Download - Diabetes mellitus pathophysiol-vnw
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ObesityDiabetes mellitus
Hypertension
“Obesity is the mother of metabolic diseases”
The 3 public health scourges of modern times
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World-wide estimated number of adults with diabetes by age group and year
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Diabetes mellitus is a group of metabolic diseases characterized by
hyperglycemia resulting from• defects in insulin secretion, • defects in insulin action (“insulin resistance”), • or both.
long-term damage, dysfunction, and failure of various organs, especially the eyes kidneynerves heart blood vessels.
“Complications”
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Classification of diabetes Type 1 ( was called “insulin- dependent DM”/ juvenile type of DM) ( 5-10%)
Type 2 (was called “non insulin- dependent DM” /adult onset DM ) (90-95%)
The “pre-diabetic stage” (impaired glucose tolerance)
Gestational DM -any degree of glucose intolerance with onset or first recognition during pregnancy [in 2-5% of all pregnancies]
Other specific types (1% - 2%)– genetic syndromes (affecting insulin secretion or action)– endocrinopathies (Acromegaly, Cushing’s syndrome, glucagonoma,
pheochromocytoma, thyrotoxicosis)– diseases of pancreas (chronic pancreatitis, cancer)– drug- or chemical-induced (corticosteroids, beta-blockers, thiazide
diuretics)– infections (viral)
The main focus of this plenary
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Type 1 Diabetes“insulin- dependent DM”
“ juvenile-onset DM”
Type 2 Diabetes “Non insulin-
dependent DM”“ adult-onset DM”
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Type 1 Diabetes“insulin- dependent DM”
“ juvenile-onset DM”
Type 2 Diabetes “Non insulin-
dependent DM”“ adult-onset DM”
Many require insulini.e. insulin- dependent
May develop when much older
Developing at younger age groups (childhood obesity)
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Type 1 Diabetes Type 2 Diabetesdiabetes due to
insulin resistance and inadequate compensatory insulin secretory response
diabetes due to absolute deficiency of
insulin
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Positive Family history
Type 1 Diabetes Type 2 Diabetes
(but ”obesity gene” not yet identified)
30 % 10 %
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Pathogenesis
Susceptibility genes identifiede.g. HLA haplotypes DR3 & DR4.
cell-mediated autoimmune destruction of the beta-cells of the pancreas by auto-antibodies
genetic predisposition environmental factors
viral infectionsstresstoxins e.g. rat poison
Type 1 Diabetes
absolute insulin deficiency
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Sequence of events in the development of
Pathogenesis
Type 1 Diabetes
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Pathogenesis
genetic predisposition environmental factors
DietPhysical inactivity
relative insulin deficiency
Obesity
insulin resistance and inadequate compensatory insulin secretory response
Type 2 Diabetes
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?Exhaustion?Glucotoxicity? Amyloid deposition
Postreceptor defects(refer to 2nd messenger
systems mediating insulin action)
Impaired insulin action
Insulin
Counter regulatory hormones:
CortisolGrowth hormone
Anti-insulin action
hyperglycaemia
Inadequate secretory response
insulin resistance
Type 2 DiabetesPathogenesis
GlucagonCatecholamines
Target cells
Pancreatic beta-cells:
Hyperglycaemic effectvs
Diabetogenic effect
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2nd messenger systems mediating insulin actionWhat and where is the postreceptor defect?
• Multiple, but unified hypothesis yet to be made
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Sympathetic nervesa cells
b cells
Glucagon
Insulin
-a receptor (-)
-b receptor (+)
-b receptor (+)
-a receptor (-)Sympathetic nerves
Net effect: incr. glucagon secretion
Net effect: decr. insulin secretion
(-)
(+)
Islets of Langerhans
Insulin-glucagon interaction in normal conditions
Para
crin
e pa
thw
ay
Start here
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Sympathetic nerves
Glucagon
Insulin
-a receptor (-)
-b receptor (+)
-b receptor (+)
-a receptor (-)Sympathetic nerves
Net effect: incr. glucagon secretion
Net effect: decr. insulin secretion
Para
crin
e pa
thw
ay
(-)
(+)
Islets of Langerhans
DM: Hyperglucagonaemia is a feature of DM Beta-blockers may further impair insulin secretion
Start here
a cells
b cells
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Natural history of Type 2 Diabetes
b cell secretory response to progressive insulin resistance
(Blood glucose normal)
b cells no longer able to compensate
Type 2
Diabetes
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Too late?
At the time of diagnosis, 50% of b cell function has already been lost ( A study on patients in the UK)
Type 2 Diabetes
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Clinical presentation of DM
• Asymptomatic (particularly type 2 DM)• Features resulting from the effects of insulin
deficiency/resistance (review insulin actions)– The 3 Polys :
• Polyuria / nocturia• Polydipsia• Polyphagia (in the presence of unintentional weight loss)
• Complications– Acute: coma (ketoacidosis) (particularly type 1 DM)– Chronic: macrovascular and microvascular
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Pancreas beta cells
Insulin actions
Glucose entry and utilization (oxidation,
storage)
Glucose entry and oxidation
TG synthesis
insulin actions: a review
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Pancreas beta cells
Insulin actions
Glucose entry and utilization (oxidation,
storage)
Glucose entry and oxidation
TG synthesis
Metabolic consequences of insulin deficiency/resistance
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Clinical Features of DM due to insulin lack
Polyphagia(decr. leptin?)
Starvation in the midst of plenty
Hyperosmolar hyperglycemic syndrome (HHS)
Lactic acidosis
Lactic acidosis
Muscle protein breakdown
Acetoacetate,0H-butyrate, acetone
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• Ketoacidosis - Life threatening – medical emergency!
Stressful situation
Positive feedback cycleStart here
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Stressful situation
Positive feedback cycleStart here
• Treatment: Fluids(normal saline), I.V. insulin. Monitor plasma glucose (and K+ as insulin promotes uptake of glucose and K+ by muscles and adipose tissue)
Insulin pump
Rehydration -fluids
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• hyperglycaemia• Excess glucose attaches nonenymatically to
amino acids of proteins [“glycosylation”]• Glycosylation of haemoglobin HbA1C refects
glycaemic control for the past 2 months (half life for RBCs)
• Glycosylation of plasma proteins fructosamine levels refects glycaemic control for the past 6 weeks(shorter half life)
Complications: pathogenesis
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Complications: pathogenesis
• Hyperglycaemia • Excess entry of glucose into non-insulin dependent
tissues– Nerves– Lens– Kidneys– Blood vessels
• Increased intracellular glucose metabolized to sorbitol fructose increased osmotic load influx of water osmotic cell injury
• E.g. lens cataract
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Vascular complications: pathogenesis
• “glyocosylation”of collagen and other long-lived proteins in tissues
• Irreversible formation of advanced glycosylation end products (AGEs) accumulation of AGEs over the lifetime of blood vessel walls – Protein cross-linking and trapping of plasma lipoproteins
in blood vessel walls– Reduction in protein breakdown– AGE binding to cell receptors/ endothelial dysfunction
• vasculopathy
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Microvascular complications
• Retinopathy
• Nephropathy
• Neuropathy
• Impaired skin healing foot ulcers
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Microvascular complications
• Diabetic Retinopathy:– Capillary microanuerysms– Macular oedema– neovascularization
– partial or total vision loss
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Microvascular complications
• Diabetic nephropathy:– Thickening of glomerular basement membrane– Mesangial cell expansion– glomerulosclerosis
Glomerular hypertensionProgressive decline in glomerular filtration rate nephrotic syndrome (leakage of albumin)/ renal
failure
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Microvascular complications
• Diabetic neuropathy– also due to direct effects of hyperglycaemia and
intracellular metabolic changes• impaired nerve function (sensory, motor)
– Symmetric polyneuropathy (distal feet and hands)– Autonomic neuropathy– Cranial neuropathy– Mononeuropathy (median neerve, peroneal nerve)– “diabetic foot”
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Macrovascular complications
• Large vessel atherosclerosis (due to hyperinsulinaemia, dyslipidaemia, hyperglycaemia)
• Coronary arteries myocardial ischaemia /infarction
• Cerebral arteries transient ischaemic attacks; cerebrovascular events stroke
• Peripheral artery disease ischaemia intermittent claudication
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(1) Symptoms (thirst, increased urination, unexplained weight loss) + a random plasma glucose concentration >200 mg/dL (11.1 mmol/L).(2) Fasting plasma glucose (FPG) >126 mg/dL (7.0 mmol/L) after an overnight (at least 8-hour) fast(3) Two-hour plasma glucose greater than 200 mg/dL (11.1 mmol/L) during a standard 75-g oral glucose tolerance test (OGTT)
[ should be confirmed on a later day with one of the three methods listed]
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Oral Glucose Tolerance Test (OGTT)(how much one can tolerate a glucose load without undue rise in plasma glucose levels; reflects how efficiently insulin can handle the glucose load))
Procedure
Overnight fast
75 g glucose in 300 ml water given orally over 5 minutes
Basal plasma glucose & every 30 minutes for 2 hours
Urine tested for sugar
Indications
Borderline fasting (FPG) or postprandial PG
Persistent glycosuria
Glycosuria of pregnancy
Pregnant women with family history of DM or had large babies
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Pla
sma
gluc
ose
(mm
ol/l)
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Symptoms of HYPOGLYCAEMIA
AUTONOMIC• Sweating • Trembling • Pounding heart • Hunger • Anxiety
NUEROGLYCOPENIC• Confusion • Drowsiness • Speech difficulty • Inability to concentrate • In-coordination
NON-SPECIFIC: Nausea, tiredness, headache
Diabetics on Insulin therapy
“Hypoglycaemia awareness”
The end
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American diabetic association. Diagnosis and classification of diabetes mellitus. Diabetic care, 2004, 27 (Suppl. 1); 55-60.
Robbins Pathologic basis of disease. Pocket companion. Saunders.
Holt RIG and Hanley N. Essential Endocrinology and Diabetes. 5th ed. 2007, Blackwell.
Merck Manual. iPhone app. Agile Parters. www.Merck Manuals.com.
Diabetes power point file. Prof. Hla-Yee-Yee, IMU.
References