Orexin-1 Receptor Co-Localizes with Pancreatic Hormones in Islet Cells and Modulates the Outcome of Streptozotocin-Induced Diabetes Mellitus

Recent studies have shown that orexins play a critical role in the regulation of sleep/wake states, feeding behaviour, and reward processes. The exocrine and endocrine pancreas are involved in the regulation of food metabolism and energy balance. This function is deranged in diabetes mellitus. This study examined the pattern of distribution of orexin-1 receptor (OX(1)R) in the endocrine cells of the pancreas of normal and diabetic Wistar (a model of type 1 diabetes), Goto-Kakizaki (GK, a model of type 2 diabetes) rats and in orexin-deficient (OX(−/−)) and wild type mice. Diabetes mellitus (DM) was induced in Wistar rats and mice by streptozotocin (STZ). At different time points (12 h, 24 h, 4 weeks, 8 months and 15 months) after the induction of DM, pancreatic fragments of normal and diabetic rats were processed for immunohistochemistry and Western blotting. OX(1)R-immunoreactive nerves were observed in the pancreas of normal and diabetic Wistar rats. OX(1)R was also discernible in the pancreatic islets of normal and diabetic Wistar and GK rats, and wild type mice. OX(1)R co-localized with insulin (INS) and glucagon (GLU) in the pancreas of Wistar and GK rats. The number of OX(1)R-positive cells in the islets increased markedly (p<0.0001) after the onset of DM. The increase in the number of OX(1)R-positive cells is associated with a high degree of co-localization with GLU. The number of GLU- positive cells expressing OX(1)R was significantly (p<0.0001) higher after the onset of DM. The tissue level of OX(1)R protein increased with the duration of DM especially in type 1 diabetes where it co-localized with cleaved caspase 3 in islet cells. In comparison to STZ-treated wild type mice, STZ-treated OX(−/−) animals exhibited reduced hyperglycemia and handled glucose more efficiently in glucose tolerance test. The findings suggest an important role for the OX-OX(1)R pathway in STZ-induced experimental diabetes.