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Ghrelin is a 28 aminoacid peptide that is naturally secreted by the stomach and circulates into 2 different forms:
- acylated ghrelin, commonly referred to ghrelin, is acylated (octanoyl moiety) on the Serine in position 3;
- unacylated ghrelin (AZP-01), also named un-octanoylated ghrelin is the ghrelin peptide devoid of the acylated moiety.
Ghrelin has been discovered in 1999 as the endogenous ligand of an orphan receptor (GHSR 1A) that had previously been identified as the receptor mediating the pharmacological effects of a new therapeutic class of compounds, the growth hormone secretagogues (GHS).
Ghrelin has been initially characterized for its property of inducing growth hormone (GH) secretion, hence its name, GH-relin, a function mediated by GHSR1a. Since unacylated ghrelin (AZP-01) does not bind to this receptor and has no physiological effect on GH secretion, it has long been considered as a product with no physiological role. As of today, the ghrelin system is known to exhibit numerous biological effects on the secretion of several pituitary hormones, on the gastric acid secretion and motility, on the exocrine and endocrine pancreatic function, on glucose metabolism, on appetite stimulation and on the cardio-vascular system. Unacylated ghrelin (AZP-01) is known to act on some of these systems, sometime agonizing, sometime antagonizing the effects of ghrelin.
Dr AJ Van der Lely (Erasmus Medical Center, Rotterdam) and Ezio Ghigo (University of Torino) were among the first to demonstrate that unacylated ghrelin (AZP-01) is not devoid of biological activity. Actually, they initially reported that ghrelin (in its acylated form) is hyperglycaemic in healthy volunteers (Broglio et al, 2001) and then showed that a co-administration of unacylated ghrelin prevented the hyperglycaemic effects of ghrelin (Broglio et al, 2004). This initial observation was followed by several laboratory and clinical works documenting the anti-diabetogenic potential of unacylated ghrelin.
Unacylated ghrelin, a 28 amino-acid peptide
Accumulated in vitro, in vivo and clinical evidence suggest that unacylated ghrelin (AZP-01):
- prevents the diabetogenic effects of acylated ghrelin: this has been evidenced in in healthy volunteers (Broglio et al, 2004) and in GH-deficient patients (Gauna et al; 2004);
- inhibits both basal and ghrelin-induced glycogenolysis by human hepatocytes (Gauna et al, 2005);
- in vitro, stimulates insulin secretion from insulinoma cells (Gauna et al, 2006) and promote proliferation and inhibit apoptosis of beta cells, a very unique property (Granata et al, 2006)
- enhances portal insulin response to glucose in rats (Gauna et al, 2007)
- may also reduce fat deposition and triglycerides levels, as evidenced in transgenic mice overexpressing unacylated ghrelin (AZP-01) (Asakawa et al, 2006)
At Endo 2007 in Toronto, clinical scientists from the University of Torino and from Erasmus University Medical Center presented data showing that, in healthy volunteers, a 16-hour continuous infusion of unacylated ghrelin (AZP-01) increased the first-phase insulin response following meal, reduced glucose levels, and decreased FFA levels, when compared to a saline infusion (Broglio F et al, 2007) 
In summary, converging in vitro, in vivo and clinical data indicate that UAG and its analogs may have a promising pharmacological and clinical profile as a potential drug for the treatment of T2DM:
- hypoglycaemic effect
- positive effect on the first phase post-prandial insulin secretion
- insulin sensitizer, potentially with insulin-sparing effect
- trophic effect on the endocrine pancreas
- induces weight loss by preventing fat deposition
- positive effect on the lipid profile, especially on triglycerides and free fatty acids
Should this profile be confirmed in controlled, long-term clinical studies in diabetic patients, it would create a new therapeutic class, with UAG being the first compound of this class for the treatment of T2DM. In addition, the proliferative and anti-apoptotic effects documented on beta cells, apparently a very unique property, support the rationale to also develop UAG in type 1 diabetes and in the pancreas islets transplantations.
Additional clinical and preclinical work is being conducted as part of the AZP-01 program as well as a Structure-Activity-Relationship and analogs design program.
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