Possible role of alpha-cell insulin resistance in exaggerated glucagon responses to arginine in type 2 diabetes

Diabetes Care. 2007 Oct;30(10):2583-7. doi: 10.2337/dc07-0066. Epub 2007 Jul 20.


Objective: Inappropriate excessive secretion of glucagon, which contributes to postprandial hyperglycemia, is a novel target for the treatment of diabetes. In this study, we sought to determine the factors associated with exaggerated glucagon secretion in response to an arginine challenge in patients with type 1 and type 2 diabetes.

Research design and methods: Changes in circulating C-peptide immunoreactivity (CPR) and immunoreactive glucagon (IRG) after an arginine challenge were investigated in 35 patients with type 1 diabetes, 130 patients with type 2 diabetes, and 35 nondiabetic control subjects.

Results: No significant differences were found in the basal level and the area under the concentration-time curve (AUC) of IRG (AUC(IRG)) among type 1 and type 2 diabetic patients and nondiabetic subjects. However, there was an inverse correlation between the AUC(IRG) and the AUC of CPR (AUC(CPR)) for type 1 (r = -0.388, P = 0.023) and type 2 (r = 0.396, P < 0.0001) diabetic patients, whereas AUC(IRG) was not correlated with AUC(CPR) in nondiabetic subjects (r = -0.079, P = 0.655). In type 1 diabetic patients, the AUC(CPR) decreased and the AUC(IRG) increased with increasing disease duration. In type 2 diabetic patients, both AUC(IRG) and AUC(CPR) increased with increasing BMI, basal CPR level, and homeostasis model assessment of insulin resistance value.

Conclusions: Our findings suggest that the pathophysiology of the exaggerated glucagon response differs between type 1 and type 2 diabetes. Intraislet insulin deficiency and alpha-cell insulin resistance may be the primary contributors to this condition in type 1 and type 2 diabetes, respectively.

MeSH terms

  • Adult
  • Aged
  • Area Under Curve
  • Arginine / pharmacology*
  • Body Mass Index
  • Diabetes Mellitus, Type 1 / physiopathology*
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Female
  • Glucagon / blood
  • Glucagon / metabolism*
  • Humans
  • Insulin Resistance*
  • Insulin-Secreting Cells / physiology*
  • Japan
  • Male
  • Middle Aged
  • Reference Values


  • Glucagon
  • Arginine