Acute Regulation of Intestinal and Hepatic Lipoprotein Production by Glucagon (Glucagon)
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|ClinicalTrials.gov Identifier: NCT01155206|
Recruitment Status : Completed
First Posted : July 1, 2010
Last Update Posted : December 2, 2015
|Condition or disease||Intervention/treatment||Phase|
|Diabetes||Drug: glucagon||Phase 4|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||9 participants|
|Intervention Model:||Crossover Assignment|
|Official Title:||Acute Regulation of Intestinal and Hepatic Lipoprotein Production by Glucagon|
|Study Start Date :||June 2009|
|Actual Primary Completion Date :||January 2010|
|Actual Study Completion Date :||January 2010|
Experimental: high glucagon
For one of the two studies to be performed in random order, the subject will receive an infusion of glucagon at a dose that has been shown to achieve high physiological plasma levels. The IV glucagon will be administered at a rate of 3ng/kg/min.
Other Name: glucagon 0.65ng/kg/min
Experimental: low glucagon
For one of the two studies to be performed in random order, the subject will receive an infusion of glucagon at a low rate that is designed to mimic basal plasma glucagon concentration. The IV glucagon will be administered at a rate of 0.65ng/kg/min.
Other Name: glucagon 0.65ng/kg/min
- Triglyceride-rich lipoprotein production rate [ Time Frame: 0-10 hours ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01155206
|University Health Network, Toronto General Hospital|
|Toronto,, Ontario, Canada, M5G 2C4|
|Principal Investigator:||Gary F Lewis, MD||University Health Network, Toronto General Hospital|