Stimulus secretion coupling in pancreatic beta-cells

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Over the last few years we developed a comprehensive model for oscillations of membrane potential and calcium on time scales ranging from seconds to minutes, reviewed in Ref. # 2. The lead to corresponding oscillations of insulin secretion. The basic hypothesis of the model is that the faster (tens of seconds) oscillations stem from feedback of calcium onto ion channels, likely calcium-activated potassium (K(Ca)) channels and ATP-dependent potassium (K(ATP)) channels, whereas the slower (five minutes) oscillations stem from oscillations in metabolism. The latter are transduced into electrical oscillations via the K(ATP) channels. The latter, notably, are a first-line target of insulin-stimulating drugs, such as the sulfonylureas (tolbutamide, glyburide) used in the treatment of Type 2 Diabetes. In the current year, we have extended the model by fleshing out the description of the mitochondria (Ref. # 1). The latter are important as the main sites of ATP generation, and in our model act to amplify the oscillatory output of glycolysis. The mitochondria are also modulated by calcium, both upward, through activation of tri-carbolic acid (TCA) cycle enzymes and downward, through the effect of calcium entry to reduce the mitochondrial membrane potential, which provides the driving force for ATP synthesis. The extension allows the model to output, in addition to ATP and ADP as before, mitochondrial membrane potential and rates of NADH and oxygen consumption for comparison with experiment. As an application we used the model to respond to a challenge raised by experiments showing that blockade of calcium entry by the K(ATP) channel opener diazoxide abolished metabolic oscillations. The latter experiments were interpreted as evidence that the metabolic oscillations were secondary to calcium oscillations. We showed that that result is in fact compatible with glycolytic oscillations as the primary driver of metabolic oscillations and hence the calcium oscillations. The explanation is that cessation of calcium entry reduces the need for ATP to pump the calcium back out of the cell, which inhibits the main controlling enzyme of the glycolytic oscillations, phospho-fructo kinase (PFK).