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A Dose-Response Study of Human Unacylated Ghrelin on Glycemia during Oral Glucose Tolerance Test in Patients with Type 2 Diabetes Mellitus.


- candidate number8390
- NTR NumberNTR2487
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR30-aug-2010
- Secondary IDsNL31332.078.10 CCMO
- Public TitleA Dose-Response Study of Human Unacylated Ghrelin on Glycemia during Oral Glucose Tolerance Test in Patients with Type 2 Diabetes Mellitus.
- Scientific TitleA Dose-Response Study of Human Unacylated Ghrelin on Glycemia during Oral Glucose Tolerance Test in Patients with Type 2 Diabetes Mellitus.
- ACRONYM
- hypothesisUnacylated Ghrelin will improve insulin sensitivity.
- Healt Condition(s) or Problem(s) studiedDiabetes Mellitus Type 2 (DM type II), Insuline, Ghrelin
- Inclusion criteria1. Female or Male subject of 18 years of age or older;
2. Documented diagnosis of type 2 diabetes as defined by American Diabetes Association;
3. Diagnosis of type 2 diabetes for at least 3 months prior to screening;
4. Metformin monotherapy for at least 3 months prior to screening is allowed;
5. Screening HbA1c between 6.5% and 8.5%;
6. Body Mass Index between 25 and 35 kg/m2.
- Exclusion criteria1. History of or presence of active concomitant conditions or disease that would interfere with the protocol conduct and study assessments, as judged by the investigator;
2. History or presence of long-term type 2 diabetes complications;
3. Clinically significant abnormalities in laboratory evaluation at screening, as judged by the investigator;
4. Use of systemic corticosteroids within 60 days prior to screening;
5. If female, pregnancy or breast feeding;
6. Drug or alcohol dependence or abuse;
7. Participation in a trial of an experimental drug or device within 60 days prior to screening.
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingNone
- controlPlacebo
- groupCrossover
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-okt-2010
- planned closingdate31-dec-2010
- Target number of participants12
- InterventionsOvernight infusion of placebo, low and high dose UAG before an oral GTT the following morning.
- Primary outcomeChange in glucose levels.
- Secondary outcomeChange in insulin levels.
- TimepointsNo interim analyzes, final analyzes after study.
- Trial web siteN/A
- statusplanned
- CONTACT FOR PUBLIC QUERIESProf. dr. A.J. Lelij, van der
- CONTACT for SCIENTIFIC QUERIESProf. dr. A.J. Lelij, van der
- Sponsor/Initiator Erasmus Medical Center, Department of Internal Medicine
- Funding
(Source(s) of Monetary or Material Support)
Erasmus Medical Center
- PublicationsN/A
- Brief summaryGhrelin is a 28 aminoacid peptide that is naturally secreted by the stomach and circulates into 2 different forms: acylated ghrelin (AG), commonly referred to ghrelin, is acylated (octanoyl moiety) on the Serine in position 3, and unacylated ghrelin (UAG), also named un-octanoylated ghrelin, 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(1;3). Since unacylated ghrelin 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 is known to act on some of these systems, sometimes agonizing, sometimes antagonizing the effects of ghrelin. In particular, unacylated ghrelin has been shown able to prevent the hyperglycaemic effects of ghrelin, when administered concomitantly, in healthy volunteers. This initial observation was followed by several laboratory and clinical works documenting the anti-diabetogenic potential of unacylated ghrelin. In the Erasmus MC we performed already 2 studies with UAG; one in GH deficient patients and one in morbid obese subjects without overt diabetes. Both of these studies used single bolus i.v. administrations. Accumulated in vitro, in vivo and clinical evidence suggest that unacylated ghrelin:
1. Prevents the diabetogenic effects of acylated ghrelin: this has been evidenced in healthy volunteers(5) and in GH-deficient patients;
2. Inhibits both basal and ghrelin-induced glycogenolysis by human hepatocytes;
3. In vitro, stimulates insulin secretion from insulinoma cells and promote proliferation and inhibit apoptosis of beta cells, a very unique property;
4. Enhances portal insulin response to glucose in rats;
5. May also reduce fat deposition and triglycerides levels, as evidenced in transgenic mice overexpressing unacylated ghrelin.
Moreover, in collaboration with the University of Turin, we observed that a 16-hour continuous infusion of unacylated ghrelin in healthy volunteers increased the first-phase insulin response following meal, reduced glucose levels, and decreased FFA levels, when compared to a saline infusion. Also, preliminary data obtained by the same groups (unpublished data; study location Turin) in diet-controlled type 2 diabetes patients suggest that the continuous infusion of UAG for 5 hours reduced fasting and post-prandial glucose as well as postprandial FFA. 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. Finally, results of recent experiments by the group in Turin on circulating angiogenic cells (CAC) suggest that UAG may beneficially impact the vascular remodeling process which is known to be impaired in type 2 diabetes patients.
ABR-formulier 31332
https://toetsingonline.ccmo.nl/ccmomon.nsf/allabrs/31332-01#SectieK[21-05-2010 16:29:51].
From literature, we know that patients with so-called neuro-endocrine tumors sometimes produce large amounts of UAG, leading to serum concentrations of more than 0.1 mcg/ml). Strikingly these patients had no specific phenotype, nor complaints that suggest a direct role of UAG in these symptoms. Moreover, we have not observed any side-effects in any of the patients that we enrolled in previous study subjects. Taken together, our data strongly suggest that UAG might have a:
1. Broad safety range, as ultra-high serum levels donít induce specific signs or symptoms;
2. Blood glucose lowering effect;
3. Positive effect on the first phase post-prandial insulin secretion;
4. Insulin sensitizer, potentially with insulin-sparing effect;
5. Trophic effect on the endocrine pancreas;
6. Induces weight loss by preventing fat deposition;
7. Positive effect on the lipid profile, especially on triglycerides and free fatty acids.
- Main changes (audit trail)
- RECORD30-aug-2010 - 9-sep-2010


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