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Full Text (PDF) Pathophysiology/Complications ORIGINAL ARTICLE Colesevelam Improves Oral but Not Intravenous Glucose Tolerance by a Mechanism Independent of Insulin Sensitivity and b-Cell Function ANNA L. MARINA, MD BRENDA K. MONTGOMERY, RN, MS, CDE currently under investigation with studies KRISTINA M. UTZSCHNEIDER, MD SANTICA M. MARCOVINA, PHD, SCD reporting conflicting results (6). There is a LORENA A. WRIGHT, MD STEVEN E. KAHN, MB, CHB complex interaction between FXR and LXR, which often have counterbalancing effects (7). LXR has been described as a OBJECTIVEd To determine the mechanism by which the bile acid sequestrant colesevelam glucose sensor (8), capable of improving improves glycemic control. glucose tolerance by promoting glucose RESEARCH DESIGN AND METHODSdWe performed a frequently sampled intrave- utilization and triglyceride synthesis and nous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) inhibiting gluconeogenesis (9,10). We in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 6 1.9 years, BMI hypothesized that independent of the 29.4 6 0.9 kg/m2) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of precise mechanism of the effects of bile colesevelam 3.75 g daily. From these tests, insulin sensitivity, b-cell function, and glucose acid sequestrants on glucose, if the FXR- tolerance were determined, along with gastrointestinal peptide levels during the MTT. LXR hypothesis is correct, treatment of humans with colesevelam would result RESULTSdFasting plasma glucose and HbA1c decreased with colesevelam (from 5.9 6 0.1 to 5.7 6 0.1 mmol/L, P , 0.05, and from 5.86 6 0.06 to 5.76 6 0.06%, P = 0.01, respectively), but in improvement in insulin sensitivity. fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the While animal studies show improvement MTT incremental area under the curve (iAUC) for both glucose (from 249.3 6 28.5 to 198.8 6 23.6 in insulin sensitivity during treatment mmol/L z min, P , 0.01) and insulin (from 20,130 [13,542–35,292] to 13,086 [9,804–21,138] with bile acid sequestrants (11,12), such pmol/L z min, P , 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose an effect has not been clearly demon- was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0–130.1] to 127.1 [47.2– strated in humans (13). 295.2] pmol/L z min, P , 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 – – z P , The ability of bile acid sequestrants to [1,346 17,661] to 2,093 [673 6,707] pg/mL min, 0.01) with colesevelam. However, iAUC for lower blood glucose also has been linked glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change. to their possible effect on intestinal glucagon- CONCLUSIONSdColesevelam improves oral but not intravenous glucose tolerance without like peptide 1 (GLP-1) secretion and, in changing insulin sensitivity, b-cell function, or incretins. This effect may be at least partially some studies, peptide Tyr-Tyr (PYY) release explained by the colesevelam-induced increase in CCK. (11,12,14). It has been suggested that se- questration of bile acids may interfere with – Diabetes Care 35:1119 1125, 2012 free fatty acid absorption in the proximal small intestine, resulting in increased free olesevelam is a bile acid sequestrant other bile acid sequestrants is mediated fatty acid delivery to the ileum and, con- Cthat is used for the treatment of hy- by the nuclear receptors farnesoid X re- sequently, enhanced GLP-1 secretion by percholesterolemia. More recent, it ceptor (FXR) and liver X receptor (LXR) the ileal L-cells (11). Furthermore, the in- has beenapprovedforuse inpatients with (3). Activation of FXR by bile acids leads creased levels of bile acids in the intestinal type 2 diabetes because it improves gly- to a negative feedback inhibition of bile lumen during treatment with bile acid se- cemic control, with decreases in HbA1c acid biosynthesis and secretion, in part questrants could also stimulate GLP-1 re- of ;0.5% compared with placebo when via increased expression of fibroblast lease via the G-protein–coupled receptor used in combination with metformin, sul- growth factor (FGF)-19 by enterocytes re- TGR5 (15). We hypothesized that if the fonylurea, or insulin (1–4). However, the sulting in diminished CYP7A1 expression glucose-lowering effect of colesevelam mechanism(s) by which colesevelam im- in the liver (5,6). Binding of bile acids by was related to increased incretin release, proves glucose tolerance is unknown. bile acid sequestrants reverses these ef- such an increase would be associated It has been suggested that the glu- fects. FXR appears to directly affect glu- with an improvement in islet (b- and/or cose-lowering effect of colesevelam and cose metabolism, but its specificroleis a-cell) function with meals. Thus, the primary objective of this ccccccccccccccccccccccccccccccccccccccccccccccccc study was to determine whether the From the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound glucose-lowering properties of colesevelam Health Care System and University of Washington, Seattle, Washington. are the result of improvements in in- Corresponding author: Steven E. Kahn, [email protected]. sulin sensitivity and/or b-anda-cell Received 20 October 2011 and accepted 4 February 2012. function. Furthermore, we wished to DOI: 10.2337/dc11-2050. Clinical trial reg. no. NCT00990184, clinicaltrials.gov. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly determine whether any improvements cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ could be attributed to changes in the re- licenses/by-nc-nd/3.0/ for details. lease of incretins or other gastrointestinal care.diabetesjournals.org DIABETES CARE, VOLUME 35, MAY 2012 1119 Colesevelam and glucose metabolism peptides. We chose to study subjects with within 3 months; or use of HIV protease the end of the study. Reported adverse impaired fasting glucose (IFG) because inhibitors, warfarin, phenytoin, or any events were recorded, and laboratory safety they are at high risk of developing type 2 investigational drug within 30 days. Other assessments (complete blood count, elec- diabetes and because with their mild im- exclusion criteria were triglycerides .5.6 trolytes, plasma creatinine, liver function pairment in glucose metabolism, it is pos- mmol/L, uncontrolled hypothyroidism, tests, lactate dehydrogenase, creatine sible to use a number of sensitive methods clinical hepatic disease or liver function phosphokinase, lipid panel, and urinaly- to quantify changes in several important tests greater than two times the upper limit sis) were performed on days 14, 42, and parameters that regulate glucose without of normal, and history of major gastroin- 70. A standard 12-lead electrocardiogram excess concern of the deleterious effects of testinal surgery (gastrectomy, gastroenter- was recorded on days 14 and 70. glucose per se. Thus, we performed insu- ostomy, and bowel resection), dysphagia, lin-modified frequently sampled intrave- swallowing disorders, intestinal motility Assays nous glucose tolerance tests (FSIGTs) to disorder, or pancreatitis. Plasma glucose was measured using the quantify insulin sensitivity and b-cell func- hexokinase method (Roche Diagnostics, tion (16) and standardized meal tolerance Study procedures Indianapolis, IN), lipids were measured by tests (MTTs) to evaluate postprandial glu- Interventions. Subjects were provided enzymatic methods (Roche Diagnostics), cose, insulin, glucagon, and incretin re- with blinded active medication (colesevelam) and dextran sulfate precipitation for HDL sponses, all before and after treatment or matching placebo. Medication was cholesterol. Insulin and C-peptide levels with colesevelam. Levels of gastrointestinal takenwiththeeveningmeal,withpla- were measured using two-site immunoen- peptides were also measured immediately cebo being consumed for 2 weeks prior zymatic assays (Tosoh Bioscience, San before and during the standardized meal, to the performance of the first set of out- Francisco, CA). Radioimmunoassays were when they were expected to produce their come assessments. Thereafter, subjects used to measure plasma levels of pro- physiological effects. started taking 3.75 g colesevelam once insulin (Millipore, St. Charles, MO; HPI- daily with the evening meal and did so for 15K, minimum detection limit 2 pmol/L, RESEARCH DESIGN AND the next 8 weeks, at the end of which they intra-assay coefficient of variation [CV] 1.5– METHODSdThe study used a single- underwent a second series of outcome as- 6.9%, interassay CV 1.5–10.1%), glucagon blind, single-treatment design with a sessments. Medication compliance was as- (Millipore; GL-32K, minimum detection 2-week placebo run-in phase followed sessed by counting the number of unused limit 20 ng/L, intra-assayCV4–6.8%, inter- by 8 weeks of treatment with unbranded tablets returned on days 14, 42, and 70. assay CV 7.3–13.5%), total PYY (Millipore; active colesevelam hydrochloride (3.75 g No subjects were excluded based on the PYYT-66HK, minimum detection limit daily) with the evening meal. Subjects protocol requirement that subjects take 10 pg/mL, intra-assay CV 2.9–9.4%, in- were blinded to treatment throughout the .80% of the prescribed medication dur- terassay CV 5.5–8.5%), and sulfated cho- study, having been told that any time ing the placebo period (first 14 days). lecystokinin (CCK) (ALPCO, Salem, NH; during the study they may receive active Subjects were asked to maintain prior ex- 13-CCK-HU-R100, minimum detection medication or placebo. An insulin-modified ercise and dietary habits throughout the limit 0.3 pmol/L, intra-assay CV 2–5.5%, FSIGT and an MTT were performed on study.
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