Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity

2013 ◽  
Vol 304 (12) ◽  
pp. F1438-F1446 ◽  
Author(s):  
Melanie Chin ◽  
Chun-Yue Ivy Lee ◽  
Jen-Chieh Chuang ◽  
Ron Bumeister ◽  
W. Christian Wigley ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
Clinical Signs ◽  
Diabetic Rats ◽  
Rodent Models ◽  
Zdf Rats ◽  
Structural Injury ◽  
Diabetes And Obesity

Bardoxolone methyl and related triterpenoids are well tolerated and efficacious in numerous animal models potentially relevant to patients with Type 2 diabetes and chronic kidney disease. These agents enhance glucose control and regulate lipid accumulation in rodent models of diabetes and obesity, and improve renal function, reduce inflammation, and prevent structural injury in models of renal disease. However, a recent study in Zucker diabetic fatty (ZDF) rats noted poor tolerability with the bardoxolone methyl analog RTA 405 within 1 mo after treatment initiation, although this study was confounded in part by the use of an impure RTA 405 batch. To investigate these discordant observations, the present studies were conducted to further characterize triterpenoids in rodent models of diabetes and obesity. A follow-up study was conducted in ZDF rats with two related triterpenoids (RTA 405 and dh404) for 1.5 mo. Consistent with previous rodent experience, and in contrast to the more recent ZDF report, ZDF rats administered RTA 405 or dh404 exhibited no adverse clinical signs, had laboratory values similar to controls, and exhibited no evidence of adverse liver or kidney histopathology. Additionally, RTA 405 was well tolerated in streptozotocin-induced Type 1 diabetic rats and high-fat-diet-induced obese mice. The present results are consistent with the overall published body of data obtained with triterpenoids and provide further evidence that these molecules are well tolerated without adverse effects on hepatobiliary or renal function in rodent models of diabetes and obesity.

scholarly journals Evolution of metabolic syndrome components in patients with autosomal-dominant polycystic kidney disease: a six-year follow-up study

2019 ◽  
Vol 73 ◽  
pp. 598-607
Author(s):  
Maria Pietrzak-Nowacka ◽  
Krzysztof Safranow ◽  
Małgorzata Marchelek-Myśliwiec ◽  
Mariusz Bodnar ◽  
Sylwia Przysiecka ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Renal Function ◽  
Uric Acid ◽  
Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Aim: Long-term studies show that some metabolic syndrome (MS) components deteriorate renal function in autosomal dominant polycystic kidney disease (ADPKD) patients. The aim of this 6-year follow-up was to analyze early changes of all MS components and their associations with kidney function in the nondiabetic ADPKD patients with normal renal function, compared to controls. Material/Methods: The follow-up physical and laboratory examinations were performed for 39 ADPKD patients (age 43.7 ± 11.4 years) and 44 controls (43.5 ± 9.1 years). Results: We noticed a significant increase in weight, body mass index (BMI), waist, total and LDL cholesterol, C-peptide, uric acid, creatinine and significant decline of HbA1c and e-GFR in the ADPKD group. Increases in waist, uric acid and creatinine concentrations were significantly higher in the ADPKD patients than controls. Both groups showed similar rates of prediabetes, while diabetes developed in 5 controls (with 4 cases of type 2 diabetes and one case of type 1), but not in the ADPKD group (11% vs 0%, P = 0.06 for diabetes, 9% vs 0%, P = 0.12 for type 2 diabetes). The ADPKD group showed a significantly higher percentage of obesity, waist circumferences, systolic/diastolic blood pressure, concentrations of creatinine, urea and uric acid and lower e-GFR. The MS prevalence was comparable; however, the number of MS components was significantly higher in the ADPKD patients (median 2 vs. 1, p = 0.001). Conclusions: The presence of MS does not influence the rate of renal failure progression in nondiabetic ADPKD patients with normal renal function at a 6-year follow-up.

scholarly journals Effect of Sodium Glucose Cotransporter 2 Inhibitors on Renal Function in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes in Japan

Diagnostics ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 86
Author(s):  
Kota Yano ◽  
Yuya Seko ◽  
Aya Takahashi ◽  
Shinya Okishio ◽  
Seita Kataoka ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
Liver Disease ◽  
Liver Function ◽  
Protective Effect ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Sodium Glucose Cotransporter

Sodium-glucose cotransporter-2 inhibitors (SGLT2I) have been reported to have renal-protective effects in patients with type 2 diabetes (T2DM). This a retrospective study aimed to evaluate the effect of SGLT2I on renal function in patients with nonalcoholic fatty liver disease (NAFLD) and T2DM. We analyzed 69 consecutive patients with a biopsy-proven NAFLD and T2DM with an estimated glomerular filtration rate (eGFR) >60 mL/min. Of these 69 patients, 22 received SGLT2I and 47 were treated without SGLT2I. Liver function and eGFR were analyzed at baseline and after three years. Body mass index, liver function and HbA1c improved significantly in both groups. In the total population, the median eGFR declined from 80.7 mL/min at the baseline to 74.9 mL/min at the end of follow-up. The median eGFR at the baseline/end of follow-up was 81.2/80.4 mL/min in patients treated with SGLT2I and 80.2/70.8 mL/min in patients treated without SGLT2I. Multivariate analysis identified an increased FIB-4 index with an odds ratio (OR) of 4.721, (p = 0.045) and SGLT2I treatment (OR 0.263, p = 0.033) as predictive factors for decreased eGFR. SGLT2I treatment has a protective effect on the renal function for NAFLD with T2DM. A long-term, randomized, controlled trial is warranted to confirm the renal protective effect of SGLT2I in NAFLD patients with T2DM.

scholarly journals DYNAMICS OF GLYCEMIC CONTROL AFTER RENAL DENERVATION IN PATIENTS WITH RESISTANT HYPERTENSION AND TYPE 2 DIABETES MELLITUS

2015 ◽  
Vol 14 (5) ◽  
pp. 82-90
Author(s):  
A. Yu. Falkovskaya ◽  
V. F. Mordovin ◽  
S. Ye. Pekarsky ◽  
A. Ye. Bayev ◽  
G. V. Semke ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Renal Function ◽  
Glycemic Control ◽  
Resistant Hypertension ◽  
Renal Denervation ◽  
Tnf Α

The aim of the study was to evaluatetheglycemic control dynamics depending on degree of blood pressure (BP) reduction and dynamic of TNF-α after 6 and 12 months of Tran catheter renal denervation (TRD) of patients with true resistant hypertension (RH) and type 2 diabetes mellitus (T2DM). Material and methods. Thirty two essentially hypertensive patients with type 2 diabetes mellitus (T2DM) and resistant hypertension were included in single-arm prospective interventional study. Office BP measurement, ambulatory 24-h BP, renal Doppler ultrasound and assessment of renal function (proteinuria, creatinine, eGFR), HbА1c and fasting plasma glucose (FPG) levels, activity of TNF-α were performed at baseline and 6 and 12 months after TRD. On average, patients were taking 4 (3–6) antihypertensive drugs. None of the patients changed the antihypertensive treatments during follow-up. A 6 months follow-up was completed by 27 patients (43–75 years old, 14 male), 12 months follow-up was completed by 26 patients. Results. Renal denervation significantly reduced the systolic office BP (SBP) as well as 24-h SBP (– 27.2/–10.7 mm Hg and–13.4/–10 mm Hg, respectively, p < 0.01 after 6-month follow-up, and –31,7/–12,8 mmHg and –13.4/–10 mm Hg, respectively, p < 0.01 after 12-month follow-up) without any negative effect on renal function. The number of responders with reduction of SBP >10 mmHg according to ABPM were 56% (15/27) after 6-month and 61.5% (16/26) after 12-month follow-up. There were significant reduction of the average HbA1c levels (from (6.9 ± 1.8)% to (5.8 ± 1.5)%, p = 0.04) and nonsignificant decreasing of FPG levels (from 8.7 ± 2.8 to 7.7 ± 2.1 mmol/L, p = 0.07) after 6-month followup. Conspicuously, the responders according to ABPM had significantly higher mean dynamics of HbA1c than the non-responders after 6-month follow-up (–2.4 ± 1.9 and –0.1 ± 0.8%, p = 0.02, respectively) as well as after 12-month follow-up (–0.12 ± 0.98 and 1,26 ± 1.11%, p = 0.04 for HbA1c, and – 0.89 ± 1.9 и 0.85 mmol/L ± 1.19, p = 0.02 for FPG levels). There were significant decreasing of TNF-α after 12-monthfollow-up (from 2.21 (1.54–3.65) to 1.4 (1.11–1.47pg/ml), p = 0.007), without relation to BP and HbA1c dynamics, and response to TRD. There were not the correlations between dynamics of HbA1c and FPG levels with BP reduction and change of TNF-α after 12-month follow-up. Conclusions. Renal denervation of patients with true resistant hypertension and diabetes mellitus type 2 after 6 and 12 months was followed by improved glycemic control, BP reduction and decreasing of mean levels of TNF-α. Glycemic control improvement after the renal denervation was more expressive in the responders. 

scholarly journals The United Kingdom’s first NHS EndoBarrier service for long-standing poorly controlled type 2 diabetes and obesity: outcomes one year after EndoBarrier removal

2021 ◽  
Author(s):  
Robert E J Ryder ◽  
Mahi Yadagiri ◽  
Wyn Burbridge ◽  
Susan P Irwin ◽  
Hardeep Gandhi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Dose ◽  
Severe Depression ◽  
Sustained Improvement ◽  
White Ethnicity ◽  
Daily Insulin Dose ◽  
One Year ◽  
Diabetes And Obesity

Aims: EndoBarrier is a 60 cm duodenal–jejunal bypass liner endoscopically implanted for up to one year. It mimics the bypass part of Roux-en-Y bariatric surgery and reduces weight and HbA1c while it is in situ. We aimed to assess the extent to which these improvements are sustained in people with diabetes in the year following removal.Methods: Between October 2014 and November 2017 we implanted 62 EndoBarriers in an NHS service with all removed by November 2018. Outcomes were monitored in a registry.Results: By November 2019, 46/62 (72%) (mean±SD age 51.5±7.7 years, 52% male, 54.3% white ethnicity, median (IQR) diabetes duration 14.5 (8–20) years, 67.4% insulin-treated and mean±SD body mass index (BMI) 41.6±7.1 kg/m2) had attended and 16/62 (28%) did not attend their one-year post-EndoBarrier follow-up appointment. In those who attended, during EndoBarrier implantation mean±SD HbA1c fell by 21.1±19.6 mmol/mol from 77.1±20.0 to 56.0±11.2 mmol/mol (p<0.001) (by 1.9±1.8% from 9.2±1.8% to 7.3±1.0% (p<0.001)), weight fell by 17.2±8.8 kg from 121.9±29.4 kg to 104.7±30.1 kg (p<0.001), BMI fell from 41.6±7.5 to 35.5±7.5 kg/m2 (p<0.001), systolic blood pressure from 139.0±14.0 to 126.0±14.6 mmHg (p<0.001) and serum alanine aminotransferase from 30.0±16.9 to 18.8±11.0 U/L (p<0.001). Median (IQR) total daily insulin dose reduced from 104 (54–162) to 30 (0–62) units (n=31, p<0.001); 10/31 (32%) insulin-treated people with diabetes were able to discontinue insulin. One year post-EndoBarrier, 18/46 (39%) demonstrated fully sustained improvement, 18/46 (39%) partially sustained improvement and 10/46 (22%) reverted to baseline. Of those deteriorating, 9/10 (90%) had depression and/or bereavement; they also had less fall in weight and HbA1c during EndoBarrier treatment. In the 16/62 (28%) who did not attend follow-up, reasons for non-attendance were too far to travel (25%), need to take time off work (6.3%), severe depression (6.3%) and death (6.3%). In 56.3% of cases no reason was given.Conclusion: Our data demonstrate that EndoBarrier is highly effective in people with long-standing poorly controlled type 2 diabetes and obesity, with maintenance of significant improvement one year after removal in 78% of cases for whom data were available. As an endoscopic procedure it is relatively simple and non-invasive and it deserves further investigation.

scholarly journals Evaluation of the University of California Diabetes Prevention Program (UC DPP) Initiative

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Maryam Gholami ◽  
Nicholas J. Jackson ◽  
Un Young Rebecca Chung ◽  
O. Kenrik Duru ◽  
Kelly Shedd ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Health Outcomes ◽  
Weight Change ◽  
Diabetes Prevention ◽  
Diabetes Prevention Program ◽  
University Of California ◽  
The University ◽  
Diabetes And Obesity

Abstract Background Type 2 diabetes can negatively impact long term health outcomes, healthcare costs and quality of life. However, intensive lifestyle interventions, including the Diabetes Prevention Program (DPP), can significantly lower risk of incident type 2 diabetes among overweight adults with prediabetes. Unfortunately, the majority of adults in the US who are at risk of developing diabetes do not engage in DPP-based lifestyle change programs. Increased adoption of evidence-based obesity and diabetes prevention interventions, such as the DPP, may help large employers reduce health risks and improve health outcomes among employees. In 2018, the University of California Office of thePresident (UCOP) implemented the UC DPP Initiative, a novel, multi-component program to address diabetes and obesity prevention across the UC system. Methods The goal of our study is to conduct a multifaceted evaluation of the UC DPP Initiative using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Our evaluation will integrate unique and diverse UC data sources, including electronic health record (EHR) data, administrative claims, campus-based DPP cohort data, qualitative interviews and site visits. Our primary outcome of interest is the mean percent weight change among three groups of overweight/obese UC beneficiaries at risk for diabetes at 12-month follow-up. Secondary outcomes include mean percent weight change at 24-month follow-up, barriers and facilitators associated with implementatio, as well as  the degree of program adoption and maintenance. Discussion Our study will help inform diabetes and obesity prevention efforts across the UC system. Findings from this evaluation will also be highly applicable to universities and large employers, as well as community organizers, healthcare organizations and insurers implementing the DPP and/or other health promotion interventions.

scholarly journals The Urinary Phosphate to Serum Fibroblast Growth Factor 23 Ratio, Deemed the Nephron Index, Is a Useful Clinical Index for Early Stage Chronic Kidney Disease in Patients with Type 2 Diabetes: An Observational Pilot Study

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Hodaka Yamada ◽  
Makoto Kuro-o ◽  
Shunsuke Funazaki ◽  
San-e Ishikawa ◽  
Masafumi Kakei ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Renal Function ◽  
Growth Factor ◽  
Kidney Disease ◽  
Early Stage ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth

Renal function decline is associated with progressive type 2 diabetes mellitus, which causes mineral and bone disorders. In the present study, we defined the ratio of urinary phosphate excretion (mg/day) to serum fibroblast growth factor 23 as the nephron index. We examined changes in the nephron index in type 2 diabetes patients with early stage chronic kidney disease (stages 1–3), enrolling 15 patients and retrospectively analysing the follow-up data. After follow-up at 5.4 years, we observed no significant changes in the estimated glomerular filtration rate; the nephron index, however, was significantly reduced between the baseline and the follow-up. We propose that the nephron index may be potentially useful as a biomarker for monitoring the decline of renal function in the early stages of diabetic chronic kidney disease patients.

scholarly journals SO022EVALUATION OF GLOMERULAR HEMODYNAMIC CHANGES BY SGLT2 INHIBITION IN TYPE 2 DIABETIC RATS USING IN VIVO IMAGING TECHNIQUES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Yoshihisa Wada ◽  
KENGO KIDOKORO ◽  
Atsuyuki Tokuyama ◽  
Megumi Kondo ◽  
Hiroyuki Kadoya ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Rats ◽  
Glomerular Hyperfiltration ◽  
Afferent Arteriole ◽  
Dose Administration ◽  
Sglt2 Inhibition ◽  
A1 Receptor ◽  
Zdf Rats

Abstract Background and Aims In recent clinical trials, the SGLT2 inhibitor (SGLT2i) slowed the progression of kidney disease compared with the placebo in patients with type 2 diabetes. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2 inhibition (SGLT2i) in diabetic kidney disease (DKD). We have successfully developed the novel method to measure single-nephron GFR (SNGFR) in mice using multiphoton laser microscopy and demonstrated that the adenosine/adenosine A1 receptor (A1aR) pathway plays a pivotal role in the TGF mechanism in the type 1 diabetic model, Akita mice (Kengo Kidokoro, David Z. I. Cherney et al. Circulation. 2019). It has been suggested that the mechanism of improvement effects in glomerular hyperfiltration by SGLT2i is different in type 1 diabetes and type 2 diabetes. However, the detailed regulatory mechanism of GFR by SGLT2i is not fully understood in type 2 diabetes. This study aims to clarify the effects of SGLT2i on glomerular hemodynamics in type 2 diabetic rats. Method Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1mg/kg) group, and insulin group. Results SNGFR in the ZDF group was significantly higher than in the ZL group. The diameter of the afferent arteriole and efferent arteriole was also wider in ZDF rats than in ZL rats. The SNGFR and diameter of the afferent arteriole were significantly decreased after a single-dose administration of SGLT2i in ZDF. However, there was no significant diameter change in the efferent arteriole. Moreover, a decrease of SNGFR was not observed in the A1aR antagonist group after SGLT2i administration. Urinary excretions of glucose and sodium showed a similar pattern in the SGLT2i and SGLT2i+ A1aR antagonist groups. Conclusion The adenosine/A1aR pathway plays an important role in the regulation of the tonus of the afferent arteriole and is involved in the suppression of glomerular hyperfiltration by SGLT2 inhibition in type 2 diabetes.

Type 2 diabetes: increased expression and contribution of IKCa channels to vasodilation in small mesenteric arteries of ZDF rats

2014 ◽  
Vol 307 (8) ◽  
pp. H1093-H1102 ◽  
Author(s):  
Christian Schach ◽  
Markus Resch ◽  
Peter M. Schmid ◽  
Guenter A. Riegger ◽  
Dierk H. Endemann
Keyword(s):  
Type 2 Diabetes ◽  
Protein Expression ◽  
Experimental Models ◽  
Diabetic Rats ◽  
Mesenteric Arteries ◽  
Rt Pcr ◽  
Mrna And Protein Expression ◽  
Zdf Rats ◽  
Endothelium Dependent Relaxation

Impaired endothelial function, which is dysregulated in diabetes, also precedes hypertension. We hypothesized that in Type 2 diabetes, the impaired endothelium-dependent relaxation is due to a loss of endothelium-derived hyperpolarization (EDH) that is regulated by impaired ion channel function. Zucker diabetic fatty (ZDF), Zucker heterozygote, and homozygote lean control rats were used as the experimental models in our study. Third-order mesenteric arteries were dissected and mounted on a pressure myograph; mRNA was quantified by RT-PCR and channel proteins by Western blotting. Under nitric oxide (NO) synthase and cyclooxygenase inhibition, endothelial stimulation with ACh fully relaxes control but not diabetic arteries. In contrast, when small-conductance calcium-activated potassium (KCa) channels and intermediate- and large-conductance KCa (I/BKCa) are inhibited with apamin and charybdotoxin, NO is able to compensate for ACh-induced relaxation in control but not in diabetic vessels. After replacement of charybdotoxin with 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34; IKCa inhibitor), ACh-induced relaxation in diabetic animals is attenuated. Specific inhibition with TRAM-34 or charybdotoxin attenuates ACh relaxation in diabetes. Stimulation with 1-ethyl-2-benzimidazolinone (IKCa activator) shows a reduced relaxation in diabetes. Activation of BKCa with 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one NS619 leads to similar relaxations of control and diabetic arteries. RT-PCR and Western blot analysis demonstrate elevated mRNA and protein expression levels of IKCa in diabetes. Our results suggest that the compensatory effect of NO and EDH-associated, endothelium-dependent relaxation is reduced in ZDF rats. Specific blockade of IKCa with TRAM-34 reduces NO and EDH-type relaxation in diabetic rats, indicating an elevated contribution of IKCa in diabetic small mesenteric artery relaxation. This finding correlates with increased IKCa mRNA and protein expression in this vessel.

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