Role of Gut Hormones in Diabetes Mellitus an Update

Abstract

Diabetes mellitus is a lifestyle-disease involving a group of metabolic disorders characterized by hyperglycemia. The etiology involves direct or indirect deficiency of insulin hormone, either because of impaired insulin secretion, impaired insulin action, or both. Diabetes mellitus is a major contributor to mortality worldwide. It is dreaded for the various microvascular and macrovascular complications it brings. The microvascular complications include neuropathy, nephropathy and retinopathy while the macrovascular complications include stroke, peripheral vascular disease and cardiovascular disease. The prevalence of Type-2 diabetes mellitus is steadily rising globally, and it has become a serious health concern [1]. Over the past decade, an important development is in the evolving concept on the role of gut hormones in diabetes mellitus and their potential roles in diabetic therapy. The gut hormones are a group of hormones secreted by entero-endocrine cells in the stomach, pancreas and small intestine that control digestion of food (Fig. 1). Gastrointestinal (GIT) hormones are proteinaceous in nature and are extensively linked to glucose tolerance and glycemic control in human body. Fig. 1.: Schematic representation of GIT hormones and its functions. Gut hormones are regulated by the autonomous nervous system. They transmit information about the metabolic state of the stomach (food intake, hunger, and nutrient composition) to the brain. The functions of gut hormone secretion, and tissue-specific hormone sensitivity are subsequently controlled by regulation of the complex brain pathways [2]. The gut-brain axis is an essential regulator of energy metabolism and hyperglycaemia. Majority of these gut hormones is involved in this axis to augment the response of pancreatic insulin to hyperglycaemia and form the entero-insular axis. The hormones involved in this axis form the potential pharmacotherapeutic targets to increase insulin secretion. These agents stand as valuable addition to the pharmacological armamentarium in treating diabetes mellitus [3]. Gut hormones which are involved in this axis include Incretins (GIP, GLP-1) Cholecystokinin (CCK), Gastrin, peptide YY, and Insulin-like peptide 5 (INSL-5). The gastric inhibitory polypeptide (GIP) is a 42 amino acid polypeptide which was discovered in 1969. It is secreted from the proximal intestine K cells (duodenum and jejunum), it is also expressed predominantly in the stomach. GIP is an important component of the entero-insular axis responsible for the incretin effect of enhanced insulin response on oral glucose load over intravenous glucose. GIP leads to increase in insulin levels in response to meals. It mediates elevation of intracellular cyclic AMP concentrations and Inhibits ATP-sensitive potassium channel on beta cells. Proglucagon undergoes alternative cleavage to produce glucagon-like peptide-1 (GLP-1), which is primarily secreted by L-neuroendocrine cells in distal small intestine in response to food consumption [4]. A complex neuroendocrine loop that includes the enteric nervous system, afferent and efferent vagus nerves, bile acid receptors, and taste receptors directly sense luminal nutrients and control secretion of GLP-1 [5,6]. GLP-1 also contributes to the incretin effect similar to GIP. It also works by increasing cyclic AMP levels by stimulating beta cells to secrete insulin promoting proliferation and resistance. The enteroendocrine cells (I cells) which situated near the k-cells, release GIP in the duodenum and proximal jejunum, while those adjacent to L-cells release GLP-1 in the distal part of the enteric glands. CCK however is secrted by both enteroendocrine cells and neurons; and exhibits a immediate effect on gastric emptying. CCK is released after a meal in response to nutrient's fat and protein [7], and the vagal afferents then send a signal to the central brain to reduce appetite. CCK lowers glucose production and increases insulin secretion. Gastrin induces islet neogenesis and promotes regeneration of beta cells. Dipeptidyl peptidase-4 (DPP-4), often termed as T-cell antigen CD26, is a key enzyme which regulates the biological activity of GLP-1. It, therefore, has been exploited as a pharmacological target through DPP-4 inhibitors like Sitagliptin [8]. Ghrelin is secreted as pro-hormone by P/D1 closed-type cells in gastric fundus. For it to act on its own receptors, the growth hormone secretagogue receptor (GHSR 1a) must be cleaved and post-transcriptionally acylated by the enzyme ghrelin O acyltransferase (GOAT) [9]. Ghrelin's orexigenic activity in the hypothalamus is regulated by NPY [10]. During fasting and in diseases such as cachexia and anorexia nervosa, ghrelin plasma levels are raised. Plasmatic ghrelin is decreased in obesity, insulin resistance, type 2 diabetes, and hypertension [11]. Ghrelin is thought to be an important regulator of glycaemic homeostasis because it increases the secretory response of GLP-1 to foods. Plasmatic ghrelin executes its effect by priming target cells to be ready to produce GLP-1 post-prandially. Ghrelin secretion peaks during fasting. Additionally, ghrelin has been linked to anti-inflammatory activity and is involved in regulation of lipid metabolism and body composition. Furthermore, it also has antiapoptotic effects [12]. Enteroendocrine cells also secrete the peptide YY(PYY) in response to meals in the proximal and distal intestinal tract. PYY is produced in large quantities in the distal ileum toward the colon in comparison to GLP-1, which is more common in the proximal tract. Its release is regulated by responses to metabolites of the gut microbiota and neurohormonal control [13]. Two proteins, PYY 1–36 and PYY 3–36, are produced by the same gene, and cleaved by DPP4. Together with cholecystokinin and GLP1, they play a major part in the ‘ileal brake’ function, a local feedback signal that inhibits gastric emptying, pancreatic secretion, and intestinal mobility brought on by food intake [14] to slow the transit and enhance nutrient absorption in the upper gut. To exert its anorectic action, PYY uses Neuropeptide Y receptors (NPYs) found on enterocytes, myenteric, and submucosal neurons, afferent fibres, and in the central nervous system (CNS). PYY analogues due to dose-dependent toxicity (nausea and anorexia) have not been found effective. In fasting humans, PYY and BMI are inversely associated. Due to the distal position of enteroendocrine cells that secrete PYY, bariatric gastric surgery results in ten times more of this hormone being generated, as increased nutrition delivery to the distal gut directly stimulates L cells to release the hormone [15]. PYY does not have a clear metabolic effect to date, and PYY infusion in humans does not alter glycemic control, insulin, or glucagon levels. PYY is likely to be secreted through paracrine and brain pathways in physiological settings. The predominant neurohormone released from the large intestine is the insulin-like peptide 5 (INSL-5), which is co-secreted with GLP-1 and PYY by the colonic L enteroendocrine cells. Insulin-like peptide 5 (INSL-5) is co-stored into distinct compartments as opposed to the PPY and GLP-1 family and works in a similar manner. Its therapeutic potential is yet to be explored [16]. Gastrointestinal Hormones are extensively involved in glycaemic control of the body which associates them tightly with the disease process of diabetes mellitus. Sub-optimal glycaemic control can contribute greatly to the morbidity and mortality of diabetic mellitus. Thus, the recent inclusions in the understanding of the patho-mechanisms of this gut-brain axis and the hormones involved can be leveraged upon to therapeutical usage for enhancing glycaemic control, thus achieving better treatment outcomes.