Glucose entrainment of high-frequency plasma insulin oscillations in control and type 2 diabetic subjects.

Abstract

Regular high-frequency oscillations of insulin secretion are characteristic of normal beta-cell function. These oscillations are easily entrainable to an exogenous rhythm by small changes in glucose concentration in vitro. We tested whether high-frequency insulin oscillations in vivo would also be entrainable by glucose and whether a lack of entrainment would characterize the diabetic beta-cell. We tested 13 control subjects and 11 patients with type 2 diabetes. Subjects underwent serial blood sampling at 1-min intervals for 60-120 min in the basal state or with small (15 mg/kg) boluses of glucose injected intravenously at exact 29-min intervals. Time series analysis was carried out using spectral analysis. Oscillations of basal plasma glucose concentrations were observed in both control and type 2 diabetic subjects, with a mean period of 11.3 +/- 3.1 and 11.6 +/- 2.0 min, respectively. These oscillations were entrained to mean periods of 15.0 +/- 0.6 and 14.2 +/- 0.9 min, respectively, by exogenous glucose. Regular high-frequency insulin oscillations were observed in control subjects; the mean period of basal plasma insulin oscillations was 10.7 +/- 1.2 min and was entrained to exogenously injected glucose, with a period of 15.2 +/- 0.1 min. In contrast, in the type 2 diabetic subjects, spontaneous insulin oscillations were unchanged by the glucose rhythm; the mean periods were 10.0 +/- 1.0 min during the basal period, and 10.1 +/- 0.0 min during glucose injections. These results demonstrate that spontaneous high-frequency insulin oscillations can be successfully entrained by glucose in control subjects. However, these oscillations in type 2 diabetic subjects are not similarly entrained. We conclude that loss of entrainment of spontaneous high-frequency insulin oscillations in type 2 diabetes is a highly sensitive manifestation of beta-cell secretory dysfunction.

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

“…In contrast, literature on glucose entrainment of high-frequency insulin pulsatility in humans is limited. In a recent study, we evaluated the present model in healthy humans (17), but another study has lately examined glucose entrainment of rapid insulin pulsatility in type 2 diabetes (27). In line with our observations, the latter report demonstrated a diminished ability of glucose to entrain high-frequency insulin secretion in type 2 diabetes.…”

“…In line with our observations, the latter report demonstrated a diminished ability of glucose to entrain high-frequency insulin secretion in type 2 diabetes. However, clear differences emerge between the study of Mao et al (27) and the current analysis in terms of design and results. First, in the former study, 15 mg/kg glucose was injected every 29 min, whereas we sought to mimic physiological glucose excursions more closely by injecting smaller amounts of glucose (6 mg/kg) even more frequently (every 10 min).…”

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.…”

The in vivo regulation of pulsatile insulin secretion

“…In vitro studies on rapid entrainment show that even the rapid pulsatile insulin secretion could be induced by a rapid oscillatory glucose infusion in the isolated perfused rat pancreas [39], and in the isolated rat islets [102]. In vivo, a similar ability of punctuate glucose infusions to control pulsatile insulin secretion has been reported [145,146]. Studies using square wave infusions of modest doses of glucose (6 mg/kg/min over 1 min) could induce a very pronounced pulsatile insulin release, with little or no breakthrough insulin secretion.…”

“…The top panels show concentrations and best fit curves from deconvolution, whereas the bottom panels show calculated secretory rates. Note the massive amplification of the insulin secretory burst amplitude, with no apparent change in frequency odical trivial glucose excursions have been shown to improve markedly the ability to separate abnormal pulsatile insulin release in Type II diabetic individuals from that of matched control subjects by both autocorrelation analysis, spectral analysis, approximate entropy [164] and by spectral analysis [145]. These findings support the use of more refined methods for the prediction of apparent beta-cell dysfunction in Type II diabetes mellitus and genetically predisposed individuals, where more simple insulin secretion tests have little predictive value when using first phase insulin secretion [165].…”