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

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.

Factors associated with improvement of fasting plasma glucose level by mealtime dosing of a rapid-acting insulin analog in type 2 diabetes.

This study investigated whether strict control of plasma glucose levels with mealtime dosing of a rapid-acting insulin analog improves early morning fasting plasma glucose (FPG) levels in patients with type 2 diabetes. A rapid-acting insulin analog was administered at each mealtime to 40 Japanese patients with type 2 diabetes whose existing antidiabetic medication was discontinued. Approximately one-half (52.5%) of the patients achieved a minimum early morning FPG levels achievable (nadir FPG) of <120mg/dL with mealtime dosing of a rapid-acting insulin analog alone; no basal insulin replacement was needed in these patients. Nadir FPG levels were independent of duration of diabetes, baseline body mass index (BMI) or glycemic control. All patients who had been treated with sulfonylureas needed basal insulin replacement. Low responses of insulin to glucagon and to arginine, and high response of glucagon to arginine may explain the failure to improve FPG levels with postprandial insulin replacement alone. In conclusion, approximately one-half of the patients with type 2 diabetes achieved appropriate control of FPG by rapid-acting insulin analog monotherapy. Basal insulin secretory defects in type 2 diabetes may be estimated by the responses of insulin to glucagon and to arginine and the response of glucagon to arginine. This study contributes to a better understanding of the pathophysiology contributing to the heterogeneity in the characteristics of insulin secretion in type 2 diabetes.