One of the he questions that remains to be answered to further elucidate the mechanism of action is whether ot not UAG improves insulin sensitivity during a euglycemis-hyperinsulinemic clampThis study aims to clarify the effects of the continuous…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Insulin levels
Secondary outcome
Not applicable
Background summary
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:
• prevents the diabetogenic effects of acylated ghrelin: this has been
evidenced in healthy volunteers(5) and in GH-deficient patients(6);
• inhibits both basal and ghrelin-induced glycogenolysis by human hepatocytes;
• in vitro, stimulates insulin secretion from insulinoma cells and promote
proliferation and inhibit apoptosis of beta cells, a very unique property;
• enhances portal insulin response to glucose in rats;
• 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 post-prandial 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.
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:
• broad safety range, as ultra-high serum levels don*t induce specific signs or
symptoms;
• blood glucose lowering 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.
Study objective
One of the he questions that remains to be answered to further elucidate the
mechanism of action is whether ot not UAG improves insulin sensitivity during a
euglycemis-hyperinsulinemic clamp
This study aims to clarify the effects of the continuous infusion of relative
low doses of UAG on the glucose and insulin response to an oral glucose load in
overweight patients with type 2 diabetes in poor metabolic control (HbA1c >
6.5%).
Study design
Single-blind, single-centre, investigator-initiated study
Intervention
Infusion of placebo or UAG during a euglycemic, hyperinsulinemic clamp
Study burden and risks
Because of the lack of side-effects in animals and human subjects during
administration of UAG sofar, the risks are considered to be low
Postbus 2040
3000 CA Rotterdam
NL
Postbus 2040
3000 CA Rotterdam
NL
Listed location countries
Age
Inclusion criteria
• Female or Male subject of 18 years of age or older;
• Documented diagnosis of type 2 diabetes as defined by American Diabetes Association;
• Diagnosis of type 2 diabetes for at least 3 months prior to screening;
• Metformin monotherapy for at least 3 months prior to screening is allowed
• Screening HbA1c between 6.5% and 8.5%;
• Body Mass Index between 25 and 35 kg/m2;
Exclusion criteria
• 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;
• History or presence of long-term type 2 diabetes complications;
• Clinically significant abnormalities in laboratory evaluation at screening, as judged by the investigator;
• Use of systemic corticosteroids within 60 days prior to screening;
• If female, pregnancy or breast feeding;
• Drug or alcohol dependence or abuse;
• Participation in a trial of an experimental drug or device within 60 days prior to screening; 30 days for subjects that pariticpated in the oGTT study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-019402-16-NL |
| CCMO | NL31349.078.10 |
| OMON | NL-OMON28343 |