Sequence of Cellular Events in Pancreatic Islets Leading to Impaired Insulin Secretion in Chronic Kidney Disease

Abstract

In chronic renal failure (CRF), a multitude of metabolic derangements occur in the pancreatic islets, resulting in impaired glucose-induced insulin secretion. These abnormalities include a rise in the basal level of cytosolic calcium ([Ca(2+)]i) in the islets, a decrease in their basal and stimulated adenosine triphosphate (ATP) and adenosine diphosphate (ADP) content, a reduction in the V(max) of Ca(2+) ATPase and Na(+)-K(+) ATPase, and an impaired glucose-induced calcium signal. The sequence of events that leads to these derangements and to the impairment in insulin secretion during the evolution of CRF has not been defined. This study examined this particular issue by measuring the metabolic profiles of pancreatic islets weekly during the evolution of CRF over a period of 6 weeks. The results showed that serum levels of parathyroid hormone (PTH) begin to rise during the first week of CRF. The V(max) of Ca(2+) ATPase and Na(+)-K(+) ATPase increased during weeks 1 to 3 of CRF but decreased to low levels thereafter. At week 3 of CRF, the basal level of [Ca(2+)]i began to rise, whereas basal and stimulated ATP and ADP content started to fall. Glucose-induced calcium signal, Δ[Ca(2+)]i, and insulin secretion became abnormally low between weeks 3 and 6 of CRF. The data obtained allow for the inference of the following formulation: as serum levels of PTH begin to rise, calcium entry into islets is augmented, which in turn will stimulate the activity of Ca(2+) ATPase and the Na(+)-Ca(2+) exchanger, and therefore, calcium extrusion out of the islets is increased. Thus, [Ca(2+)]i remains normal during the first 2 weeks of CRF. Activation of the Na(+)-Ca(2+) exchanger may result in accumulation of sodium in the islets, an event that would activate the Na(+)-K(+) ATPase. Because calcium entry is further augmented by the progressive rise in serum PTH levels, mitochondrial oxidation and ATP production would be reduced, resulting in lower ATP content. This fall in ATP causes a reduction in the V(max) of Ca(2+) ATPase and Na(+)-K(+) ATPase, and therefore calcium extrusion out of the islets is reduced; consequently, [Ca(2+)]i rises. With the decrease in ATP content and the rise in [Ca(2+)]i, glucose-induced insulin secretion is impaired because of alterations in the closure of ATP-dependent potassium channels and reduction in the glucose-induced calcium signal (Δ[Ca(2+)])i.