• Diabetes mellitus is a chronic disease characterized by derangement in
carbohydrates, fat and protein metabolism
Type 2 diabetes mellitus comprises an array of dysfunctions resulting from:
1. the combination of resistance to insulin action2. inadequate insulin secretion. It is disorders are characterized by hyperglycemia
and associated with microvascular (ie, retinal, renal, possibly neuropathic), macrovascular (ie, coronary, peripheral vascular), and neuropathic (ie, autonomic, peripheral) complications.
Type 2diabetes
Insulinresistance
-celldysfunction
Obesity
Insulin resistance
Abnormal insulin secretion
Excess glucose production
Beta-cell failure
• Insulin resistance is a condition in which the body produces insulin but does not use it properly.
The circulating free fatty acids associated with obesity also responsible for insulin resistance of the muscle and liver.
• Decreased glucose uptake by skeletal muscle and adipose tissue.
• Increased glucose output by Liver-Gluconeogenesis.
• In the early stages of obesity the pancreas compensates for the IR by overproducing insulin so that glucose homeostasis is maintained.
• This leads to HYPERGLYCEMIA & HYPER INSULINEMIA
Chronic hyperglycemia
Glucotoxicity2
Lipotoxicity3
Oversecretion of insulin to compensate for insulin resistance1,2
-celldysfunction
• The elevated levels of free fatty acids and or cytokines lead to gradual loss of the ability of the pancreas to overproduce insulin , a process called decompensation-Lipotoxity
• Glucose, the main regulator of insulin secretion and production, exerts negative effects on beta-cell function when present in excessive amounts over a prolonged period-glucotoxicity.
IR
Insulinresistance
Liver
Muscle
Adiposetissue
Glucose output Glucose uptake Glucose uptake
Hyperglycemia
• It rarely develops in DM-II
• Insulin present in DM-II is enough to prevent uncontrollable release of fatty acids from adipocytes and fattyacids reaching the liver or synthesized de novo are directed to triacyglycerol.
If it is develops:Insulin Deficiency
Increased GlycogenolysisIncreased Gluconeogenesis Increased Hepatic glucose
outputDecreased Peripheral glucose
uptakeElevates blood glucose
Increased LipolysisIncreased Release of FFA in
liverIncreased VLDL & ketones Ketonemia and hyperTG
Acidosis & Diuresis
It is a characteristics of DM-IIResults from an increase in VLDL without
hyperchylomicronemia.This happens by hepatic synthesis of fatty
acids and diversion of free fatty acids reaching the liver in to triacylglycerol and VLDL.
Normal Normal TGNormal TG
Type 2 diabetes
High TGHigh TGLow HDL cholesterolLow HDL cholesterolSmall dense LDLSmall dense LDL(diabetic dyslipidaemia)(diabetic dyslipidaemia)
Normal insulin levelNormal insulin level
Impaired insulin actionto inhibitVLDL production
Increased liver fat
Insulin deficiency exacerbates hypertriglyceridaemia
• Chronic complications – Microvascular- retinopathy,
nephropathy, neuropathy.
Macrovascular - cardiovascular, cerebrovascular, peripheral vascular diseases.
Acute complications – diabetic ketoacidosis, hyperosmalor coma.
• Hyperglycaemia in insulin independent tissues (nerve, lens, retina) gives rise to polyol formation.
• The enzyme aldose reductase catalyses the reduction of glucose to sorbitol, which is converted to fructose.
• Sorbitol does not easily easily cross cell membranes and its accumulation may cause damage by osmotic effect (e.g. in the lens).
• Sorbitol trapped in retinal cells, the cells of the lens, and the Schwann cells that myelinate peripheral nerves can damage these cells, leading to retinopathy, cataracts and peripheral neuropathy.
Carbohydrate
Glucose(
G)-I
(I)-Insulin
Carbohydrate
AcarboseReduces absorption
SulphonylureaRepaglinide
Stimulates pancreas
MetforminReduces hepatic glucose output
(??muscle/fat effects)
ThiazolidinedionesReduce Insulin Resistance
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