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 recent review article that details how the model developed through the work of ourselves and others over 40 years (PMID: 37802364). 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. Most research in this area has focused on responses to super-threshold glucose (8 - 15 mM), corresponding to post-prandial levels. However, pulsatile insulin secretion is also observed in sub-threshold glucose (< 5 mM), corresponding to basal or fasting conditions. At these low glucose levels, calcium entry is negligible. We therefore proposed in a 2020 paper (PMID: 35378996) that glycolytic oscillations were responsible for the pulses of insulin secretion. Their effect on secretion was attributed to the metabolic amplification factor or factors exported from the mitochondria. A prominent candidate is NAD(P)H, but definitive identification is lacking. A key prediction of the model is that metabolic oscillations in the absence of meaningful calcium oscillations should be observed in subthreshold glucose. Our experimental partners at the University of Michigan (laboratory of Les Satin) have obtained some evidence for oscillations in the ATP/ADP ratio that are not explained by calcium oscillations. The work continues, and a manuscript is in preparation.