Loss of Early Phase of Insulin Release in Humans Impairs Glucose Tolerance and Blunts Thermic Effect of Glucose

Abstract

Loss of the early phase of insulin release has been documented in both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes; however, the physiological importanceof this loss is unsettled. We created a model of loss of the early phase of insulin release in normal volunteers. Somatostatin (SRIF) was briefly infused (from −5 to 15 min) during intravenous (IVGTT) and oral (OGTT) glucose tolerance tests. The thermic response to oral glucose was determined under these conditions by indirect calorimetry. Early insulin release was totally blocked during IVGTT and OGTT by SRIF infusion. During the IVGTT, glucose tolerance was deteriorated in association with loss of the early phase of insulin release as indicated by a decrease in the K value (control 1.9 ± 0.36 vs. SRIF 1.1 ± 0.27, P < .001). Higher plasma glucose concentrations were observed during SRIF tests in the OGTT at 60, 90, 120, 150, and 180 min; total glycemic excursion was larger during the SRIF test (9473 ± 3089 mg · dl−1 · 5 h−1) when compared with the control condition (6583 ± 2329 mg dl−1 5 h−1). During the OGTT the total amount of glucose oxidized (control 56 ± 4.2 vs. SRIF 55 ± 3.4 g/5 h) was similar in both conditions, suggesting that nonoxidative pathways of glucose disposal were responsible for the deterioration in glucose tolerance. Surprisingly, we found that glucose-induced thermogenesis was reduced in association with loss of the early phase of insulin release (control 102 ± 21.3 vs. SRIF 72 ± 27.8 J/5 h, P < .001). Thus, loss of the early phase of insulin release is associated with deterioration of glucose tolerance and blunted glucose-induced thermogenesis. These data underscore the key role of the early phase of insulin release in glucose homeostasis and provide a possible mechanism that could lead eventually to obesity and diabetes.