Acute Regulation of Intestinal and Hepatic Lipoprotein Production by Glucagon
Condition: Diabetes
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): glucagon
Intervention type(s): Drug
Intervention description(s): glucagon 3ng/kg/min
Other intervention name(s): glucagon 0.65ng/kg/min
Intervention MeSH terms: Glucagon; Glucagon-Like Peptide 1
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Diagnostic
Keywords: glucagon,; high physiological dose and basal dose of glucagon; hepatic lipoprotein production,; free fatty acid; intestinal lipoprotein production; particle; glucagon affects production of fat in intestine and liver.