Caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β cells
Approximately 90 to 95 % of cases of diabetes are type 2 diabetes
Though its called as adult onset but can occur in children and adolescents due to increase rates of obesity
Pathogenesis
Type 2 diabetes is complex disease involving an interplay of genetic, environmental factors and proinflammatory state
Genetic factors
Genetic susceptibility in monozygotic twins and 1st degree relatives are at 5 to 10 folds increased risk of developing Diabetes
Polymorphisms in many genes associated with insulin gene are identified
Environmental factors
Most important – obesity particularly central and visceral obesity
Obesity contributes to metabolic abnormalities of diabetes and to insulin resistance
Sedentary life style is another risk factor independent of obesity
Metabolic defects in Type 2 Diabetes
Two important metabolic defects that characterise type 2 diabetes are
Decreased response of peripheral tissues, especially skeletal muscles, adipose tissue and liver to insulin
Inadequate insulin secretion in the face of insulin resistance and hyperglycemia (β cell dysfunction)
In the early stages, there is compensatory β cell hyperfunction and hyperinsulinemia but later β cells cannot adapt and lead to chronic hyperglycemia leading to complications
Insulin resistance
Insulin resistance results in
Failure to inhibit endogenous glucose production in the liver which contributes to high fasting blood glucose levels
Failure of glucose uptake and glycogen synthesis that occurs in skeletal muscle following a meal contributes to high post prandial blood glucose
Failure to inhibit lipoprotein lipase in adipose tissue, leading to excess of circulating FFA which inturn amplify insulin resistance
In insulin resistance
´Defects in signaling pathways leading to decreased tyrosine phosphorylation of insulin receptor and IRS proteins
´This leads to decreased levels of GLUT 4 levels on the surface of the cell
Exercise causes increased translocation of GLUT 4 to the surface
Obesity and insulin resistance
Risk of diabetes increases as the body mass index increases. Central obesity has more risk than peripheral fat depots
Free fatty acids
Levels of FFA are inversely related to insulin sensitivity
Central adipose tissue is more lipolytic than peripheral sites
Excess of free fatty acids overwhelm intracellular fatty acid oxidation pathways, leading to accumulation of diacylglycerol (DAG) which attenuates the insulin signaling pathway by serine phosphorylation of insulin receptors
Insulin normally inhibits hepatic gluconeogenesis by blocking the activity of phosphoenol pyruvate carboxykinase, which is the first enzymatic step in this process
Attenuated insulin signaling leads to increased phophoenolpyruvate carboxykinase activity that causes increased gluconeogenesis
Adipokines
Adipose tissue acts as endocrine organ releasing hormones called adipokines which include pro hyperglycemic adipokines and anti hyperglycemic adipokines (Leptin and Adiponectin)
Leptin and adiponectin improves the insulin secretion
Adiponectin levels are decreased in obesity this contributes to insulin resistance
Inflammation
Proinflammatory cytokines are secreted in response to excess nutrients such as Free fatty acids and glucose
Excess FFA with in macrophages and B cells activate the inflammasome, a multipotent complex which leads to secretion of the cytokine interleukin IL-1β
Interleukin IL-1β mediates secretion of proinflammatory cytokines from macrophages, islet cells and other cells
interleukin IL-1β and other cyokines released into circulation acts on the sites of insulin action and cause resistance
B cell dysfunction
along with insulin resistance B cell dysfunction is also required for the development of Type 2 diabetes
In the initial stages there is β cell function increase inorder to compensate the insulin resistance but later the β cells are exhausted
Mechanisms that promote β cell dysfunction are
Excess FFA attenuate insulin release and compromise the β cell function (Lipotoxicity)
Chronic hyperglycemia (Glucotoxixity)
an abnormal incretin effect
Amyloid deposition in the islets
Polymorphisms in genes that control insulin secretion
