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Comments to Lee et al: Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice.

04/27/2011

Diabetes 60:391-397, 2011.

Accumulating evidence during the last several decades has suggested that glucagon is of key importance for diabetes hyperglycemia. Thus, patients with type 2 diabetes have hyperglucagonemia and increased hepatic glucose output, and the hyperglycemia seems to be caused by a defective suppression of glucagon during hyperglycemia (1). A recent experimental study by Lee and collaborators examined the role of glucagon in mice with type 1 diabetes induced by streptozotin (2). They approached this aim by using a mouse model with genetic deletion of the glucagon receptors. This model has been characterized before and shown to be associated with reduced fasting and prandial glycemia (3). The authors challenged these mice with a high dose of streptozotocin, a beta cell toxin completely destroying beta cell function. Wild type mice became severely diabetic after this challenge with massive hyperglycemia. However, the mice with the glucagon receptor knockout remained in good health with low glucose and had normal glucose tolerance after a glucose challenge, even in the absence of any insulin response.

The study therefore shows that in the presence of glucagon deficiency, complete lack of insulin does not result in hyperglycemia, which suggests that a main function of insulin is to restrain the hepatic action of glucagon. The mechanism by which glucose tolerance remains normal after streptocotozin administration in glucagon receptor knockout mice remains now to be studied. The authors hypothesize that leptin or insulin-like growth factors may contribute, although no evidence for this is presented. Nevertheless, the main conclusion of the study strengthens the hypothesis that glucagon is a major player behind hyperglycemia in diabetes.

Bo Ahrén – Sweden

1. Dunning BE, Gerich JE 2007 The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev 28:253-283.
2. Lee Y, Wang MY, Du XQ, Charron MJ, Unger RH 2011 Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60:391-397.
3. Gelling RW, Du XQ, Dichmann DS, et al. 2003 Lower blood glucose, hyperglycagonemia, and pancfreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 100:1438-1443.