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Interleukin (IL)-1[beta], the sole proinflammatory cytokine released from pancreas-infiltrating macrophages, inhibits glucose-stimulated insulin secretion (GSIS), causing hyperglycemia in Cohen diabetes-sensitive (CDs) rats fed a diabetogenic-diet (CDs-HSD). Because IL-1[beta] blockade is a potential therapeutic target in diabetes, we examined whether treating CDs rats with IL-1[beta] antibody (IL-1[beta]Ab; 0.5 mg/kg body weight) could counteract the inhibition of GSIS and hyperglycemia. We found that daily IL-1[beta]Ab injections had a beneficial effect on glucose tolerance and insulin secretion in CDs-HSD rats. In the oral glucose tolerance test, IL-1[beta]Ab-treated CDs-HSD rats showed lower blood glucose concentrations (P < 0.001) and higher GSIS (P < 0.05) compared with nontreated CDs-HSD rats. IL-1[beta]Ab treatment also protected the exocrine pancreas; the number of infiltrating macrophages decreased by 70% (P < 0.01) and IL-1[beta] expression decreased by 85% (P < 0.01). In parallel, a 50% reduction (P < 0.01) in the rate of apoptosis and in fat infiltration (P < 0.05) was noted in the exocrine parenchyma of IL-1[beta]Ab-treated CDs-HSD rats compared with nontreated CDs-HSD rats. Altogether, these data demonstrate that blocking IL-1[beta] action by IL-1[beta]Ab counteracted [beta]-cell dysfunction and glucose intolerance, supporting the notion that prevention of pancreas infiltration by macrophages producing IL-1[beta] is of crucial importance for the preservation of [beta]-cell function and prevention of diabetes. [ABSTRACT FROM AUTHOR]

The article discusses a randomized controlled study on the safety and efficacy of sulodexide, a glycosaminoglycans, in the treatment of diabetic nephropathy with microalbuminuria on maximal therapy with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The study showed a strong trend favoring sulodexide in lowering urine albumin excretion. There were similarity in incidence and type of adverse events among the subjects.

The article focuses on the findings of a study on the effect of the oral administration of sulodexide for the treatment of diabetic nephropathy on coagulation or fibrinolytic activity. It notes that the activity of sulodexide can be evaluated in-vitro through the use of anti-Xa and anti-IIa assays. It mentions that there were no statistically significant differences in fibrinolytic activity that were detected in either the placebo or sulodexide treated group.

The incidence of diabetes has been rapidly escalating in the past decades. One major hurdle for diabetes prevention and care is the absence of reliable surrogate markers to predict disease long before disruption in blood glucose regulation is evident. Such an early test will enable the mitigation and perhaps the complete elimination of the grave, multi organ damage inflicted by type 2 diabetes (T2D). We applied various proteomics approaches to identify disease-specific biomarkers in serum samples from Cohen Diabetic (CD) Rat Model, as well as from ethnically homogeneous T2D patients and matched healthy individuals participating in a 30 year study. The CD rat model is model manifesting many common clinical features exhibited by non-obese, T2D patients. The CD rat serum samples were profiled using Surface-Enhanced Laser Desorption/Ionization mass spectrometry (SELDI), two-dimensional liquid chromatography (2D/LC) and 2-dimensional gel electrophoresis (2DE). The candidate protein markers were sequenced using liquid chromatography tandem mass spectrometry (LC/MS/MS). A pattern of differentially expressed proteins emerged. The panel included over 20 distinct biomarkers and consisted of proteins associated with lipid metabolism (Apolipoprotein C-III precursor, Apolipoprotein C2, A, polipoprotein A-1, Apolipoprotein E, and Liver regneration-related protein), inflammatory mediators (Complement component C9), protease inhibitors (Thrombin, Serpin A, 3M, LMW T-kininogen I precursor, inter-alpha-inhibitor H4 heavy chain, and α 2 macroglobulin), Insulin signaling (Feutin) and several unknown proteins. A protein member of serpina family was shown to be upregulated in CD resistant rats, indicating a potential novel mechanism in the development of T2D through modification of insulin signaling pathway-related proteins. A pilot profile of differentially expressed biomarkers (p<0.001) with various molecular weights were delineated for human serum samples such as 6.45 kDa, (downregulated in T2D) and 10 kDa (upregulated in T2D). Studies to characterize these candidate disease-specific biomarkers and elucidate their functions are underway. [ABSTRACT FROM AUTHOR]

The Cohen diabetic (CD) rat is a versatile animal model comprised of 2 rodent swains that manifest many of the common features of type 2 diabetes (T2D) in humans. The sensitive swain (CDs) develops diabetes within 30 days when maintained on a high sucrose/copper poor diet (HSD), whereas the resistant strain (CDr) retains normal blood glucose levels. Neither strain shows any signs of diabetes when provided regular rodent diet (RD). To further characterize the genomic and proteomic changes responsible for either resistance or predisposition to T2D, pancreatic transcriptome changes of these two strains were studied by microarray analyses using the rat expression arrays (Affymetrix). Of 1178 transcripts upregulated at least three folds, 352 transcripts have been reported to be involved in T2D-related signaling pathways or metabolisms. Such transcripts include 39 markers related to insulin signaling and several others related lipid and glucose pathways, protein modifications and proteinase inhibitors and amino acid transporters. While several of these markers have been previously reported in human diabetic patients and mouse models, others, whose role in the development of the disease remain unknown, will be analyzed further. Moreover, several proteinases and proteinase inhibitors including members of serpina family were observed as upregulated genes in Cohen diabetic resistance rats, indicating a potential novel mechanism in the development of T2D through modification of insulin signaling pathway-related proteins or related receptors. In conclusion, our analyses using the Cohen rat models could indicate novel modification mechanism involved in T2D. Quantitative analyses of individual transcripts as well as modifications of their respective proteins will determine the role of such transcripts in the development of the disease and will contribute in the selection of a handful of predictive markers for the progression or resistance of the disease. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a major cause of morbidity and mortality in patients with diabetes. Diabetes is the most common cause of end-stage renal disease (ESRD). Despite advances in clinical care, including improvements in glycemic and blood pressure control, the number of new cases of diabetes-related ESRD continues to increase. The characteristic glomerular abnormalities of DN can be divided into two categories: pathological alterations of the renal filtering mechanism and mesangial expansion involving increases in mesangial matrix and in the mesangial cellular compartment. It is generally recognized that the lowering of pathological urinary albumin has clinical benefit in patients with DN. A retrospective analysis of 12 clinical trials suggests that sulodexide has potential to make a majorpositive impact in the lives of patients with DN facing eventual complications of ESRD. A total of 12 studies enrolling approximately 600 patients with diabetes comprise the clinical database used to evaluate the potential of sulodexide in the treatment of DN. Seven of the studies were rather short in duration, 2 months or less. Five of the studies treated patients for four months or greater. In all of these studies, it has been shown that sulodexide has anti-albuminuric effects and lower albumin excretion ratio in patients with diabetes and either microalbtuninuria or macroalbumlnuria, ha most of these studies it was demonstrated that the effect of sulodexide on reducing albuminuria was sustained up to four months after cessation of treatment; strongly suggesting that a biochemical-anatomic remodeling is potentially initiated in renal tissue by sulodexide. The safety profile of sulodexide from these 12 clinical studies suggests that both im and oral administered dose of sulodexide ranging from 50 mg to 400 mg is well tolerated and safe. [ABSTRACT FROM AUTHOR]

The Cohen diabetic (CD) rat is a versatile animal model comprised of 2 rodent strains that manifest many of the common features of type 2 diabetes (T2D) in humans. The sensitive strain (CDs) develops diabetes within 30 days when maintained on a high sucrose/copper poor diet (HSD), whereas the resistant strain (CDr) retains normal blood glucose levels. Neither strain shows any signs of diabetes when provided regular rodent diet (RD). We aimed to conduct protein expression profiling of the CDr and CDs phenotypes, using electrophoresis and bi-directional immunological contrasting, to better understand the critical molecules involved in the disease development process, and to determine their roles in resistance or sensitivity to T2D in this model. Studies were implemented using whole cell extracts were prepared from pancreas, heart, spleen, kidney and muscle tissues obtained from both CDr and CDs rats fed either RD or HSD for 30 days. Using CDr-HSD and CDs-HSD pancreatic extracts and a proprietary immunization strategy, we developed a panel of murine monoclonal antibodies (mAbs) directed against differentially expressed proteins. Of 133 total hybridoma clones, 13 produced mAbs that were uniquely specific for only one of the pancreatic extracts by ELISA(4 against CDr-HSD and 9 against CDs-HSD). Using immunoblotting, we have identified several differentially expressed species: 50 kDa, 55 kDa and 60kDa proteins that are only evident in CDs-HSD pancreas, and a 75 and 80 kDa doublet with down regulated expression in CDs-HSD rats, particularly the 80 kDa isoform. Work is continuing to identify these differentially expressed biomarkers using trypsin digestion and liquid chromatography tandem mass spectrometry in an effort to determine their respective roles in resistance or susceptibility to disease. [ABSTRACT FROM AUTHOR]