Colestimide Lowers Plasma Glucose Levels and Increases Plasma Glucagon-like Peptide-1 (7-36) Levels in Patients with Type 2 Diabetes Mellitus Complicated by Hypercholesterolemia

Suzuki, Tatsuya; Oba, Koji; Igari, Yoshimasa; Matsumura, Noriaki; Watanabe, Kentaro; Futami-Suda, Shoko; Yasuoka, Hiroko; Ouchi, Motoshi; Suzuki, Kazunari; Kigawa, Yoshiaki; Nakano, Hiroshi

doi:10.1272/jnms.74.338

Cited by 89 publications

(56 citation statements)

References 20 publications

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“…Liver samples were collected for RNA extraction, and qPCR was performed using gene-specific primers and probes. T2DM treated with colestimide had increased GLP-1 levels in 2 h. (Suzuki et al, 2007). Our results also indicated a reduction of TGR5 mRNA expression in duodenum, jejunum, and descending colon of control ZDF rats versus the lean controls (Fig.…”

Section: Table 1 Gene Expression In the Liver (Arbitrary Units)supporting

confidence: 73%

Cholestyramine Reverses Hyperglycemia and Enhances Glucose-Stimulated Glucagon-Like Peptide 1 Release in Zucker Diabetic Fatty Rats

Chen

McNulty²,

Anderson³

et al. 2010

J Pharmacol Exp Ther

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Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagonlike peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic ␤-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.In the last decade, the traditional view of bile acids as essential players in dietary lipid absorption and cholesterol catabolism has changed. The discovery of bile acids as endogenous ligands for the nuclear receptor farnesoid X receptor (FXR; NR1H4) and the G-protein-coupled bile acid receptor (TGR5; GPBAR1) transformed bile acids from lipid absorption facilitator into autocrine, paracrine, and endocrine factors (Parks et al., 1999;Kawamata et al., 2003). In addition to negative feedback regulation of bile acid synthesis in the liver (Makishima et al., 1999), FXR influences many pathways involved in lipid and glucose metabolism (Lefebvre et al., 2009). FXR agonists have been shown to lower circulating cholesterol, triglycerides, and glucose and improve insulin sensitivity in multiple preclinical models (Duran-Sandoval et al., 2005;Stayrook et al., 2005;Cariou et al., 2006;Ma et al., 2006;Zhang et al., 2006). Similar to FXR, TGR5 mediates some hormonal actions of bile acids, including glucose metabolism. It has been demonstrated that bile acids promote glucagon-like-peptide 1 (GLP-1) secretion through TGR5 in STC-1, a murine enteroendocrine cell line (Katsuma et al., Article, publication date, and citation information can be found at

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Section: Table 1 Gene Expression In the Liver (Arbitrary Units)supporting

confidence: 73%

Cholestyramine Reverses Hyperglycemia and Enhances Glucose-Stimulated Glucagon-Like Peptide 1 Release in Zucker Diabetic Fatty Rats

Chen

McNulty²,

Anderson³

et al. 2010

J Pharmacol Exp Ther

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“…We show here for the first time in humans that colesevelam treatment increases plasma GLP-1 and GIP concentrations. An increase in GLP-1 concentrations (2 h postprandial) in humans had previously been reported with colestimide [37]. Bile acids activate the cell surface Gprotein-coupled receptor TGR5, which is expressed in enteroendocrine L cells and stimulates the secretion of GLP-1 [9].…”

Section: Discussionmentioning

confidence: 73%

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

et al. 2011

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Aims/hypothesis The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). Methods Participants with type 2 diabetes (HbA 1c 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n=30) or placebo (n=30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. Conclusions/interpretation Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents.Trial registration: ClinicalTrials.gov NCT00596427 Funding: The study was funded by Daiichi Sankyo.

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“…Surprisingly, the glucose-lowering effect of BAS appears not to be mediated by an improvement of insulin sensitivity as measured by hyperinsulinemic euglycemic clamps ( 158 ), glucose, or meal tolerance tests (159)(160)(161). In contrast, one week administration of colestimide in T2D patients (n = 16) lowers plasma glucose and increases postprandial GLP-1 ( 162 ). A second study evaluating glucose kinetics in T2D patients after BAS treatment fi nds improved glucose clearance and increased GLP-1 and gastric inhibitory peptide (GIP) concentrations ( 163 ).…”

Section: Tgr5 Agonistsmentioning

confidence: 99%

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

Porez

Prawitt²,

Gross³

et al. 2012

Journal of Lipid Research

252

173

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Colestimide Lowers Plasma Glucose Levels and Increases Plasma Glucagon-like Peptide-1 (7-36) Levels in Patients with Type 2 Diabetes Mellitus Complicated by Hypercholesterolemia

Cited by 89 publications

References 20 publications

Cholestyramine Reverses Hyperglycemia and Enhances Glucose-Stimulated Glucagon-Like Peptide 1 Release in Zucker Diabetic Fatty Rats

Cholestyramine Reverses Hyperglycemia and Enhances Glucose-Stimulated Glucagon-Like Peptide 1 Release in Zucker Diabetic Fatty Rats

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

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