Diabetes, Ghrelin And Related Peptides: From Pathophysiology To Vasculopathy

Abstract

Ghrelin and obestatin are two different peptides originated from the same gene isolated in the stomach. Numerous actions have been described where these two peptides are implicated in metabolism, appetite regulation, glucose levels regulation, and a wide range of systemic effects. In this article, we summarize (1) the cellular receptors implicated in ghrelin and obestatin effects; (2) the role of ghrelin and obestatin in metabolism and appetite regulation; (3) their role in the glucose homeostasis regulation and its implication in diabetes patho-physiology; (5) the effects of ghrelin and obestatin in regulation of normal angiogenesis and (6) their possible role in the regulation of diabetes-induced pathologic angiogenesis.Keywords: Ghrelin, obestatin, diabetes pathophysiology, appetite regulation, peptides, diabetes vascular complications. GHRELINGhrelin is an acylated, 28-amino-acid peptide that promotes the release of GH in the hypothalamus. It is the natural ligand of the GHSR-1a receptor [1]. For it to act on the GHSR-1a ghrelin has an n-octanoic acid modification on serine 3 residue [2].The ghrelin gene is located in chromosome 3 (3p25-26) [1], contains four preproghrelin-coding exons, and encodes a precursor of 117aa (preproghrelin) with 82% of homology between species [3]. As a result of alternative splicing of this gene, a 27 aa acylated peptide was identified with the same activity potency as ghrelin (des-Gln14-ghrelin) [4]. 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 [2,4,5]. 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) [6,7]. Several minor forms of ghrelin were described with modifications on the peptide chain or on the acidic chain and are only present in low amounts [4,8]. Some of these are independently produced and regulated and their levels are not directly related to those of ghrelin [3]. Finally, in a posttranslational process, this gene can originate a 23 aa peptide named obestatin that has some different and even opposite actions than ghrelin [9].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, *Address correspondence to this author at the Department of Physiology, Faculty of Medicine, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Tel: +351 225513644; Fax: +351 225513646; E.mail: arsousa@med.up.pt # Both authors had the same contribution to the article gonads, adrenal, thyroid gland, heart, lung, pituitary, hypothalamus, eye [10], human B-and T-lymphocytes, neutrophils [1,[10][11][12], morula, blastocyts and embryos [13]. Ghelardoni observed that ghrelin gene expression and its protein were, in some tissues, dissociated [14].In fetal lif...

Study of the effects of the ghrelin-associated peptide obestatin on stress-related behaviors

“…Ghrelin is considered essential in maintaining glucose homeostasis during undernutrition, by activating gluconeogenic and/or growth hormone-regulated pathways (21). Howewer, it was also reported to negatively influence glucose homeostasis by inhibiting insulin secretion in the pancreatic β cells and increasing hepatic glucose production in normal feeding states or obesity (16,21,70). Furthermore, reduced plasma ghrelin levels were found in insulin-resistant conditions such as obesity, type 2 diabetes and hypertension (74).…”