen activator inhibitor–1) → endothelial dysfunction → atherosclerosis↑.
Increased risk for type 2 diabetes and cardiovascular complications!

most patients are older, obese, sedentary, and have degree of insulin resistance.

PREVENTION & TREATMEWNT:
1. Healthy lifestyle - increased physical activity + healthy, reduced calorie diet (esp.
reduced amount of fast digesting carbohydrates, specifically starches and sugars) +
stop smoking.
2. Drugs for individual components.
CANCER

diabetics have 1.4-fold increased risk of colon cancer (need more careful screening!).
DIABETES MELLITUS
2750 (83)
DERMATOLOGICAL MANIFESTATIONS OF DIABETES
NECROBIOSIS LIPOIDICA
- one or more yellowish to red-brown atrophic shiny plaques on legs (typically pretibial); histology - indistinct
areas of cutis necrosis;
ACANTHOSIS NIGRICANS
DIABETES MELLITUS
ERYTHRASMA
- prevalent among diabetics and in warm climates. further see INFECTION
SUMMARY
Long-term goals of diabetes care:
2750 (84)
DIABETES MELLITUS
2750 (85)
1. Minimizing vascular and neurologic complications.
2. Maintaining sense of well-being.
Diabetes care must be comprehensive rather than limited to glycemic control.
Because diabetes complications develop slowly and are not readily reversible, it is crucial for clinicians to take
prospective approach:
GESTATIONAL DIABETES
- any degree of glucose intolerance that appears (or is first detected) during pregnancy.
N.B. diabetes known before conception is not gestational!

diabetes affects ≈ 2-5% pregnancies (iš jų 90% - gestational).

only mild, asymptomatic hyperglycemia, but fetus is affected!
see above (special circumstances – pregnancy).
PATHOGENESIS (pregnancy is metabolic stress test for diabetes):
a) usually appears in 2nd ÷ 3rd trimester - pregnancy-associated peak of insulin antagonistic hormones
(estrogens, progesterone, human placental lactogen) + placental insulinase.
b) pregnancy may precipitate type 1 diabetes.
c) pregnancy makes any glucose intolerance worse.
DIABETES MELLITUS
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DIAGNOSIS
Mild glucose elevations may have adverse effects (fetal and neonatal loss) - all pregnant women should be
screened for diabetes;
 aggressive diagnostic approach is recommended for high-risk patients:
a) obese
b) family history of diabetes
c) prior gestational DM, previous macrosomic / malformed infant, prior polyhydramnios
d) unexplained stillbirths or miscarriages
e) persistent glycosuria (normal pregnancy may induce lower renal threshold)
f)
ethnic group with high diabetes prevalence (Mexican-Americans, American Indians, Asians, Indians,
Pacific Islanders).
Screening 50-g OGTT at 24-28 week of gestation (many authorities recommend this screening for all pregnant
women); at random time (without fasting)

if 1-hour OGTT value is ≥ 140 mg/dL (or fasting glucose is > 105 mg/dL) → extended (3-hour) 100-g OGTT.

GESTATIONAL DIABETES is diagnosed if two values equal (or exceed) upper limits of normal:
fasting, 105 mg/dL
1 hour, 190 mg/dL
2 hour, 165 mg/dL
DIABETES MELLITUS
2750 (87)
3 hour, 145 mg/dL.
TREATMENT

see above (special circumstances – pregnancy, labor).
diet and regular exercise; if glycemia ↑ after one week → initiate insulin.
Rigorous treatment (often with regular insulin) is required to protect against hyperglycemiaassociated fetal morbidity and mortality.

prolonged gestation (> 42 weeks) should be avoided.

after delivery, glucose tolerance generally (but not always) reverts to normal - resume normal diet; no
insulin required.
PROGNOSIS

women should have 75-g OGTT at 6-12 wk postpartum (to determine whether they are normal, clearly
diabetic, or have impaired glucose tolerance).

in 30-50%, glucose intolerance or type 2 diabetes develops within 5-10 years.
Panaudota literatūra:
Rakel & Bope: Conn's Current Therapy 2008 (ch. 142-144)
Chan ‘Treatment Guidelines for Medicine and Primary Care, 2008 Edition”
Cecil Textbook of Medicine, 2000
Merck Manual 1999
NMS Medicine, Pediatrics, Surgery, Emergency Medicine, Pathological Anatomy, Physiology, Pharmacology
Robbins Pathologic Basis of Disease, 1999
Lippincott’s Pharmacology Review, 2000
Viktor’s Notes℠ for the Neurosurgery Resident
Please visit website at www.NeurosurgeryResident.net