Recurrent hypoglycemia dampens functional regulation mediated via Neurexin-1, Neuroligin-2 and Mint-1 docking proteins: Intensified complications during diabetes

Abstract

Glycemic regulation is important for maintaining critical physiological functions. Extreme variation in levels of circulating glucose are known to affect insulin secretion. Elevated insulin levels result in lowering of circulating glycemic levels culminating into hypoglycemia. Recurrence of hypoglycemia are often noted owing to fasting conditions, untimely meals, irregular dietary consumption, or as a side-effect of disease pathophysiology. Such events of hypoglycemia threaten to hamper the patterns of insulin secretion in diabetic condition. Insulin vesicle docking is a prerequisite phase which ensures anchoring of the vesicles to the β-cell membrane in order to expel the insulin cargo. Neurexin and Neuroligin are the marker docking proteins which assists in the tethering of the insulin granules to the secretory membrane. However, these cell adhesion molecules indirectly affect the glycemic levels by regulating insulin secretion. The effect of extreme levels of glycemic fluctuations on these molecules, and how it affects the docking machinery remains obscure. Our current study demonstrates down-regulated expression of Neurexin-1, Neuroligin-2 and Mint-1 molecules during hyperglycemia, hypoglycemia and diabetic hypoglycemia in rodents as well as for an in-vitro system using MIN6 cell-line. Studies with fluorescently labelled insulin revealed presence of lessened functional insulin secretory granules, concomitant with the alterations in morphology and as a result of hypoglycemia in control and diabetic condition which was found to be further deteriorating. Our studies indicate towards a feeble vesicular anchorage, which may partly be responsible for dwindled insulin secretion during diabetes. However, hypoglycemia poses as a potent diabetic complication in further deteriorating the docking machinery. To the best of our knowledge this is the first report which demonstrates the effect of hypoglycemic events in affecting insulin secretion by weakening insulin vesicular anchorage in normal and diabetic individuals.