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-His 1 -Glu 9 ]glucagon (5 μg/h via an osmotic minipump), [Des-His 1 -Glu 9 ]glucagon alone or a high glucose load alone (2 % glucose in the drinking water) for 4 weeks. Glucagon infusion increased serum glucagon by 129 % (P < 0.05), raised systolic BP (blood pressure) by 21 mmHg (P < 0.01), elevated fasting blood glucose by 42 % (P < 0.01), impaired glucose tolerance (P < 0.01), increased the kidney weight/body weight ratio (P < 0.05) and 24 h urinary albumin excretion by 108 % (P < 0.01) and induced glomerular mesangial expansion and extracellular matrix deposition. These responses were associated with marked increases in phosphorylated ERK1/2 (extracellular-signalregulated kinase 1/2) and Akt signalling proteins in the liver and kidney (P < 0.01). Serum insulin did not increase proportionally. Concurrent administration of [Des-His 1 -Glu 9 ]glucagon with glucagon significantly attenuated glucagon-increased BP, fasting blood glucose, kidney weight/body weight ratio and 24 h urinary albumin excretion. [Des-His 1 -Glu 9 ]glucagon also improved glucagoninpaired glucose tolerance, increased serum insulin by 56 % (P < 0.05) and attenuated glomerular injury. However, [Des-His 1 -Glu 9 ]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.

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

“…The specific control of glucagon secretion by pharmacological modulation is complex since several components of the a-cell stimulus-secretion coupling are also present in b-and d-cells. Thus, the manipulation of glucagon action by modulating the glucagon receptor signalling seems to be an effective alternative (Li et al 2008). This strategy has been supported by several studies.…”

“…At present, there exists multiple clinical and experimental evidence that support this hypothesis. The rate of hepatic glucose output has been correlated with the hyperglycaemia found in animal models of diabetes as well as in human diabetes, and the maintenance of this abnormality has also been associated with hyperglucagonaemia (Baron et al 1987, Consoli et al 1989, Gastaldelli et al 2000, Dunning & Gerich 2007, Li et al 2008. In type 2 diabetes, the impairment of insulin release and development of insulin resistance is often accompanied by absolute or relative increased levels of glucagon in the fasting and postprandial states (Reaven et al 1987, Larsson & Ahren 2000.…”

Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes

“…Although the role of glucagon in the control of renal glucose output remains uncertain, glucagon regulates the rate of kidney filtration, urea excretion, and water reabsorption by the kidney (26) via direct and indirect mechanisms (4). Paradoxically, long-term infusion of glucagon in mice leads to kidney injury through the development of hypertension, hypertrophy, and increased proliferation of mesangial cells (40). Although the Gcgr is also expressed in the gut, where it regulates motility (58, 69), very little is known about the physiological role of glucagon in the gut.…”

Targeting glucagon receptor signalling in treating metabolic syndrome and renal injury in Type 2 diabetes: theory versus promise

“…We have studied the interactions between glucagon and AngII or AngII receptor signalling in cultured rat mesangial cells as well as in glucagon-infused mice [48,49,58,59]. The findings suggest that hyperglucagonaemia may cause mesangial cell or glomerular injury by interacting with AngII/AT 1 receptor signalling [49,58,59].…”