TY - JOUR

T1 - The combination of colesevelam with sitagliptin enhances glycemic control in diabetic ZDF rat model

AU - Shang, Quan

AU - Liu, Matthew K

AU - Saumoy, Monica

AU - Holst, Jens Juul

AU - Salen, Gerald

AU - Xu, Guorong

PY - 2012

Y1 - 2012

N2 - 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 ß-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.

AB - 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 ß-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.

KW - Allylamine

KW - Animals

KW - Anticholesteremic Agents

KW - Apoptosis

KW - Bile Acids and Salts

KW - Blood Glucose

KW - Body Weight

KW - Cell Proliferation

KW - Cell Size

KW - Diabetes Mellitus, Type 2

KW - Diet

KW - Drug Synergism

KW - Fluorescent Antibody Technique

KW - Glucagon-Like Peptide 1

KW - Glucose Tolerance Test

KW - Hypoglycemic Agents

KW - In Situ Nick-End Labeling

KW - Insulin

KW - Insulin-Secreting Cells

KW - Ki-67 Antigen

KW - Male

KW - Postprandial Period

KW - Pyrazines

KW - RNA, Messenger

KW - Rats

KW - Rats, Zucker

KW - Receptors, G-Protein-Coupled

KW - Triazoles

U2 - 10.1152/ajpgi.00295.2011

DO - 10.1152/ajpgi.00295.2011

M3 - Journal article

C2 - 22281473

VL - 302

SP - G815-23

JO - American Journal of Physiology: Gastrointestinal and Liver Physiology

JF - American Journal of Physiology: Gastrointestinal and Liver Physiology

SN - 0193-1857

IS - 8

ER -