Neuronal regulation of glucagon secretion and gluconeogenesis

Hypoglycemia almost never develops in healthy individuals because multiple hypoglycemia sensing systems, located in the periphery and in the central nervous system trigger a coordinated counterregulatory hormonal response to restore normoglycemia. This involves not only the secretion of glucagon but also of epinephrine, norepinephrine, cortisol and growth hormone. Increased hepatic glucose production is also stimulated by direct autonomous nervous connections to the liver that stimulate glycogenolysis and gluconeogenesis. This counterregulatory response, however, becomes deregulated in a significant fraction of diabetic patients that receive insulin therapy. This leads to risk of developing hypoglycemic episodes, of increasing severity, which negatively impact the quality of life of the patients. How hypoglycemia is detected by the central nervous system is being actively investigated. Recent studies using novel molecular biological, optogenetic and chemogenetic techniques, allow the characterization of glucose sensing neurons, the mechanisms of hypoglycemia detection, the neuronal circuits in which they are integrated and the physiological responses they control. This review will discuss recent studies aimed at identifying central hypoglycemia sensing neuronal circuits, how neurons are activated by hypoglycemia, and how they restore normoglycemia.