Colesevelam Improves Oral but Not Intravenous Glucose Tolerance by a Mechanism Independent of Insulin Sensitivity and -Cell Function

Division of Metabolism, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington, USA.
Diabetes care (Impact Factor: 8.42). 03/2012; 35(5):1119-25. DOI: 10.2337/dc11-2050
Source: PubMed


To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control.
We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT.
Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L · min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L · min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2-295.2] pmol/L · min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL · min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change.
Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.

1 Follower
11 Reads
  • Source
    • "Nutrient sensing in gut lumen has been reported to play important roles in glucose homeostasis. Especially, jejunum and duodenum are known to play an important role in glucose sensing to regulate glucose production in the liver (Breen et al. 2012, 2013, Marina et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oral ingestion of carbohydrate triggers glucagon-like peptide 1 (GLP1) secretion, but the molecular mechanism remains elusive. By measuring GLP1 concentrations in murine portal vein, we found that the ATP sensitive K+ (KATP) channel is not essential for glucose-induced GLP1 secretion from enteroendocrine L cells, while the sodium glucose transporter 1 (SGLT1) is required, at least in the early phase (5 min) of secretion. By contrast, co-administration of the α-glucosidase inhibitor (α-GI) miglitol plus maltose evoked late phase secretion in a glucose transporter 2 (GLUT2)-dependent manner. We found that GLP1 secretion induced by miglitol plus maltose was significantly higher than that by another α-GI, acarbose, plus maltose, despite the fact that acarbose inhibits maltase more potently than miglitol. Since miglitol activates sodium glucose transporter 3 (SGLT3), we compared the effects of miglitol on GLP1 secretion with those of acarbose, which failed to depolarize the Xenopus laevis oocytes expressing hSGLT3. Oral administration of miglitol activated duodenal enterochromaffin cells as assessed by immunostaining of phosphorylated calcium-calmodulin kinase 2 (phospho-CaMK2). In contrast, acarbose activated much fewer enteroendocrine cells, having only modest phospho-CaMK2 immunoreactivity. Single administration of miglitol triggered no GLP1 secretion, and GLP1 secretion by miglitol plus maltose was significantly attenuated by atropine pretreatment, suggesting regulation via vagal nerve. Thus, while α-GIs generally delay carbohydrate absorption and potentiate GLP1 secretion, miglitol also activates duodenal enterochromaffin (EC) cells, possibly via SGLT3, and potentiates GLP1 secretion through the parasympathetic nervous system.
    Journal of Endocrinology 12/2014; 224(3). DOI:10.1530/JOE-14-0555 · 3.72 Impact Factor
  • Source
    • "In small studies, several newer agents were administered to patients with prediabetes, but not for diabetes prevention. The bile acid sequestrant colesevelam has been shown to improve insulin sensitivity and β-cell function similarly in subjects with prediabetes (IFG) and T2DM.145 Although the mechanism of action is unknown, the observation that A1c improved after colesevelam treatment in the lipid-lowering trials led to studies of glucose regulation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical trials have demonstrated that it is possible to prevent diabetes through lifestyle modification, pharmacological intervention, and surgery. This review aims to summarize the effectiveness of these various therapeutic interventions in reducing the risk of progression of prediabetes to diabetes, and address the challenges to implement a diabetes prevention program at a community level. Strategies focusing on intensive lifestyle changes are not only efficient but cost-effective and/or cost-saving. Indeed, lifestyle intervention in people at high risk for type 2 diabetes mellitus (T2DM) has been successful in achieving sustained behavioral changes and a reduction in diabetes incidence even after the counseling is stopped. Although prediabetes is associated with health and economic burdens, it has not been adequately addressed by interventions or regulatory agencies in terms of prevention or disease management. Lifestyle intervention strategies to prevent T2DM should be distinct for different populations around the globe and should emphasize sex, age, ethnicity, and cultural and geographical considerations to be feasible and to promote better compliance. The translation of diabetes prevention research at a population level, especially finding the most effective methods of preventing T2DM in various societies and cultural settings remains challenging, but must be accomplished to stop this worldwide epidemic.
    Therapeutics and Clinical Risk Management 03/2014; 10(1):173-188. DOI:10.2147/TCRM.S39564 · 1.47 Impact Factor
  • Source
    • "In another study in subjects with impaired fasting glucose, results from a frequently sampled intravenous glucose tolerance test followed by a meal tolerance test showed no effect of colesevelam on insulin sensitivity index (ISI), acute insulin (AIRg), C-peptide, proinsulin responses to glucose, or disposition index (the product of AIRg and ISI). In addition, plasma glucagon levels were unaffected.27 Thus, these findings suggest that the mechanism(s) of glucose lowering by colesevelam is not like that of DPP-4 inhibitors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Colesevelam's glucose-lowering mechanism of action is not completely understood. Clinical trials of colesevelam suggest that its mechanism, and often adverse effects, differ from those of other oral antidiabetes drugs. Colesevelam does not affect insulin sensitivity (unlike thiazolidinediones), insulin secretion (unlike sulfonylureas and meglitinides), or early insulin response or glucagon (unlike dipeptidyl peptidase-4 inhibitors). Colesevelam may have some effect on glucose absorption, but likely via a different mechanism than α-glucosidase inhibitors. Colesevelam and metformin have similarities regarding hepatic glucose production, but divergent effects on gluconeogenesis versus glycogenolysis, suggesting differing mechanisms of drug action for improving glycemic control. Colesevelam is thought to be a portal glucagon-like peptide-1 (GLP-1) secretagogue with primarily hepatic effects. Bile acid binding by colesevelam leads to TGR5 activation, increased secretion of GLP-1 or other incretins, and inhibition of hepatic glycogenolysis. Colesevelam's mechanism of action appears to be atypical of other antidiabetes medications, making it a potentially suitable component of many combination regimens in the treatment of type 2 diabetes.
    12/2013; 6:75-79. DOI:10.4137/CMED.S12590
Show more

Preview (2 Sources)

11 Reads
Available from