Hepatic regulation of pancreatic α-cell function

Abstract

The direct feedback regulation between the endocrine gland and its target organ is an expected biological relationship. However, such a phenomenon is far from being well established in the case of the endocrine pancreas and its major target organ, the liver, especially since plasma glucose has been established as the prime regulator. In this perspective, I have reexamined the feedback regulation between plasma glucose and glucagon secretion by the pancreatic α cell. Surprisingly, available data in the literature appear to document a frequent breakdown of this well-established interdependence between plasma glucose and pancreatic α cells, as reflected by a sustained elevation of plasma glucagon levels in several physiologic and pathologic states with concurrent euglycemia or hyperglycemia. Moreover, normal or low glucagon concentrations in the presence of fasting hypoglycemia in patients with insulinoma or non-islet cell tumors secreting insulin-like peptides and in patients with hepatic glycogen storage disorders may enhance our hypothesis that plasma glucose level may not be the major regulator of glucagon secretion. Extensive data in the literature show that hyperglucagonemic states are characterized by a unique metabolic environment, namely hepatic glycogen depletion. Similarly, hepatic glycogen stores are abundant in the presence of normal or low glucagon concentrations. These findings imply a distinct relationship between hepatic glycogen content and plasma glucagon level. Moreover, both the restoration of normal glucagon concentrations in hyperglucagonemic states following replenishment of the depleted hepatic glycogen stores during the postabsorptive period, ie, after an overnight fast, and a decrease in normal glucagon concentrations while continuing to maintain euglycemia by concurrent insulin and glucose infusion, ie, the euglycemic clamp technique, appear to corroborate this relationship between hepatic glycogen content and plasma glucagon level. Finally, a significant negative correlation between fasting plasma glucagon level and the glucose response to intravenous (IV) glucagon administered after an overnight fast, a reliable determinant of hepatic glycogen stores, also indicates that hepatic glycogen content rather than plasma glucose level may be the prime regulator of pancreatic α-cell function. The role of the liver in regulation of glucagon secretion may be further evidenced by the documentation of an extremely high glucagon concentration in the presence of euglycemia in hepatectomized animals. Since the kidney, not the liver, is the main site of glucagon degradation and clearance, it is possible that hepatectomy induces a deficiency of a putative glucagon inhibitory factor secreted by the liver, resulting in uninhibited release of glucagon by the pancreatic α cell. Therefore, I propose a new hypothesis that the liver secretes a hormonal factor in response to its glycogen replenishment, a substance that inhibits pancreatic α cells. Conversely, if hepatic glycogen stores are depleted, secretion of such a factor is suppressed, resulting in unopposed and sustained pancreatic α-cell stimulation since hyperglucagonemia, thus achieved, is the crucial hormonal change required for initiating and maintaining gluconeogenesis to sustain the plasma glucose level and to provide glucose as a fuel for functioning of the body tissues. Finally, it is more than likely that such a feedback regulation may also exist between the liver and pancreatic β cells; however, further studies are required to assess this hypothesis.