Insulin resistance, impaired insulin secretion, excessive hepatic glucose production and abnormal fat metabolism are the characteristic features of type 2 diabetes mellitus.
PATHOPHYSIOLOGY OF TYPE 2 DIABETES:
Insulin resistance is the failure of target tissues to respond normally to insulin. So, there is a decreased uptake of glucose by muscles, there is also reduced glycolysis and reduced fatty acid oxidation in liver. These lead to conditions like hyperglycemia, lack of energy and fatigue. Due to insulin resistance, there is also inability to suppress hepatic gluconeogenesis which leads to hyperglycemia. Experiments in mice have demonstrated that loss of insulin sensitivity by hepatocytes is the largest contributor for the pathological changes in type 2 diabetes. Many types of functional defects have been identified in the signalling pathway of insulin (e.g., defect in tyrosine kinase function, increased serine phosphorylation). There are some factors responsible for development of insulin resistance. (e.g., obesity)
OBESITY AND INSULIN RESISTANCE:’
Most of the type 2 diabetics cases have been associated with obesity and more than 80% of the cases have been associated with visceral obesity. Even body fat has a profound effect in reducing insulin sensitivity. Mostly central fat i.e., fat in abdomen is more likely to cause insulin resistance rather than peripheral fat i.e., gluteal and subcutaneous fat. Obesity leads to insulin resistance in the following ways:
1. NONESTERIFIED FATTY ACIDS:
Increase in nonesterified fatty acids leads to increased insulin resistance. The excess nonesterified fatty acids circulating in the blood get deposited in the visceral organs leading to increased triglycerides in muscles and liver. Excess fat or nonesterified fatty acids in the cells overwhelm fatty acid oxidation leading to accumulation of intermediates like diacylglycerols and ceramide in the cells. These substances are toxic and activate serine kinases which lead to phosphorylation of serine which leads to insulin resistance. Insulin is needed for blocking hepatic gluconeogenesis which is not possible due to insulin resisytance thereby leading to hyperglycemia.
A variety of proteins secreted by adipose tissues are collectively termed as adipokines. Some adipokines favor hyperglycemia while some inhibit them. Leptin and adiponectin are anti hyperglycemic. In obese people there is reduction in levels of adiponectin which is the cause of insulin resistance. Adiponectin is needed for improving insulin sensitivity.
Pro-inflammatory cytokines like tumor necrosis factor (TNF), Interleukin 6 (IL-6) etc. are secreted by the adipose tissue. These cytokines increase insulin resistance by increasing the stress on the cells. The stress on the cells activates several other signalling cascades which have a negative or antagonistic effect on the insulin signalling pathway, thereby leading to insulin resistance.
4.PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA:
Activation of the receptors of the above name lead to secretion of anti hyperglycemic adipokines like adiponectin thereby helping in improving insulin sensitivity. Drugs of the group thiazolidinediones act as ligands to these receptors.
BETA CELL DYSFUNCTION:
Initially to compensate for the insulin resistance there is an increased secretion of insulin from beta cells which leads to hypoglycemia. But later on there is exhaustion of beta cells and they are unable to meet the demands of the body. The beta cells get exhausted and finally they fail which leads to elevated levels of blood glucose in later years of life.
All the above sited mechanisms lead to the characteristic features of type 2 diabetes like insulin resistance, impaired glucose and fat metabolism and decreased secretion of insulin.