Insulin resistance beta-cell survival, and apoptosis in type 2 diabetes: animal models and human implications

The genetically endowed quality of beta-cells determines their potential to cope with nutritionally enhanced insulinogenesis, Certain species may resp ond to the inherent hyperphagia with long-lasting compensatory insulin secr etion entailing obesity. Other animal species and certain human populations with labile pancreas are unable to maintain the hypersecretion of insulin in response to the imposed nutrient load, thus causing the transition from type 2 to type 1 diabetes. Insulin resistance is most probably an inherited trait proximal to the insulin receptor responsible for the cellular signal ing defect that leads to the development of type 2 diabetes with the possib ility of consequent beta-cell failure in both animals and humans, The fact that obese Individuals often do not progress to full-fledged diabetes indic ates that they may be endowed with particularly resilient beta-cells. The l asting hyperinsulinemia promotes the conversion of glucose to fat and restr ains fat release from adipose tissue, protecting beta-cells from gluco- or lipotoxic lesion, similar to the obese animal species mentioned here. The i mpaired glucose tolerance and hyperglycemia should not be considered as mar kers of beta-cell function, but as an incitement of oversecretion culminati ng in apoptosis, Apoptosis is a pathophysiologic process distinct front, an d preceding, necrosis, Insulin resistance can be reversed and apoptosis pre vented by reducing the nutritionally induced hyperglycemia in time. Psammom ys obesus illustrates this course of events and is an excellent model of hu man transition from type 2 to type 1 diabetes, demonstrating the reversibil ity of the process and manifesting beta-cell nuclear fragmentation, which c auses a failure of biosynthetic capacity in the final stage of nutritionall y induced diabetes.