Insulin modulation of glucagon secretion: The role of insulin and other factors in the regulation of glucagon secretion

Glucagon plays a critical counter-regulatory role to insulin to maintain optimal glucose homeostasis. Glucagon secretion from pancreatic α-cells is regulated by glycemia, neural input, and secretion from neighboring β-cells. Recently, we provided direct genetic evidence of a critical role for insulin signaling in the regulation of glucagon secretion in vivo. Pancreatic α-cell targeted disruption of insulin receptor expression in mice resulted in glucose intolerance, hyperglycemia and hyperglucagonemia coupled with an abnormal glucagon response to hypoglycemia. Furthermore, streptozotocin treated mice exhibited paradoxically increased plasma glucagon suggesting a dominant role for insulin in the regulation of glucagon secretion compared with glucose. In fact, normalization of hyperglycemia by phrolidzin treatment decreased plasma glucagon levels suggesting a stimulatory effect of glucose on glucagon secretion and also revealed the significance of insulin in hyperglycemic states. Together these studies provide novel insights into intra-islet regulatory pathways in the modulation of glucagon secretion and provide potential opportunities to develop therapeutic approaches for the correction of α-cell dysfunction in diabetes.