Glucagon as a Critical Factor in the Pathology of Diabetes

Studies from the laboratory of Roger Unger presented in the current issue of Diabetes highlight the potential benefit of reducing glucagon action by examining the effects of glucagon receptor knockout (Gcgr) on the phenotype of type 1 diabetes in the mouse (1). The aim of the study was to determine if glucagon action, by itself, causes the lethal consequences of insulin deficiency. Because treatment of Gcgr mice with the b-cell toxin streptozotocin (STZ) previously had no effect on circulating insulin levels or pancreatic islet architecture (2), Lee et al. (1) administered a double dose of STZ to maximize b-cell destruction. Unlike STZ treated wild-type Gcgr mice, which became severely hyperglycemic, STZ-treated mice lacking glucagon signaling appeared to be in a normal state of health and were completely protected from the manifestations of diabetes (1), as shown previously by the same group in alloxan treated Gcgr mice (3) and by Hancock et al. (4) in STZtreated mice lacking glucagon because of a-cell deletion. Fasting hyperglycemia did not occur in STZ-treated Gcgr mice, and astonishingly, the animals demonstrated normal or even improved glucose disposal in response to a glucose tolerance test, despite the absence of a rise in plasma insulin. These results led the authors to speculate that insulin action during glucose absorption is largely directed toward overcoming the hepatic actions of glucagon. They theorized that insulin would have little or no role in a liver not exposed to the action of glucagon because it would be in a permanent glucose storage mode. Glucagon antagonistic peptides, neutralizing antibodies, receptor antisense oligonucleotides, and/or receptor nonpeptidyl antagonists have previously been shown to lower plasma glucose in several rodent models of diabetes (5,6). Likewise, reversal of diabetes by leptin therapy in the rodent has been attributed to a reduction in plasma glucagon (3,7), although other actions of leptin could not be ruled out. Reduction of glucagon in pancreatectomized canines caused a marked decrease in hepatic glucose production (8) and suppression of glucagon in diabetic humans improved glucose tolerance (9,10). Thus, there is strong evidence supporting a role for glucagon in contributing to diabetic hyperglycemia. Insulin deficient glucagon receptor-null mice are functionally pancreatectomized. Thus, based on the results of Lee et al. (1), normal glucose metabolism might be expected in humans with total pancreatectomy, but this is not the case. Measurement of glucagon is complicated by nonspecific cross reacting materials (6), leading to controversy as to whether pancreatectomized patients actually lack glucagon or not. The consensus, however, appears to support the concept that glucagon is produced by the gut in such patients, but at a reduced rate relative to that produced by the pancreas in individuals with type 1 diabetes (11). This probably explains the less severe, nonketotic, form of diabetes found in this population (12). In the pancreatectomized canine, elevated levels of gut derived glucagon have been shown to contribute to the severity of the diabetic phenotype (13). The surprise in the data of Lee et al. (1) comes not from the improvement in glycemia caused by a lack of glucagon action, but from the complete normalization of glucose tolerance that occurred. Transition from the fasted to fed state involves a reduction in glucose production by the liver and an increase in glucose disposal by insulin sensitive tissues (skeletal muscle, liver, and adipose tissue). Studies in the human and canine have indicated that following an oral glucose load of moderate size (;1 g/kg BW), the liver and skeletal muscle are each responsible for approximately a third of glucose disposal, with noninsulin dependant tissues accounting for the remainder (14). In nondiabetic individuals, the changes in muscle and liver glucose metabolism are thought to be chiefly mediated by insulin (14). The fact that oral glucose tolerance was normal in the STZ treated Gcgr mice of Lee et al. (1), despite no rise in insulin, suggests that in a net sense glucose uptake by liver and muscle was normal. Whether both tissues took up glucose normally, or one compensated for a defect in the other, is not clear. Nevertheless, this raises the question as to what is driving glucose disposal if not insulin. Lee et al. (1) argue that insulin overcomes glucagon’s inhibitory effects on hepatic glucose uptake (HGU) and that in the absence of glucagon, the liver will take up glucose without insulin. Indeed, insulin and glucagon have opposing effects on many glucoregulatory pathways in the liver, including transcription of glucokinase and regulation of glycogen synthesis and breakdown (Fig. 1A). However, in the normal canine made acutely deficient in insulin and glucagon using somatostatin and/or pancreatectomy, the liver did not take up or store glucose when exposed to a hyperglycemic challenge, despite the lack of glucagon (15). Likewise, an acute deficiency of both insulin and glucagon in the human (16) or canine (17) led to a transient fall in glucose production followed by a return to the basal rate, despite hyperglycemia secondary to decreased muscle glucose clearance. These data could be interpreted to suggest that glucagon plays a lesser role in hepatic From the Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. Corresponding author: Dale S. Edgerton, [email protected]. DOI: 10.2337/db10-1594 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 391.