ASSOCIATION OF TYPE 2 DIABETES MELLITUS

THE METABOLIC SYNDROME AND OBESITY

Type 2 diabetes occurs in patients with hyperinsulinaemia syndrome (also known as Reaven’s syndrome, syndrome X or metabolic syndrome). Features include insulin resistance, dyslipidaemia, obesity (abdominal) and hypertension. Individuals with metabolic syndrome with or without type 2 diabetes has increased risk of atherosclerosis. MS can occurs both in obese and in slim subjects. The natural history of type 2 diabetes involves an evolution from normal glucose tolerance through impaired glucose tolerance to onset of frank diabetes, followed by continuing beta cell failure leading to the need for exogenous insulin. 

Morphological association of type 2 diabetes include short stature, android type (apple type, central or visceral obesity) obesity, high waist: hip ratio, etc. Insulin resistant is the predominant feature of obesity even in the absence of diabetes. The insulin resistant syndrome (known as syndrome X or metabolic syndrome) consists of insulin resistance, hyperinsulinemia, obesity, dyslipidemia (high Tg and low HDL-C), and hypertension. The metabolic syndrome is diagnosed if an individual has three or more of the following criteria:

a.      Abdominal obesity: waist circumference >35 inches (women) or >40 inches (men)

b.      Triglycerides >150 mg/dL

c.       HDL-C < 50 mg/dL (women) or <40 mg/dL (men)

d.      Blood pressure ≥ 130/85 mm Hg

e.      FPG ≥ 110 mg/dL or ≥ 100 mg/dL

Individuals with these syndromes are at increased risk for cardiovascular disease.  

Insulin resistance is a state which requires more amount of insulin to perform normal function. This is seen in type 2 diabetic subjects because these individuals are hyperglycemic despite of hyperinsulinaemia and hence termed relative insulin deficient or insulin resistant. Hyperinsulinaemia with euglycemia or hyperglycemia indicates insulin resistance.

Insulin resistance is manifested mainly as hepatic unresponsiveness to insulin to prevent flux of glucose, resistant to insulin induced uptake, utilization and storage of glucose by muscle and also adipose tissue.

High circulating level of alternative fuel like NEFA, Triacylglycerol, lactate, ketone bodies compete with glucose for uptake and in their presence glucose clearance is reduced (Randle cycle).

Insulin resistance can be due to cellular satiety seen whenever intracellular sensors like uridine diphosphate (UDP)-glucosamine detects excess supply of energy (glucose). Some suggest reduced number of insulin receptors, reduced receptor function, dysfunction of second messenger systems, etc.

ENVIRONMENT

Environmental factors like diet and exercise are important determinants in pathogenesis of type 2 diabetes. Obesity is most likely to develop diabetes, but only 60% to 80% of patients with T-2 diabetes are obese, diabetes develops in fewer than 15% of obese subjects. In contrast, virtually all obese subjects, even those with normal carbohydrate tolerance have hyperinsulinemia are insulin resistant. Other factors are family history of diabetes (genetic predisposition), duration of obesity (BMI ≥30 kg/m²). Life style changes like weight reduction and exercise can reduce the incidence of type 2 diabetes. The protective effect of exercise is thought to be an increased sensitivity to insulin in skeletal muscle and adipose tissue.

HYPERTENSION:

There is strong association between hypertension and type 2 diabetes. Patients with both type 1 and type 2 diabetes and hypertension have sodium retention and impaired natriuresis which is seen even before development of diabetes. Possible sodium retaining mechanism include hyperinsulinaemia-induced overactivity of tubular sodium transporters, increased glomerular filtration of glucose leading to enhanced proximal tubule sodium-glucose cotransport, extravascular shift of fluid with sodium and in later stages renal impairment.

DYSLIPIDAEMIA

Various mechanisms are proposed. Non-enzymatic glycation of apolipoproteins impairs lipoprotein clearance. Lack of inhibitory effect of insulin on hormone sensitive lipase cause excessive lipolysis. As a result there is increased availability of non-esterified fatty acids (NEFAs) for re-esterification in the liver to produce VLDL. Peripheral VLDL clearance may be impaired because insulin is needed to synthesize and secrete lipoprotein lipase (LPL). Type 2 diabetes is associated with low HDL-cholesterol and elevated VLDL-cholesterol and Tg concentration. Total cholesterol concentration is often normal.

In type 1 diabetes poor glycaemic controls is associated with high VLDL-cholesterol, LDL-C and total Tg, and sometimes low HDL-C.