Mitigating effects of vildagliptin in experimental diabetes with metabolic syndrome

Rajesh Kumar Suman, Ipseeta Ray Mohanty, Ujwala Maheshwari, Manjusha K. Borde, Y. A. Deshmukh


Background: Vildagliptin has multiple beneficial effects reported in isolated studies like anti-diabetic, cardio protective, anti-inflammatory and antioxidant. However, there is no experimental evidence presently available with regard to the possible beneficial effects of vildagliptin on attenuating changes observed in metabolic syndrome co-existing with diabetes in experimental rats. Thus, the present study was designed to evaluate potential effects of vildagliptin on various components of metabolic syndrome. Also to elucidate the underlying mechanisms: DPP-IV, anti-inflammatory, antioxidant pathways were studied.

Methods: A combination of high fat diet (HFD) and low dose of streptozotocin (STZ) 40 mg/kg was used to induce metabolic syndrome co-existing with diabetes mellitus in wistar rats. The HFD were fed to rats for 10 weeks to induce metabolic syndrome. At the end of 3 weeks, diabetes was induced by a single STZ injection (40 mg/kg body weight). Vildagliptin (10 mg/kg) was administered to rat from 5th to 10th weeks daily and various parameters of Diabetes and metabolic syndrome were studied. Also to understand the mechanisms; DPP-IV pathway, anti-inflammatory, antioxidant parameters were studied. Biochemical indices of injury (pancreatic, liver and renal function) and histopathological assessment of injury was evaluated in experimental groups. Immunohistochemistry of pancreas was done to assess beta cell mass.

Results: The vildagliptin treatment ameliorated the deleterious effects associated with metabolic syndrome and diabetes. The beneficial effects demonstrated by vildagliptin on various parameters include: anti-diabetic (reduced blood glucose, HbA1c, HOMA-IR, increased serum insulin, HOMA-β and restoration of pancreatic function), central obesity (reduced body weight, abdominal circumference (AC), thoracic circumference (TC), AC/TC ratio) and hypolipidemic (favourable lipid profile, artherogenic index) activity. A significant restoration of cardiac injury as indicated by CPK-MB levels was observed. In addition, DPP-IV pathway (reduced serum DPP-IV), anti-inflammatory (reduced hs-CRP levels), and antioxidant (reduced MDA) contributed its beneficial effects in diabetes with metabolic syndrome model. The protective effects on heart, pancreas, liver and kidney were confirmed by histopathological report. The immunohistochemical report of pancreas showed preservation of beta cell mass in vildagliptin treated rats.

Conclusions: Vildagliptin treatment ameliorates deleterious changes of diabetes with metabolic syndrome. Beneficial effects of vildagliptin can be attributed to hypoglycemic, hypolipidemic, antioxidant, cardioprotective and anti-inflammatory effects.


Vildagliptin, Diabetes, Metabolic syndrome, HFD, STZ

Full Text:



Hu X, Wang M, Bei W, Han Z, Guo J. The Chinese herbal medicine FTZ attenuates insulin resistance via IRS1 and PI3K in vitro and in rats with metabolic syndrome. Journal of Translational Medicine. 2014;12:47.

Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon like peptide-1. Diabetes Metab Res Rev. 2002;18:430-41.

Ahren B, Larsson H, Holst JJ. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997;82:473-8.

D’Alessio DA, Kahn SE, Leusner CR, Ensinck JW. Glucagon-like peptide-1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Investig. 1994;93:2263-6.

Prigeon RL, Quddusi S, Paty B, D’Alessio DA. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol. 2003;285:701-7.

Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 1993;214:829-35.

Pederson RA, White HA, Schlenzig D, Pauly RP, McIntosh CH, Demuth HU. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes. 1998;47:1253-8.

Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates cell survival and islet neogenesis in streptozotocin-induceddiabetic rats. Diabetes. 2003;52:741-50.

Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2874-80.

Apaijai N, Chinda K, Palee S, Chattipakorn S. Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats. PLOS ONE. 2014;9(7):1-13.

Suman RK, Mohanty IR, Borde MK, Maheshwari U, Deshmukh YA. Development of an experimental model of diabetes co-existing with metabolic syndrome in rats. Advances in pharmacological sciences. 2016;1-11.

Burkey BF, Li X, Bolognese L, Balkan B, Mone M, Russell M, et al. Acute and chronic effects of the incretin enhancer vildagliptin in insulin-resistant rats. Journal of pharmacology and experimental therapeutics. 2005;315(2):688-95.

Kuate D, Pascale A, Kengne N, Biapa CPN, Azantsa BGK, Muda WB. Tertapleura tetraptera spice attenuates high-carbohydrate, high fat diet-induced obese and type 2 diabetic rats with metabolic syndrome. Lipids in Health and Disease. 2015;15(50):1-13.

Nora M, El-Sheikh. Mangifera indica leaves extract modulates serum leptin. Asymmetric Dimethylarginine and Endothelin-1 leaves in experimental Diabetes mellitus. The Egptian J Bio and Mol Bio. 2012;30(2):229-44.

Stoffers DA. The development of beta cell mass: Recent progress and potential role of GLP 1. Horm Metab Res. 2004;36:811:21.

Butler AE, Janson J, Bonner Weir S, Ritzel R, Rizza RA, Butler PC. Beta cell deficit and increased beta cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102-10.

Renna NF, Diez EA, Miatello RM. Effects of dipeptidyl-peptidase 4 inhibitor about vascular inflammation in a metabolic syndrome model. PLOS ONE. 2014;9(9):1-7.

Shamim A, Mehmood T, Siddiqui HH, Bagga P, Roy S. Effect of tinospora cordifolia (guduchi) root extract on cardiotoxicity in streptozotocin induced diabetic rats. Asian Journal of Biomedical and Pharmacutical Sciences. 2015;5(45):12-9.

Erbey JR, Silberman C, Lydick E. Prevalence of abnormal serum alanine aminotransferase levels in obese patients and patients with type 2 diabetes. Am J Med. 2000:109:588-90.