A role for PKD1 in insulin secretion downstream of P2Y receptor activation in mouse and human islets.

Along with insulin, β-cells co-secrete the neurotransmitter ATP which acts as a positive autocrine signal via P2Y receptors to activate phospholipase C and increase the production of diacylglycerol (DAG). However, the downstream signaling that couples P2Y activation to insulin secretion remains to be fully elucidated. Since DAG activates protein kinase D1 (PKD1) to potentiate glucose-stimulated insulin release, we hypothesized that autocrine ATP signaling activates downstream PKD1 to regulate insulin secretion.

A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes.

The secretion of insulin from pancreatic islet β-cells is critical for glucose homeostasis. Disrupted insulin secretion underlies almost all forms of diabetes, including the most common form, type 2 diabetes (T2D). The control of insulin secretion is complex and affected by circulating nutrients, neuronal inputs, and local signaling.

Autocrine activation of P2Y1 receptors couples Ca (2+) influx to Ca (2+) release in human pancreatic beta cells.

Aims/hypothesis: There is evidence that ATP acts as an autocrine signal in beta cells but the receptors and pathways involved are incompletely understood. Here we investigate the receptor subtype(s) and mechanism(s) mediating the effects of ATP on human beta cells.

Methods: We examined the effects of purinergic agonists and antagonists on membrane potential, membrane currents, intracellular Ca(2+) ([Ca(2+)]i) and insulin secretion in human beta cells.

SUMO1 enhances cAMP-dependent exocytosis and glucagon secretion from pancreatic α-cells.

Post-translational modification by the small ubiquitin-like modifier-1 (SUMO1) limits insulin secretion from β-cells by inhibiting insulin exocytosis and glucagon-like peptide-1 (GLP-1) receptor signalling. The secretion of glucagon from α-cells is regulated in a manner opposite to that of insulin; it is inhibited by elevated glucose and GLP-1, and increased by adrenergic signalling. We therefore sought to determine whether SUMO1 modulates mouse and human α-cell function.