Abstract
Pancreatic beta-cells are the only cells in the body that can synthesize and secrete insulin. Through the process of glucose-stimulated insulin secretion, beta-cells release insulin into circulation, stimulating GLUT4-dependent glucose uptake into peripheral tissue. Insulin is normally secreted in pulses that promote signaling at the liver. Long before type 2 diabetes is diagnosed, beta-cells become oversensitive to glucose, causing impaired pulsatility and overstimulation in fasting levels of glucose. The resulting hypersecretion of insulin can cause poor insulin signaling and clearance at the liver, leading to hyperinsulinemia and insulin resistance. Continued overactivity can eventually lead to beta-cell exhaustion and failure at which point type 2 diabetes begins. To prevent or reverse the negative effects of overstimulation, beta-cell activity can be reduced. Clinical studies have revealed the potential of beta-cell rest to reverse new cases of diabetes, but treatments lack durable benefits. In this perspective, we propose an intervention that reduces overactive glucokinase activity in the beta-cell. Glucokinase is known as the glucose sensor of the beta-cell due to its high control over insulin secretion. Therefore, glycolytic overactivity may be responsible for hyperinsulinemia early in the disease and can be reduced to restore normal stimulus-secretion coupling. We have previously reported that reducing glucokinase activity in prediabetic mouse islets can restore pulsatility and enhance insulin secretion. Building on this counterintuitive finding, we review the importance of pulsatile insulin secretion and highlight how normalizing glucose sensing in the beta cell during prediabetic hyperinsulinemia may restore pulsatility and improve glucose homeostasis.
Highlights
An important part of normal insulin secretion is proper glucose sensing; as blood glucose rises, insulin secretion needs to increase in a dose-dependent manner
While it is still up for debate if hyperinsulinemia or insulin resistance happens first in the pathogenesis of type 2 diabetes (T2D) [8,9,10,11,12], it is well-established that islets become hypersecretory before glycemic control is lost [13,14,15,16]
The gradual loss of pulsatile insulin secretion precedes the onset of T2D, with type 2 diabetics having no discernable pulses in insulin [21]
Summary
An important part of normal insulin secretion is proper glucose sensing; as blood glucose rises, insulin secretion needs to increase in a dose-dependent manner. Glucose sensing becomes aberrant and causes hyperinsulinemia along with the loss of pulsatile insulin secretion within its normal range of glucose stimulation [17,18,19,20]. Due to its ability to control insulin secretion, the sustained catalytic activation of GK in the beta cell has been proposed as a culprit for the increased sensitivity to glucose seen early in the disease [35, 36].
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