Central effect of estrogen on recurrent insulin induced hypoglycemia---Role of neuropeptide Y

Hypoglycemia is, by far the most dangerous and inevitable side effect in the clinical management of insulin-dependent diabetes mellitus. Antecedent hypoglycemia is a primary factor in the development of hypoglycemia associated autonomic failure, a pathophysiological condition characterized by diminished counterregulatory and behavioral responses. Clinical and experimental studies show that males, but not females exhibit exacerbated hypoglycemia coincident with blunted counterregulatory hormone secretion and behavioral responses during recurring insulin induced hypoglycemia (RIIH). The role of estradiol in the body's response to recurrent glucose deficits has not been studied. To address this issue, we examined the impact of estrogen during RIIH. We have demonstrated that estrogen maintains uniform glycemic responses by modulating counterregulatory and behavioral responses. The activation of the key metabolic sensing sites in the brain was also maintained in these conditions. Our studies have also demonstrated that this action of estrogen is mediated centrally, in part through the arcuate nucleus of the hypothalamus (ARH) to maintain uniformity in glycemic responses. Our subsequent efforts were focused on the neuronal population within the ARH which mediates the glucoregulatory role of estrogen during repeated hypoglycemia. Pharmacological and molecular approaches to evaluate the mechanisms underlying estrogenic regulation have provided us with clear evidence on the potential involvement of Neuropeptide Y-1 receptor. Our studies have laid the foundation and stressed the need for understanding the NPY neuronal circuitry in detail, which can translate into the development of therapeutic strategies to circumvent the counterregulatory collapse associated with diabetic patients.