Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin.
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.


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 beta-cell mass, function, and turnover were measured in each group.


RESULTS
Sitagliptin plus metformin had synergistic effects to preserve beta-cell mass in HIP rats. Metformin more than sitagliptin inhibited beta-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. beta-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 beta-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.
Matveyenko
Aleksey V
AV
Larry Hillblom Islet Research Center, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. amatveyenko@mednet.ucla.ed
Dry
Sarah
S
Cox
Heather I
HI
Moshtaghian
Artemis
A
Gurlo
Tatyana
T
Galasso
Ryan
R
Butler
Alexandra E
AE
Butler
Peter C
PC
D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001120:Arginine / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D006946:Hyperinsulinism / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000627:therapeutic use*
D000682:Amyloid; D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D011719:Pyrazines; D014230:Triazoles; D008687:Metformin; D001120:Arginine; D000068900:Sitagliptin Phosphate