TY - JOUR
T1 - Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes
T2 - Interactions with metformin
AU - Matveyenko, Aleksey V.
AU - Dry, Sarah
AU - Cox, Heather I.
AU - Moshtaghian, Artemis
AU - Gurlo, Tatyana
AU - Galasso, Ryan
AU - Butler, Alexandra E.
AU - Butler, Peter C.
PY - 2009/7
Y1 - 2009/7
N2 - OBJECTIVE-We sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes. RESEARCH DESIGN AND METHODS-HIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and β-cell mass, function, and turnover were measured in each group. RESULTS-Sitagliptin plus metformin had synergistic effects to preserve β-cell mass in HIP rats. Metformin more than sitagliptin inhibited β-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. β-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis. CONCLUSIONS-The combination of metformin and sitagliptin had synergistic actions to preserve β-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation.
AB - OBJECTIVE-We sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes. RESEARCH DESIGN AND METHODS-HIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and β-cell mass, function, and turnover were measured in each group. RESULTS-Sitagliptin plus metformin had synergistic effects to preserve β-cell mass in HIP rats. Metformin more than sitagliptin inhibited β-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. β-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis. CONCLUSIONS-The combination of metformin and sitagliptin had synergistic actions to preserve β-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation.
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U2 - 10.2337/db09-0058
DO - 10.2337/db09-0058
M3 - Article
C2 - 19403868
AN - SCOPUS:67650245531
SN - 0012-1797
VL - 58
SP - 1604
EP - 1615
JO - Diabetes
JF - Diabetes
IS - 7
ER -