Failure of physiological plasma glucose excursions to entrain high-frequency pulsatile insulin secretion in type 2 diabetes.

Abstract

Insulin is released in high-frequency pulsatile bursts at intervals of 6-13 min. Intrapancreatic mechanisms are assumed to coordinate pulsatile insulin release, but small oscillations in plasma glucose concentrations may contribute further. To gain additional insight into ␤-cell (patho)physiology, we explored the ability of repetitive small glucose infusions (6 mg/kg over 1 min every 10 min) to modify rapid pulsatile insulin secretion in 10 type 2 diabetic individuals (plasma glucose 9.3 ± 1.0 mmol/l, HbA 1c 7.9 ± 0.5%, mean ± SE) and 10 healthy subjects. All subjects were investigated twice in randomly assigned order: during saline and during glucose exposure. Blood was collected every minute for 90 min to create a plasma insulin concentration time-series for analysis using 3 complementary algorithms: namely, spectral analysis, autocorrelation analysis, and approximate entropy (ApEn). During saline infusion, none of the algorithms were able to discriminate between diabetic and control subjects (P > 0.20). During glucose entrainment, spectral density peaks (SP) and autocorrelation coefficients (AC) increased significantly (P < 0.001), and ApEn decreased (P < 0.01), indicating more regular insulin time-series in the healthy volunteers. However, no differences were observed in the diabetic individuals between the glucose and saline conditions. Even elevating the glucose infusion rate in the diabetic subjects to achieve comparable relative (and hence higher absolute) glucose excursions (~4.9%) failed to entrain pulsatile insulin secretion in this group. In conclusion, the present study demonstrates that failure to respond adequately with regular oscillatory insulin secretion to recurrent high-frequency and (near)-physiological glucose excursion is a manifest feature of ␤-cell malfunction in type 2 diabetes. Whether the model will be useful in unmasking subtle (possible prediabetic) defects in ␤-cell sensitivity to glucose drive remains to be determined.

Bedtime Administration of NN2211, a Long-Acting GLP-1 Derivative, Substantially Reduces Fasting and Postprandial Glycemia in Type 2 Diabetes

“…Repeated low-dose glucose injections have recently been demonstrated to enforce endogenous insulin pulsatility in healthy individuals but not in patients with type 2 diabetes (32,33). We therefore performed analysis for baseline as well as glucose-entrained insulin pulsatility.…”

Glucocorticoid induced insulin resistance impairs basal but not glucose entrained high-frequency insulin pulsatility in humans

“…Analyses were done on the residuals. This detrending method was used to preserve pulsatility with a periodicity near 10 min, which would be expected both spontaneously and after the glucose-entrainment protocol [20].…”

“…We therefore assessed baseline insulin pulsatility, as well as glucose-pulse-entrainment, a recently established method for in vivo pulsatility studies [16]. This method has been shown to enable the detection of beta-cell dysfunction in vitro [17,18] and in Type II diabetic patients [19,20].…”

Loss of beta-cell mass leads to a reduction of pulse mass with normal periodicity, regularity and entrainment of pulsatile insulin secretion in G�ttingen minipigs

“…glucose intolerance [7] and in glucose tolerant first-degree relatives of Type 2 diabetic patients [8]. Furthermore, glucose entrainment has been reported to improve the ability to detect abnormal insulin secretion in Type 2 diabetes [10]. The failure to show impairment of regularity suggests that loss of beta-cell mass might not be the cause of impaired pulsatility in Type 2 diabetes.…”

“…The recently introduced glucose pulse induction technique seems to further improve the sensitivity in detecting early defects in pulsatility in humans [10].…”