Abnormal Patterns of Insulin Secretion in Non-Insulin-Dependent Diabetes Mellitus

Abstract

To determine whether non-insulin-dependent diabetes is associated with specific alterations in the pattern of insulin secretion, we studied 16 patients with untreated diabetes and 14 matched controls. The rates of insulin secretion were calculated from measurements of peripheral C-peptide in blood samples taken at 15- to 20-minute intervals during a 24-hour period in which the subjects ate three mixed meals. Incremental responses of insulin secretion to meals were significantly lower in the diabetic patients (P less than 0.005), and the increases and decreases in insulin secretion after meals were more sluggish. These disruptions in secretory response were more marked after dinner than after breakfast, and a clear secretory response to dinner often could not be identified. Both the control and diabetic subjects secreted insulin in a series of discrete pulses. In the controls, a total of seven to eight pulses were identified in the period from 9 a.m. to 11 p.m., including the three post-meal periods (an average frequency of one pulse per 105 to 120 minutes), and two to four pulses were identified in the remaining 10 hours. The number of pulses in the patients and controls did not differ significantly. However, in the patients, the pulses after meals had a smaller amplitude (P less than 0.03) and were less frequently concomitant with a glucose pulse (54.7 +/- 4.9 vs. 82.2 +/- 5.0, P less than 0.001). Pulses also appeared less regularly in the patients. During glucose clamping to produce hyperglycemia (glucose level, 16.7 mmol per liter [300 mg per deciliter]), the diabetic subjects secreted, on the average, 70 percent less insulin than matched controls (P less than 0.001). These data suggest that profound alterations in the amount and temporal organization of stimulated insulin secretion may be important in the pathophysiology of beta-cell dysfunction in diabetes.

Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

“…19-21 These Ca 2+ oscillations drive pulsatile insulin release 22 – a secretory pattern that enhances hepatic insulin action, 23 protects against insulin resistance, 24 and is lost in T2DM. 25-28 To understand how these Ca 2+ oscillations become defective in T2DM, it is important to first understand how an islet generates and maintains these oscillations.…”

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia

“…By restoring a more physiologic insulin profile, nateglinide is more effective than repaglinide in controlling prandial glucose excursions with less hyperinsulinaemia. It has been shown convincingly that in Type 2 (noninsulin-dependent) diabetes mellitus [1,2] and even in precursors thereof [3] the kinetics of insulin secretion are disrupted despite the existence of absolute (if not relative) hyperinsulinaemia. The disrupted insulin secretory kinetics can be confirmed by either the absence of the acute insulin response to i.v.…”

Insulin expressed from endogenously active glucose-responsive EGR1 promoter in bone marrow mesenchymal stromal cells as diabetes therapy

“…32 In fact, the response time of our modified cells to high glucose challenge closely mimics pancreatic response to a mixed meal challenge in normal human subjects. 33 Furthermore, clinically acceptable glycemic control was achieved in diabetic recipients of pancreas allografts or islet transplants despite abnormal insulin secretion kinetics. 34,35 Indeed, recent data from the NIDDK and JDRF-funded Collaborative Islet Transplant Registry showed that 31-53% of a total of 325 adult recipients of islet transplants suffered severe hypoglycemic episodes.…”