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

Abstract

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 (OX1R) 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. OX1R-immunoreactive nerves were observed in the pancreas of normal and diabetic Wistar rats. OX1R was also discernible in the pancreatic islets of normal and diabetic Wistar and GK rats, and wild type mice. OX1R co-localized with insulin (INS) and glucagon (GLU) in the pancreas of Wistar and GK rats. The number of OX1R-positive cells in the islets increased markedly (p<0.0001) after the onset of DM. The increase in the number of OX1R-positive cells is associated with a high degree of co-localization with GLU. The number of GLU- positive cells expressing OX1R was significantly (p<0.0001) higher after the onset of DM. The tissue level of OX1R 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-OX1R pathway in STZ-induced experimental diabetes.

Orexin A regulates plasma insulin and leptin levels in a time-dependent manner following a glucose load in mice

“…7. Previous studies have demonstrated that OXR1 is clearly expressed in pancreatic islets and beta cells of pigs, rats and mice [9][10][11]. Here, we showed that OXA influenced insulin secretion in pancreatic islets through OXR1, but not OXR2.…”

“…OXRs have been demonstrated not only in central neurons but also in some peripheral endocrine cells. Recent studies have demonstrated that OXR1 is expressed in the pancreatic alpha and beta cells of pigs, rats and mice [9][10][11] and in human and rat adipocytes [12,13]. Therefore, it is likely that orexins contribute to important endocrine functions.…”

Enhanced Glucose Tolerance and Pancreatic Beta Cell Function by Low Dose Aspirin in Hyperglycemic Insulin-Resistant Type 2 Diabetic Goto-Kakizaki (GK) Rats

“…Localization of insulin and glucagon in pancreatic islets of control Wistar and GK rats was performed by a double-labeled immunofluorescence method as described by Adeghate et al [24]. Briefly, pancreatic tissue pieces were fixed overnight in Zamboni's solution, dehydrated in graded concentration of ethanol, cleared using xylene and embedded in paraffin wax at 55°C.…”

Immunohistochemical expression and distribution of orexin, orphanin and leptin in the major salivary glands of some mammals

“…Therefore, these neuropeptides were con- www.fhc.viamedica.pl sidered to be exclusively expressed in the Central Nervous System (CNS) [14][15][16] and responsible for the central regulation of nutritional balance, relaying orexigenic effects after activation of their receptors Ox1R and Ox2R for the orexin, and ORL-1 for nociceptin/orphanin FQ [17,18]. Further immunohistochemical studies identified the presence of these neuropeptides in peripheral organs and tissues associated with the energy balance such as the gastrointestinal tract and pancreas [19][20][21][22].…”