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Urinary protein profiles in a rat model for diabetic complications.

ABSTRACT: Diabetes mellitus is estimated to affect approximately 24 million people in the United States and more than 150 million people worldwide. There are numerous end organ complications of diabetes, the onset of which can be delayed by early diagnosis and treatment. Although assays for diabetes are well founded, tests for its complications lack sufficient specificity and sensitivity to adequately guide these treatment options. In our study, we employed a streptozotocin-induced rat model of diabetes to determine changes in urinary protein profiles that occur during the initial response to the attendant hyperglycemia (e.g. the first two months) with the goal of developing a reliable and reproducible method of analyzing multiple urine samples as well as providing clues to early markers of disease progression. After filtration and buffer exchange, urinary proteins were digested with a specific protease, and the relative amounts of several thousand peptides were compared across rat urine samples representing various times after administration of drug or sham control. Extensive data analysis, including imputation of missing values and normalization of all data was followed by ANOVA analysis to discover peptides that were significantly changing as a function of time, treatment and interaction of the two variables. The data demonstrated significant differences in protein abundance in urine before observable pathophysiological changes occur in this animal model and as function of the measured variables. These included decreases in relative abundance of major urinary protein precursor and increases in pro-alpha collagen, the expression of which is known to be regulated by circulating levels of insulin and/or glucose. Peptides from these proteins represent potential biomarkers, which can be used to stage urogenital complications from diabetes. The expression changes of a pro-alpha 1 collagen peptide was also confirmed via selected reaction monitoring.

SUBMITTER: Schlatzer DM

PROVIDER: S-EPMC2742441 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Urinary protein profiles in a rat model for diabetic complications.

Schlatzer Daniela M DM Dazard Jean-Eudes JE Dharsee Moyez M Ewing Rob M RM Ilchenko Serguei S Stewart Ian I Christ George G Chance Mark R MR

Molecular & cellular proteomics : MCP 20090604 9

Diabetes mellitus is estimated to affect approximately 24 million people in the United States and more than 150 million people worldwide. There are numerous end organ complications of diabetes, the onset of which can be delayed by early diagnosis and treatment. Although assays for diabetes are well founded, tests for its complications lack sufficient specificity and sensitivity to adequately guide these treatment options. In our study, we employed a streptozotocin-induced rat model of diabetes t ...[more]

PMID: 19497846

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Project description:BackgroundType 2 diabetes (T2D) in lean individuals is not well studied and up to 26% of diabetes occurs in these individuals. Although the cause is not well understood, it has been primarily attributed to nutritional issues during early development.ObjectiveOur objective was to develop a lean T2D model using gestational low-protein (LP) programming.Study designPregnant rats were fed control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery. Standard diet was given to dams after delivery and to pups after weaning. Glucose tolerance test was done at 2, 4, and 6 months of age. Magnetic resonance imaging of body fat for females was done at 4 months. Rats were sacrificed at 4 and 8 months of age and their perigonadal, perirenal, inguinal, and brown fat were weighed and expressed relative to their body weight. Euglycemic-hyperinsulinemic clamp was done around 6 months of age.ResultsMale and female offspring exposed to a LP diet during gestation developed glucose intolerance and insulin resistance (IR). Further, glucose intolerance progressed with increasing age and occurred earlier and was more severe in females when compared to males. Euglycemic-hyperinsulinemic clamp showed whole body IR in both sexes, with females demonstrating increased IR compared to males. LP females showed a 4.5-fold increase in IR while males showed a 2.5-fold increase when compared to their respective controls. Data from magnetic resonance imaging on female offspring showed no difference in the subcutaneous, inguinal, and visceral fat content. We were able to validate this observation by sacrificing the rats at 4 and 8 months and measuring total body fat content. This showed no differences in body fat content between control and LP offspring in either males or females. Additionally, diabetic rats had a similar body mass index to that of the controls.ConclusionLP gestational programming produces a progressively worsening T2D model in rats with a lean phenotype without obesity.

Project description:Background and objectivesIn the present article, we explore a novel strategy of selenium nanoparticles (Se-NPs) for the treatment of type 2 diabetes mellitus (T2DM) by investigating the effect of Se-NPs alone and in combination with standard anti-diabetic drug metformin (MET) in high-fat diet/streptozotocin (HFD/STZ)-induced T2DM.MethodsHFD was supplemented daily to experimental rats for 8 weeks, followed by a single low dose injection of 35 mg/kg of STZ to induce T2DM. The synergistic effect of the different therapeutic strategies on diabetic complications was evaluated after the Se-NPs and MET administration for 8 weeks. Molecular and biochemical analyses were conducted to figure out the effectiveness of our treatment on insulin sensitivity, oxidative mediators and inflammatory markers.ResultsOur observations demonstrated that HFD/STZ-induced rats have a toxic effect on serum and hepatic tissues resulted in inducing remarkable oxidative damage and hyper-inflammation with a significant disturbance in the insulin signaling pathway. Experimental animals either treated with mono-therapeutic-two doses Se-NPs (0.1 and 0.4 mg/kg) and/or MET (100 mg/kg) alone as well as the combined therapy resulted in a remarkable protective anti-diabetic effect illustrated by significant decreases in fasting blood glucose and insulin levels after 8 weeks treatment. At the same time, the levels of active insulin signaling proteins pIRS1/pAKT/pGSK-3β/pAMPK were significantly improved. Moreover, Se-NPs exhibited an anti-inflammatory effect by the mitigation of cytokine expression and a balance between oxidative stress and antioxidant status was restored. Furthermore, the anti-diabetic drug MET administration also exhibited a significant improvement in diabetic complications after the treatment period.ConclusionThis study provides mightily the mechanism of action of combined Se-NPs and MET as a promising therapeutic alternative that synergistically alleviates most of diabetic complications and insulin resistance.

Project description:Aims/introductionTo investigate the protective effect of Polygonatum sibiricum polysaccharide (PSP) on the retina in diabetic rats.Materials and methodsA total of 120 Sprague-Dawley rats were randomly divided into blank control, control model (meaning diabetes mellitus), and diabetes mellitus with PSP intervention of high, medium and low doses groups. The difference of retinal vascularization between groups was evaluated by fluorescein isothiocyanate-dextran perfusion. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was used to assess apoptosis in the retinal ganglion cells; reverse transcriptase polymerase chain reaction and western blotting were utilized to evaluate the expression of Bcl2-associated X protein, B-cell lymphoma-2 factor, epidermal growth factor, p38 mitogen-activated protein kinases, transforming growth factor-β and vascular endothelial growth factor at the messenger ribonucleic acid and protein level.ResultsFluorescein isothiocyanate-dextran perfusion showed retinal vascular anomaly in diabetes mellitus rats, but vascular tortuosity and leakage were relatively alleviated after PSP intervention. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining showed numerous terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive retinal cells in the diabetes mellitus group, which then were reduced by PSP treatment. Reverse transcriptase polymerase chain reaction showed that PSP intervention decreased Bcl2-associated X protein, epidermal growth factor, p38 mitogen-activated protein kinases, vascular endothelial growth factor and transforming growth factor-β messenger ribonucleic acid expression, but increased B-cell lymphoma-2 factor messenger ribonucleic acid expression. Western blot showed that PSP intervention upregulated the expression of B-cell lymphoma-2 factor, and downregulated the expression of Bcl2-associated X protein, epidermal growth factor, p38 mitogen-activated protein kinases, vascular endothelial growth factor and transforming growth factor-β proteins.ConclusionsPolygonatum sibiricum polysaccharide shows a protective effect against diabetes-induced retinal injury in a dose-dependent manner. The mechanism of action deserves further study and exploration.

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Urinary protein profiles in a rat model for diabetic complications.

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Urinary protein profiles in a rat model for diabetic complications.

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