Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice

Abstract

Clinical studies have shown that patients with early Type 2 diabetes often have elevated serum glucagon rather than insulin deficiency. Imbalance of insulin and glucagon in favouring the latter may contribute to impaired glucose tolerance, persistent hyperglycaemia, microalbuminuria and glomerular injury. In the present study, we tested the hypothesis that long-term glucagon infusion induces early metabolic and renal phenotypes of Type 2 diabetes in mice by activating glucagon receptors. Five groups of adult male C57BL/6J mice were treated with vehicle, glucagon alone (1 μg/h via an osmotic minipump, intraperitoneally), glucagon plus the glucagon receptor antagonist [Des-His¹-Glu⁹]glucagon (5 μg/h via an osmotic minipump), [Des-His¹-Glu⁹]glucagon alone or a high glucose load alone (2% glucose in the drinking water) for 4 weeks. Glucagon infusion increased serum glucagon by 129% (PPPPPPP1-Glu⁹]glucagon with glucagon significantly attenuated glucagon-increased BP, fasting blood glucose, kidney weight/body weight ratio and 24 h urinary albumin excretion. [Des-His¹-Glu⁹]glucagon also improved glucagon-inpaired glucose tolerance, increased serum insulin by 56% (P1-Glu⁹]glucagon or high glucose administration alone did not elevate fasting blood glucose levels, impair glucose tolerance or induce renal injury. These results demonstrate for the first time that long-term hyperglucagonaemia in mice induces early metabolic and renal phenotypes of Type 2 diabetes by activating glucagon receptors. This supports the idea that glucagon receptor blockade may be beneficial in treating insulin resistance and Type 2 diabetic renal complications.