New insights into relationship between orexin and diabetes mellitus

New insights into relationship between orexin and diabetes mellitus
Amir Hossein Kheirkhah,^1,* Sanaz Raeisi,²
1. Master of Medical Biotechnology, Department of Genetics, Shahid Sadoughi University of Medical Sciences, Yazd
2. Master of Medical Biotechnology, Department of Genetics, Shahid Sadoughi University of Medical Sciences, Yazd
Introduction: Diabetes mellitus (DM) is one of the largest epidemics the world has faced, both in developed and developing nations. DM may be classified into type 1 (T1D) and type 2 (T2D). T1D results from an absolute deficiency of insulin due to autoimmune destruction of pancreatic b cells, while T2D is defined by impaired insulin secretion and increased insulin resistance. Orexins A and B are hypothalamic neuropeptides involved in regulating feeding behavior, sleep-wakefulness rhythm, and neuroendocrine homeostasis. Orexin-producing neurons are located in the lateral hypothalamic area (LHA), perifornical area (PF), and posterior hypothalamus. The orexin actions are mediated by two G-protein-coupled receptors, orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R) differentially distributed in the brain. Within the hypothalamus, OX1R mRNA is most abundant in the ventromedial hypothalamic nucleus (VMH), whereas OX2R is highly expressed in the tuberomammillary nucleus, paraventricular nucleus, arcuate nucleus (ARC), and LHA including PF. Orexin neurons can directly sense the nutritional status by responding to peripheral metabolic signals, such as glucose, leptin, and ghrelin. The expression of prepro-orexin mRNA is enhanced when blood glucose levels are low, and vice versa. On the other hand, orexin deficiency causes narcolepsy in humans, accompanied by an increased risk of obesity and type 2 diabetes. Therefore, considering the critical role of orexin in regulating blood sugar and its effects on diabetes, an attempt has been made to review this peptide hormone and its role in diabetes mellitus.
Methods: Orexin is involved in pancreatic hormone secretion. Therefore, It may be a modulator of insulin. Immunostaining of the human pancreas has shown that about two-thirds of insulin-immunopositive cells are contemporaneously positive for orexin. Peripheral orexin may originate from hypothalamus cells traveling through the blood-brain barrier or maybe produced peripherally by cells like the enterochromaffin cells of the intestines and pancreatic islet cells. The possible association of orexin with insulin resistance in type 2 diabetes mellitus (T2DM) has rarely been studied. Therefore, we attained to investigate the association between serum orexin concentrations and insulin resistance in type 2 diabetes mellitus.
Results: The previous studies found that Orexin-A (OXA) inhibits insulin secretion and stimulates glucagon secretion. In turn, others demonstrated that OXA exerts insulin secretion in vivo and in vitro; also, OXA lowered blood glucose level in mice with experimentally induced diabetes. An animal study showed that orexin receptor agonist protects against diet-induced obesity and the development of type 2 diabetes, whereas orexin-deficient mice were insulin-resistant. This evidence suggests that orexin signaling plays an important role in the development of high-fat-diet-induced insulin resistance and type 2 diabetes mellitus.
Conclusion: According to animal experiments, orexin has been shown to reduce blood glucose by stimulating insulin secretion from beta cells and reducing glucagon secretion, as well as a delayed but sustained increase in leptin levels. Orexin has also been shown to improve glucose intolerance through a direct effect on target organs such as adipose tissue in model mice. Therefore, changes in orexin secretion can affect blood sugar metabolism and directly or indirectly play a role in the development of diabetes mellitus. However, this issue needs further research in the future.
Keywords: Orexin, Diabetes mellitus, Insulin