Combination of Telmisartan and Linagliptin Preserves Pancreatic Islet Cell Function and Morphology in db/db Mice.
OBJECTIVE
The present study aimed to investigate the synergistic action of telmisartan and linagliptin in ameliorating pancreatic islet functions and morphology in type 2 diabetes mellitus and to delineate the molecular signaling pathway involved.


METHODS
db/db mice were given telmisartan (3 mg/kg) or linagliptin (3 mg/kg) alone or in combination, daily for 8 weeks, and were studied in vivo by fasting and random blood glucose tests, oral glucose tolerance tests, and intraperitoneal insulin tolerance tests, as well as ex vivo by glucose-stimulated insulin secretion and morphology of pancreatic islets. The underlying signaling pathways were examined by Western blot, real-time quantitative polymerase chain reaction, and dihydroethidium staining analyses using mouse pancreatic islets and rat β-insulinoma cells.


RESULTS
Telmisartan/linagliptin combination induced significantly better glucose homeostasis than the monotherapies. Posttreatment reactive oxygen species level was suppressed most significantly after the telmisartan/linagliptin combined therapy, whereas no significant change in peroxisome proliferator-activated receptor γ expressions was observed after treatments.


CONCLUSIONS
The telmisartan/linagliptin combination preserved pancreatic islet cell functions and morphology via reduction of oxidative stress but independent of the peroxisome proliferator-activated receptor γ pathway. Our data shed light on the therapeutic potential of using the telmisartan/linagliptin combination in the treatment of human type 2 diabetes mellitus and its related complications.
From the *School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China; and †Department of Metabolic Diseases, Boehringer-Ingelheim Pharmaceuticals, Biberach, Germany.
Shuiling
S
Zhao
Leo Ka Yu
LK
Chan
Lihua
L
Chen
Tsz Wai
TW
Cheng
Thomas
T
Klein
Po Sing
PS
Leung
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D000069476:Linagliptin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D054873:Dipeptidyl-Peptidase IV Inhibitors; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D000069476:Linagliptin; D000077333:Telmisartan