Hyperglycemia in type 2 diabetes: physiological and clinical implications of a brain centered model.

Classically type 2 diabetes is believed to be a result of insulin resistance and relative insulin deficiency. However, evidences have been accumulating against the insulin resistance centered models. Absence of fasting hyperglycemia by insulin receptor knockouts or insulin suppression, evidence for hyperinsulinemia preceding insulin resistance, the perplexing hyperinsulinemic normoglycemic state, reduced glucose transport to the brain preceding hyperglycemia, signs of vasculopathy preceding hyperglycemia, absent or poor correlation between fasting glucose and insulin, very strong positive correlation between indices of insulin resistance and {beta} cell function in population data are some of the anomalous findings which glucose homeostasis models have not addressed so far. With increasing evidence for neuronal involvement in glucose regulation, we propose a refined model of glucose regulation that considers brain glucose and insulin levels as the ultimate target of homeostasis and combines central and peripheral mechanisms of regulation. A model considering reduced rate of blood to brain transportation of glucose and insulin as primary pathology explains most of the patterns, with or without insulin resistance. Apart from resolving multiple anomalies the model also accounts for the limited and inconsistent success of glucose normalization in effectively reducing diabetic complications and mortality.