Download Type 1 diabetes

DIABETES
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Introduction
 Diabetes mellitus is not a single disease entity but rather a
group of metabolic disorders sharing the common
underlying feature of hyperglycemia. Hyperglycemia in
diabetes results from defects in insulin secretion, insulin
action, or, most commonly, both. The chronic
hyperglycemia and attendant metabolic dysregulation may
be associated with secondary damage in multiple organ
systems, especially the kidneys, eyes, nerves, and blood
vessels.
 The total number of people with diabetes worldwide was
estimated to be between 151 million and 171 million at the
turn of the century, and is expected to rise to 366 million by
2030. The prevalence of diabetes is increasingly sharply in
the developing world as people adopt more sedentary life
styles, with India and China being the largest contributors
to the world's diabetic load.
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National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes mellitus in United
States by age (≥20 years of age) 1988-1994 and 1999-2002
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National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes mellitus in United
States by age (≥20 years of age) 1988-1994 and 1999-2002
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Classification
 Although all forms of diabetes mellitus share
hyperglycemia as a common feature, the underlying
abnormalities involved in the development of
hyperglycemia vary widely. The previous classification
schemes of diabetes mellitus were based on the age at
onset of the disease or on the mode of therapy; in
contrast, the etiologic classification reflects our greater
understanding of the pathogenesis of each variant.
The vast majority of cases of diabetes fall into the
following classes:
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Diabetes Classification
 Majority of diabetics classified in 2 categories:
 type 1: absolute deficiency of insulin
 type 2: presence of insulin resistance with reduced
insulin secretion
 Gestational diabetes
 triggered by stress of pregnancy
 Other specific types:
 infections, drugs, endocrinopathies, pancreatic
destruction, genetic defects
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Classification of Diabetes Mellitus - summary

1. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)
Immune-mediated
Idiopathic
2. Type 2 diabetes (combination of insulin resistance and β-cell dysfunction)
3. Genetic defects of β-cell function
Maturity-onset diabetes of the young (MODY), caused by mutations in: Hepatocyte nuclear factor 4α
(HNF4A), MODY1
Glucokinase (GCK), MODY2
Hepatocyte nuclear factor 1α (HNF1A), MODY3
Pancreatic and duodenal homeobox 1 (PDX1), MODY4
Hepatocyte nuclear factor 1β (HNF1B), MODY5
Neurogenic differentiation factor 1 (NEUROD1), MODY6
Neonatal diabetes (activating mutations in KCNJ11 and ABCC8, encoding Kir6.2 and SUR1, respectively)
Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (m.3243A→G)
Defects in proinsulin conversion
Insulin gene mutations
4. Genetic defects in insulin action
Type A insulin resistance
Lipoatrophic diabetes, including mutations in PPARG
5. Exocrine pancreatic defects
Chronic pancreatitis
Pancreatectomy/trauma
Neoplasia
Cystic fibrosis
Hemachromatosis
Fibrocalculous pancreatopathy
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
6. Endocrinopathies
Acromegaly
Cushing syndrome
Hyperthyroidism
Pheochromocytoma
Glucagonoma
7. Infections
Cytomegalovirus
Coxsackie B virus
Congenital rubella
8. Drugs
Glucocorticoids
Thyroid hormone
Interferon-α
Protease inhibitors
β-adrenergic agonists
Thiazides
Nicotinic acid
Phenytoin (Dilantin)
Vacor
9. Genetic syndromes associated with diabetes
Down syndrome
Kleinfelter syndrome
Turner syndrome
Prader-Willi syndrome
10. Gestational diabetes mellitus
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 Type 1 diabetes is an autoimmune disease characterized by
pancreatic β-cell destruction and an absolute deficiency of
insulin. It accounts for approximately 5% to 10% of all cases,
and is the most common subtype diagnosed in patients
younger than 20 years of age.
 Type 2 diabetes is caused by a combination of peripheral
resistance to insulin action and an inadequate secretory
response by the pancreatic β cells (“relative insulin
deficiency”). Approximately 90% to 95% of diabetic patients
have type 2 diabetes, and the vast majority of such individuals
are overweight. Although classically considered “adult-onset,”
the prevalence of type 2 diabetes in children and adolescents
is increasing at an alarming pace
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Pathogenesis of Type I Diabetes
 Type 1 diabetes is an autoimmune disease in which islet destruction
is caused primarily by immune effector cells reacting against
endogenous β-cell antigens. Type 1 diabetes most commonly
develops in childhood, becomes manifest at puberty, and
progresses with age.
 Since the disease can develop at any age, including late adulthood,
the appellation “juvenile diabetes” is now considered obsolete.
Similarly, the older moniker “insulin-dependent diabetes mellitus”
has been excluded from the recent classification of diabetes
because insulin dependence is not a consistent distinguishing
feature. Nevertheless, most patients with type 1 diabetes depend on
insulin for survival;
 without insulin they develop serious metabolic complications such
as ketoacidosis and coma. A rare form of “idiopathic” type 1
diabetes has been described in which the evidence for
autoimmunity is not definitive. Here we will focus on the typical
immune-mediated type 1 diabetes.
 As with most autoimmune diseases, the pathogenesis of type 1
diabetes represents interplay of genetic susceptibility and
environmental factors.
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Type 1-continue
 Epidemiologic studies, such as those demonstrating
higher concordance rates for disease in monozygotic vs
dizygotic twins, have convincingly established a
genetic basis for type 1 diabetes. More recently,
genome-wide association studies have identified
multiple genetic susceptibility loci for type 1 diabetes,
as well as for type 2 diabetes. Over a dozen
susceptibility loci for type 1 diabetes are now known.
Of these, by far the most important is the HLA locus
on chromosome 6p21; according to some estimates,
the HLA locus contributes as much as 50% of the
genetic susceptibility to type 1 diabetes.
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Type 1 DM Pathogenesis
1. Preclinical period
 immune markers present
 β-cell destruction
2. Hyperglycemia
 80 to 90% of β-cells destroyed
3. Transient remission
 honeymoon phase
4. Established disease
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Type 1 DM Pathogenesis
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Type 1 DM
 Autoimmune destruction of pancreatic β-cells
 ~90% of patients have markers of immune β-cell
destruction at diagnosis
 children & adolescents often have rapid β-cell
destruction & present with ketoacidosis
 may occur at any age
 A subgroup of Type I diabetes is known as latent
autoimmune diabetes in adults (LADA)
 slowly progressive
 sufficient insulin secretion to prevent ketoacidosis for
many years
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 There is evidence that environmental factors, especially
viral infections, may be involved in triggering islet cell
destruction in type 1 diabetes. Epidemiologic
associations have been reported between type 1 diabetes
and infection with mumps, rubella, coxsackie B, or
cytomegalovirus, among others. At least three different
mechanisms have been proposed to explain the role of
viruses in the induction of autoimmunity. The first is
“bystander” damage, wherein viral infections induce
islet injury and inflammation, leading to the release of
sequestered β-cell antigens and the activation of
autoreactive cells. The second possibility is that the
viruses produce proteins that mimic β-cell antigens,
and the immune response to the viral protein crossreacts with the self-tissue (“molecular mimicry”).
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 The third hypothesis suggests that viral infections incurred
early in life (“predisposing virus”) might persist in the tissue
of interest, and subsequent re-infection with a related virus
(“precipitating virus”) that shares antigenic epitopes leads to
an immune response against the infected islet cells. This last
mechanism, also known as “viral déj vu,” might explain the
latency between infections and the onset of diabetes. It is
unclear whether any of these mechanisms contribute to βcell damage, and no causative viral infection is established.
In fact, some epidemiologic data and studies of
experimental models suggest that infections may be
protective; the underlying mechanisms of such a protective
effect are unknown. An epidemiologic study has also
established no causal association between childhood
vaccinations and the risk of developing type 1 diabetes.
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Type 2 DM
 Insulin resistance, relative lack of insulin secretion
 Usually presents with cluster of abnormalities known
as metabolic syndrome:
 abdominal obesity
 hypertension
 dyslipidemia
 elevated PAI-1 levels
 Increased macrovascular complication risk
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Pathogenesis of Type II Diabetes
 Type 2 diabetes is a prototypic multifactorial complex disease.
Environmental factors, such as a sedentary life style and dietary
habits, unequivocally play a role, as will become evident when the
association with obesity is considered. Genetic factors are also
involved in the pathogenesis, as evidenced by the disease
concordance rate of 35% to 60% in monozygotic twins compared
with nearly half that in dizygotic twins. Such concordance is even
greater than in type 1 diabetes, suggesting perhaps an even larger
genetic component in type 2 diabetes.
 The two metabolic defects that characterize type 2 diabetes are (1) a
decreased response of peripheral tissues to insulin (insulin
resistance) and (2) β-cell dysfunction that is manifested as
inadequate insulin secretion in the face of insulin resistance and
hyperglycemia. Insulin resistance predates the development of
hyperglycemia and is usually accompanied by compensatory β-cell
hyperfunction and hyperinsulinemia in the early stages of the
evolution of diabetes
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Insulin resistance
Nonesterified fatty acids (NEFAs): Cross-sectional studies have
demonstrated an inverse correlation between fasting plasma NEFAs and
insulin sensitivity. The level of intracellular triglycerides is often markedly
increased in muscle and liver tissues of obese individuals, presumably
because excess circulating NEFAs are deposited in these organs. Central
adipose tissue is more “lipolytic” than peripheral sites, which might explain
the particularly deleterious consequences of this pattern of fat distribution.
Excess intracellular NEFAs overwhelm the fatty acid oxidation pathways,
leading to accumulation of cytoplasmic intermediates like diacylglycerol
(DAG) and ceramide. These “toxic” intermediates can activate
serine/threonine kinases, which cause aberrant serine phosphorylation of
the insulin receptor and IRS proteins.
Unlike tyrosine modification, phosphorylation at serine residues
attenuates insulin signaling. Insulin normally inhibits hepatic
gluconeogenesis by blocking the activity of phosphoenolpyruvate
carboxykinase, the first enzymatic step in this process. Attenuated insulin
signaling allows phosphoenolpyruvate carboxykinase to “ramp up”
gluconeogenesis. Excess NEFAs also compete with glucose for substrate
oxidation, leading to feedback inhibition of glycolytic enzymes, and
thereby further exacerbating the existing glucose imbalance.
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
Adipokines: It is recognized that adipose tissue is not merely a passive storage
depot for fat but is a functional endocrine organ that releases hormones in
response to changes in the metabolic status. A variety of proteins secreted into the
systemic circulation by adipose tissue have been identified, and these are
collectively termed adipokines (or adipose cytokines). Both pro-hyperglycemic
adipokines (e.g., resistin, retinol binding protein 4 [RBP4]) and anti-hyperglycemic
adipokines (leptin, adiponectin) have been identified. Leptin and adiponectin
improve insulin sensitivity by directly enhancing the activity of the AMP-activated
protein kinase (AMPK), an enzyme that promotes fatty acid oxidation, in liver and
skeletal muscle. Adiponectin levels are reduced in obesity, thus contributing to
insulin resistance. Notably, AMPK is also the target for metformin, a
commonly used oral antidiabetic medication.

Inflammation: Adipose tissue also secretes a variety of pro-inflammatory
cytokines like tumor necrosis factor, interleukin-6, and macrophage
chemoattractant protein-1, the last attracting macrophages to fat deposits. Studies
in experimental models have demonstrated that reducing the levels of proinflammatory cytokines enhances insulin sensitivity. These cytokines induce
insulin resistance by increasing cellular “stress,” which in turn, activates multiple
signaling cascades that antagonize insulin action on peripheral tissues.

Peroxisome proliferator-activated receptor γ (PPAR γ): PPARγ is a nuclear
receptor and transcription factor expressed in adipose tissue, and plays a seminal
role in adipocyte differentiation. A class of antidiabetic medications known as
thiazolidinediones acts as agonist ligands for PPARγ and improves insulin
sensitivity. Activation of PPARγ promotes secretion of anti-hyperglycemic
adipokines like adiponectin, and shifts the deposition of NEFAs toward adipose
tissue and away from liver and skeletal muscle. As discussed below, rare mutations
of PPARG that cause profound loss of protein function can result in monogenic
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Type 2 DM Risk Factors




BMI ≥ 25
 CV disease
Physical inactivity
 HDL < 35 mg/dL
1st degree relative with DM  Triglycerides > 250 mg/dL
High risk ethnic group
 Delivery of > 9 lb baby
(Latino, African American,  History of GDM
Native American, Asian
American, Pacific Islander)  Insulin resistance
 acanthosis nigricans,
 IFG, IGT
severe obesity
 HTN: ≥ 140/90 mmHg or
 Polycystic ovary syndrome
on therapy for HTN
American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.
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Clinical Presentation of Diabetesa
Characteristic
Age
Onset
Body habitus
Insulin resistance
Autoantibodies
Symptoms
Ketones at diagnosis
Need for insulin therapy
Acute complications
Microvascular complications at
diagnosis
Macrovascular complications at
or before diagnosis
Type 1 DM
< 30 yearsb
Abrupt
Lean
Absent
Often present
Symptomaticc
Present
Immediate
Diabetic ketoacidosis
No
Type 2 DM
> 30 yearsb
Gradual
Obese or history of obesity
Present
Rarely present
Often asymptomatic
Absentd
Years after diagnosis
Hyperosmolar hyperglycemic state
Common
Rare
Common
aClinical
presentation can vary widely. bAge of onset for type 1 DM is generally < 20
years of age but can present at any age. The prevalence of type 2 DM in children,
adolescents, and young adults is increasing. This is especially true in ethnic and
minority children. cType 1 can present acutely with symptoms of polyuria, nocturia,
polydipisia, polyphagia, weight loss. dType 2 children and adolescents are more likely
to present with ketones but after the acute phase can treated with oral agents.
Prolonged fasting can also produce ketones in individuals.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/
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Diagnosis
Blood glucose values are normally maintained in a very narrow range,
usually 70 to 120 mg/dL. The diagnosis of diabetes is established by
noting elevation of blood glucose by any one of 4 criteria:
 1. A random glucose concentration greater than 200 mg/dL, with
classical signs and symptoms
 2.
A fasting glucose concentration greater than 126 mg/dL on more
than one occasion
 3.
An abnormal oral glucose tolerance test (OGTT), in which the
glucose concentration is greater than 200 mg/dL 2 hours after a
standard carbohydrate load
 4.
An Hb A1c level of more than 6.5 %.
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HbA1c (Hemoglobin A1c): gold standard for monitoring glycemic control
HbA1c reflects glucose levels for the previous 2 to 3 months
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 Levels of blood glucose proceed along a continuum.
Individuals with fasting glucose concentrations less than 100
mg/dL, or less than 140 mg/dL following an OGTT, are
considered to be euglycemic. However, those with fasting
glucose concentrations greater than 100 mg/dL but less than
126 mg/dL, or OGTT values greater than 140 mg/dL but less
than 200 mg/dL, are considered to have impaired glucose
tolerance, also known as “pre-diabetes.”
 Pre-diabetic individuals have a significant risk of progressing
to overt diabetes over time, with as many as 5% to 10%
advancing to diabetes mellitus per year. In addition, prediabetics are at risk for cardiovascular disease, as a result of
the abnormal carbohydrate metabolism as well as the
coexistence of other risk factors such as low levels of highdensity lipoprotein, hypertriglyceridemia, and increased
plasminogen activator inhibitor-1 (PAI-1)
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Glucose Homeostasis
Normal glucose homeostasis is tightly regulated by three interrelated
processes:
 glucose production in the liver;
 glucose uptake and utilization by peripheral tissues, chiefly skeletal
muscle;
 and actions of insulin and counter-regulatory hormones, including
glucagon, on glucose uptake and metabolism.
Insulin and glucagon have opposing regulatory effects on glucose
homeostasis. During fasting states, low insulin and high glucagon
levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen
breakdown) while decreasing glycogen synthesis, thereby preventing
hypoglycemia. Thus, fasting plasma glucose levels are determined
primarily by hepatic glucose output. Following a meal, insulin
levels rise and glucagon levels fall in response to the large glucose
load. Insulin promotes glucose uptake and utilization in tissues. The
skeletal muscle is the major insulin-responsive site for
postprandial glucose utilization, and is critical for preventing
hyperglycemia and maintaining glucose homeostasis.
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Insulin secretion
 The insulin gene is expressed in the β cells of the pancreatic islets. Preproinsulin is
synthesized in the rough endoplasmic reticulum from insulin mRNA and delivered to the
Golgi apparatus. There, a series of proteolytic cleavage steps generate mature insulin and a
cleavage peptide, C-peptide. Both insulin and C-peptide are then stored in secretory
granules and secreted in equimolar quantities after physiologic stimulation; thus, C-peptide
levels serve as a surrogate for β-cell function, decreasing with loss of β-cell mass in type 1
diabetes, or increasing with insulin resistance–associated hyperinsulinemia.
 The most important stimulus for insulin synthesis and release is glucose itself. A rise
in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by an
insulinin-dependent glucose-transporter, GLUT-2. β cells express an ATP-sensitive K+
channel on the membrane, which comprises two subunits: an inward rectifying K+ channel
(Kir6.2) and the sulfonylurea receptor (SUR1), the latter being the binding site for oral
hypoglycemic agents (sulfonylureas) used in the treatment of diabetes (see next slide).
Metabolism of glucose by glycolysis generates ATP, resulting in an increase in β-cell
cytoplasmic ATP/ADP ratios. This inhibits the activity of the ATP-sensitive K+ channel,
leading to membrane depolarization and the influx of extracellular Ca through voltagedependent Ca channels. The resultant increase in intracellular Ca stimulates secretion of
insulin, presumably from stored hormone within the β-cell granules. This is the phase of
immediate release of insulin.

If the secretory stimulus persists, a delayed and protracted response follows that involves
active synthesis of insulin. Other factors, including intestinal hormones and certain amino
acids (leucine and arginine), also stimulate insulin release, but not its synthesis.
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Structure of human proinsulin and some commercially available insulin analogs. Insulin is shown as
the shaded (darker color) peptide chains, A and B. Differences in the A and B chains and amino acid
modifications for insulin aspart, lispro, and glulisine are noted
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The relationship between
fasting plasma insulin and
fasting plasma glucose in 177
normal weight individuals.
Plasma insulin and glucose
increase together up to a fasting
glucose of 140 mg/dL.
When the fasting glucose
exceeds 140 mg/dL, the β cell
makes progressively less
insulin, which leads to an
overproduction of glucose by
the liver and results in a
progressive increase in fasting
glucose.
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The loss of the incretin effect in type 2 diabetes mellitus.
The plasma insulin responses to oral and intravenous glucose in nondiabetic subjects
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(left figure), compared to patients with diabetes (right figure).
Glucose Tolerance Test
Blood glucose curves of a normal
and a diabetic person after oral
administration of 1 g of
glucose/kg body weight.
Note the initial raised
concentration in the fasting
diabetic.
A criterion of normality is the
return of the curve to the initial
value within 2 hours.
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Relationship between insulin & glucose over course of a day
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Insulin actions
 Insulin is the most potent anabolic hormone known, with multiple
synthetic and growth-promoting effects. Its principal metabolic
function is to increase the rate of glucose transport into certain cells
in the body, thus providing an increased source of energy.
 These cells are the striated muscle cells (including myocardial cells)
and to a lesser extent, adipocytes, which together represent about two
thirds of the entire body weight.
 Glucose uptake in other peripheral tissues, most notably the brain, is
insulin independent.
 In muscle cells, glucose is then either stored as glycogen or oxidized
to generate ATP. In adipose tissue, glucose is primarily stored as lipid.
Besides promoting lipid synthesis, insulin also inhibits lipid
degradation in adipocytes. Similarly, insulin promotes amino acid
uptake and protein synthesis, while inhibiting protein degradation.
Thus, the anabolic effects of insulin are attributable to increased
synthesis and reduced degradation of glycogen, lipids, and proteins. In
addition, insulin has several mitogenic functions, including initiation
of DNA synthesis in certain cells and stimulation of their growth and
differentiation.
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Insulin stimulates hepatic glucose storage as glycogen; in adipose tissue as triglycerides; and amino acid storage in
muscle as protein; it also promotes utilization of glucose in muscle for energy. These pathways, which also are
enhanced by feeding, are indicated by the solid blue arrows. Insulin inhibits the breakdown of triglycerides, glycogen,
& protein and conversion of amino acids to glucose (gluconeogenesis), as indicated by the white arrows. These
pathways are increased during fasting and in diabetic states. Conversion of amino acids to glucose & glucose to fatty
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acids occurs primarily in the liver.
Effects of Insulin on Various Tissues
Adipose Tissue
Increased glucose entry
Increased fatty acid synthesis
Increased glycerol phosphate synthesis
Activation of lipoprotein lipase
Inhibition of hormone-sensitive lipase
Increased K+ uptake
Muscle
Increased glucose entry
Increased glycogen synthesis
Increased amino acid uptake
Increased protein synthesis in ribosomes
Decreased release of gluconeogenic amino acids
Increased ketone uptake
Increased K+ uptake
Liver
Decreased ketogenesis
Increased protein synthesis
Increased lipid synthesis
Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysis
General
Increased cell growth
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Insulin signaling pathways
 Elucidation of the insulin signaling pathway has been central to our
understanding of the pathogenesis of diabetes. The insulin receptor is a
tetrameric protein composed of two α- and two βsubunits. The βsubunit cytosolic domain possesses tyrosine kinase activity. Insulin
binding to the α-subunit extracellular domain activates the β-subunit
tyrosine kinase, resulting in autophosphorylation of the receptor and
the phosphorylation (activation) of several intracellular substrate
proteins, such as the family of insulin receptor substrate (IRS) proteins,
which includes IRS1–IRS4 and GAB1.
 The substrate proteins, in turn, activate multiple downstream signaling
cascades, including the PI-3K and the MAP kinase pathways, which
mediate the metabolic and mitogenic activities of insulin on the cell.
 Insulin signaling facilitates the trafficking and docking of vesicles
containing the glucose transporter protein GLUT-4 to the plasma
membrane, which promotes glucose uptake. This process is mediated
by AKT, the principal effector of the PI-3K pathway, but also
independently by the cytoplasmic protein CBL, which is a direct
phosphorylation target of the insulin receptor.
 Insulin signaling is attenuated in vivo by several endogenous inhibitors
that act along components of the pathway. For example, protein
tyrosine phosphatase 1B (PTPN1B) dephosphorylates the insulin
receptor and inhibits insulin signaling. The phosphatase PTEN can
attenuate insulin signaling by blocking AKT activation by the PI-3K
pathway.
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Whole body glucose disposal, a measure of insulin resistance, is reduced 40% to 50% in
obese nondiabetic and lean type 2 diabetic individuals. Obese diabetic individuals are
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slightly more resistant than lean diabetic patients.
NCEP ATP III: Components of the
Metabolic Syndrome (> 3 for diagnosis)
Risk Factor
Abdominal obesitya
Defining Level
Men (waist circumference)b
> 102 cm (> 40 in.)
Women
> 88 cm (> 35 in.)
Triglycerides
> 1.7 mmol/L (> 150 mg/dL)
HDL cholesterol
Men
< 1.0 mmol/L (< 40 mg/dL)
Women
< 1.3 mmol/L (< 50 mg/dL)
Blood Pressure
≥ 130/≥ 85 mmHg
Fasting glucose
> 6.1 mmol/L ( > 110 mg/dL)
aOverweight/obesity associated
with insulin resistance & metabolic syndrome. The presence of
abdominal obesity more highly correlated with metabolic risk factors than elevated body-mass
index (BMI).
bSome male patients can develop multiple metabolic risk factors when waist circumference is
only marginally increased; benefit from life-style changes.
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Clinical features
Type 1 diabetes was formerly thought to occur
primarily in those under age 18 but is now known to
occur at any age. In the initial 1 or 2 years following
the onset of overt type 1 diabetes, the exogenous
insulin requirements may be minimal because of
ongoing endogenous insulin secretion (referred to as
the honeymoon period). Thereafter, any residual βcell reserve is exhausted and insulin requirements
increase dramatically. Although β-cell destruction is a
prolonged process, the transition from impaired
glucose tolerance to overt diabetes may be abrupt,
and is often brought on by an event, such as
infection, that is also associated with increased
insulin requirements.
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The onset is marked by polyuria, polydipsia, polyphagia, and, when severe,
ketoacidosis, all resulting from metabolic derangements. Since insulin is a major
anabolic hormone in the body, deficiency of insulin results in a catabolic
state that affects not only glucose metabolism but also fat and protein
metabolism. Unopposed secretion of counter-regulatory hormones (glucagon,
growth hormone, epinephrine) also plays a role in these metabolic derangements.
The assimilation of glucose into muscle and adipose tissue is sharply diminished or
abolished. Not only does storage of glycogen in liver and muscle cease, but also
reserves are depleted by glycogenolysis. The resultant hyperglycemia exceeds
the renal threshold for reabsorption, and glycosuria ensues. The glycosuria
induces an osmotic diuresis and thus polyuria, causing a profound loss of
water and electrolytes. The obligatory renal water loss combined with the
hyperosmolarity resulting from the increased levels of glucose in the blood tends to
deplete intracellular water, triggering the osmoreceptors of the thirst centers
of the brain. In this manner, intense thirst (polydipsia) appears. With a
deficiency of insulin the scales swing from insulin-promoted anabolism to
catabolism of proteins and fats. Proteolysis follows, and the gluconeogenic amino
acids are removed by the liver and used as building blocks for glucose. The
catabolism of proteins and fats tends to induce a negative energy balance,
which in turn leads to increasing appetite (polyphagia), thus completing the
classic triad of diabetes: polyuria, polydipsia, and polyphagia. Despite the increased
appetite, catabolic effects prevail, resulting in weight loss and muscle weakness.
The combination of polyphagia and weight loss is paradoxical and should always
raise the suspicion of diabetes.
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Diabetic ketoacidosis
Diabetic ketoacidosis is a serious complication of type 1 diabetes but may
also occur in type 2 diabetes, though not as commonly and not to as
marked an extent. These patients have marked insulin deficiency, and
the release of the catecholamine hormone epinephrine blocks any
residual insulin action and stimulates the secretion of glucagon. The
insulin deficiency coupled with glucagon excess decreases peripheral
utilization of glucose while increasing gluconeogenesis, severely
exacerbating hyperglycemia (the plasma glucose levels are usually in
the range of 500 to 700 mg/dL). The hyperglycemia causes an osmotic
diuresis and dehydration characteristic of the ketoacidotic state. The
second major effect of an alteration in the insulin-to-glucagon
ratio is activation of the ketogenic machinery. Insulin deficiency
stimulates lipoprotein lipase, with resultant breakdown of adipose
stores, and an increase in levels of free fatty acids. When these free fatty
acids reach the liver, they are esterified to fatty acyl coenzyme A.
Oxidation of fatty acyl coenzyme A molecules within the hepatic
mitochondria produces ketone bodies (acetoacetic acid and βhydroxybutyric acid). The rate at which ketone bodies are formed may
exceed the rate at which acetoacetic acid and β-hydroxybutyric acid can
be utilized by peripheral tissues, leading to ketonemia and ketonuria. If
the urinary excretion of ketones is compromised by dehydration,
systemic metabolic ketoacidosis results. Release of ketogenic amino
acids by protein catabolism aggravates the ketotic state.
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Diabetic Ketoacidosis
 Diabetic emergency
 Precipitating Factors
 insulin omission
 illness, infection
 initial DM presentation
 Diagnostic laboratory values
 hyperglycemia
 anion gap acidosis
 ketonemia, ketonuria
 fluid deficits
 Na+, K+ deficits
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 Ketogenesis due to insulin deficiency leads to increased serum levels
of ketones, ketonuria
 Acetoacetate, β-hydroxybutyrate: ketone bodies produced by the
liver; organic acids that cause metabolic acidosis
 Respiration partially compensates; reduces PCO2: when pH < 7.20,
deep, rapid respirations (Kussmaul breathing)
 Acetone: minor product of ketogenesis; can smell fruity odor on
breath of diabetic ketoacidosis patients
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Diabetic Ketoacidosis
 Treatment: restore intravascular volume 1st
 normal saline given acutely


switch fluids to D5W or D5W1/2NS when glucose ~250 mg/dL
hypotonic fluids to replace free H2O
 K+ supplementation

potassium phosphate often used; no evidence of benefits
 constant insulin infusion
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Diabetic Ketoacidosis
 Frequent glucose & K+ monitoring essential
 K+ must be WNL before insulin is administered
 Metabolic improvement: increased serum bicarbonate
& pH
 Glucose will fall before the anion gap closes
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Hyperosmaolar hyperglycemic crisis
Type 2 diabetes mellitus may also present with polyuria and polydipsia,
but unlike in type 1 diabetes, patients are often older (over 40 years)
and frequently obese. However, with the increase in obesity and
sedentary life style in our society, type 2 diabetes is now seen in
children and adolescents with increasing frequency. In some cases
medical attention is sought because of unexplained weakness or weight
loss. Most frequently, however, the diagnosis is made after routine blood
or urine testing in asymptomatic persons. The infrequency of
ketoacidosis and milder presentation in type 2 diabetes is presumably
because of higher portal vein insulin levels in these patients than in
type 1 diabetics, which prevents unrestricted hepatic fatty acid
oxidation and keeps the formation of ketone bodies in check. In the
decompensated state, these patients may develop hyperosmolar
nonketotic coma due to severe dehydration resulting from
sustained osmotic diuresis (particularly in patients who do not
drink enough water to compensate for urinary losses from
chronic hyperglycemia). Typically, the patient is an elderly diabetic
who is disabled by a stroke or an infection and is unable to maintain
adequate water intake. Furthermore, the absence of ketoacidosis and
its symptoms (nausea, vomiting, respiratory difficulties) delays the
seeking of medical attention until severe dehydration and coma occur.
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Hyperosmolar Hyperglycemia
 Diabetic emergency
 Typically older type 2 DM patients
 Fluid deficits & blood glucose concentrations
generally greater than DKA
 Precipitating Factors
 infection/illness
 prolonged hyperglycemia
 dehydration
 renal insufficiency
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Hyperosmolar Hyperglycemia
 Lower blood glucose levels gradually
 Treatment
 Fluid replacement

hypotonic fluids (0.45% saline) should be used if serum
sodium > 150 meq/L
 low-dose insulin infusions (1 to 2 units/hour)
 Avoid rapid correction of glucose levels
 no greater than 75 to 100 mg/dL
 may result in cerebral edema
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