Acute Regulation of Intestinal and Hepatic Lipoprotein Production by Glucagon
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Diagnostic
|Official Title:||Acute Regulation of Intestinal and Hepatic Lipoprotein Production by Glucagon|
- The subject will be in a steady fed state and lipoprotein kinetics will be assessed. [ Time Frame: One year ] [ Designated as safety issue: No ]blood samples will be collected at regular time intercvals for 10 hours after administration of glucerol and leucine, for the assessment of lipoprotein kinetics. At the same time points we will measure triglycerides, free fatty acid, insulin, growth hormone and glucagon.
|Study Start Date:||June 2009|
|Study Completion Date:||January 2010|
|Primary Completion Date:||January 2010 (Final data collection date for primary outcome measure)|
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 other study will infuse glucagon at a low rate that is designed to mimic basal plasma glucagon concentration. The IV glucagon will be administered at a rate of 3ng/kg/min for the high physiological study and for the basal glucagon infusion study, glucagon will be infused at 0.65ng/kg/min. Both glucagon infusion studies will be perfomed under conditions of pancreatic clamp with infusionof somatosatin and basal insulin and growth hormone.
Other Name: glucagon 0.65ng/kg/min
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.
|University Health Network, Toronto General Hospital|
|Toronto,, Ontario, Canada, M5G 2C4|
|Principal Investigator:||Gary F Lewis, MD||University Health Network, Toronto General Hospital|