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Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing the release of GLP-1.

Abstract
Bile acid sequestrants have been shown to lower glucose levels in patients with type 2 diabetes. To investigate how colesevelam (CL) HCl improves hyperglycemia, studies were conducted in diet-induced obesity (F-DIO) rats, which develop insulin resistance when fed a high-energy (high fat/high sucrose) diet (HE). The rats were fed HE; HE + 2% CL; HE + 0.02% SC-435 (SC), an apical sodium-dependent bile acid transporter inhibitor; and regular chow (controls). After 4 wk of treatment, both in the HE group and the SC + HE group, plasma glucose and insulin levels remained elevated compared with baseline values throughout an oral glucose tolerance test (OGTT). In contrast, in the CL + HE group, plasma glucose levels returned to baseline by the end of the test, and insulin peaked in 15-30 min and then returned to baseline. CL induced release of glucagon-like peptide-1 (GLP-1) because the area under the curve of plasma total GLP-1 in the CL + HE group was significantly greater than in the HE group during the OGTT. Bile acid concentrations in the portal blood did not decrease in the HE group but declined significantly both in the CL + HE and SC + HE groups with reduced farnesoid X receptor activation compared with controls. We concluded that CL reduces plasma glucose levels by improving insulin resistance in this rat model. It is unlikely that the improvement is attributable to decreased bile acid flux to the liver but is likely secondary to induced GLP-1 secretion, which improves insulin release.
AuthorsQuan Shang, Monica Saumoy, Jens Juul Holst, Gerald Salen, Guorong Xu
JournalAmerican journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 298 Issue 3 Pg. G419-24 (Mar 2010) ISSN: 1522-1547 [Electronic] United States
PMID20044510 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • 1-(4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)butyl)-4-aza-1-azoniabicyclo(2.2.2)octane
  • Anticholesteremic Agents
  • Bile Acids and Salts
  • Blood Glucose
  • Carrier Proteins
  • Cyclic N-Oxides
  • Dietary Carbohydrates
  • Dietary Fats
  • Insulin
  • Membrane Glycoproteins
  • Organic Anion Transporters, Sodium-Dependent
  • Receptors, Cytoplasmic and Nuclear
  • Symporters
  • Triglycerides
  • Tropanes
  • bile acid binding proteins
  • nuclear receptor subfamily 0, group B, member 2
  • sodium-bile acid cotransporter
  • Allylamine
  • Glucagon-Like Peptide 1
  • Cholesterol
  • CYP7A1 protein, rat
  • Cholesterol 7-alpha-Hydroxylase
  • Colesevelam Hydrochloride
Topics
  • Allylamine (analogs & derivatives, pharmacology, therapeutic use)
  • Animals
  • Anticholesteremic Agents (pharmacology)
  • Bile Acids and Salts (blood)
  • Blood Glucose (drug effects)
  • Body Weight (drug effects)
  • Carrier Proteins (genetics)
  • Cholesterol (blood)
  • Cholesterol 7-alpha-Hydroxylase (genetics)
  • Colesevelam Hydrochloride
  • Cyclic N-Oxides (pharmacology, therapeutic use)
  • Dietary Carbohydrates (pharmacology)
  • Dietary Fats (pharmacology)
  • Gene Expression (drug effects, genetics)
  • Glucagon-Like Peptide 1 (blood)
  • Glucose Tolerance Test
  • Ileum (drug effects, metabolism)
  • Insulin (blood)
  • Insulin Resistance (physiology)
  • Liver (drug effects, metabolism)
  • Male
  • Membrane Glycoproteins (genetics)
  • Obesity (blood, chemically induced, drug therapy, metabolism)
  • Organic Anion Transporters, Sodium-Dependent (antagonists & inhibitors, genetics)
  • Portal Vein (drug effects, metabolism)
  • Rats
  • Rats, Inbred F344
  • Receptors, Cytoplasmic and Nuclear (genetics)
  • Symporters (antagonists & inhibitors, genetics)
  • Triglycerides (blood)
  • Tropanes (pharmacology, therapeutic use)

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