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Objectives: Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy., Background: SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart., Methods: We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress., Results: Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected., Conclusions: In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism., Competing Interests: Declaration of competing interest N.M. has received support for clinical trial leadership from Boehringer Ingelheim, N.M. has served as a consultant to Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk and has received grant support from Boehringer Ingelheim and MSD. In addition, N.M. has served as speaker for Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk. N.M. declines all personal compensation from pharma or device companies. M.L. has received grant support for experimental and clinical studies from Boehringer Ingelheim and MSD; has served as a consultant to Boehringer Ingelheim, Sanofi-Aventis, MSD, AstraZeneca, Lilly, NovoNordisk, Amgen and Bayer. Has served as a speaker for Boehringer Ingelheim Sanofi-Aventis, MSD, AstraZeneca, Lilly, NovoNordisk and Bayer. S.V. has received speaker honoraria from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, and Sanofi; and received research grant support from Amgen, AstraZeneca, Boehringer Ingelheim, and Eli Lilly. G.D.L.: shareholder in Metabolic Modulators Research Ltd., received grant support from Servier, Boehringer Ingelheim, Sanofi, REMED Biopharmaceuticals. K.S. has received grant support for experimental studies from Boehringer Ingelheim and has served as speaker for Boehringer Ingelheim, Amgen, MSD, Omniamed and NovoNordisk. All other authors report no relevant disclosures., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Establishment of noninvasive and efficient islet transplantation site together with the avoidance of immunosuppressive drugs for islet engraftment is currently the two major tasks for islet transplantation approach to treat patients with type 1 diabetes. Here, we proposed a method to achieve long-term allogeneic islet graft function without immunosuppression after transplantation in subcutaneous sites. Two agarose rods with basic fibroblast growth factor and heparin were implanted for 1 week in dorsal subcutaneous sites in diabetic rats. After rod removal, 1500 islets were transplanted into the prevascularized pockets. Islets transplanted in prevascularized but not nontreated subcutaneous sites rapidly reverted hyperglycemia in all streptozotocin-induced diabetic rats. In contrast to transient normalization of blood glucose when allogeneic islets were transplanted into liver, allogeneic islets transplanted into this prevascularized subcutaneous site demonstrated long-term graft survival and function in all three rat strain combinations (Fisher 344 to ACI, Lewis to ACI and Fisher 344 to Wistar), evidenced by nonfasting blood glucose level, plasma insulin concentration, intraperitoneal glucose tolerance test and immunohistochemistry. These results indicated that a subcutaneous site prevascularized by this method is potentially a suitable site for successful allogeneic islet transplantation without immunosuppression., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Increased myocyte apoptosis in diabetic hearts has been previously reported. The purpose of this study was to evaluate the effects of exercise training on cardiac survival pathways in streptozotocin (STZ)-induced diabetic rats., Methods: Forty-eight male Wistar rats were randomly divided into control group (Control), STZ-induced (65 mg/kg, i.p.) diabetes (DM), and DM rats with moderate aerobic exercise training (DM-EX) on a treadmill 60 min/day, 5 days/week, for 10 weeks. Histopathological analysis, positive TUNEL assays and Western blotting were performed on the excised cardiac left ventricles from all three groups., Results: The components of cardiac survival pathway (insulin-like growth factor I (IGFI), IGFI-receptor (IGFI-R), phosphatidylinositol 3'-kinase (PI3K), and Akt) and the pro-survival Bcl-2 family proteins (Bcl-2, Bcl-xL, and p-BAD) were all significantly decreased in the DM group compared with the Control group whereas they were increased in the DM-EX group. In addition, the abnormal myocardial architecture, enlarged interstitial space and increased cardiac TUNEL-positive apoptotic cells were observed in the DM group, but they were reduced in the DM-EX group. The apoptotic key component, caspase-3, was significantly increased in the DM group relative to the Control group whereas it was decreased in the DM-EX group., Conclusions: Exercise training enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways, which provides one of the new beneficial effects for exercise training in diabetes., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Effect of HMGCoA Reductase Inhibitors on Cardiac Remodelling and Mortality in Rats. Following Hyperglycemia and Myocardial Infarction., Aims: The presence of diabetes mellitus (DM) in patients with myocardial infarction (MI) increases mortality, due in part to the presence of known cardiovascular risk factors. However little is known about the impact of DM on cardiac remodelling and on clinical outcomes. We aimed to investigate whether hyperglycaemia may adversely and additionally affect LV remodelling post-MI, and whether the addition of a statin, known to reduce mortality both post MI and in humans with DM, has an effect on these outcomes., Methods: Eight week old Sprague-Dawley rats were allocated to 5 groups--control (non-DM)/sham, control-MI, DM-sham, DM-MI and DM-MI with statin gavage (DM-MI/ATV). Echocardiogram and invasive pressure volume analysis were performed prior to sacrifice for estimation of cardiac function. Tissue was analysed for total cardiac collagen, collagen I and III., Results: Hyperglycaemia in the remodelling period significantly increased mortality (70% survival in the C-MI group vs 27% in the DM-MI group), worsened cardiac function and increased fibrosis. All of these variables were attenuated by the addition of a statin., Conclusion: Hyperglycaemia increased mortality in MI and exacerbated LV remodeling, and this was attenuated with statin use. This study confirms the importance of early and intensive treatment of hyperglycaemia in patients with MI and suggests that in humans with both DM and MI the addition of a statin may be beneficial., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

This study was designed to investigate the effects of dietary fish oil on survival rates, plasma amino acid profiles, and inflammatory-related mediators in diabetic rats with sepsis. Diabetes mellitus (DM) was induced in rats by streptozotocin. The DM rats were maintained for 4 weeks on medium fat (10%, w/w) diets containing either fish oil or safflower oil. After that, sepsis was induced by cecal ligation and puncture (CLP). There were 2 groups in this study: fish oil sepsis group (FOS) and safflower oil sepsis group (SOS). The survival rate was observed after CLP. Also, changes of the amino acid pattern as well as interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, prostaglandin (PG) E(2)at 6, 12, and 24 h after CLP were investigated. The results demonstrated that survival rates were not significantly different between the 2 groups. Plasma arginine levels were significantly lower in sepsis groups than that in the DM-chow group, regardless of whether the diabetic rats were fed fish oil or safflower oil. No significant differences were observed in plasma valine, leucine, isoleucine, glutamine, or arginine concentrations between the FOS and SOS groups at different time points. Concentrations of IL-1 beta in peritoneal lavage fluid (PLF) at 6 h and TNF-alpha at 6 h as well as at 12 h after CLP in the FOS group were significantly higher than those in the SOS group. PGE(2)levels in PLF, by contrast, were lower in the FOS group at 6 and 12 h after CLP than in the SOS group. These results suggest that differences in IL-1 beta, TNF-alpha, and PGE(2)levels in PLF in the early period of sepsis did not influence the survival rates and plasma amino acid profiles of the FOS and SOS groups. Compared with safflower oil, feeding diabetic rats with fish oil had no beneficial effects on survival rates and muscle protein breakdown. The immunologic impact of dietary n-3 polyunsaturated fatty acids on diabetic rats with sepsis requires further investigation., (Copyright 2000 Harcourt Publishers Ltd.)

The present study was designed to compare the effect of three programs of exercise of different intensity on the survival rate of normal and streptozotocin-diabetic rats (60 mg/kg) submitted to acute experimental myocardial infarction. The animals were trained progressively on a treadmill once a day, five days per week for eight weeks at a 10 degree incline according to one of the following treadmill running programs: light (30 mins/day at 20 m/min), moderate (30 mins/day at 25 m/min) or heavy (60 mins/day at 25 m/min). Myocardial infarction was produced by left coronary artery ligation under ether anesthesia three days after the last bout of exercise. Successful ligation was demonstrated by elevated plasma creatine kinase MB isoenzyme levels 4 h later or by dye injection in rats with early death. In sedentary diabetic rats (n = 33), the early survival rate was decreased in comparison to sedentary controls (n = 22), although statistical significance was not reached, (30 versus 45%; P = 0.1952 by Fisher's exact test). These values were not significantly modified by light or heavy training in control (light n = 18, 61%; heavy n = 25, 56%) nor in diabetic animals (light n = 28, 32%; heavy n = 23, 39%). While the survival rate was not altered by moderate exercise in control animals (n = 26, 62%), it was greatly improved in diabetic rats (n = 23, 64%, P = 0.0108 versus sedentary diabetics). These data suggest that it is possible to improve the early survival rate of diabetic rats submitted to experimental myocardial infarction by a previous training program at a moderate level of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats and rabbits parenterally treated with a large daily dose of ferric nitrilotriacetate manifested diabetic symptoms such as hypergycemia, glycosuria, ketonemia, and ketonuria after approximately 60 days fo treatment. The blood insulin response to oral glucose loading was poor. Heavy iron deposits were found in liver parenchymal cells and in pancreatic exocrine cells, although some iron was deposited in the macrophages and reticuloendothelial cells of the organs. Faint iron staining was found in some pancreatic islet cells, with a reduction in beta granules and weak zinc staining. Cirrhotic liver changes and skin pigment deposition were not observed. Repeated blood withdrawals from ferric-nitrilotriacetate-treated animals resulted in disappearance of hypergycmia, glycosuria, ketonemia, and ketonuria; disappearance of iron from the liver and pancreas; and restoration of islet beta granules to the control level.

The effects on cardiac function of feeding a diet high in sucrose to male Wistar rats over an extended period of time (15 months) was examined. This diet produced a diabetic condition which resembled noninsulin dependent diabetes mellitus. Resting hyperglycemia, high circulating insulin and triglyceride levels were observed in these animals. Further, the sucrose fed animals were overweight in comparison to chow fed control animals. Contractile protein Ca2+-ATPase activity was measured as a biochemical estimate of cardiac contractile function. Myosin and actomyosin Ca2+-ATPase activities of isolated myofibrillar fractions from hearts of experimental animals were depressed in comparison to chow fed control rats. Myosin K+-EDTA activity was also altered. The results demonstrate for the first time a defect in contractile protein Ca2+-ATPase activity in rat hearts using a model of noninsulin dependent diabetes mellitus. As the animals were euthyroid, thyroid hormone alterations in these animals were unlikely to influence the results. The results also demonstrate that insulin could not be a direct factor associated with cardiac pathology in diabetes. Instead, cardiac dysfunction may be associated with other, as yet undefined, metabolic abnormalities which accompany the diabetic state.