173 research outputs found
Effect of Corncob bedding on feed conversion efficiency in a high-fat diet-induced prediabetic model in C57Bl/6J mice
Laboratory facilities use many varieties of contact bedding, including wood chips, paper products, and corncob, each with its own advantages and disadvantages. Corncob bedding, for example, is often used because of its high absorbency, ability to minimize detectable ammonia, and low cost. However, observations that mice eat the corncob lead to concerns that its use can interfere with dietary studies. We evaluated the effect of corncob bedding on feed conversion (change in body weight relative to the apparent number of kcal consumed over 7 d) in mice. Four groups of mice (6 to 12 per group) were housed in an individually ventilated caging system: (1) low-fat diet housed on recycled paper bedding, (2) low-fat diet housed on corncob bedding, (3) high-fat diet housed on recycled paper bedding, and (4) high-fat diet housed on corncob bedding. After 4 wk of the high-fat diet, feed conversion and percentage body weight change both were lower in corncob-bedded mice compared with paper-bedded mice. Low-fat-fed mice on corncob bedding versus paper bedding did not show statistically significant differences in feed conversion or change in percentage body weight. Average apparent daily feed consumption did not differ among the 4 groups. In conclusion, these data suggest that corncob bedding reduces the efficiency of feed conversion in mice fed a high-fat diet and that other bedding choices should be favored in these models
Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a westernâstyle highâfat diet
Insulin action and glucose disposal are enhanced by exercise, yet the mechanisms involved remain imperfectly understood. While the causes of skeletal muscle insulin resistance also remain poorly understood, new evidence suggest excess plasma membrane (PM) cholesterol may contribute by damaging the cortical filamentous actin (Fâactin) structure essential for GLUT4 glucose transporter redistribution to the PM upon insulin stimulation. Here, we investigated whether PM cholesterol toxicity was mitigated by exercise. Male C57BL/6J mice were placed on lowâfat (LF, 10% kCal) or highâfat (HF, 45% kCal) diets for a total of 8 weeks. During the last 3 weeks of this LF/HF diet intervention, all mice were familiarized with a treadmill for 1 week and then either shamâexercised (0 m/min, 10% grade, 50 min) or exercised (13.5 m/min, 10% grade, 50 min) daily for 2 weeks. HFâfeeding induced a significant gain in body mass by 3 weeks. Sham or chronic exercise did not affect food consumption, water intake, or body mass gain. Prior to sham and chronic exercise, âpreâinterventionâ glucose tolerance tests were performed on all animals and demonstrated that HFâfed mice were glucose intolerant. While sham exercise did not affect glucose tolerance in the LF or HF mice, exercised mice showed an improvement in glucose tolerance. Muscle from shamâexercised HFâfed mice showed a significant increase in PM cholesterol, loss of cortical Fâactin, and decrease in insulinâstimulated glucose transport compared to shamâexercised LFâfed mice. These HFâfed skeletal muscle membrane/cytoskeletal abnormalities and insulin resistance were improved in exercised mice. These data reveal a new therapeutic aspect of exercise being regulation of skeletal muscle PM cholesterol homeostasis. Further studies on this mechanism of insulin resistance and the benefits of exercise on its prevention are needed
Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial
Background:
Sodiumâglucose co-transporter 2 inhibitors (SGLT2is) are part of the standard of care for patients with chronic kidney disease (CKD), both with and without type 2 diabetes. Endothelin A (ETA) receptor antagonists have also been shown to slow progression of CKD. Differing mechanisms of action of SGLT2 and ETA receptor antagonists may enhance efficacy. We outline a study to evaluate the effect of combination zibotentan/dapagliflozin versus dapagliflozin alone on albuminuria and estimated glomerular filtration rate (eGFR).
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Methods:
We are conducting a double-blind, active-controlled, Phase 2b study to evaluate the efficacy and safety of ETA receptor antagonist zibotentan and SGLT2i dapagliflozin in a planned 415 adults with CKD (Zibotentan and Dapagliflozin for the Treatment of CKD; ZENITH-CKD). Participants are being randomized (1:2:2) to zibotentan 0.25 mg/dapagliflozin 10 mg once daily (QD), zibotentan 1.5 mg/dapagliflozin 10 mg QD and dapagliflozin 10 mg QD alone, for 12 weeks followed by a 2-week off-treatment wash-out period. The primary endpoint is the change in log-transformed urinary albumin-to-creatinine ratio (UACR) from baseline to Week 12. Other outcomes include change in blood pressure from baseline to Week 12 and change in eGFR the study. The incidence of adverse events will be monitored. Study protocolâdefined events of special interest include changes in fluid-related measures (weight gain or B-type natriuretic peptide).
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Results:
A total of 447 patients were randomized and received treatment in placebo/dapagliflozin (n = 177), zibotentan 0.25 mg/dapagliflozin (n = 91) and zibotentan 1.5 mg/dapagliflozin (n = 179). The mean age was 62.8 years, 30.9% were female and 68.2% were white. At baseline, the mean eGFR of the enrolled population was 46.7 mL/min/1.73 m2 and the geometric mean UACR was 538.3 mg/g.
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Conclusion:
This study evaluates the UACR-lowering efficacy and safety of zibotentan with dapagliflozin as a potential new treatment for CKD. The study will provide information about an effective and safe zibotentan dose to be further investigated in a Phase 3 clinical outcome trial.
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Clinical Trial Registration Number:
NCT0472483
Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes
Follicular helper T (TFH) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether TFH cells were decreased by costimulation blockade using the CTLA-4âimmunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)+ TFH cells and other ICOS+ populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment TFH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS+ TFH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, TFH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade
Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease
AIM: To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease. MATERIALS AND METHODS: In this phase 2a study (NCT03550378), patients with body mass index 25â45âkg/m(2), estimated glomerular filtration rate 30â59âml/min/1.73âm(2) and type 2 diabetes [glycated haemoglobin 6.5â10.5% (48â91âmmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to onceâdaily subcutaneous cotadutide (50â300âÎŒg) or placebo for 32âdays. The primary endpoint was plasma glucose concentration assessed using a mixedâmeal tolerance test. RESULTS: Participants receiving cotadutide (n = 21) had significant reductions in the mixedâmeal tolerance test area under the glucose concentrationâtime curve (â26.71% vs. +3.68%, pâ<â.001), more time in target glucose range on continuous glucose monitoring (+14.79% vs. â21.23%, p = .001) and significant reductions in absolute bodyweight (â3.41âkg vs. â0.13âkg, pâ<â.001) versus placebo (n = 20). In patients with baseline microâ or macroalbuminuria (n = 18), urinary albuminâtoâcreatinine ratios decreased by 51% at day 32 with cotadutide versus placebo (p = .0504). No statistically significant difference was observed in mean change in estimated glomerular filtration rate between treatments. Mild/moderate adverse events occurred in 71.4% of participants receiving cotadutide and 35.0% receiving placebo. CONCLUSIONS: We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albuminâtoâcreatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longerâterm clinical trials
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