Diabetes Mellitus and its Relation with Ghrelin-A Mini- Review

Mini Review

Austin J Endocrinol Diabetes. 2016; 3(2): 1044.

Diabetes Mellitus and its Relation with Ghrelin-A Mini- Review

De A1* and Singh MF2

1Department of Pharmaceutical Technology, Bengal School of Technology, India

2Department of Pharmaceutical Science, Sardar Bhagwan Singh Post Graduate Institute of Biomedical Science and Research, India

*Corresponding author: AAbhijit De, Department of Pharmaceutical Technology, Bengal School of Technology, Sugandha, Hooghly, Westbengal, India

Received: June 29, 2016; Accepted: July 29, 2016; Published: August 05, 2016l

Abstract

Diabetes Mellitus is a metabolic disorder associated with abnormal glucose and insulin resistance. In type 1 diabetes, insulin cannot be synthesized by the pancreas to maintain glycemic condition and in type 2 normal production of insulin hormone occurs but the body cells are resistant to insulin, a condition in which cells fail to use insulin properly or sometimes combined with an absolute insulin deficiency. Diabetic condition is directly related to endocrinological parameters. Elevated level of various hormones has been accounted in this disorder. The recent area of interest has been grown behind the relationship between ghrelin and diabetes mellitus. Ghrelin hormone is synthesized mainly in the gastric oxyntic mucosa in the X/A cells and of intestine, pancreas, kidney, placenta, lymphatics, gonads, adrenal, thyroid gland, heart, lung, pituitary, hypothalamus, eye, human B- and T-lymphocytes, neutrophils, morula, blastocyts and embryos. Ghrelin acts on the Growth Hormone Secretogogue Receptor (GHSR) activate phospholipase C to generate IP3 and diacylglycerol, resulting in an increase of intracellular calcium ion. Various researches have been recorded that ghrelin is diabetogenic as it possesses a negative effect on the insulin secretion from islet β cells. Ghrelin stimulates glucose synthesis andoutput from hepatocytes and hampers insulin’s capacity to inhibit endogenous glucose production. Moreover the recently discovered Uncoupling Protein-2 (UCP2) expression contributes a new concept behind the role of ghrelin in type 2 diabetes. Ghrelin also induces the expression of IA- 2β, a β cell auto antigen for type 1 diabetes, which is an integral membrane glycoprotein expressed in neuro-endocrinetissues.

Keywords: Diabetes; Ghrelin; Oxyntic mucosa; Growth Hormone Secretagogue Receptor; Uncoupling protein-2

Background of Diabetes Mellitus

Diabetes Mellitus is associated with altered carbohydrate metabolism and insulin resistance. It is a group of metabolic disorders in which a person gains high blood glucose either due to the less production of insulin by body or due to the unresponsiveness of the cells for the insulin that is produced by the pancreas. This result in high blood sugar with some classical symptoms like polyuria i.e, frequent urination, polydipsia (increased thirst) and polyphagia (increased hunger) [1]. Type 1 diabetes results from the body’s incapability to produce insulin either due to autoimmune or idiopathic destruction of cells. In type 1 diabetes, insulin cannot be synthesized by the pancreas to maintain glycemic condition. It is more common among children and young adults. To counteract this problem, insulininjections are used for treatment, hence type 1 diabetes is also termed as Insulin Dependent Diabetes Mellitus (IDDM) or Juvenile Diabetes [1,2]. In case of type II diabetes, there is normal production of insulin hormone but the body cells are resistant to insulin, a condition in which cells fail to use insulin properly, or sometimes combined with an absolute insulin deficiency. Cells and tissues are not responsive to insulin, so glucose remains elevated in the bloodstream. Type 2 diabetes is commonly manifested by middle-to-late-aged adults (40 years); however, its prevalence is increasing in younger populations. As insulin was initially not considered necessary for treatment of type 2 diabetes, it is known as Noninsulin Dependent Diabetes Mellitus (NIDDM) or Adult Onset Diabetes [1,3].

A diabetic patient cannot metabolize carbohydrates, proteins or fats due to improper production of insulin, a blood glucose regulator, or resistance to insulin. Insulin helps cells use glucose as a main energy source. However, diabetic patients’ cells do not make use of glucose from the blood due to abnormal insulin metabolism, resulting in elevated blood glucose levels or hyperglycemia. Over time, high glucose levels in the bloodstream can lead to severe complications such as vision loss, cardiovascular diseases, kidney disorder, and nerve damage [1-3].

The adipose tissue, however, is crucial in the normal regulation of the insulin action all over the body. Adipocytes can store excess lipids in obesity but when they become saturated, lipids begin to accumulate inside other organs, and tissues making them insulin resistant. Adipocytes also can produce adipokines such as leptin and adiponectin which have been proved as insulin sensitizers due to their ability to decrease Triglycerides (TG) synthesis, to stimulate beta oxidation of fatty acids, and thus to enhance insulin action in both skeletal muscle and liver [4-6]. Genetically modified animals deficient in white adipose tissue usually have severe insulin resistance in liver and muscle [7]. Transplantation of normal fat tissue into white adipose tissue deficient mice restores the insulin sensitivity. Mice with a knockout of the insulin receptor in muscle have normal glucose tolerance [8], whereas those with a knockout of the insulinsensitive GLUT4 glucose transporter in adipose tissue have impaired glucose tolerance, apparently due to insulin resistance being induced in muscle and liver [9].

Ghrelin and its receptors

In mammals, ghrelin homologs have been identified in human, rhesus monkey, rat, mouse and mongolian gerbil [10,11]. Ghrelin is an acylated, 28-amino-acid peptide that promotesthe release of GH in the hypothalamus. It is the naturalligand of the GHSR-1a receptor [12]. The ghrelin gene is located in chromosome 3 (3p25-26), contains four preproghrelin-coding exons, and encodes aprecursor of 117aa (preproghrelin) with 82% of homologybetween species [13]. Another form of ghrelin, des-acyl ghrelin, exists at significant levels in both stomach and blood. This variant lacks the octanoyl chain in serine 3 and represents more than 90% of the circulating peptide - [14-16]. In plasma, acyl ghrelin levels are 10–20 fmol/ml while total ghrelin levels are 100–150 fmol/ml (including both acyl and non-acyl forms) [17]. Ghrelin is the natural ligand of the Growth Hormone Secretagogue Receptor (GHS-R), and was first found to induce GH secretion in various species [15,16,18]. Ghrelin has been primarily detected in the A-cells of stomach, however, both ghrelin and the GHS-R are also expressed in a large spectrum of tissues including brain, kidney, pancreas, uterus and testis [19,20]. It was found that ghrelin is then only peripheral hormone which stimulates food intake by acting in hypothalamus and is involved in multiple endocrine and non-endocrine processes such as metabolic and cardiovascular effects, regulation of gastric motility and acid secretion, regulation of glucose metabolism and insulin secretion and modulation of cell proliferation [21,22]. During adult life ghrelin is synthesized mainly in the gastric oxyntic mucosa in the X/A cells. Ghrelin is also produced in the X/A cells of the intestine and in some others tissues such as the pancreas, kidney, placenta, lymphatics, gonads, adrenal, thyroid gland, heart, lung, pituitary, hypothalamus, eye [23], human B- and T-lymphocytes, neutrophils [23-25], morula, blastocyts and embryos [26]. In fetal life, ghrelin is mainly produced in the pancreas and lung [27]. The pancreas expresses ghrelin mRNA atmid-gestation being its mRNA levels six to seven times higher than in the fetal stomach [28]. In this period ghrelin’s production in the stomach is very low and only increases after birth [28]. In the fetal lung, this peptide is highly expressed after the pseudo glandular stage of the development [29,30].

Ghrelin receptor, or GHS-R, is a typical GPCR with seven transmembrane domains (7-TM) [31-33].Two distinct ghrelin receptor cDNAs have been isolated [31]. The first, GHS-R type 1a, encodes a 7-TM GPCR with binding and functional properties consistent with its role as ghrelin’s receptor. This type 1a receptor has features characteristic of a typical GPCR, including conservedcysteine residues in the first two extracellular loops, several potential sites for posttranslational modifications (N-linked glycosylation and phosphorylation), andan aromatic triplet sequence (E/DRY) located immediately after TM-3 in the second intracellular loop. Another GHS-R cDNA, type 1b, is produced by an alternative splicing mechanism [31]. The GHS-R geneconsists of two exons; the first exon encodes TM-1 to TM-5, and the second exon encodes TM-6 to TM-7. Type1b is derived from only the first exon and encodes only five of the seven predicted TM domains. The type 1breceptor is thus a COOH-terminal truncated form of thetype 1a receptor and is pharmacologically inactive. The GHS-R has several homologs, whose endogenousligands are gastrointestinal peptides or neuropeptides. The ghrelin receptor is most homologous to the motilin receptor; the human forms share 52% identical amino acids [34-36]. Ghrelin acts on the GHS-R and activates phospholipase C to generate IP3 and diacylglycerol, resulting in an increase of intracellular calcium ion, indicating that the ghrelin receptor is coupled to a Gq subunit as shown in Figure 1.