Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

Abstract

Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and temporal pattern, has been understudied. Most of the insulin secreted from pancreatic beta cells of the pancreas is released in a pulsatile pattern, which is disrupted in T2DM. Here we review the evidence that changes in beta cell pulsatility occur during the progression from glucose intolerance to T2DM in humans, and contribute significantly to the etiology of the disease. We review the evidence that insulin pulsatility improves the efficacy of secreted insulin on its targets, particularly hepatic glucose production, but also examine evidence that pulsatility alters or is altered by changes in peripheral glucose uptake. Finally, we summarize our current understanding of the biophysical mechanisms responsible for oscillatory insulin secretion. Understanding how insulin pulsatility contributes to normal glucose homeostasis and is altered in metabolic disease states may help improve the treatment of T2DM.

Keywords: Diabetes; Insulin pulsatility; Insulin resistance; Islets; Oscillations.

FIG. 1

Oscillations in plasma insulin, C-peptide, and glucose measured in a peripheral vein in a fasted human subject. Dashed lines show unsmoothed data, continuous lines show three point moving averages of the data. Reprinted from [10] with permission of the New England Journal of Medicine.

FIG. 2

The time course of IRS-1 activation by insulin in liver of rats exposed to either full amplitude insulin pulses, diminished pulses (to mimic T2DM), or constant insulin for up to 10 minutes. After portal vein infusion of these insulin patterns, livers were biopsied and IRS-1 activation was analyzed by immunoprecipitation with IRS-1 antibody, followed by immunoblotting with pY or p85/PI3K antibodies. Full amplitude insulin pulses potentiated insulin signaling in the liver, as evidenced by increases in pY-IRS-1 and p85-IRS-1. Similar results were obtained for IRS-2 activation (not shown). Statistics were ANOVA followed by Fisher’s post hoc test; p<0.05 was deemed significant. Reprinted from [37] with permission of Diabetes.

FIG. 3

A model of the insulin receptor signaling pathway demonstrating that due to frictional resistance, insulin receptor signaling is potentiated by insulin applied in a pulsatile rather than continuous manner. As shown, negative feedback in the signaling pathway facilitates insulin pulse responses because frictional resistance is allowed to fade between applied pulses of insulin. Details are provided in the text.

FIG. 4

Glucose increases insulin pulse amplitude. A. Glucose ingestion (arrow) causes an increase in insulin secretory burst mass and frequency in the portal circulation of catheterized dogs (top left). The data from two representative dogs are shown. Deconvolution shows potentiation of insulin secretory pulse amplitude and frequency (top right), which are plotted for a total of 15 dogs in the lower part of the figure. Reprinted from [58] with permission of Diabetes. B. Insulin pulses in the portal circulation of human subjects (as well as in the periphery) are also increased in amplitude after glucose is increased. Samples taken during first 40 minutes of the experiment under basal conditions are shown on the left, while samples collected during the second 40 minutes of samples once hyperglycemia was established are shown on the right of the figure. Note the profound differences in scale of for the respective ordinates shown. Reprinted from [59] with permission of The Journal of Clinical Endocrinology and Metabolism.

FIG. 5

Three types of oscillations typically observed in islets. Top row of panels is from islet measurements of Ca²⁺. Middle row shows simulated Ca²⁺ oscillations using the Dual Oscillator Model (DOM). Bottom row shows simulations of the glycolytic intermediate fructose 1,6 bisphosphate (FBP), indicating that glycolysis is stationary (c) or oscillatory (f, i). Reprinted from [41] with permission of the American Journal of Physiology.

FIG. 6

The Metronome Hypothesis. A. Simulation obtained using a model of an isolated ‘compound bursting’ islet showing that increasing the plateau fraction of an islet Ca²⁺ oscillation as glucose is raised results in a dramatic increase in insulin pulse amplitude, but little or no change in oscillation frequency. Note that there was a small increase in the Ca²⁺ baseline as well. B. Simulation showing that increasing the duration of the islet Ca²⁺ oscillations in a slow islet lacking faster oscillations superimposed on the slower ones also results in potentiation of the insulin pulse amplitude, but no change in pulse frequency.

FIG. 7

Tolbutamide infused into the portal vein of three representative dogs results in increased insulin pulse amplitude (left hand side of the figure). Deconvolution of the data reveals that tolbutamide greatly increased the amplitudes of the insulin secretory rates. Tolbutamide infusion occurred from 40–110 minutes.