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CARBOHYDRATES
METABOLISM
DISORDERS
GLUCOSE METABOLISM
 the
cornerstone of life
 neurons are especially dependent on
glucose
 regulatory mechanisms:


hyperglycemic hormones = glycogenolysis,
gluconeogenesis
hypoglycemic hormone = insulin
carbohydrates
digestion
absobtion
postprandial hyperglicemia
insulin release
liver storage
glycogen
glucose moves into
insulin-dependent cells
(muscle, adipose)
insulin-independent cells
protein synthesis
IN LIVER
inhibition:
lipolysis
glycogenolysis
gluconeogenesis
HYPERGLICEMIA
(diabetes mellitus)
 Diabetes
- Greek word = to siphon or to
pass thru.
 Mellitus - Latin word = sweet or honey.
 group
of chronic disorders
 insulin
deficiency ABSOLUTE/RELATIVE
!!! also affects protein and fat metabolism
CLASSIFICATION
1 DM - autoimmune pancreatic β-cell
destruction = absolute insulin deficiency;
 type 2 DM - insulin resistance = relative
insulin deficiency;
 “other” specific types of DM (associated
with identifiable clinical conditions or
syndromes);
 gestational DM - appears or is first
detected during pregnancy.
 type
!!! pre-diabetes
 impaired
glucose tolerance (IGT)
 impaired fasting glucose (IFG)
ADA diagnosis of DM
1. classic symptoms of diabetes (polyuria,
polydipsia, and unexplained weight loss) plus
random plasma glucose concentration ≥ 200
mg/dL (≥11.1 mmol/L);
or
2. fasting (≥8-hour) plasma glucose concentration
≥ 126 mg/dL (≥7.0 mmol/L);
or
3. a 2-hour postload plasma glucose
concentration ≥ 200 mg/dL (≥11.1 mmol/L)
during a 75-g oral glucose tolerance test.
ETIOLOGY
Type 1 diabetes
 Genetic
 Environmental
 Autoimmune
Type 2 diabetes
= relative insulin deficiency – insulin
resistance / inadequate secretory
response
 complex
genetic interactions unrelated
to HLA genes
 environmental factors such as body
weight (obesity) and exercise (lack of
physical activity).
MODY
 autosomal
dominant inheritance
 onset in at least 1 family member younger
than 25 years
 absence of autoantibodies
 correction of fasting hyperglycemia without
insulin for at least 2 years
 absence of ketosis.
Type 2 DM pathogenic
mechanisms:

progressive loss of insulin secretory capacity.
impaired insulin action :





impaired mitochondrial function and the resulting accumulation
of free fatty acids in insulin-responsive tissues.
defects of the insulin receptor.
defects in “postreceptor” pathways
Adipocyte-Derived Hormones and Cytokines




Leptin
Adiponectin
other adipocyte-derived factors (resistin, angiotensinogen,
interleukin-6, transforming growth factor-β, plasminogen
activator inhibitor 1)
TNF-α.

Glucotoxicity.

Lipotoxicity.
 accelerate hepatic gluconeogenesis
 inhibit muscle glucose metabolism
 impair pancreatic β-cell function.
1 DM produces profound β-cell
failure and insulin deficiency with
secondary insulin resistance,
 Type
 Type
2 DM is associated with less severe
insulin deficiency but greater insulin
resistance.
Glucose
homeostasis
Glucose
homeostasis
Glucose
homeostasis
Glucose
homeostasis
Glucose
homeostasis
Fasting state
state 

Fasting
Fed state
state 
 insulin
insulin
Fed
Fasting
state

Fasting
state

Fed
state

insulin
Fed state  insulin
state

Fasting
glucagon
 insulin
insulin

glucagon

Fed
state

insulin
glucagon
insulin

glucagon

insulin
glucagon  insulin
peripheral
peripheral uptake
uptake of
of

peripheraluptake
uptakeof
of

peripheral
peripheral uptake of
glucose
glucose
 peripheral
peripheral uptake
uptake

glucose
glucose
peripheraluptake
uptake

peripheral
glucose
hepatic
hepatic

 peripheral
uptake
of
glucose
of
glucose
hepatic

hepatic
ofglucose
glucose
of

hepatic
glycogenesis
glycogenesis
of glucose
 hepatic
hepatic

glycogenesis
glycogenesis
hepatic
hepatic
glycogenesis
glycogenolysis
glycogenolysis
and

and
 hepatic
glycogenesis
glycogenesis

glycogenolysis
and

glycogenolysis
and
glycogenesis
glycogenesis

glycogenolysis
and
gluconeogenesis
gluconeogenesis
glycogenesis
 gluconeogenesis
gluconeogenesis

gluconeogenesis
gluconeogenesis
gluconeogenesis
gluconeogenesis
gluconeogenesis
lypolisis
lypolisis
and

and

gluconeogenesis
 lypolisis
lypolisis


lypolisisand
and

lypolisis
lypolisis
lypolisis
lypolisis and
ketogenesis
ketogenesis
 lypolisis
ketogenesis
ketogenesis
ketogenesis
diabetes mellitus pathogenesis
ABSOLUTE/RELATIVE
LACK OF INSULIN
HYPERGLYCEMIA
NON-INSULIN-DEPENDENT INSULIN-DEPENDENT
CELLS
CELL
EXCESS
DEFICIENT IN GLUCOSE
GLUCOSE DEPOSITS
GLUCOSE LOST
IN URINE
fasting hyperglycemia

mobilization of
substrates from muscle
and adipose tissue
 accelerated hepatic
gluconeogenesis,
glycogenolysis,
ketogenesis
 impaired removal of
endogenous and
exogenous fuels by
insulin-responsive
tissues.
fasting free fatty acids



Insuline deficiency - increase lipolysis
Glucagon - accelerating hepatic ketogenesis
Catecholamines growth hormone, and cortisol increase lipolysis.


type 1 diabetes - converted to ketone bodies
type 2 diabetes – insulin suppress the conversion of free
fatty acids to ketones
!!! The increase in substrate delivery - hepatic
steatosis and severe hypertriglyceridemia
(endogenous).
Postprandial Hyperglycemia
1 diabetes – insulin deficiency
 type 2 diabetes - delayed insulin
secretion + hepatic insulin resistance
 the liver fails to arrest glucose
production
 fails to appropriately take up glucose
for storage as glycogen
 glucose uptake by peripheral tissues is
impaired
 type
Hyperglycaemia

renal threshold for glucose surpassed
(>170mg/dl)

GLUCOSURIA

osmotic diuresis  POLYURIA

dehydration  thirst  POLYDIPSIA
 Type
1 diabetic - defects in the disposal
of ingested proteins and fats as well.

Hyperaminoacidemia

Hypertriglyceridemia (exogenous)
ACUTE METABOLIC
COMPLICATIONS
 diabetic
ketoacidosis (DKA)
 hyperosmolar hyperglycemic
syndrome (HHS)
 hypoglycemia
DKA
 deficient
circulating insulin activity
 excessive secretion of counterregulatory hormones.
 hyperglycemia, ketosis, acidosis
!!! osmotic diuresis - dehydration and
electrolyte loss.
Hyperosmolar Hyperglycemic
Syndrome (HHS)
 patients
cannot drink enough liquid to
keep pace with a vigorous osmotic
diuresis.


Severe hyperosmolarity (>320 mOsm/L)
Severe hyperglycemia (>600 mg/dL).
 severe
acidosis and ketosis are
generally absent in the HHS!!!
Hypoglycemia

the earliest subjective warning signs =
autonomic symptoms (sweating, tremor,
palpitations)
 Central nervous system symptoms and signs =
neuroglycopenia:




nonspecific (e.g., fatigue or weakness)
more clearly neurologic (e.g., double vision, oral
paresthesias, slurring of speech, apraxia, personality
change, or behavioral disturbances).
irreversible brain damage.
Hypoglycemic unawareness syndrome



duration of diabetes
autonomic neuropathy
switched to intensive insulin regimens.

Somogyi phenomenon –
1.
2.
3.

normal or increased blood glucose levels at bedtime
blood glucose drops in early morning hours (2 to 3
A.M.) usually because nighttime insulin dose is too
high.
compensate by producing counterregulatory
hormones resulting in hyperglycemia on awakening.
Dawn phenomenon = Decrease in the tissue
sensitivity to insulin between 5 and 8 A.M. prebreakfast hyperglycemia
??? release of nocturnal growth hormone
CHRONIC DIABETIC COMPLICATIONS
MICROVASCULAR AND NEUROPATHIC COMPLICATIONS

Intracellular glucose





advanced glycation end products (AGEs)
accelerated polyol pathway
reactive oxygen species
Others: cytokines, angiotensin II, endothelin, growth
factor stimulation, depletion of basement membrane
glycosaminoglycans
Hemodynamic changes in the microcirculation
Diabetic retinopathy
 vascular-neuroinflammatory
disease.
breakdown of the blood-retinal
barrier (BRB) function and loss of
retinal neurons.
 activated macroglia and neuronal
death.
 activated microglia exacerbate the
damage.

Diabetic Nephropathy

rise in glomerular filtration rate.
 glomerular lesions
 increased glomerular permeability.
 microalbuminuria (30 to 300 mg/day)

diffuse glomerulosclerosis
 massive proteinuria - nephrotic syndrome
 Systemic hypertension
 progression to ESRD.
Diabetic Neuropathy
 metabolic
factors
 vascular
 Nerve
growth factor diminished
 Autoimmune mechanisms.
 Distal
symmetrical (sensorimotor)
polyneuropathy
 Acute sensory neuropathy
 Focal
diabetic neuropathies
(mononeuropathies) – pain
 Entrapment syndromes
 Proximal
motor neuropathy (diabetic
amyotrophy)
Autonomic neuropathy
 Cardiovascular


preferential dysfunction of
parasympathetic fibers
impaired sympathetic vasoconstrictor
response and impaired cardiac reflexes.
 Altered


abnormalities
gastrointestinal function
hypermotility / hypomotility
Gastroparesis
 Genitourinary


bladder hypotonia
Erectile dysfunction
 Abnormal



alterations
sweat production
Xerosis.
Distal anhidrosis - truncal-facial sweating
Generalized anhidrosis
atherosclerosis
 lipid
abnormalities
 procoagulant state = accentuated
platelet aggregation and adhesion,
endothelial cell dysfunction.
 hyperinsulinemia
The diabetic foot



chronic sensorimotor neuropathy
vascular disease
abnormal immune function
HYPOGLICEMIA
 Physiological

hypoglycaemia
3-5 hours after ingestion of glucose or during
prolonged fast
 Pathological
HYPOGLICEMIA
Whipple’s triad:



LOW BLOOD GLUCOSE below 50 mg/dl
symptoms of hypoglycaemia
symptoms relieved by glucose
Classification:
 Fasting


hypoglycaemia
With hyperinsulinemia
Without hyperinsulinemia
 Non-fasting,
postprandial or
reactive hypoglycaemia
Fasting hypoglycemia with
hyperinsulinemia
 diabetes
 islet
cell tumours
 factitious hypoglycemia
 autoimmune hypoglycaemia
 drugs
Fasting hypoglycemia without
hyperinsulinemia

Chronic renal impairment


Decreased renal gluconeogenesis
impaired hepatic glycogenolysis and gluconeogenesis
!!!


increased insulin half-life due to decreased renal
degradation
exaggerated glucose-induces insulin secretion
severe
liver disease =
hepatogenous hypoglycaemia
 deficient
caloric intake and exerciseinduced hypoglycaemia
septicaemia
early phase - hyperglycemia
• decrease in insulin-stimulated phosphorylation of
insulin receptor
• increased clearance of insulin
• increased production of corticosteroids.
late phase – hypoglycemia
• cytokines from macrophages stimulates insulin
secretion
• direct hypoglycemic effect of endotoxins (inhibit
gluconeogenesis)
• association of renal failure.
non-islet cell tumours:






Increased uptake of glucose to tumors
reduced production of glucose
reduced gluconeogenesis due to weight loss
produce peptides with insulin-like activity
cytokines release ? (IGF-2, TNF)
drugs :



Salicylates
non-selective beta-blockers
endocrine insufficiency




hypopituitarism
Addison’s disease
isolate GH or ACTH deficiency
Reactive hypoglycaemia



Organic causes may lead to rapid emptying of
gastric contents
Type 2 diabetes mellitus
Alcohol




potentates the hypoglycaemic effect of insulin
potentates the insulin-stimulating effect of glucose
Idiopathic
Inborn errors of metabolism



Disorders of carbohydrates metabolism (galactosemia,
hereditary fructose intolerance….)
Disorders of amino acid metabolism (maple syrup urine
disease….)
Disorders of fatty acid metabolism (systemic carnitine
deficiency….)