Abnormal glucagon response to arginine and its normalization in obese hyperinsulinaemic patients with glucose intolerance: importance of insulin action on pancreatic Alpha cells

An excessive glucagon secretion to intravenous arginine infusion was found in obese hyperinsulinaemic patients with glucose intolerance. This study was designed to determine whether the glucagon hyperresponsiveness to arginine in these patients would improve by insulin infused at a high enough dose to overcome insulin resistance. By infusing high dose insulin during arginine infusion, the previously exaggerated glucagon response to arginine could be normalized. To normalize the abnormal glucagon response, insulin doses of 4.2±0.7 and 3.8±0.5 IU were required during arginine infusion in obese hyperinsulinaemic patients with impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetes mellitus, respectively. This achieved plasma peak insulin levels 3 to 4 times higher than those observed in non-obese healthy subjects. Furthermore, we clarified whether or not the effect of normalizing insulin action and/or glycaemic excursions contributed to normalizing the exaggerated glucagon response to arginine in these patients. Blood glucose was clamped while high dose insulin was infused at the same levels as observed during the arginine infusion test with no insulin infusion. As a result, normalization of the exaggerated plasma glucagon response was achieved, whether hyperglycaemia existed or not. These results clearly demonstrate that, similar to non-obese hypoinsulinaemic Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients, the exaggerated Alpha-cell response to arginine infusion in obese hyperinsulinaemic patients with glucose intolerance is secondary to the reduction of insulin action on the pancreatic Alpha cell, and that the expression of insulin action plays an important part in normalizing these abnormalities.