title: The combination of colesevelam with sitagliptin enhances glycemic control in diabetic ZDF rat model.
abstract: Bile acid sequestrants have been shown to reduce glucose levels in patients with type 2 diabetes. We previously reported that the bile acid sequestrant colesevelam HCl (Welchol) (COL) induced the release of glucagon-like peptide (GLP)-1 and improved glycemic control in insulin-resistant rats. In the present study, we tested whether adding sitagliptin (Januvia) (SIT), which prolongs bioactive GLP-1 half life, to COL would further enhance glycemic control. Male Zucker diabetic fatty (ZDF) rats were assigned to four groups: diabetic model without treatment (the model), the model treated with 2% COL or 0.4% (120 mg/day) SIT alone, or with the combination (COL+SIT). After 4 wk of treatment, the glucose area under the curve (AUC) was reduced more in the COL+SIT than the COL although both groups showed decreased glucose AUC with increased AUC of bioactive GLP-1 (GLP-1A) compared with the model group. The above changes were not observed after 8 wk. Increasing the SIT dose by 50% (180 mg SIT/day) in the diet reduced the glucose AUC in the COL+SIT group even after 8 wk but still not in the SIT alone group compared with the model. It was noteworthy that, after 8 wk, insulin levels in the SIT group declined to levels similar to the model. Histological examination of the pancreatic β-cell islets showed that islet sizes were larger, proliferation enhanced, and cell apoptosis reduced in the COL+SIT but not the SIT alone group compared with the model. We hypothesize that the combination of COL with SIT extends the half life of COL-induced GLP-1A and benefits preservation of the islets that delay the development of diabetes and improve glycemic control. This study suggests that the combined therapy (COL+SIT) is more effective than either drug alone for reducing glucose levels in diabetes.
authors.affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Shang
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Liu
authors.forename: Monica
authors.initials: M
authors.lastname: Saumoy
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.forename: Guorong
authors.initials: G
authors.lastname: Xu
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D000069472:Colesevelam Hydrochloride; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D004032:Diet; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000097:blood / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D019518:Postprandial Period / Q000502:physiology; D011719:Pyrazines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D001786:Blood Glucose; C518268:Gpbar1 protein, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D019394:Ki-67 Antigen; D011719:Pyrazines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; D000499:Allylamine; D052216:Glucagon-Like Peptide 1; D000069472:Colesevelam Hydrochloride; D000068900:Sitagliptin Phosphate