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Glucagon as a Critical Factor in the Pathology of Diabetes

2011; American Diabetes Association; Volume: 60; Issue: 2 Linguagem: Inglês

10.2337/db10-1594

1939-327X

Dale S. Edgerton, Alan D. Cherrington,

Metabolism, Diabetes, and Cancer

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 β-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 β-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 STZ-treated mice lacking glucagon because of α-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 …