Stimulus secretion coupling in pancreatic beta-cells

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Impaired insulin secretion is a key step in the pathogenesis of type 2 diabetes, along with inefficient use of insulin by target tissues. The two main components of secretion are calcium entry into pancreatic beta cells and triggering of insulin granule exocytosis by that calcium. We have modeled both components and their contributions to diabetes. We have focused mainly on the mechanisms of calcium oscillations over a range of periods, from seconds to minutes. The slower class of oscillations (5 - 10 minute period) is the main driver of pulsatile insulin concentration in the circulation, which has been shown to be optimal for the response of insulin-sensitive tissues, especially the liver. Details of the historical development of the model can be found in our reports from previous years and in a current review article (ref. #1). We call the resulting model the integrated oscillator model (IOM) to indicate that the oscillations result from the partnership of an electrical oscillator (EO) and a metabolic oscillator (MO). The electrical oscillator (EO) is based on negative feedback of calcium onto ion channels, directly onto calcium-activated potassium (K(Ca)) channels and indirectly onto ATP-dependent potassium (K(ATP)) channels because calcium reduces the ATP/ADP ratio. The metabolic oscillator (MO) is governed by positive feedback of fructose 1,6 bisphosphate (FBP) on the enzyme in glycolysis that produces it, phosphofructokinase (PFK). The MO communicates with the EO via the K(ATP) channels, which transduce the metabolic state of the cell (ATP/ADP ratio) into electrical depolarization. K(ATP) channels are of clinical significance as they are a target of insulin-stimulating drugs, such as the sulfonylureas tolbutamide and glyburide, the first class of oral medications developed for the treatment of Type 2 Diabetes. Severe gain-of-function mutations of K(ATP) are a major cause of neo-natal diabetes mellitus, whereas moderate gain-of-function mutations have been linked in genome-wide association studies (GWAS) to the milder but more common adult-onset form of diabetes, type 2 diabetes. Conversely, loss-of-function mutations of K(ATP) are a major cause of familial hyperinsulinism, a hereditary disease found in children in which beta cells are persistently electrically active and secrete insulin in the face of normal or low glucose, causing life-threatening hypoglycemia. Another major cause of hyperinsulinism is excessive activity of the enzyme glucokinase (GK), which also plays a key role in the DOM. Our history of work in this area over four decades resulted in an invitation to give a plenary lecture at the biannual meeting on Dynamical Systems hosted by the Society for Industrial and Applied Mathematics (June, 2023). The well-received talk led to a further invitation to write a short news article highlighting some of the key messages of the talk, including the role of mathematical modeling in solving problems of key biological and medical interest in insulin secretion and the role of these biological applications in generating new mathematical knowledge. Though it has had many successes, the IOM was challenged this year by new data and a proposal for a new model. The new model holds that the oscillations in calcium and insulin secretion result not from calcium entry through plasma membrane ion channels under the control of K(ATP) channels but from calcium release from the primary intracellular storage organelle, the endoplasmic reticulum (ER). Such calcium release based oscillations are found in other cell types, but we argued in Ref. #1 that this mechanism cannot account for the large body of experimental observations that have been made in beta cells and are well accounted for by the canonical calcium entry model. We showed further that the canonical model can in fact account for the new observations that were claimed to invalidate it. We argued that the new observations nonetheless have value because they draw attention to a previously underappreciated role of calcium release and related mechanisms to modulate the threshold level at which oscillations begin. This is of great physiological importance because the threshold divides the basal (fasting) regime where insulin secretion must be throttled down to avoid hypoglycemia from the post-prandial regime where insulin secretion must be promptly increased by an order of magnitude to effectively restrain the rise in glucose from ingested carbohydrates. The highly successful family of glucagon-like peptide 1 (GLP-1) receptor agonists for treating T2D work in part by mediating small downward shifts in the threshold.