• 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