Acute and Chronic Effects of the Incretin Enhancer Vildagliptin in Insulin-Resistant Rats

Burkey, Bryan F.; Li, Xue; Bolognese, Lori; Balkan, Börk; Mone, Manisha; Russell, Mary E.; Hughes, Thomas E.; Wang, Pei-Ran

doi:10.1124/jpet.105.087064

Cited by 102 publications

(82 citation statements)

References 32 publications

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“…6). This effect on insulin impairment has also been reported in GK and neonatal streptozotocin (nSTZ)-induced rats (in the case of SU agents) [12,13] as well as ZDF and ZF rats (in the case of DPP IV inhibitors) [2,25]. The results of our in vivo study on the effects agreed with the finding in isolated islets of SDT rats that insulin secretion is enhanced by tGLP-1 or tolbutamide stimulation (Fig.…”

Section: Discussionsupporting

confidence: 82%

Pancreatic Function of Spontaneously Diabetic Torii Rats in Pre-Diabetic Stage

et al. 2009

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Abstract:The Spontaneously Diabetic Torii (SDT) rat is a new model for non-obese type 2 diabetes. In the present study, we investigated changes in insulin secretion from the pancreas of male SDT rats aged 8, 16, and 24 weeks in order to analyze pancreatic function. An analysis of glucose-stimulated insulin secretion (GSIS) in isolated islets showed a marked reduction in insulin secretion in pre-diabetic 16-week-old SDT rats. When the islets were treated with tolbutamide or glucagon-like peptide-1 (7-36) amide (tGLP-1) in the presence of 11.2 mM glucose, however, insulin levels were restored to levels of normal rats. In vivo study, SDT rats exhibited a marked reduction in GSIS from 16 weeks of age. However, tolbutamide or JTP-76209, which is a novel dipeptidyl peptidase IV (DPP IV) inhibitor, increased insulin release after glucose loading and improved glucose tolerance. A marked reduction in GSIS was observed in pre-diabetic SDT rats and the reduction was improved by tolbutamide, tGLP-1, and the DPP IV inhibitor. Therefore, we concluded that the SDT rat is useful, as a model of non-obese insulin secretory disorder, for the analysis of the onset of type 2 diabetes and the development of antidiabetic agents.

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Section: Discussionsupporting

confidence: 82%

Pancreatic Function of Spontaneously Diabetic Torii Rats in Pre-Diabetic Stage

et al. 2009

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“…Previously we have shown that vildagliptin (also called LAF-237) improves glucose tolerance in high-fat fed glucose intolerant mice (25). Vildagliptin also has been shown to augment the insulin response to oral glucose and glucose tolerance in obese Zucker rats (20) and to improve glucose tolerance in ob/ob mice (26) and Zucker diabetic fatty rats (27). The antidiabetic action of vildagliptin relies on increased concentrations of active (intact) GLP-1, since DPP-4 inhibition prevents the inactivation of the incretin hormone (1-3).…”

Section: Discussionmentioning

confidence: 99%

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Åhrén

Winzell

Wierup

et al. 2007

Regulatory Peptides

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Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with β-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3µmol/mouse daily) to female mice with β-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated.Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located α-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with specific ß cell transgenic overexpression of human IAPP.

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“…At the end of the 12th week, rats in each group were divided into three subgroups (nZ10/subgroup) to receive vehicle (normal saline solution; 2 ml/kg per day), vildagliptin (Galvus, Novartis; 3 mg/kg per day), or sitagliptin (Januvia, MSD, Bangkok, Thailand; 30 mg/kg per day) (Chen et al 2011a) via gavage feeding for 21 days. It has been shown that 3 mg/kg per day of vildagliptin and 30 mg/kg per day of sitagliptin reduces peripheral insulin resistance in insulin-resistant and diabetic rat models (Burkey et al 2005).…”

Section: Animal Modelsmentioning

confidence: 99%

“…Recently developed oral anti-diabetic drugs, DDP-4 inhibitors including sitagliptin and vildagliptin, have been used to treat T2DM patients. Previous studies have shown that DDP-4 inhibitors decrease insulin resistance without causing severe hypoglycemia (Burkey et al 2005, Richter et al 2008, via prolonged levels of endogenous active GLP-1(7-36) amide (Rosenstock & Zinman 2007, Richter et al 2008. GLP-1 is an incretin hormone secreted from intestinal L-cells following nutrient digestion, which causes decreased glucagon secretion and increased insulin sensitivity (Baggio & Drucker 2007).…”

Section: Introductionmentioning

confidence: 99%

DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats

Pintana

Apaijai²,

Chattipakorn³

2013

Journal of Endocrinology

172

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Recent evidence has demonstrated that insulin resistance is related to the development of type 2 diabetes mellitus. Our previous study found that high-fat diet (HFD) consumption caused not only peripheral and brain insulin resistance but also brain mitochondrial dysfunction and cognitive impairment. Vildagliptin and sitagliptin, dipeptidyl-peptidase-4 inhibitors, are recently developed anti-diabetic drugs. However, the effects of both drugs on cognitive behaviors and brain mitochondrial function in HFD-induced insulin-resistant rats have not yet been investigated. Sixty male Wistar rats were divided into two groups to receive either normal diet or HFD for 12 weeks. Rats in each group were then further divided into three treatment groups to receive either vehicle, vildagliptin (3 mg/kg per day), or sitagliptin (30 mg/kg per day) for 21 days. The cognitive behaviors of the rats were tested using the Morris Water Maze test. Blood samples were collected to determine metabolic parameters and plasma oxidative stress levels. Upon completion of the study, the animals were killed and the brains were removed to investigate brain and hippocampal mitochondrial function as well as to determine oxidative stress levels. We demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in HFD-induced insulin-resistant rats. In addition, both drugs completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by the HFD. Our findings suggest that the inhibition of dipeptidyl-peptidase-4 enzymes with vildagliptin or sitagliptin in insulinresistant rats not only increases peripheral insulin sensitivity but also decreases brain dysfunction. Key Words" insulin resistance " high-fat diet " DDP-4 inhibitors " memory decline " brain mitochondrial dysfunction

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Acute and Chronic Effects of the Incretin Enhancer Vildagliptin in Insulin-Resistant Rats

Cited by 102 publications

References 32 publications

Pancreatic Function of Spontaneously Diabetic Torii Rats in Pre-Diabetic Stage

Pancreatic Function of Spontaneously Diabetic Torii Rats in Pre-Diabetic Stage

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats

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