Browsing by Subject "type 2 diabetes"
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Item Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease: A FIDELITY Pooled Secondary Analysis(American Medical Association, 2022-10) Pitt, Bertram; Agarwal, Rajiv; Anker, Stefan D.; Ruilope, Luis M.; Rossing, Peter; Ahlers, Christiane; Brinker, Meike; Joseph, Amer; Lambelet, Marc; Lawatscheck, Robert; Filippatos, Gerasimos S.; Medicine, School of MedicineImportance Patients with chronic kidney disease and type 2 diabetes have a higher risk of developing pneumonia as well as an increased risk of severe COVID-19–associated adverse events and mortality. Therefore, the anti-inflammatory effects of mineralocorticoid receptor antagonists via blockade of the mineralocorticoid receptor may alter the risk of pneumonia and COVID-19–associated adverse events in patients with chronic kidney disease and type 2 diabetes. Objective To evaluate whether the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone is associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Design, Setting, and Participants This secondary analysis used patient-level data from FIDELITY, a prespecified pooled analysis of 2 multicenter, double-blind, placebo-controlled, event-driven, phase 3 randomized clinical trials: FIDELIO-DKD and FIGARO-DKD, conducted between September 2015 and February 2021. Patients in FIDELIO-DKD or FIGARO-DKD with type 2 diabetes and chronic kidney disease (urine albumin to creatine ratio, 30-5000 mg/g, estimated glomerular filtration rate ≥25 mL/min/1.73 m2) were assessed. Data were analyzed from May 15, 2021, to July 28, 2022. Exposure Patients were randomized to finerenone (10 or 20 mg once daily) or matching placebo. Main Outcomes and Measures The main outcomes were investigator-reported incidences of treatment-emergent infective pneumonia adverse events and serious adverse events (during and up to 3 days after treatment) and any COVID-19 adverse events. Results Of 13 026 randomized patients (mean [SD] age, 64.8 [9.5] years; 9088 [69.8%] men), 12 999 were included in the FIDELITY safety population (6510 patients receiving finerenone; 6489 patients receiving placebo). Over a median (range) treatment duration of 2.6 (0-5.1) years, finerenone was consistently associated with reduced risk of pneumonia and serious pneumonia vs placebo. Overall, 307 patients (4.7%) treated with finerenone and 434 patients (6.7%) treated with placebo experienced pneumonia (hazard ratio [HR], 0.71; 95% CI, 0.64-0.79; P < .001). Serious pneumonia occurred in 171 patients (2.6%) treated with finerenone and 250 patients (3.9%) treated with placebo (HR, 0.69; 95% CI, 0.60-0.79; P < .001). Incidence proportions of COVID-19 adverse events were 86 patients (1.3%) in the finerenone group and 118 patients (1.8%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002). Conclusions and Relevance These findings suggest that mineralocorticoid receptor blockade with finerenone was associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Further clinical studies may be warranted. Trial Registration ClinicalTrials.gov identifiers: FIDELIO-DKD: NCT02540993; FIGARO-DKD: NCT02545049Item Attenuated PTH Responsiveness to Vitamin D Deficiency among Patients with Type 2 Diabetes and Chronic Hyperglycemia(Elsevier, 2017-06) Al-Jebawi, Ahmed F.; YoussefAgha, Ahmed H.; Al Suwaidi, Hanan Sulaiman; Albadwawi, Moza Saif; Al Marzooqi, Asma Shabib; Banihammond, Ashjan Hassan; Almarzooqi, Samia Hussain; Alkaabi, Mouza Khalifa; Department of Medicine, IU School of MedicineBackground The short and long-term relationship between hyperglycemia and PTH level among patients suffering from both diabetes type 2 and vitamin D deficiency were evaluated. Methods This was a cross sectional study performed at Dubai Diabetes Center, UAE. To demonstrate the relationship between hyperglycemia and PTH level, subjects with type 2 diabetes and vitamin D deficiency (124 adults) were divided into 4 groups based on their FPG and HbA1c levels. Results Mean vitamin D and PTH levels among subjects with HbA1c ≤ 7% (53 mmol/mol) were 14.05 ng/ml and 19.51 pg/ml respectively. On the other hand, mean vitamin D and PTH levels among subjects with HbA1c ≥ 10% (86 mmol/mol) were significantly lower at 11.77 ng/ml and 17.75 pg/ml respectively. The product of vitamin D and PTH among subjects with an HbA1c ≤ 7% (53 mmol/mol) was 250.380, compared with only 197.710 among subjects with HbA1c ≥ 10 (86 mmol/mol). Regression analysis for subjects older than 50 years shows a significant negative effect of HbA1c on the PTH level. Mean calcium level among subjects with HbA1c ≤ 7% (53 mmol/mol) was 8.80 mg/dl compared with 8.94 mg/dl when HbA1c is ≥10% (86 mmol/mol) with no statistical difference. Although high FPG was associated with a lower PTH level, such association was not statistically significant. Conclusions Chronic hyperglycemia, as assessed by A1C level, is associated with a significantly attenuated PTH responsiveness to vitamin D deficiency without a significant change in calcium level. On the other hand, there was no significant association between FPG and PTH level.Item Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing(MDPI, 2020-10-01) Demine, Stephane; Schulte, Michael L.; Territo, Paul R.; Eizirik, Decio L.; Radiology and Imaging Sciences, School of MedicineThere are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2γa as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.Item Blood Pressure and Cardiorenal Outcomes With Finerenone in Chronic Kidney Disease in Type 2 Diabetes(Wolters Kluwer, 2022-12) Ruilope, Luis M.; Agarwal, Rajiv; Anker, Stefan D.; Filippatos, Gerasimos; Pitt, Bertram; Rossin, Peter; Sarafidis, Pantelis; Schmieder, Roland E.; Joseph, Amer; Rethemeier, Nicole; Nowack, Christina; Bakris, George L.; Medicine, School of MedicineBackground: Chronic kidney disease is frequently associated with hypertension and poorly controlled blood pressure can lead to chronic kidney disease progression. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, significantly improves cardiorenal outcomes in patients with chronic kidney disease and type 2 diabetes. This analysis explored the relationship between office systolic blood pressure (SBP) and cardiorenal outcomes with finerenone in FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease). Methods: Patients with type 2 diabetes, urine albumin-to-creatinine ratio 30 to 5000 mg/g, and estimated glomerular filtration rate of 25 to <75 mL/min per 1.73 m2 receiving optimized renin-angiotensin system blockade, were randomized to finerenone or placebo. For this analysis, patients (N=5669) were grouped by baseline office SBP quartiles. Results: Finerenone reduced office SBP across the baseline office SBP quartiles, including patients with baseline office SBP of >148 mm Hg. Overall, patients with lower baseline office SBP quartile and greater declines from baseline in SBP were associated with better cardiorenal outcomes. The risk of primary kidney and key secondary cardiovascular composite outcomes was consistently reduced with finerenone versus placebo irrespective of baseline office SBP quartiles (P for interaction 0.87 and 0.78, respectively). A time-varying analysis revealed that 13.8% and 12.6% of the treatment effect with finerenone was attributed to the change in office SBP for the primary kidney composite outcome and the key secondary cardiovascular outcome, respectively. Conclusions: In FIDELIO-DKD, cardiorenal outcomes improved with finerenone irrespective of baseline office SBP. Reductions in office SBP accounted for a small proportion of the treatment effect on cardiorenal outcomes.Item Blood Sugar, Your Pancreas, and Unicorns: The Development of Health Education Materials for Youth With Prediabetes(Sage, 2018) Yazel-Smith, Lisa G.; Pike, Julie; Lynch, Dustin; Moore, Courtney; Haberlin, Kathryn; Taylor, Jennifer; Hannon, Tamara S.; Health Policy and Management, School of Public HealthBackground. The obesity epidemic has led to an increase in prediabetes in youth, causing a serious public health concern. Education on diabetes risk and initiation of lifestyle change are the primary treatment modalities. There are few existing age-appropriate health education tools to address diabetes prevention for high-risk youth. Aim. To develop an age-appropriate health education tool(s) to help youth better understand type 2 diabetes risk factors and the reversibility of risk. Method. Health education tool development took place in five phases: exploration, design, analysis, refinement, and process evaluation. Results. The project resulted in (1) booklet designed to increase knowledge of risk, (2) meme generator that mirrors the booklet graphics and allows youth to create their own meme based on their pancreas’ current mood, (3) environmental posters for clinic, and (4) brief self-assessment that acts as a conversation starter for the health educators. Conclusion. Patients reported high likability and satisfaction with the health education tools, with the majority of patients giving the materials an “A” rating. The process evaluation indicated a high level of fidelity and related measures regarding how the health education tools were intended to be used and how they were actually used in the clinic setting.Item Calcium release channel RyR2 regulates insulin release and glucose homeostasis(2015-04) Santulli, Gaetano; Pagano, Gennaro; Sardu, Celestino; Xie, Wenjun; Reiken, Steven; D'Ascia, Salvatore Luca; Cannone, Michele; Marziliano, Nicola; Trimarco, Bruno; Guise, Theresa A.; Lacampagne, Alain; Marks, Andrew R.; Department of Medicine, IU School of MedicineThe type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a “leaky” RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.Item Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy(Massachusetts Medical Society, 2019-06) Perkovic, Vlado; Jardine, Meg J.; Neal, Bruce; Bompoint, Severine; Heerspink, Hiddo J. L.; Charytan, David M.; Edwards, Robert; Agarwal, Rajiv; Bakris, George; Bull, Scott; Cannon, Christopher P.; Capuano, George; Medicine, School of MedicineBACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.Item Cellular and Molecular Targets in the Neuroendocrine System That Defend Against Diabetes, Obesity, and Alzheimer's Disease(2021-09) Reilly, Austin Michael; Sheets, Patrick; Ren, Hongxia; Baucum, Anthony II; Evans-Molina, Carmella; Landreth, GaryMetabolic survival mechanisms that defend body weight and conserve energy are currently at odds with modernized society which has a food supply that is ubiquitous, calorie dense, and highly palatable. Chronic overnutrition leads to a metabolic syndrome of obesity, insulin resistance, inflammation, and cardiovascular diseases that is increasingly prevalent and threatens health on a global scale. The brain is both a victim and culprit of metabolic diseases, and prolonged metabolic dysfunction can exacerbate the pathological mechanisms underlying both metabolic and neurodegenerative diseases. Since neuroendocrine pathways comprise an essential feedback mechanism that detects circulating hormones and nutrients in order to regulate satiety, energy expenditure, and glucose homeostasis, our research goals were to characterize molecular mechanisms within neuroendocrine pathways that could be leveraged for treating obesity, diabetes, and Alzheimer’s disease. First, we identified the expression of a G protein-coupled receptor, Gpr17, in POMC neurons and discovered that it protects aged mice from high-fat diet (HFD)-induced metabolic derangements. We examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, Pomc-Cre-driven Gpr17 knockout (PGKO) mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Second, we generated a highly insulin resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in muscle, adipose, and GLUT4-expressing neuronal subpopulations. This genetic approach recapitulates the primary defect preceding type 2 diabetes (T2D) and revealed additional factors/mechanisms that drive the ultimate progression of overt diabetes. Third, we used 5xFAD mice as a model of Alzheimer’s disease and showed that they were more susceptible to HFD-induced metabolic dysregulation and expression of AD pathological markers in the hippocampus. Our results helped elucidate the molecular and cellular mechanisms responsible for increased AD pathology in high-fat diet-fed 5xFAD mice and suggest that metabolic dysfunctions are a therapeutic target to ameliorate AD pathology. In conclusion, metabolic diseases are pervasive and require nuanced approaches that target the neuroendocrine system in order to restore metabolic homeostasis and protect the brain from neurodegenerative processes that are associated with obesity and diabetes.Item Changes in Weight and Glucose Can Protect Against Progression in Early Diabetes Independent of Improvements in β-Cell Function(Oxford University Press, 2016-11) Patel, Y. R.; Kirkman, M. S.; Considine, R. V.; Hannon, T. S.; Mather, K. J.; Medicine, School of MedicineReductions in fasting glucose, via reductions in weight, provided protection from progressive dysglycemia in EDIP. Lifestyle change can contribute importantly to glycemic control in early diabetes.Item Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection Versus Insulin Alone in Type 2 Diabetes(Oxford, 2018-07) Mather, Kieren J.; Considine, Robert V.; Hamilton, LaTonya; Patel, Niral A.; Mathias, Carla; Territo, Wendy; Goodwill, Adam; Tune, Johnathan D.; Green, Mark A.; Hutchins, Gary D.; Medicine, School of MedicineContext Glucagon-like peptide-1 (GLP-1) and the clinically available GLP-1 agonists have been shown to exert effects on the heart. It is unclear whether these effects occur at clinically used doses in vivo in humans, possibly contributing to CVD risk reduction. Objective To determine whether liraglutide at clinical dosing augments myocardial glucose uptake alone or in combination with insulin compared to insulin alone in metformin-treated Type 2 diabetes mellitus. Design Comparison of myocardial fuel utilization after 3 months of treatment with insulin detemir, liraglutide, or combination detemir+liraglutide. Setting Academic hospital Participants Type 2 diabetes treated with metformin plus oral agents or basal insulin. Interventions Insulin detemir, liraglutide, or combination added to background metformin Main Outcome Measures Myocardial blood flow, fuel selection and rates of fuel utilization evaluated using positron emission tomography, powered to demonstrate large effects. Results We observed greater myocardial blood flow in the insulin-treated groups (median[25th, 75th percentile]: detemir 0.64[0.50, 0.69], liraglutide 0.52[0.46, 0.58] and detemir+liraglutide 0.75[0.55, 0.77] mL/g/min, p=0.035 comparing 3 groups and p=0.01 comparing detemir groups to liraglutide alone). There were no evident differences between groups in myocardial glucose uptake (detemir 0.040[0.013, 0.049], liraglutide 0.055[0.019, 0.105], detemir+liraglutide 0.037[0.009, 0.046] µmol/g/min, p=0.68 comparing 3 groups). Similarly there were no treatment group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. Conclusions These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection.