Browsing by Subject "Type 2 diabetes"
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Item A prespecified exploratory analysis from FIDELITY examined finerenone use and kidney outcomes in patients with chronic kidney disease and type 2 diabetes(Elsevier, 2023) Bakris, George L.; Ruilope, Luis M.; Anker, Stefan D.; Filippatos, Gerasimos; Pitt, Bertram; Rossing, Peter; Fried, Linda; Roy-Chaudhury, Prabir; Sarafidis, Pantelis; Ahlers, Christiane; Brinker, Meike; Joseph, Amer; Lawatscheck, Robert; Agarwal, Rajiv; FIDELIO-DKD and FIGARO-DKD Investigators; Medicine, School of MedicineIn FIDELITY, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies, finerenone was found to improve cardiorenal outcomes in patients with type 2 diabetes, a urine albumin-to-creatinine ratio of 30-5000 mg/g, an estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2 or more and also receiving optimized renin-angiotensin system blockade treatment. This present analysis focused on the efficacy and safety of finerenone on kidney outcomes. Among 13,026 patients with a median follow-up of three years, finerenone significantly reduced the hazard of a kidney composite outcome (time to kidney failure, sustained 57% or more decrease in eGFR from baseline, or kidney death) by 23% versus placebo (hazard ratio, 0.77; 95% confidence interval, 0.67-0.88), with a three-year absolute between-group difference of 1.7% (95% confidence interval, 0.7-2.6). Hazard ratios were directionally consistent for a prespecified baseline eGFR and urine albumin-to-creatinine ratio categories (Pinteraction = 0.62 and Pinteraction = 0.67, respectively), although there was a high degree of uncertainty in the 30-300 mg/g subgroup. Finerenone significantly reduced the hazard of end-stage kidney disease (ESKD) by 20% versus placebo (0.80; 0.64-0.99). Adverse events were similar between treatment arms, although hyperkalemia leading to treatment discontinuation occurred significantly more frequently with finerenone versus placebo (2.4% vs 0.8% and 0.6% vs 0.3% in patients with eGFR less than 60 vs. greater than or equal to 60 ml/min per 1.73 m2, respectively). Thus, finerenone improved kidney outcomes, reduced the hazard of ESKD, and is well tolerated in patients with chronic kidney disease and type 2 diabetes.Item Activities and support provided by family caregivers of persons with type 2 diabetes(2016-03-11) Scarton, Lisa J.; Bakas, Tamilyn; Miller, Wendy; McLennon, Susan M.; Huber, LesaType 2 diabetes, a chronic condition affecting millions, continues to rise in epidemic proportions. Type 2 diabetes, managed through lifestyle changes, affects the entire family. Family caregivers provide vital support to these individuals; however, little research has been conducted surrounding the perceived difficulty or ease of caregiver activity and supportive behaviors. The purpose of this dissertation was to develop and psychometrically test a scale that measures this difficulty or ease of activities and behaviors. This was accomplished through the compilation of three distinct manuscripts. First, an integrative review was conducted to identify what is known regarding needs and concerns of family caregivers of persons with type 2 diabetes; findings revealed a need for more research. Then, based on these recommendations, a qualitative study was conducted that explored the needs and concerns identified by 33 American Indian, African American, and White family caregivers. All these caregivers had similar concerns related to needing general diabetes information, providing support to the family member, and taking care of their own health. Study themes were used to develop items for a new instrument, the Diabetes Caregiver Activity and Support Scale (D-CASS) that was psychometrically tested with 101 American Indian, African American, and White family caregivers of persons with type 2 diabetes. This study used a cross-sectional, descriptive-correlational design and provided evidence of internal consistency reliability (α = .82) and two-week test-retest reliability (intraclass correlation coefficient = .70) for the D-CASS. Criterion-related validity was established using a single-item criterion measuring overall how easy or difficult it was for caregivers to provide care for their loved ones (r = .65, p < .01). Unidimensionality was supported by factor analysis, with loadings ranging from .45 to .70, with 32% of the variance explained by the first factor (eigenvalue = 4.02). Model testing through a series of three hierarchical multiple regressions guided by a conceptual model provided further evidence of construct validity for the D-CASS. This dissertation provided better understanding of needs and concerns of family caregivers of persons with type 2 diabetes and led to the development of a psychometrically sound diabetes-specific instrument for future research.Item Adequacy of glycemic control in early pregnancy with Type 2 diabetes and perinatal outcomes(2023-02-09) Izewski, Joanna; Tang, Rachel; Crites, Kundai; Campbell, Meredith; Pelton, Sarah; Saiko-Blair, Morgan; Scifres, ChristinaObjective In non-pregnant individuals with type 2 DM (T2DM), an HbA1c target < 7% is recommended. We sought to assess if an HbA1c < 7% in early pregnancy is associated with a lower risk for adverse pregnancy outcomes. Study Design We conducted a retrospective cohort study of individuals with T2DM and a singleton gestation who delivered at 2 health systems between 2018-2020. Demographics, markers of health care utilization, and perinatal outcomes were abstracted from the medical record. Race and ethnicity were self-reported. The primary exposure was levels of glycemic control at less than 20 weeks’ gestation using recommended HbA1c targets in non-pregnant individuals (HbA1c < 7% vs. HbA1c ≥7%). Patients without documentation of HbA1c prior to 20 weeks were excluded. Perinatal outcomes were abstracted from the medical record, and logistic regression was used to adjust for covariates. Results Of the individuals who had a documented HbA1c < 20 weeks of gestation, 128/281 (46%) had a HbA1c < 7%, and 153/281 (54%) had a HbA1c ≥7%. Patients with HbA1c < 7% were more likely to be of White race and have private insurance. They also had the first HbA1c measured earlier in pregnancy, a lower mean HbA1c across gestation, less overall weight gain, and were less likely to require insulin at the time of delivery. There were no significant differences in other demographics or markers of healthcare utilization (Table 1). Outcomes are shown in Table 2. After adjusting for covariates, those with a HbA1c ≥7% were more likely to have a preterm birth < 37 weeks (aOR 2.3, 95% CI 1.3-4.0), cesarean delivery (aOR 1.9, 95% CI 1.1-3.3), and a neonate requiring NICU admission (aOR 2.9, 95% CI 1.7-4.9). Conclusion Adverse perinatal outcomes are common among individuals with T2DM even when early pregnancy HbA1c values are within recommended targets for non-pregnant individuals. Those who present with a HbA1c ≥7% are at even higher risk for several outcomes. We observed important disparities in HbA1c values in early pregnancy that likely represent barriers in accessing medical care prior to pregnancy.Item Advanced Glycation End-Products Suppress Mitochondrial Function and Proliferative Capacity of Achilles Tendon-Derived Fibroblasts(Springer Nature, 2019-08-30) Patel, Shivam H.; Yue, Feng; Saw, Shannon K.; Foguth, Rachel; Cannon, Jason R.; Shannahan, Jonathan H.; Kuang, Shihuan; Sabbaghi, Arman; Carroll, Chad C.; Medicine, School of MedicineDebilitating cases of tendon pain and degeneration affect the majority of diabetic individuals. The high rate of tendon degeneration persists even when glucose levels are well controlled, suggesting that other mechanisms may drive tendon degeneration in diabetic patients. The purpose of this study was to investigate the impact of advanced glycation end-products on tendon fibroblasts to further our mechanistic understanding of the development and progression of diabetic tendinopathy. We proposed that advanced glycation end-products would induce limitations to mitochondrial function and proliferative capacity in tendon-derived fibroblasts, restricting their ability to maintain biosynthesis of tendon extracellular matrix. Using an in-vitro cell culture system, rat Achilles tendon fibroblasts were treated with glycolaldehyde-derived advanced glycation end-products (0, 50, 100, and 200 μg/ml) for 48 hours in normal glucose (5.5 mM) and high glucose (25 mM) conditions. We demonstrate that tendon fibroblasts treated with advanced glycation end-products display reduced ATP production, electron transport efficiency, and proliferative capacity. These impairments were coupled with alterations in mitochondrial DNA content and expression of genes associated with extracellular matrix remodeling, mitochondrial energy metabolism, and apoptosis. Our findings suggest that advanced glycation end-products disrupt tendon fibroblast homeostasis and may be involved in the development and progression of diabetic tendinopathy.Item Assessing Disparities in Care Utilization and Outcomes Among Pregnant Women with T2D Based on Race and Ethnicity(2022-07-29) Pelton, Sarah; Izewski, Joanna; Scifres, ChristinaBackground/Objective: Disparities faced by individuals with type 2 diabetes (T2D) or gestational diabetes mellitus have been identified. However, because less is known about disparities faced by pregnant women with T2D and since the prevalence of T2D is increasing, we sought to investigate this issue. Methods: We performed a retrospective cohort study that included 369 women with singleton gestation and T2D that delivered from 2018-2020. Using maternal self-reported race and ethnicity abstracted from the electronic medical record, we categorized the women as Non-Hispanic White, Non-Hispanic Black, or Hispanic. Demographics, health care utilization, and maternal and neonatal outcomes were also abstracted. One way ANOVA and chi-squared tests were utilized to compare outcomes among the groups, and logistic regression was used to control for co-variates. Results: Non-Hispanic White and Non-Hispanic Black women had a higher BMI at their first prenatal visit and were more likely to be nulliparous. They were also more likely to have a prior caesarean delivery and chronic hypertension. Non-Hispanic Black women were more likely to have ≥12 prenatal visits compared to Non-Hispanic White and Hispanic women (70 vs. 43 vs. 45%, p<0.001), and non-Hispanic Black women had the lowest early pregnancy HbA1c (7.0±1.6 vs. 7.9±2.1 vs. 7.5±1.7%, p<0.001). Additionally, caesarean delivery rates were lowest for Hispanic women compared to Non-Hispanic White and Non-Hispanic Black women (45 vs. 63 vs. 71%, p<0.001); this difference persisted after controlling for co-variates (aOR 0.53, 95% CI 0.30-0.92). Conversely, there were no differences in birth weight category, preterm birth <37 weeks, hypertensive disorders of pregnancy, or NICU admission. Conclusion and Potential Impact: Pregnancies complicated by T2D have an increased risk of poor maternal and neonatal outcomes. For some outcomes, there is a significant difference among Non-Hispanic White, Non-Hispanic Black, and Hispanic women. Future studies are therefore needed to investigate causative factors and potential interventions. Presentation recording available online: https://purl.dlib.indiana.edu/iudl/media/h04d673g6hItem The Association Between Kidney Disease and Diabetes Remission in Bariatric Surgery Patients With Type 2 Diabetes(Elsevier, 2019-12) Friedman, Allon N.; Wang, Junyao; Wahed, Abdus S.; Docherty, Neil G.; Fennern, Erin; Pomp, Alfons; Purnell, Jonathan Q.; le Roux, Carel W.; Wolfe, Bruce; Medicine, School of MedicineRationale & objective: The association between bariatric surgery, type 2 diabetes, and chronic kidney disease (CKD) is poorly understood. We studied whether remission of type 2 diabetes induced by bariatric surgery influences markers of kidney disease, if CKD is associated with remission of diabetes after bariatric surgery, and if baseline levels of gut hormones and peptides modify these associations. Study design: Prospective observational study. Study participants: 737 bariatric surgery patients with type 2 diabetes who participated in a multicenter cohort study for up to 5 years. Predictors: Demographics, blood pressure, medications, type of bariatric surgery, anthropometrics, markers of kidney disease, and circulating levels of gut hormones and peptides. Outcomes: Estimated glomerular filtration rate (eGFR), urinary albumin excretion, prognostic risk for CKD, and remission of diabetes. Analytical approach: Linear mixed models for eGFR; generalized linear mixed models with logit link for albuminuria, prognostic risk for CKD, and diabetes remission. Results: Remission of diabetes at 5 years post-bariatric surgery was not independently associated with eGFR but was associated with lower risk for moderate/severe increase in albuminuria (risk ratio, 0.66; 95% CI, 0.48-0.90) and stabilization in prognostic risk for CKD. These findings were modified by baseline ghrelin level. Lower preoperative eGFR and greater prognostic risk for CKD were independently associated with reduced likelihood of diabetes remission. The association with preoperative GFR was modified by C-peptide level. Higher baseline circulating ghrelin level was independently associated with a lower prognostic risk for CKD. Limitations: A minority of participants had baseline CKD; lack of comparison group; no information on duration of diabetes, other clinical end points, or kidney biopsy results. Conclusions: Remission of type 2 diabetes 5 years after bariatric surgery was associated with improvements in albuminuria and stabilized prognostic risk for CKD, but not with eGFR. Lower kidney function and greater prognostic risk at the time of bariatric surgery was linked to a lower likelihood of diabetes remission. These results highlight the need to identify the mechanisms through which bariatric surgery may delay the long-term progression of CKD in type 2 diabetes. Keywords: C-peptide; CKD risk; Obesity; Roux-en-Y gastric bypass (RYGB); albuminuria; bariatric surgery; chronic kidney disease (CKD); diabetes remission; estimated glomerular filtration rate (eGFR); ghrelin; gut peptides; insulin; laparoscopic adjustable gastric banding (LAGB); modifiable risk factor; type 2 diabetes mellitus (T2DM); urinary albumin-creatinine ratio (UACR); weight loss.Item Association of erythrocyte n-3 polyunsaturated fatty acids with incident type 2 diabetes in a Chinese population(Elsevier, 2018-09-26) Zheng, Ju-Sheng; Lin, Jie-sheng; Dong, Hong-li; Zeng, Fang-fang; Li, Duo; Song, Yiqing; Chen, Yu-ming; Epidemiology, School of Public HealthSummary Background & aims The association between circulating n-3 polyunsaturated fatty acid (PUFA) biomarkers and incident type 2 diabetes in Asian populations remains unclear. We aimed to examine the association of erythrocyte n-3 PUFA with incident type 2 diabetes in a Chinese population. Methods A total of 2671 participants, aged 40–75 y, free of type 2 diabetes at baseline, were included in the present analysis. Incident type 2 diabetes cases (n = 213) were ascertained during median follow-up of 5.6 years. Baseline erythrocyte fatty acids were measured by gas chromatography. We used multivariable Cox regression models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of type 2 diabetes across quartiles of erythrocyte n-3 PUFA. Results After adjustment for potential confounders, HRs (95% CIs) of type 2 diabetes were 0.68 (0.47, 1.00), 0.77 (0.52, 1.15), and 0.63 (0.41, 0.95) in quartiles 2–4 of docosapentaenoic acid (C22:5n-3) (P-trend = 0.07), compared with quartile 1; and 1.08 (0.74, 1.60), 1.03 (0.70, 1.51), and 0.57 (0.38, 0.86) for eicosapentaenoic acid (C20:5n-3) (P-trend = 0.007). No association was found for docosahexaenoic acid (C22:6n-3) or alpha-linolenic acid (C18:3n-3). Conclusions Erythrocyte n-3 PUFA from marine sources (C22:5n-3 and C20:5n-3), as biomarkers of dietary marine n-3 PUFA, were inversely associated with incident type 2 diabetes in this Chinese population. Future prospective investigations in other Asian populations are necessary to confirm our findings.Item Association of Glycemia with Insulin Sensitivity and β-cell Function in Adults with Early Type 2 Diabetes on Metformin Alone(Elsevier, 2021) Utzschneider, Kristina M.; Younes, Naji; Rasouli, Neda; Barzilay, Joshua; Banerji, Mary Ann; Cohen, Robert M.; Gonzalez, Erica V.; Mather, Kieren J.; Ismail-Beigi, Faramarz; Raskin, Philip; Wexler, Deborah J.; Lachin, John M.; Kahn, Steven E.; GRADE Research Group; Medicine, School of MedicineAims: Evaluate the relationship between measures of glycemia with β-cell function and insulin sensitivity in adults with early type 2 diabetes mellitus (T2DM). Methods: This cross-sectional analysis evaluated baseline data from 3108 adults with T2DM <10 years treated with metformin alone enrolled in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study. Insulin and C-peptide responses and insulin sensitivity were calculated from 2-hour oral glucose tolerance tests. Regression models evaluated the relationships between glycemic measures (HbA1c, fasting and 2-hour glucose), measures of β-cell function and insulin sensitivity. Results: Insulin and C-peptide responses were inversely associated with insulin sensitivity. Glycemic measures were inversely associated with insulin and C-peptide responses adjusted for insulin sensitivity. HbA1c demonstrated modest associations with β-cell function (range: r −0.22 to −0.35). Fasting and 2-hour glucose were associated with early insulin and C-peptide responses (range: r −0.37 to −0.40) as well as late insulin and total insulin and C-peptide responses (range: r −0.50 to −0.60). Conclusion: Glycemia is strongly associated with β-cell dysfunction in adults with early T2DM treated with metformin alone. Efforts to improve glycemia should focus on interventions aimed at improving β-cell function.Item Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis(Oxford University Press, 2022) Agarwal, Rajiv; Filippatos, Gerasimos; Pitt, Bertram; Anker, Stefan D.; Rossing, Peter; Joseph, Amer; Kolkhof, Peter; Nowack, Christina; Gebel, Martin; Ruilope, Luis M.; Bakris, George L.; Medicine, School of MedicineAims: The complementary studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease (CKD) examined cardiovascular and kidney outcomes in different, overlapping stages of CKD. The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of safety and efficacy of finerenone compared with placebo. Methods and results: For this prespecified analysis, two phase III, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death. Among 13 026 patients with a median follow-up of 3.0 years (interquartile range 2.3-3.8 years), the composite cardiovascular outcome occurred in 825 (12.7%) patients receiving finerenone and 939 (14.4%) receiving placebo [hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.78-0.95; P = 0.0018]. The composite kidney outcome occurred in 360 (5.5%) patients receiving finerenone and 465 (7.1%) receiving placebo (HR, 0.77; 95% CI, 0.67-0.88; P = 0.0002). Overall safety outcomes were generally similar between treatment arms. Hyperkalaemia leading to permanent treatment discontinuation occurred more frequently in patients receiving finerenone (1.7%) than placebo (0.6%). Conclusion: Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes. Key question: Does finerenone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerated renin-angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease in patients with type 2 diabetes? Key finding: In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of >60 mL/min/1.73m2 they were identified solely on the basis of albuminuria. Take home message: Finerenone reduces the risk of clinical cardiovascular outcomes and kidney disease progression in a broad range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates reduction of both cardiovascular and kidney disease burden.Item Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping(Elsevier, 2020-08) Liu, Zhipeng; Zhang, Yang; Graham, Sarah; Wang, Xiaokun; Cai, Defeng; Huang, Menghao; Pique-Regi, Roger; Dong, Xiaocheng Charlie; Chen, Y. Eugene; Willer, Cristen; Liu, Wanqing; Biochemistry and Molecular Biology, School of MedicineBackground & aims: Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships between them remain incompletely understood. We aimed to explore the causal relationships between the 3 diseases. Methods: Using both UK Biobank and publicly available genome-wide association study data, we performed a 2-sample bidirectional Mendelian randomization analysis to test the causal inter-relationships between NAFLD, T2D, and obesity. Transgenic mice expressing the human PNPLA3-I148M isoforms (TghPNPLA3-I148M) were used as an example to validate causal effects and explore underlying mechanisms. Results: Genetically driven NAFLD significantly increased the risk of T2D and central obesity but not insulin resistance or generalized obesity, while genetically driven T2D, body mass index and WHRadjBMI causally increased NAFLD risk. The animal study focusing on PNPLA3 corroborated these causal effects: compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed glucose intolerance and increased visceral fat, but maintained normal insulin sensitivity, reduced body weight, and decreased circulating total cholesterol. Mechanistically, the TghPNPLA3-I148M mice demonstrated decreased pancreatic insulin but increased glucagon secretion, which was associated with increased pancreatic inflammation. In addition, transcription of hepatic cholesterol biosynthesis pathway genes was significantly suppressed, while transcription of thermogenic pathway genes was activated in subcutaneous and brown adipose tissues but not in visceral fat in TghPNPLA3-I148M mice. Conclusions: Our study suggests that lifelong, genetically driven NAFLD causally promotes T2D with a late-onset type 1-like diabetic subphenotype and central obesity; while genetically driven T2D, obesity, and central obesity all causally increase the risk of NAFLD. This causal relationship revealed new insights into how nature and nurture drive these diseases, providing novel hypotheses for disease subphenotyping. Lay summary: Non-alcoholic fatty liver disease, type 2 diabetes and obesity are epidemiologically correlated with each other, but their causal relationships were incompletely understood. Herein, we identified causal relationships between these conditions, which suggest that each of these closely related diseases should be further stratified into subtypes. This is important for accurate diagnosis, prevention and treatment of these diseases.