Sitagliptin protects renal ischemia reperfusion induced renal damage in diabetes
TL;DR: The results of present investigation established sitagliptin treatment attenuated renal damage induced by renal ischemia reperfusion (I/R) in diabetic rats, and confirmed protection against renal I/R in diabetes.
About: This article is published in Regulatory Peptides.The article was published on 2011-01-17. It has received 99 citations till now. The article focuses on the topics: Sitagliptin Phosphate & Renal ischemia.
Citations
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TL;DR: The role of GLp-1 and the actions of associated therapies on glucose metabolism, the gut–renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM are reviewed.
Abstract: The gastrointestinal tract - the largest endocrine network in human physiology - orchestrates signals from the external environment to maintain neural and hormonal control of homeostasis. Advances in understanding entero-endocrine cell biology in health and disease have important translational relevance. The gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) is secreted upon meal ingestion and controls glucose metabolism by modulating pancreatic islet cell function, food intake and gastrointestinal motility, amongst other effects. The observation that the insulinotropic actions of GLP-1 are reduced in type 2 diabetes mellitus (T2DM) led to the development of incretin-based therapies - GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors - for the treatment of hyperglycaemia in these patients. Considerable interest exists in identifying effects of these drugs beyond glucose-lowering, possibly resulting in improved macrovascular and microvascular outcomes, including in diabetic kidney disease. As GLP-1 has been implicated as a mediator in the putative gut-renal axis (a rapid-acting feed-forward loop that regulates postprandial fluid and electrolyte homeostasis), direct actions on the kidney have been proposed. Here, we review the role of GLP-1 and the actions of associated therapies on glucose metabolism, the gut-renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM.
217 citations
TL;DR: Post-hoc analyses of phase II–III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents, but the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven.
Abstract: Dipeptidyl peptidase 4 (DPP-4) inhibitors (commonly referred to as gliptins) are a novel class of oral antihyperglycaemic agents with demonstrated efficacy in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data and mechanistic studies have indicated a possible beneficial action on blood vessels and the heart, via both glucagon-like peptide 1 (GLP-1)-dependent and GLP-1-independent effects. DPP-4 inhibition increases the concentration of many peptides with potential vasoactive and cardioprotective effects. Clinically, DPP-4 inhibitors improve several risk factors in patients with T2DM. They improve blood glucose control (mainly by reducing postprandial glycaemia), are weight neutral (or even induce modest weight loss), lower blood pressure, improve postprandial lipaemia, reduce inflammatory markers, diminish oxidative stress, and improve endothelial function. Some positive effects on the heart have also been described in patients with ischaemic heart disease or congestive heart failure, although their clinical relevance requires further investigation. Post-hoc analyses of phase II-III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents. However, the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven. Major prospective clinical trials with predefined cardiovascular outcomes and involving various DPP-4 inhibitors are now underway in patients with T2DM and a high-risk cardiovascular profile.
166 citations
TL;DR: Therapeutic agents from these two drug classes improve pancreatic islet function and induce extrapancreatic effects that ameliorate various phenotypic defects of type 2 diabetes mellitus that are beyond glucose control.
Abstract: Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, and is associated with a high risk of cardiovascular morbidity and mortality. Intensive control of glucose levels and blood pressure is currently the mainstay of both prevention and treatment of diabetic nephropathy. However, this strategy cannot fully prevent the development and progression of diabetic nephropathy, and an unmet need remains for additional novel therapies. The incretin-based agents--agonists of glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades glucagon-like peptide 1--are novel blood-glucose-lowering drugs used in the treatment of type 2 diabetes mellitus (T2DM). Therapeutic agents from these two drug classes improve pancreatic islet function and induce extrapancreatic effects that ameliorate various phenotypic defects of T2DM that are beyond glucose control. Agonists of GLP-1R and inhibitors of DPP-4 reduce blood pressure, dyslipidaemia and inflammation, although only GLP-1R agonists decrease body weight. Both types of incretin-based agents inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in rodents and humans. In rodents, incretin-based therapies also prevent onset of the morphological abnormalities of diabetic nephropathy.
160 citations
TL;DR: Chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication.
Abstract: This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker diabetic fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea, and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semiquantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0–2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c, and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial, and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication.
150 citations
Cites background or result from "Sitagliptin protects renal ischemia..."
...(2011) which have reported a significant decrease in renal lipidic peroxidation by sitagliptin in diabetic rats with renal damage [53]....
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...…reduced amount of lipid peroxidation, which might be further confirmed with additional parameters, but that is in agreement with recent studies from Vaghasiya et al. (2011) which have reported a significant decrease in renal lipidic peroxidation by sitagliptin in diabetic rats with renal damage…...
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TL;DR: It is demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in HFD-induced insulin-resistant rats and completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by the HFD.
Abstract: 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 insulin-resistant rats not only increases peripheral insulin sensitivity but also decreases brain dysfunction.
149 citations
Cites background from "Sitagliptin protects renal ischemia..."
...Increased plasma GLP-1 levels have been shown to increase insulin sensitivity, increase insulin secretion, but decrease plasma cholesterol and plasma MDA levels (D’Alessio et al. 1994, Pospisilik et al. 2002, Vaghasiya et al. 2010)....
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References
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TL;DR: In this article, the catalytic activity of catalase has been investigated using ultraviolet (UV) spectrophotometry and Titrimetric methods, which is suitable for comparative studies for large series of measurements.
Abstract: Publisher Summary Catalase exerts a dual function: (1) decomposition of H 2 O 2 to give H 2 O and O 2 (catalytic activity) and (2) oxidation of H donors, for example, methanol, ethanol, formic acid, phenols, with the consumption of 1 mol of peroxide (peroxide activity) The kinetics of catalase does not obey the normal pattern Measurements of enzyme activity at substrate saturation or determination of the K s is therefore impossible In contrast to reactions proceeding at substrate saturation, the enzymic decomposition of H 2 O 2 is a first-order reaction, the rate of which is always proportional to the peroxide concentration present Consequently, to avoid a rapid decrease in the initial rate of the reaction, the assay must be carried out with relatively low concentrations of H 2 O 2 (about 001 M) This chapter discusses the catalytic activity of catalase The method of choice for biological material, however, is ultraviolet (UV) spectrophotometry Titrimetric methods are suitable for comparative studies For large series of measurements, there are either simple screening tests, which give a quick indication of the approximative catalase activity, or automated methods
20,238 citations
TL;DR: Glutathione peroxidase activity is found to be associated with a relatively stable, nondialyzable, heat-labile, intracellular component which is separable from hemoglobin, by gel filtration and ammonium sulfate precipitation.
10,439 citations
"Sitagliptin protects renal ischemia..." refers methods in this paper
...The clear supernatant was used for assays of lipid peroxidation (MDA content) [19] and endogenous antioxidant enzymes like reduced glutathione (GSH) [20], superoxide dismutase (SOD) [21], catalase (CAT) [22], and glutathione peroxidase (GSHPx) [23]....
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TL;DR: It is proposed that the autoxidation of epinephrine proceeds by at least two distinct pathways, only one of which is a free radical chain reaction involving O2- and hence inhibitable by superoxide dismutase.
7,872 citations
"Sitagliptin protects renal ischemia..." refers methods in this paper
...The results of the present work demonstrated, sitagliptin treatment caused decrease in lipid peroxidation in renal tissue after renal I/R. Antioxidant enzymes like GSH, GSHPx, CAT and SOD were increased after sitagliptin treatment, followed by renal damage in diabetic rats....
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...05), SOD (pb0....
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...The clear supernatant was used for assays of lipid peroxidation (MDA content) [19] and endogenous antioxidant enzymes like reduced glutathione (GSH) [20], superoxide dismutase (SOD) [21], catalase (CAT) [22], and glutathione peroxidase (GSHPx) [23]....
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...001), SOD (pb0....
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TL;DR: This chapter discusses methods to determine carbonyl content in oxidatively modified proteins and quantitated protein-bound pyruvoyl groups through formation of a Schiff base with p-aminobenzoic acid followed by reduction with cyanoborohydride.
Abstract: Publisher Summary This chapter discusses methods to determine carbonyl content in oxidatively modified proteins. The methods described are (1) reduction of the carbonyl group to an alcohol with tritiated borohydride; (2) reaction of the carbonyl group with 2,4-dinitrophenylhydrazine to form the 2,4-dinitrophenylhydrazone; (3) reaction of the carbonyl with fluorescein thiosemicarbazide to form the thiosemicarbazone; and (4) reaction of the carbonyl group with fluorescein amine to form a Schiff base followed by reduction to the secondary amine with cyanoborohydride. Van Poelje and Snell have also quantitated protein-bound pyruvoyl groups through formation of a Schiff base with p-aminobenzoic acid followed by reduction with cyanoborohydride. Although a systematic investigation has not appeared, this method should also be useful in detecting other protein-bound carbonyl groups. Carbonyl content of proteins is expressed as moles carbonyl/mole subunit for purified proteins of known molecular weight. For extracts, the results may be given as nanomoles carbonyl/milligram protein. For a protein having a molecular weight of 50,000, a carbonyl content of 1 mol carbonyl/mol protein corresponds to 20 nmol carbonyl/mg proteins.
5,408 citations
"Sitagliptin protects renal ischemia..." refers background in this paper
...Demonstration of lipid peroxidation helps to explain better the exact mechanism of effect of renal I/R on renal tissue, and it was found significantly higher in our study, indicating generation of oxidative stress [28]....
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TL;DR: The activities of some glutathione-metabolizing enzymes were observed to be 5-to 60-fold lower in lung tissue than in the liver, and that phenobarbital nor methylcholanthrene had a significant effect on the levels of reduced glutATHione in lung and liver.
3,842 citations
"Sitagliptin protects renal ischemia..." refers methods in this paper
...The results of the present work demonstrated, sitagliptin treatment caused decrease in lipid peroxidation in renal tissue after renal I/R. Antioxidant enzymes like GSH, GSHPx, CAT and SOD were increased after sitagliptin treatment, followed by renal damage in diabetic rats....
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...Renal I/R in diabetic rats resulted in a significant decrease in renal tissue GSH (pb0....
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...Diabetic animals that underwent renal I/R demonstrated significant decrease in renal tissue GSHPx (pb0....
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...05), GSHPx (pb0....
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...The clear supernatant was used for assays of lipid peroxidation (MDA content) [19] and endogenous antioxidant enzymes like reduced glutathione (GSH) [20], superoxide dismutase (SOD) [21], catalase (CAT) [22], and glutathione peroxidase (GSHPx) [23]....
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