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Combining a dipeptidyl peptidase‐4 inhibitor, alogliptin, with pioglitazone improves glycaemic control, lipid profiles and β‐cell function in db/db mice
Author(s) -
Moritoh Y,
Takeuchi K,
Asakawa T,
Kataoka O,
Odaka H
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00145.x
Subject(s) - alogliptin , pioglitazone , medicine , endocrinology , incretin , dipeptidyl peptidase 4 inhibitor , insulin , type 2 diabetes , beta cell , dipeptidyl peptidase , chemistry , glucagon like peptide 1 , diabetes mellitus , dipeptidyl peptidase 4 , pharmacology , islet , biochemistry , enzyme
Background and purpose: Alogliptin, a highly selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor, enhances incretin action and pioglitazone enhances hepatic and peripheral insulin actions. Here, we have evaluated the effects of combining these agents in diabetic mice. Experimental approach: Effects of short‐term treatment with alogliptin alone (0.01%–0.1% in diet), and chronic combination treatment with alogliptin (0.03% in diet) and pioglitazone (0.0075% in diet) were evaluated in db/db mice exhibiting early stages of diabetes. Key results: Alogliptin inhibited plasma DPP‐4 activity up to 84% and increased plasma active glucagon‐like peptide‐1 by 4.4‐ to 4.9‐fold. Unexpectedly, alogliptin alone lacked clear efficacy for improving glucose levels. However, alogliptin in combination with pioglitazone clearly enhanced the effects of pioglitazone alone. After 3–4 weeks of treatment, combination treatment increased plasma insulin by 3.8‐fold, decreased plasma glucagon by 41%, both of which were greater than each drug alone, and increased plasma adiponectin by 2.4‐fold. In addition, combination treatment decreased glycosylated haemoglobin by 2.2%, plasma glucose by 52%, plasma triglycerides by 77% and non‐esterified fatty acids by 48%, all of which were greater than each drug alone. Combination treatment also increased expression of insulin and pancreatic and duodenal homeobox 1 (PDX1), maintained normal β‐cell/α‐cell distribution in islets and restored pancreatic insulin content to levels comparable to non‐diabetic mice. Conclusions and implications: These results indicate that combination treatment with alogliptin and pioglitazone at an early stage of diabetes improved metabolic profiles and indices that measure β‐cell function, and maintained islet structure in db/db mice, compared with either alogliptin or pioglitazone monotherapy.