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 microg/h via an osmotic minipump, intraperitoneally),
glucagon plus the
glucagon receptor antagonist [Des-His(1)-Glu(9)]
glucagon (5 microg/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-signal-regulated 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
glucagon-inpaired
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.