IV- Role of glucagon in metabolism

The radioimmunoassay described by Unger and coworkers in 1959 has made it possible to establish the physiological role of glucagon as the “hormone of energy need” in circumstances like hypoglycemia, starvation, physical exercise, and adaptation to extrauterine life (Lefebvre, Lecture).


1. Physiological role of glucagon

Both glucagon and insulin are pivotal in systemic energy homeostasis, and the balance between these two hormones determines the metabolic state of various organs in response to changes in energy status. During postprandial hyperglycemia, insulin secretion by β-cells is stimulated while glucagon secretion by α-cells is suppressed, leading to a lowering of blood glucose levels. In contrast, in starvation-induced hypoglycemia, glucagon secretion is promoted while insulin secretion is reduced, causing elevated blood glucose levels (Kulkarni, Lecture). Note that the response to hypoglycemia is not only the suppression of the hyperglycemic responses, but also a set of positive counterregulation mechanisms aimed at preventing a fall in blood glucose concentrations that could otherwise threaten brain function and survival of the individual (detailed in Chapter 2).
Glucagon action is mediated by a G protein-coupled receptor (GCGR/Gcgr) that is coupled to adenyl cyclase. Glucagon also mediates an increase in intracellular calciumin a phospholipase C−dependent manner and activates AMP-activated kinase and c-Jun N-terminal kinase. Binding sites for glucagon have been identified in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, and β-cells. There is controversy regarding the presence of the Gcgr in pancreatic α-cells. Activation of the Gcgr in hepatocytes mediates the primary actions of glucagon: ketogenesis and increased hepatic glucose production—glucagon increases the net hepatic glucose output through increased expression of gluconeogenesis enzyme and glycogen degradation without altering the gluconeogenesis flux (Cherrington, Lecture). Glucagon has potent hypolipidemic actions and reduces triglycerides and very-low-density lipoprotein release aswell as the deposition of triacylglycerol in the liver, in addition to reducing cholesterol levels and stimulating fatty acid oxidation46 (Charron, Lecture).
The mechanisms regulating the degradation and clearance of glucagon remain incompletely understood. Glucagon is catabolized by the enzyme neutral endopeptidase 24.11 in pigs, as well as in vitro by dipeptidyl peptidase-4 at pharmacological levels. Hepatic clearance of glucagon seems to be 20%-30% of the portal content, with the kidneycontributing to the major portion of peripheral glucagon removal (D’Alessio, Charron, Cherrington, Lectures; D’Alessio, unpublished).
Using knockout and transgenic technology, genetically modified animal models have been developed to clarify the physiological role of glucagon.47 Homozygous glucagon-GFP knock-in mice (Gcggfp/gfp) lack most, if not all, peptides derived from the glucagon gene48 and thus provide an opportunity to analyze the metabolic impact of glucagon deficiency without the influence of GLP-1 overexpression. The mutant displays α-cell hyperplasia but normoglycemia, despite complete glucagon deficiency, probably allowed by the lower plasma insulin levels and glucagon-independent mechanisms that maintain gluconeogenesis (Hayashi, Lecture; Hayashi, unpublished). Mutant mice with glucagon receptor deficiency (Gcgr-/-) are characterized by severe α-cell hyperplasia, hyperglucagonemia, and profound elevations of GLP1. They show decreased blood glucose (with decreased glycogenolysis and gluconeogenesis), decreased capacity of the liver to oxidize lipid, with development of hepatic steatosis in some instances, but are protected from diet-induced obesity (D’Alessio, Lecture; D’Alessio, unpublished; Hayashi, Lecture; Hayashi, unpublished). Interestingly, in Gcgr-/- mice administration of a double dose of STZ led to β-cell destruction, as in wild-type mice, but none of the foregoing clinical or laboratory manifestations of diabetes appeared, unlike in wild-type mice. Fasting glucose levels and oral and intraperitoneal glucose tolerance test results were normal with no increase in insulin level above the basal value, suggesting that insulin is not involved in the normal glucose tolerance of Gcgr-/- mice.49 Finally, in transgenic mice that over-express Gcgr in insulin-producing cells (RiPGcgr),50 islets displayed a significant increase in insulin secretion in response to glucagon compared with that of controls, suggesting that the regulatory role of glucagon ininsulin release may be associated with the number of glucagon-binding sites on insulin cells. Furthermore, RiP-Gcgr mice displayed enhanced glucose tolerance and a small, but significant increase in insulin cell volume compared with littermate controls. Thus glucagon action also seems to be involved in the regulation of insulin cell mass and in the potentiation of glucose-stimulated insulin secretion by increasing insulin cell competency (Charron, Lecture; Vuguin and Charron, unpublished).


2. Altered glucagon secretion and counterregulation in diabetes

While elevations in blood glucose suppress glucagon levels in nondiabetic subjects, diabetic individuals, in contrast, have a blunted or absent α-cell response to hyperglycemia and plasma glucagon remains inappropriately elevated at comparable levels of blood glucose.2 T2D patients have hepatic insulin resistance and inappropriate fasting glucagon secretion to drive excessive hepatic glucose production. The postprandialrise of glucagon is increased in T2D, providing an additional factor to impair insulin action, working against glucose homeostasis. Moreover, glucagon secretion is increased by normal α-cell stimuli, such as intravenous arginine and protein-richmeals, to a greater extent in T2D than nondiabetic individuals2 (D’Alessio, Lecture;D’Alessio, unpublished).
In health, early defenses against hypoglycemia include reduction in β-cell insulin secretion, pancreatic glucagon release, epinephrine secretion by the adrenal medulla, and sympathetic nervous system activation. Later defenses include cortisol and GH secretion as well as hepatic auto-regulation which may also help to restore euglycemia. The first of the hormone defenses lost during the course of T1D is glucagon, which occurs despite the normal number and histological appearance of α-cells in the pancreatic islets. Glucagon counterregulation (GCR) is also defective in advanced T2D. The mechanism by which hypoglycemia stimulates GCR and how it is impaired ininsulin-deficient diabetes is still unclear and may include impaired blood glucose−sensing in the α-cells, autonomic dysfunction, and/or loss of an insulin “switchoff” signal from the β-cells. Using mathematical modeling to analyze and reconstruct the GCR control network, it was predicted that lack of β-cell signaling to the α-cells can be viewed as a key network deficiency which impairs the GCR by contributing to two separate network abnormalities: (i) absence of a β-cell switch-off trigger andmainly (ii) increase in intra islet auto-feedback−independent glucagon release. Importantly, in vivo defective GCR can be repaired by two different α-cell inhibitor signals, insulin and somatostatin, which upon switch-off trigger pulsatile GCR.51 Suchan α-cell inhibitor−based GCR repair treatment can be added to a variety of existing insulin replacement therapies to treat diabetes and is expected to stabilize blood glucose control and improve safety by reducing the risk of hypoglycemia (Farhy, Lecture; Farhy and McCall, unpublished).

“Pancreatic α-cells and glucagon—neglected metabolic actors”
I- Birth and death of the α-cell
II- Regulation of glucagon expression
III- Regulation of glucagon secretion
IV- Role of glucagon in metabolism
V- Therapeutic perspectives
VI- Conclusion
Lectures during IGIS meeting and unpublished reviews