Acute Regulation of Intestinal and Hepatic Lipoprotein Production by Glucagon
Information source: University Health Network, Toronto
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Diabetes
Intervention: glucagon (Drug)
Phase: Phase 4
Status: Completed
Sponsored by: University Health Network, Toronto Official(s) and/or principal investigator(s): Gary F Lewis, MD, Principal Investigator, Affiliation: University Health Network, Toronto General Hospital
Summary
Insulin resistant states are characterized by hepatic lipoprotein (VLDL) particle
overproduction. Numerous hormonal and nutritional factors are known to influence hepatic
lipoprotein particle production, including insulin and free fatty acids (FFA). In contrast
to the liver, the intestine has traditionally been viewed as a 'passive' organ with respect
to lipoprotein production, with intestinal lipoprotein particle production determined mainly
by the amount of fat ingested and absorbed. Glucagon plays a key role in the regulation of
carbohydrate and fatty acid metabolism and has recently been shown for the first time to
regulate hepatic lipoprotein production in mice. Ours will be the first study to
investigate the effect of glucagon on hepatic and intestinal lipoprotein production in
humans.
Clinical Details
Official title: Acute Regulation of Intestinal and Hepatic Lipoprotein Production by Glucagon
Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Diagnostic
Secondary outcome: The subject will be in a steady fed state and lipoprotein kinetics will be assessed.
Detailed description:
Potential role of glucagon in intestinal and hepatic lipoprotein production. Although
glucagon, the main hormone that opposes insulin action, is known to exert profound effects
on carbohydrate (stimulation of hepatic glucose production) and fatty acid metabolism
(stimulation of hepatic b-oxidation and ketogenesis), its potential role in the regulation
of lipoprotein metabolism has been largely overlooked and the mechanism whereby glucagon
modulates hepatic lipid metabolism in humans has not previously been examined. Longuet et
al recently showed that glucagon receptor (Gcgr) signaling is essential for control of
hepatic lipid homeostasis in mice (44). They showed that Gcgr-/- mice exhibit higher plasma
TG levels and increased hepatic TG production compared to littermate controls. Conversely,
glucagon administration to wildtype mice decreased hepatic lipid production and plasma TGs.
A combination of microarray and RealTime PCR analyses demonstrated that a period of fasting
increased the expression of genes regulating fatty acid b-oxidation in +/+ but not in
Gcgr-/- mice. Furthermore, exogenous glucagon administration mimicked the increase in
expression of enzymes involved in b-oxidation during fasting in +/+ mice. Enzymes involved
in fatty acid synthesis were not regulated by exogenous glucagon. Gcgr-/- mice were much
more susceptible to the accumulation of lipids in the liver, known to be associated with the
development of non-alcoholic steatohepatitis. To date, glucagon regulation of intestinal
lipoprotein production has not been examined in animals or humans.
There is convincing evidence from mouse studies that glucagon plays a major role in the
regulation of hepatic lipoprotein production and may also play a role in intestinal
lipoprotein assembly and secretion. Ours will be the first study to examine the role of
glucagon in hepatic and intestinal lipoprotein production in humans. Since inhibition of
glucagon receptor activity is currently being explored as a therapeutic approach for the
treatment of Type 2 diabetes, our study will provide important information regarding
potential implications of this therapeutic approach for control of lipid homeostasis and
general metabolic health.
Eligibility
Minimum age: 18 Years.
Maximum age: 40 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Men and women, aged 18 to 40 years
2. Body mass index 20 kg/m2 to 25 kg/m2
3. Hemoglobin above 130g/L.
4. Normal glucose tolerance in response to a 75g, 2-hr OGTT
Exclusion Criteria:
1. Subject has a history of hepatitis/hepatic disease that has been active within the
previous two years.
2. Any significant active (over the past 12 months) disease of the gastrointestinal,
pulmonary, neurological, renal (Cr > 1. 5 mg/dL), genitourinary, hematological
systems, or has severe uncontrolled treated or untreated hypertension (sitting
diastolic BP > 100 or systolic > 180) or proliferative retinopathy
3. Fasting blood glucose > 6. 0 mmol/l or known diabetes.
4. Any history of a MI or clinically significant, active, cardiovascular history
including a history of arrhythmia's or conduction delays on ECG, unstable angina, or
decompensated heart failure.
5. Any laboratory values: AST > 2x ULN; ALT > 2x ULN TSH > 6 mU/l
6. Current addiction to alcohol or substances of abuse as determined by the
investigator.
7. Mental incapacity, unwillingness or language barrier precluding adequate
understanding or cooperation
8. Taking any prescription or non-prescription medications at the time of the study
9. Having donated blood three months prior to and three months post study procedures
10. A pregnancy test will be performed 1 to 3 days prior to each study in all female
subjects. Those who test positive for pregnancy will be excluded.
Locations and Contacts
University Health Network, Toronto General Hospital, Toronto,, Ontario M5G 2C4, Canada
Additional Information
Starting date: June 2009
Last updated: June 29, 2010
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