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

Abstract

The hyperglycemia of type 2 diabetes has been classically believed to be a result of insulin resistance and relative insulin deficiency. However, the unexpected outcomes of insulin receptor knockout and insulin suppression experiments and the unexplained patterns in clinical data have exposed the limitations of the peripheral regulation 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, absent or poor correlation between fasting glucose and insulin, very strong positive correlation between indices of insulin resistance and β cell function in population data are some of the anomalous findings which glucose homeostasis models have not addressed so far. On the other hand the increasing evidence of central neuronal mechanisms of glucose regulation necessitates incorporation of brain glucose regulation in the models. Although models considering brain glucose regulation have been suggested, their multiple physiological and clinical implications have not been thoroughly examined. Based on updated evidence, we propose a refined model of glucose regulation that considers brain glucose levels as the ultimate target of homeostasis and combines central and peripheral mechanisms of regulation. In this model, considering reduced rate of blood to brain transmission of glucose and insulin as primary pathology explains most of the patterns including apparent anomalies with or without including insulin resistance. A brain centered model accounts for the limited and inconsistent success of glucose normalization in effectively reducing diabetic complications and mortality. A serious attempt to reevaluate alternative models is required since the brain centered model implies radical changes in the target and the course of diabetes treatment.