XPR1 Mediates the Pancreatic β-Cell Phosphate Flush.

Glucose-stimulated insulin secretion is the hallmark of the pancreatic β-cell, a critical player in the regulation of blood glucose concentration. In 1974, the remarkable observation was made that an efflux of intracellular inorganic phosphate (P) accompanied the events of stimulated insulin secretion. The mechanism behind this "phosphate flush," its association with insulin secretion, and its regulation have since then remained a mystery.

Inositol pyrophosphates and Akt/PKB: Is the pancreatic β-cell the exception to the rule?

The inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP), is thought to negatively regulate the critical insulin signaling protein Akt/PKB. Knockdown of the IP-generating inositol hexakisphosphate kinase 1 (IP6K1) results in a concomitant increase in signaling through Akt/PKB in most cell types so far examined. Total in vivo knockout of IP6K1 is associated with a phenotype resistant to high-fat diet, due to enhanced Akt/PKB signaling in classic insulin regulated tissues, counteracting insulin resistance.

Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic β-cells.

Diphosphoinositol pentakisphosphate (IP) is critical for the exocytotic capacity of the pancreatic β-cell, but its regulation by the primary instigator of β-cell exocytosis, glucose, is unknown. The high K for ATP of the IP-generating enzymes, the inositol hexakisphosphate kinases (IP6K1 and 2) suggests that these enzymes might serve as metabolic sensors in insulin secreting β-cells and act as translators of disrupted metabolism in diabetes. We investigated this hypothesis and now show that glucose stimulation, which increases the ATP/ADP ratio, leads to an early rise in IP concentration in β-cells.

Protein kinase- and lipase inhibitors of inositide metabolism deplete IP indirectly in pancreatic β-cells: Off-target effects on cellular bioenergetics and direct effects on IP6K activity.

Inositol pyrophosphates have emerged as important regulators of many critical cellular processes from vesicle trafficking and cytoskeletal rearrangement to telomere length regulation and apoptosis. We have previously demonstrated that 5-di-phosphoinositol pentakisphosphate, IP, is at a high level in pancreatic β-cells and is important for insulin exocytosis. To better understand IP regulation in β-cells, we used an insulin secreting cell line, HIT-T15, to screen a number of different pharmacological inhibitors of inositide metabolism for their impact on cellular IP.

One-step purification of functional human and rat pancreatic alpha cells.

Pancreatic alpha cells contribute to glucose homeostasis by the regulated secretion of glucagon, which increases glycogenolysis and hepatic gluconeogenesis in response to hypoglycemia. Alterations of glucagon secretion are observed in diabetic patients and exacerbate the disease. The restricted availability of purified primary alpha cells has limited our understanding of their function in health and disease.