PMID- 24424056
OWN - NLM
STAT- MEDLINE
DCOM- 20140430
LR  - 20151119
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Linking)
VI  - 155
IP  - 3
DP  - 2014 Mar
TI  - Characterization of the exocrine pancreas in the male Zucker diabetic fatty rat 
      model of type 2 diabetes mellitus following 3 months of treatment with 
      sitagliptin.
PG  - 783-92
LID - 10.1210/en.2013-1781 [doi]
AB  - Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor-based incretin therapy 
      intended for the treatment of type 2 diabetes mellitus (T2DM), has not been 
      linked to adverse effects on the pancreas in prospective clinical trials or in 
      nonclinical toxicology studies. To further assess potential pancreatic effects, 
      sitagliptin was studied in the male Zucker diabetic fatty (ZDF) rat model of 
      T2DM. Following 3 months of oral dosing with vehicle, or sitagliptin at doses 3- 
      to 19-fold above the clinically therapeutic plasma concentration, which increased 
      active plasma glucagon-like peptide-1 levels up to approximately 3-fold, or 
      following 3 months of oral dosing with metformin, a non-incretin-based reference 
      T2DM treatment, the pancreas of male ZDF rats was evaluated using qualitative and 
      quantitative histopathology techniques. In the quantitative evaluation, 
      proliferative index was calculated in exocrine pancreatic ducts and ductules 
      using computer-based image analysis on sections stained by immunohistochemistry 
      for cytokeratin (a cytoplasmic epithelial cell marker) and Ki-67 (a nuclear 
      marker of recent cell division). Relative to controls, sitagliptin treatment did 
      not alter disease progression based on detailed clinical signs and clinical 
      pathology assessments. Sitagliptin treatment did not result in pancreatitis or 
      any adverse effect on the pancreas based on a qualitative histopathology 
      evaluation. Proliferative index did not increase with sitagliptin treatment based 
      on quantitative assessment of more than 5000 sections of pancreas, where control 
      group means ranged from 0.698-0.845% and sitagliptin-treated group means ranged 
      from 0.679-0.701% (P = .874). Metformin treatment was similarly evaluated and 
      found not to have adverse effects on pancreas.
FAU - Forest, Thomas
AU  - Forest T
AD  - Merck & Co, Inc, Whitehouse Station, New Jersey.
FAU - Holder, Daniel
AU  - Holder D
FAU - Smith, Adam
AU  - Smith A
FAU - Cunningham, Caron
AU  - Cunningham C
FAU - Yao, Xiaorui
AU  - Yao X
FAU - Dey, Markus
AU  - Dey M
FAU - Frederick, Clay
AU  - Frederick C
FAU - Prahalada, Srinivasa
AU  - Prahalada S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140101
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Blood Glucose)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Ki-67 Antigen)
RN  - 0 (Pyrazines)
RN  - 0 (Triazoles)
RN  - 68238-35-7 (Keratins)
RN  - 9100L32L2N (Metformin)
RN  - TS63EW8X6F (Sitagliptin Phosphate)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Blood Glucose/drug effects
MH  - Body Weight
MH  - Cell Proliferation
MH  - Diabetes Mellitus, Experimental/*metabolism
MH  - Diabetes Mellitus, Type 2/*metabolism
MH  - Disease Models, Animal
MH  - Hypoglycemic Agents/administration & dosage
MH  - Keratins/metabolism
MH  - Ki-67 Antigen/metabolism
MH  - Male
MH  - Metformin/administration & dosage
MH  - Pancreas, Exocrine/*drug effects/*pathology
MH  - Pyrazines/administration & dosage
MH  - Rats
MH  - Rats, Zucker
MH  - Sitagliptin Phosphate
MH  - Triazoles/administration & dosage
EDAT- 2014/01/16 06:00
MHDA- 2014/05/03 06:00
CRDT- 2014/01/16 06:00
PHST- 2014/01/16 06:00 [entrez]
PHST- 2014/01/16 06:00 [pubmed]
PHST- 2014/05/03 06:00 [medline]
AID - 10.1210/en.2013-1781 [doi]
PST - ppublish
SO  - Endocrinology. 2014 Mar;155(3):783-92. doi: 10.1210/en.2013-1781. Epub 2014 Jan 
      1.