Acute Regulation of Intestinal and Hepatic Lipoprotein Production by Glucagon
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.
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.
Study Design
Allocation: Randomized, Control: Dose Comparison, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Diagnostic
Conditions
Diabetes
Intervention
glucagon
Location
University Health Network, Toronto General Hospital
Toronto,
Ontario
Canada
M5G 2C4
Status
Completed
Source
University Health Network, Toronto
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT01155206
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Dipeptidyl-peptidase Iv Inhibitors
Compounds that supress the degradation of INCRETINS by blocking the action of DIPEPTIDYL-PEPTIDASE IV. This helps to correct the defective INSULIN and GLUCAGON secretion characteristic of TYPE 2 DIABETES MELLITUS by stimulating insulin secretion and suppressing glucagon release.
Glucagon-like Peptides
Peptides derived from proglucagon which is also the precursor of pancreatic GLUCAGON. Despite expression of proglucagon in multiple tissues, the major production site of glucagon-like peptides (GLPs) is the INTESTINAL L CELLS. GLPs include glucagon-like peptide 1, glucagon-like peptide 2, and the various truncated forms.
Receptors, Glucagon
Cell surface receptors that bind glucagon with high affinity and trigger intracellular changes which influence the behavior of cells. Activation of glucagon receptors causes a variety of effects; the best understood is the initiation of a complex enzymatic cascade in the liver which ultimately increases the availability of glucose to body organs.
Insulin
A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1).
Glucagon
A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal GLUCAGON-LIKE PEPTIDES. Glucagon is secreted by PANCREATIC ALPHA CELLS and plays an important role in regulation of BLOOD GLUCOSE concentration, ketone metabolism, and several other biochemical and physiological processes. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1511)
Clinical Trials
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The Effects of GIP and GLP-2 on the Secretion of Glucagon in Patients With Type 1 Diabetes
The purpose of this study is to determine whether Glucose-dependent Insulinotropic Polypeptide (GIP) or Glucagon Like Peptide 2 (GLP-2) has an affect on the secretion of Glucagon from the...
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The purpose of this study is to assess the GLP-1 and non-GLP-1 effects of LAF237 on glucagon secretion, using treatment observations of the overall glycemic response.
The Role of Amylin and Glucagon in T1DM
The purpose of this study is to see if giving pramlintide and insulin before a meal would lower high blood sugar and if a glucagon (a naturally made hormone in the body but reduced in diab...
PubMed Articles
Background: Short-term intensive insulin therapy in patients with type 2 diabetes mellitus has beneficial effects on insulin secretion. However, intensive insulin therapy effect on glucagon and glucag...
AIMS/HYPOTHESIS: Type 2 diabetes is caused by relative deficiency of insulin secretion and is associated with dysregulation of glucagon secretion during the late stage of diabetes development. Like in...
Insulin Reciprocally Regulates Glucagon Secretion in Humans.
AbstractObjective - We tested the hypothesis that an increase in insulin per se, i.e., in the absence of zinc, suppresses glucagon secretion during euglycemia and a decrease in insulin per se stimulat...
Most patients with type 1 diabetes do not achieve their glycemic targets. We aimed to assess the efficacy of glucose-responsive insulin and glucagon closed-loop delivery for controlling glucose levels...
BACKGROUND: Variants in TCF7L2 have been associated with the age of onset of type 2 diabetes in Mexican Americans. However, there is a lack of data on this relationship in Caucasians. Furthermore, ris...
