Effect of Dipeptidyl Peptidase-IV (DPP-IV) Inhibitor (Vildagliptin) on Peripheral Nerves in Streptozotocin-induced Diabetic Rats

Jin, Heung Yong; Liu, Wei Jing; Park, Ji Hyun; Baek, Hong Sun; Park, Tae Sun

doi:10.1016/j.arcmed.2009.09.005

Cited by 76 publications

(76 citation statements)

References 29 publications

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“…LAF237 (4 or 8 mg/day) treatment did not significantly attenuate the changes. Plasma insulin content remained at rather low levels in STZ-induced diabetic rats in our study, indicating that single DPP IV inhibitor therapy had less of a hypoglycemic effect in STZ-induced type 1 diabetes than typical type 2 diabetes (Jin et al, 2009) (Table 1).…”

Section: Resultsmentioning

confidence: 83%

“…Thus, in addition to the inhibition of DPP IV activity, enhancement of the circulating level of active GLP-1 by binding GLP-1R to mediate several pathological processes represents another possible mechanism underlying the observed renoprotection. Therapeutic intervention based on GLP-1 pathways, such as GLP-1 level elevation and receptor activation, has been shown to have a beneficial effect on diabetic neu- ropathy and retinopathy (Jin et al, 2009;Zhang et al, 2009). In insulin-resistant obese men, intravenous infusions of GLP-1 reduce glomerular hyperfiltration and enhance sodium excretion, suggesting an action mediated by GLP-1R in the kidneys (Gutzwiller et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…These findings indicate that the change of DPP IV in urine is probably associated with diabetic nephropathy. DPP IV inhibitors or incretin-based agents reportedly ameliorate diabetic neuropathy and retinopathy, at least in part, through delaying the degradation of GLP-1 and its binding affinity to the GLP-1R (Jin et al, 2009;Zhang et al, 2009). These observations suggest that DPP IV inhibitors, partly by increasing GLP-1 level, can exert renoprotective effects in the hyperglycemic state, because dia-betic nephropathy has a close relationship with other diabetic microvascular complications (Girach and Vignati, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Liu¹,

Xie²,

Liu³

et al. 2011

J Pharmacol Exp Ther

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198

164

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Dipeptidyl peptidase (DPP) IV inhibitors are probably beneficial for preventing diabetic complication and modulating glucagonlike peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine whether the DPP IV inhibitor LAF237 (vildagliptin) has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and nondiabetic rats were treated with an oral dose of 4 or 8 mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, active GLP-1 level, cAMP and 8-hydroxy-deoxyguanosine excretion, and GLP-1R, cleaved caspase 3, and transforming growth factor-␤1 (TGF-␤1) expression. LAF237 significantly decreased proteinuria, albuminuria, and urinary albumin/creatinine ratio, improved creatinine clearance, and dose-dependently inhibited interstitial expansion, glomerulosclerosis, and the thickening of the glomerular basement membrane in diabetic rats. It is noteworthy that LAF237 markedly down-regulated DPP IV activity and increased active GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating the GLP-1R and modulating cAMP. Renoprotection was also associated with a reduction in TGF-␤1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-␤1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.

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Section: Resultsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Liu¹,

Xie²,

Liu³

et al. 2011

J Pharmacol Exp Ther

Self Cite

198

164

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“…GLP-1 receptor activation was reported to be associated with both histological and functional improvements in a rat model of pyridoxine-induced peripheral sensory neuropathy [83]. Diabetesinduced peripheral nerve degeneration was reduced in studies using a GLP-1 receptor agonist or a DPP-4 inhibitor to enhance endogenous GLP-1 levels [84,85], while hyperglycemia-induced reductions of motor nerve conduction velocity were attenuated by GLP-1 receptor agonism in diabetic mice [86]. However, as yet, no studies have addressed potential neuroprotective properties of GLP-1 in humans.…”

Section: Incretin Hormone Actionmentioning

confidence: 99%

Physiology of Incretins in Health and Disease

Deacon

Åhrén²

2011

Rev Diabet Stud

112

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■ AbstractThe incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gut peptides which are secreted by endocrine cells in the intestinal mucosa. Their plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.

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“…These samples were then embedded in JB-4 solution (Polysciences, Inc., Eppelheim, Germany), and transverse sections with a thickness of 1.5 mm were stained with toluidine blue. Immunohistochemical staining was done as previously described (18). Skin tissue specimens were fixed with periodate-lysine-paraformaldehyde (PLP) (2% paraformaldehyde, 0.075 m lysine, 0.05 m phosphate buffer pH 7.4, and 0.01 m sodium m-periodate) solution for 24 h. After thorough rinsing in PBS containing 20% glycerol-0.1 m phosphate buffer for 48 h at 4˚C, the tissue specimens were cryoprotected with Tissue-Tec ® (OCT compound) (Miles, Elkhart, IN).…”

Section: The Measurement Of Levels Of Ngf Tumor Necrosis Factor (Tnfmentioning

confidence: 99%

The Protective Effects of DA-9801 (Dioscorea Extract) on the Peripheral Nerves in Streptozotocin-Induced Diabetic Rats

Lee

Jin

Baek

et al. 2013

J Nutr Sci Vitaminol

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Summary It has been reported that DA-9801, an extract mixture of Dioscorea japonica Thunb and Dioscorea nipponica Makino, produces a neurotrophic activity. Therefore, this study was conducted to examine the neuroprotective effects of DA-9801 in streptozotocininduced diabetic rats. The experimental rats were divided into six groups: the control group, Group I (non-diabetic rats treated with DA-9801), Group II (diabetic, non-treated rats) and Groups III, IV, and V (diabetic rats treated with DA-9801 at doses of 10, 50 or 100 mg/ kg/d). Following a 16-wk course of oral treatment with DA-9801, functional parameters (von Frey filament test, hot plate test), biochemical parameters (nerve growth factor (NGF), tumor necrosis factor (TNF)-a, interleukin (IL)-6) were measured. An immunohistochemical staining was done to assess the neuroprotective effects of DA-9081 in the skin, sciatic nerve, gastric mucosa and renal cortex. In Week 8, pain was evoked by either tactile or thermal stimuli, whose threshold was significantly higher in Group III, IV and V than Group II. Western blot analysis showed a more significant increase in NGF and decrease in TNF-a and IL-6 in Group III, IV and V than in Group II (p,0.05). Moreover, following the treatment with DA-9801, a loss of intraepidermal nerve fibers (IENFs) was inhibited to a significant level in the skin, myelinated axonal fibers of the sciatic nerve and small nerve fibers innervating the gastric mucosa or renal cortex (p,0.05). Our results demonstrated that DA-9801 is a beneficial agent that protects the peripheral nerves in diabetic rats.

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Effect of Dipeptidyl Peptidase-IV (DPP-IV) Inhibitor (Vildagliptin) on Peripheral Nerves in Streptozotocin-induced Diabetic Rats

Cited by 76 publications

References 29 publications

Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Physiology of Incretins in Health and Disease

The Protective Effects of DA-9801 (Dioscorea Extract) on the Peripheral Nerves in Streptozotocin-Induced Diabetic Rats

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