Studies from the laboratory of Roger Unger pre-sented in the current issue of Diabetes highlight the potential benefit of reducing glucagon action by examining the effects of glucagon receptor knockout (Gcgr J/J) 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 J/J 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 J/J mice (3) and by Hancock et al.(4) in STZ-treated mice lacking glucagon because of a-cell deletion. Fasting hyperglycemia did not occur in STZ-treated Gcgr J/J 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 …