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The Role of Melatonin in Diabetes: Therapeutic Implications

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The Role of Melatonin in Diabetes: Therapeutic Implications review The role of melatonin in diabetes: therapeutic implications Shweta Sharma1, Hemant Singh1, Nabeel Ahmad2, Priyanka Mishra1, Archana Tiwari1 ABSTRACT Melatonin referred as the hormone of darkness is mainly secreted by pineal gland, its levels being 1 School of Biotechnology, Rajiv elevated during night and low during the day. The effects of melatonin on insulin secretion are me- Gandhi Technical University, Gandhi diated through the melatonin receptors (MT1 and MT2). It decreases insulin secretion by inhibiting Nagar, Bhopal, Madhya Pradesh cAMP and cGMP pathways but activates the phospholipaseC/IP3 pathway, which mobilizes Ca2+ from 2 School of Biotechnology, organelles and, consequently increases insulin secretion. Both in vivo and in vitro, insulin secretion IFTM University, Lodhipur Rajput, Uttar Pradesh by the pancreatic islets in a circadian manner, is due to the melatonin action on the melatonin recep- tors inducing a phase shift in the cells. Melatonin may be involved in the genesis of diabetes as a Correspondence to: reduction in melatonin levels and a functional interrelationship between melatonin and insulin was Shweta Sharma School of Biotechnology observed in diabetic patients. Evidences from experimental studies proved that melatonin induces Rajiv Gandhi Technical University production of insulin growth factor and promotes insulin receptor tyrosine phosphorylation. The dis- Airport Bypass Road, Gandhi Nagar turbance of internal circadian system induces glucose intolerance and insulin resistance, which could 462036 – Bhopal, Madhya Pradesh [email protected] be restored by melatonin supplementation. Therefore, the presence of melatonin receptors on hu- man pancreatic islets may have an impact on pharmacotherapy of type 2 diabetes. Arch Endocrinol Metab. Received on June/8/2015 2015;59(5):391-9 Accepted on July/6/2015 DOI: 10.1590/2359-3997000000098 Keywords Melatonin; diabetes; insulin; beta cells; calcium; circadian rhythm INTRODUCTION tomy of rodents causes hyperinsulinemia (7). Moreo- ver, diabetes is coupled with lower melatonin levels as iabetes is an endocrine disease, consist of insu- reduction in serum melatonin and higher insulin level lin resistance, a diminished pancreatic beta-cell D is observed in type 2 diabetic Goto Kakizaki rats (6). function, abnormally high glucagon levels and a re- Genome-wide association studies has shown that spe- duced incretin effect (1). Diabetes is classified into cific single-nucleotide polymorphisms of the melatonin two main categories: type 1 (an autoimmune disease of receptor 2 (MTNR1B) locus is linked with an increased younger patients with a lack of insulin production caus- blood glucose concentration and type 2 diabetes (8-13). ing hyperglycemia) and type 2 (a metabolic disorder Melatonin can be able to bring anti-hyperglycemic resulting from the body’s inability to produce enough effect either by improving insulin sensitization or by or properly utilize insulin hence patients have hypergly- improvement of insulin secretion, or both. cemia). Changing lifestyle trends such as a tendency to nocturnality and intake of excessively rich diets, cause disturbance of the sleep/wake cycle along with other MELATONIN AND ITS FUNCTION circadian rhythms (2). Deviation in circadian patterns Melatonin is known as the hormone of darkness, is an favors the occurrence of diabetes (3). indoleamine with the chemical name N-acetyl-5-me- Inconsistent data have been reported concerning thoxytryptamine. Circulating plasma concentrations the effect of pineal hormone on the secretion of in- are secreted by the pineal gland. In mammals, the con- sulin, on blood glucose and carbohydrate metabolism. centration in plasma during night was found to be (80– Melatonin (N-acetyl-5-methoxytryptamine), a trypto- 100 pg/mL) and low levels during the day (10–20 pg/ phan derived small indolic molecule, is mainly secreted mL) (14). It maintains homeostasis in the body, helps by the pineal gland locally in several other tissues (4,5). adjust the timing or reinforces oscillations of the bio- Experimental evidences proposed the diurnal profiles logical clock (15). Its synthesis comprised of two steps, AE&M all rights reserved. of blood glucose due to melatonin and increased insu- initially the conversion of amino acid tryptophan into © lin levels in diabetic animals and humans (6). Pinealec- serotonin (5-hydroxytryptamine, 5-HT), further acety- Copyright Arch Endocrinol Metab. 2015;59/5 391 Melatonin and type 2 diabetes lation by arylalkylamine N-acetyltransferase (AA-NAT), the distal skin regions in persons with disrupted cir- the rate-limiting step in melatonin biosynthesis, before cadian rhythm as well as in healthy individuals, from finally being converted into melatonin by hydroxyin- younger children to old folk. (17); stabilize sleep-wake dole-O-methyltransferase (HIOMT) (16). Pinealo- cycles (18). Melatonin stimulates several antioxidative cytes in the pineal gland secrete melatonin. Figure 1 enzymes (19) and acts on bone metabolism (20). The illustrates melatonin secretion and signaling pathway hormone exerts its effects both through activation of through melatonin receptors in maintaining circadian its receptors (21), through the circulating levels of the rhythm within the cell. The pineal gland is activated hormone or in a more autocrine/paracrine fashion near or deactivated by light exposure to the eyes. During target tissues (22,23). In addition, melatonin brings the day, melatonin production is inhibited while at about vasoconstriction through the MT1 and vasodila- the night time, it is stimulated. When melatonin binds tion through the MT2 receptors (24). It lowers cortisol with melatonin receptors, it activates Gi and Gq proteins secretion (25) in the adrenal cortex, similar to the action which in turn inhibit adenylate cyclase/cAMP pathway shared with insulin (23). Moreover, human adipocytes, and activates phospholipase C/IP3 pathway respective- a major target tissue for insulin, express MT2 and have ly. Due to phosphorylating activity of protein kinases, been shown to reduce expression of the insulin-depen- CREB and MSK1 regulates expression of Clock genes dent glucose transporter, Glut4, after melatonin stimu- and thus maintain circadian rhythm. lation (26). It also stimulates glucose uptake in muscle Melatonin has several functions ranging from co- cells by phosphorylation of insulin receptor substrate-1 ordination of circadian activity, which is generally con- (IRS-1) through MT2 signaling (27). Hepatocytes ex- sidered as a sleep-promoting effect; melatonin admi- press MT2 receptors and melatonin injections elevated nistration induces hypothermic effect and heat loss via glucose release from the liver in mice (28). A B Figure 1. (A) Schematic representation of the melatonin secretion and signaling mechanism in maintaining circadian rhythm within the cell. MT1: melatonin receptor type 1A; MT2: melatonin receptor type 1B; Gi: guanine nucleotide binding protein (adenylate cyclase inhibitor); Gq: phospholipase C activator; AC: adenylate cyclase; PLC: phospholipase C; cAMP: cyclic adenosine monophosphate; DAG: diacyl glycerol; PKA: protein kinase A; PKC: protein AE&M all rights reserved. © kinase C; MSK1: MAPK signaling pathway; CREB: cyclic AMP responsive element binding protein; Clock genes include Per, Cry, Dec, Rev-erba, Bmal1, Copyright Clock, Dbp; --------> -indirect effect. (B) Graphical representation of variation in melatonin level at different time of the day. 392 Arch Endocrinol Metab. 2015;59/5 Melatonin and type 2 diabetes MELATONIN RECEPTORS AND ITS real-time RT-PCR (39,40). The results established the CLASSIFICATION role of a circadian pacemaker in the rat pancreas and the existence of a circadian oscillator within islets. In addi- Melatonin receptors belong to a family of receptors re- tion to the SCN, clock activities have been identified in ferred to as G protein coupled receptors (GPCR) (29). numerous peripheral tissues including the liver, white Melatonin mediates circadian rhythms and other physi- adipose tissue, and pancreas that control metabolic pro- ological functions via membrane receptors on the cell cesses (41,42). surface. Melatonin is considered as membrane-perme- Melatonin exerts its effect through melatonin recep- able substance owing to its chemical structure so it has both receptor-independent and receptor-dependent tors of different peripheral tissues, thus maintaining cir- effects. All of its cellular actions and effects are likely cadian rhythms. Likewise other physiological functions, transmitted via two known GPCR isoforms, denoted glucose metabolism is regulated by circadian system MT1 and MT2 previously known as Mel1a and Mel1b (43,44). In an experiment, study Clock mutant mice (30,31). The two receptors exhibit a high degree of showed lack of rhythmicity in the action of insulin, a homology (31). There are mainly two types of mela- condition which was reversible once the clock protein tonin receptors found in humans, melatonin receptor 1 was reintroduced (43). The removal of pancreatic Clock (MT1; MTNR1A) and melatonin receptor 2 (MT2; and Bmal1 in mice resulted in functional defects in in- MTNR1B), a third melatonin receptor supposed to ex- sulin secretion and decreases in islet size and survival, ist and has been identified that belong to the family of signifies a key role of peripheral clocks in the regulation quinone reductases (32). of glucose homeostasis (45). In this manner, melatonin The melatonin influences exocytosis of
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