Pathophysiology and the Pathogenesis of Type 2 Diabetes

Type 2 diabetes mellitus is a heterogeneous disorder with varying prevalence among different ethnic groups. In the United States the populations most affected are native Americans, particularly in the desert Southwest, Hispanic-Americans, African-Americans, and Asian-Americans. The pathophysiology of type 2 diabetes mellitus is characterized by peripheral insulin resistance, impaired regulation of hepatic glucose production, and declining ß-cell function, eventually leading to ß-cell failure.

The primary events are believed to be an initial deficit ininsulin secretion and, in many patients, relative insulin deficiency in association with peripheral insulin resistance.

The ß-cell Dysfunction

ß-Cell dysfunction is initially characterized by an impairment inthe first phase of insulin secretion during glucose stimulationand may antedate the onset of glucose intolerance in type 2 diabetes.

Initiation of the insulin response depends upon the transmembranous transport of glucose and coupling of glucose to the glucose sensor. The glucose/glucosesensor complex then induces an increase in glucokinase by stabilizing the protein and impairing its degradation. The induction of glucokinase serves as the first step in linking intermediary metabolism with the insulin secretory apparatus. Glucose transport in ß-cells of type 2 diabetes patients appears to be greatly reduced, thus shifting the control point for insulin secretion from glucokinase to the glucose transport system.

Later in the course of the disease, the second phase release of newly synthesized insulin is impaired, an effect that can be reversed, in part at least in some patients, by restoring strict control of glycemia. This secondary phenomenon, termed desensitization or ß-cell glucotoxicity, is the result of a paradoxical inhibitory effect of glucose upon insulin release and may be attributable to the accumulation of glycogen within the ß-cell as a result of sustained hyperglycemia. Other candidates that have been proposed are sorbitol accumulation in the ß-cell or the non-enzymatic glycation of ß-cell proteins.

Other defects in ß-cell function in type 2 diabetes mellitus include defective glucose potentiation in response to non-glucose insulin secretagogues, asynchronous insulin release, and a decreased conversion of proinsulin to insulin.

An impairment in first phase insulin secretion may serve as a marker of risk for type 2 diabetes mellitus in family members of individuals with type 2 diabetes mellitus and may be seen in patients with prior gestational diabetes. However, impaired first phase insulin secretion alone will not cause impaired glucose tolerance.

Autoimmune destruction of pancreatic ß-cells may be a factor in a small subset of type 2 diabetic patients and has been termed the syndrome of latent autoimmune diabetes in adults.This group may represent as many as 10% of Scandinavian patients with type 2 diabetes and has been identified in the recent United Kingdom study, but has not been well characterized in other populations.

Glucokinase is absent within the ß-cell in some familieswith maturity-onset diabetes of young . However, deficienciesof glucokinase have not been found in other forms of type 2diabetes.

In summary, the delay in the first phase of insulin secretion, although of some diagnostic import, does not appear to act independently in the pathogenesis of type 2 diabetes. In some early-onset patients with type 2 diabetes (perhaps as many as 20%), there may be a deficiency in insulin secretion that may or may not be due to autoimmune destruction of the ß-cell and is not due to a deficiency in the glucokinase gene. In the great majority of patients with type 2 diabetes (±80%), the delay in immediate insulin response is accompanied by a secondary hypersecretory phase of insulin release as a result of either an inherited or acquired defect within the ß-cell or a compensatory response to peripheral insulin resistance.

Over a prolonged period of time, perhaps years, insulin secretion gradually declines, possibly as a result of intra-islet accumulation of glucose intermediary metabolites. In view of the decline in ß-cell mass, sulfonylureas appear to serve a diminishing role in the long term management of type 2 diabetes. Unanswered is whether amelioration of insulin resistance with earlier detection or newer insulin-sensitizing drugs will retard the progressionof ß-cell failure, obviating or delaying the need for insulin therapy. Superior nutritional therapy may provide the best solution for this disease.

Insulin Resistance
The presence of hyperinsulinism in type 2 diabetes, insulin resistance has been considered to play an integral role in the pathogenesis of the disease. Recent critical reviews, however, have questioned the primacy, specificity, and contribution ofinsulin resistance to the disease state. As chronic hyperinsulinemia inhibits both insulin secretion and action, and hyperglycemia can impair both the insulin secretoryresponse to glucose as well as cellular insulin sensitivity, the precise relation between glucose and insulin level as a surrogate measure of insulin resistance has been questioned. Lean type 2 diabetic patients over 65 years of age have been found to be as insulin sensitive as their age-matched non-diabetic controls.

Moreover, in the majority of type 2 diabetic patients who are insulin resistant, obesity is almost invariably present. As obesity or an increase in intra-abdominal adiposetissue is associated with insulin resistance in the absence of diabetes, it is believed by some that insulin resistance in type 2 diabetes is entirely due to the coexistence of increased adiposity. Additionally, insulin resistance is found in hypertension, hyperlipidemia, and ischemic heart disease, entities commonly found in association with diabetes, again raising the question as to whether insulin resistance results from different pathogenetic disease processes or is unique to the presence of type 2 diabetes.

Prospective studies have demonstrated the presence of either insulin deficiency or insulin resistance before the onset of type 2 diabetes. Two studies have reported the presence of insulin resistance in non-diabetic relatives of diabetic patients at a time when their glucose tolerance was still normal. In addition, first degree relatives of patients with type 2 diabetes have been found to have impaired insulin action upon skeletal muscle glycogen synthesis due to both decreased stimulation of tyrosine kinase activity of the insulin receptor and reduced glycogen synthase activity.

Other studies in this high risk group have failed to demonstrate insulin resistance, and in the same group, impaired early phase insulin release and loss of normal oscillatory pattern of insulin release have been described. Based upon these divergent studies, it is still impossible to dissociate insulin resistance from insulin deficiency in the pathogenesis of type 2 diabetes. However,both entities unequivocally contribute to the fully established disease.

The Liver
The ability of insulin to suppress hepatic glucose production both in the fasting state and postprandially is normal in first degree relatives of type 2 diabetic patients . It is the increase in the rate of postprandial glucose production that heralds the evolution of IGT. Eventually, both fastingand postprandial glucose production increase as type 2 diabetes progresses.

Hepatic insulin resistance is characterized by a marked decrease in glucokinase activity and a catalytic increased conversion of substrates to glucose despite the presence of insulin. Thus, the liver in type 2 diabetes is programmed to both overproduce and under-use glucose. The elevated free fatty acid levels found in type 2 diabetes may also play a role in increased hepatic glucose production. In addition, recent evidence suggests an important role for the kidney in glucose production via gluconeogenesis, which is unrestrained in the presence of type 2 diabetes.