Calcium Channel α2δ-1 Subunit Knockout Causes Diabetes Due to Impaired Insulin Release

Abstract

Pancreatic β-cells, the major cellular component of the island of Langerhans, are responsible for the synthesis of insulin and its secretion in response to elevated blood glucose. High voltage-gated calcium channels (HVCC) are intimately involved in excitation-secretion coupling in pancreatic islet cells and calcium entering through HVCC is an important regulator of insulin synthesis. HVCC are multi-subunit protein complexes comprised of the main pore-forming α1 subunit and auxiliary extracellular α2δ and intracellular β subunits. Here we show that genetic ablation of the α2δ-1 subunit (the main pancreatic α2δ isoform) results in the postnatal development of diabetes. Homozygous α2δ-1 KO mice show highly elevated urine production and develop ∼9-fold higher blood glucose levels compared to WT littermates. Morphological analysis of the pancreas shows a reduction in the number of islets and their size due to a dramatic decrease in β-cell mass in an age-dependant manner. The reduced β-cell mass is not caused by an islet-specific autoimmune reaction, but might result from prolonged hyperglycaemia toxicity. Voltage-clamp recording in dissociated pancreatic β-cells shows a more than two-fold decrease in calcium current amplitude. Glucose stimulated calcium oscillations in whole isolated pancreatic islets shows a strong decrease in amplitude of both the first and second phase of insulin release, and an increased oscillation frequency of the second phase. On-going pharmacological experiments will identify which pore-forming α1 subunits are primarily affected by α2δ-1 deletion and how this effects insulin secretion. These findings indicate that α2δ-1 is an important determinant of normal β-cell physiology, critical for insulin release. Support: FWF W1101, P23479, LFU-P7400-027-011.