Type-2 diabetes is non-insulin dependent (insulin is not must for management), insulin resistance, abnormal insulin secretion and impaired pancreatic beta cell functions are central to the development of type-2 diabetes. Most studies suggest that insulin resistance precedes defect in insulin secretion, but diabetes develops only when insulin secretion becomes inadequate or insulin resistance becomes very high that the insulin secreted by beta cells become inadequate to maintain glucose level. Type-2 diabetes develops much later in life in compare to type-1 diabetes and generally seen only after 3^rd or 4^th decades of life.

Pathogenesis of type-2 diabetes is complex and involves a complex interaction between genetic and environmental factors. The genetic factor is much stronger in causation of type-2 diabetes, than type-1 diabetes and concordance of type-2 diabetes in identical twins is between 70 and 90%, in compare to 30% to 70% in type-1 diabetes. Many environmental factors are also implicated in the development of type-2 diabetes, such as sedentary lifestyle, excess food (calorie) intake which results in overweight and obesity (BMI of more than 30 is obesity).

Pathophysiologicaly there are three major abnormalities which individuals with type-2 diabetes demonstrate:

1. Insulin resistance in the peripheral tissues in muscles and fats and also in liver.
2. Defective insulin secretion (may be more than normal or less than normal) in response to glucose stimulus.
3. Increase production of glucose and fat in liver and hyperglycemia and increased lipids as a result.

An underlying genetic predisposition and environmental factors such as obesity, especially visceral or central obesity (measured by the hip-waist ratio), sedentary lifestyle, increased calorie intake etc. initiates the process of development of type-2 diabetes. At the beginnings and early stages of development of type-2 diabetes, the glucose tolerance remains near-normal, although there is insulin resistance, because the pancreatic beta cells can compensate by increasing insulin secretion. As insulin resistance and compensatory hyperinsulinemia (increase insulin level) continues to progress, the pancreatic beta cells are unable (in certain individuals) to sustain the hyperinsulinemic state and Impaired Glucose Tolerance (IGT) develops, which is characterized by increase in postprandial blood glucose. Insulin secretion reduces further and hepatic glucose production increases which lead to overt diabetes with fasting hyperglycemia and ultimately, beta cell failure may occur.

Insulin resistance in the peripheral tissues in muscles and fats:

Insulin resistance is the hallmark of type-2 diabetes, is decreased ability of insulin to act effectively on target tissues such as muscle, liver, fat etc. which results due to combination of genetic susceptibility and obesity. Insulin resistance is relative, as high (above normal) levels of circulating insulin normalize glucose tolerance and the plasma glucose. In type-2 diabetes there is reduced sensitivity to insulin and a reduced maximal response and an overall decrease in maximum glucose utilization (30% to 60% lower than in normal individuals).

Insulin resistance impairs glucose utilization by insulin-sensitive tissues (muscle, liver, fat) and also increases glucose output from liver; both of these effects contribute to the hyperglycemia. Increased glucose output from liver predominantly causes increase in fasting plasma glucose levels, decreased peripheral glucose usage by muscles, liver, and fat results in postprandial hyperglycemia. In skeletal muscle, the impairment in nonoxidative glucose usage, which is glycogen formation, is greater than oxidative glucose metabolism which is glycolysis. Glucose metabolism in insulin-independent tissues is not altered in type-2 diabetes.

The exact mechanism of insulin resistance which causes type-2 diabetes is not clear. The numbers of insulin receptor is reduced and also there is reduced tyrosine kinase activity in skeletal muscle, although these are due to secondary hyperinsulinemia and are not a primary defect. So, “postreceptor” defects in insulin-regulated phosphorylation/dephosphorylation may be the reason of insulin resistance. A PI-3-kinase signaling defect may reduce translocation of GLUT4 (glucose transporter-4) to the plasma membrane is an example of “postreceptor” defect.

Insulin resistance does not affect all the insulin signal transduction pathways, such as those controlling cell growth and cell differentiation using the mitogenic-activated protein kinase pathway, and as a result, hyperinsulinemia (high level of insulin) may increase the insulin action through these pathways, which accelerates the diabetes-related conditions such as atherosclerosis.

Obesity, especially central or visceral obesity, which generally accompany type-2 diabetes, is part (thought to be) of pathogenic process of type-2 diabetes. Increased fat cell (adipocytes) numbers/mass leads to increased levels of circulating free fatty acids and other fat cell products (known as adipokines), such as TNF-alpha, leptin, nonesterified free fatty acids, retinol-binding protein-4, resistin, and adiponectin. The adipokines regulates body weight, appetite, and energy expenditure, as well as modulate insulin sensitivity. The increase level of some adipokines, such as free fatty acids (as free fatty acids impair glucose utilization in skeletal muscle as well as promote glucose production by the liver, and thereby impair beta cell function) and others may cause insulin resistance in skeletal muscle and liver.

In obese people the production of adiponectin, an insulin-sensitizing peptide, by adipocytes, is reduced and may contribute to insulin resistance.

Defective/Impaired Insulin Secretion:

Insulin secretion and insulin resistance are interrelated and in type-2 diabetes, due to insulin resistance the secretion of insulin is increased to maintain normal glucose tolerance. At the initial stages of type-2 diabetes, the insulin secretory defect is mild and selectively involves glucose-stimulated insulin secretion, while maintaining the normal insulin secretion to other nonglucose insulin secretagogues, such as arginine. But later insulin secretory defect becomes grossly inadequate, involving all insulin secretagogues (glucose as well as nonglucose insulin secretagogues).

The reason(s) for the decline in insulin secretion in type-2 diabetes is not clearly understood, although it is assumed that a second genetic defect is superimposed upon already present insulin resistance, due to genetic (the first genetic cause) cause and results in beta cell failure/dysfunction. It is seen that chronic hyperglycemia paradoxically impairs islet function due to, which is known as “glucose toxicity” and results in worsening of hyperglycemia and normal glycemic control improves islet cell function. High level of free fatty acid in blood known as “lipotoxicity” and high dietary lipids can also worsen islet function. The beta cell mass is decreased in long standing type-2 diabetes.

Amyloid fibrillar deposits are found in the islets of individuals with long-standing type-2 diabetes, which is due to deposition of amyloid polypeptide or amylin, which is cosecreted by the beta cells, although the islet amyloid deposits are a primary or secondary to type-2 diabetes is not known.

Increase production of glucose and fats in liver:

In type-2 diabetes the production of glucose by liver is increased due to suppression of gluconeogenesis and there is also decreased glycogen storage in the liver and lipid level increase due to increase free fatty acid (FFA) flux from adipocytes (fat cells). The lipid (very low density lipoprotein or VLDL and triglyceride) level is also increased due to synthesis in hepatocytes of liver and dyslipidemia.