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Browsing by Author "Goldberg, Ronald B."
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Item Circulating natriuretic peptide concentrations reflect changes in insulin sensitivity over time in the Diabetes Prevention Program(Springer, 2014-05) Walford, Geoffrey A.; Ma, Yong; Christophi, Costas A.; Goldberg, Ronald B.; Jarolim, Petr; Horton, Edward; Mather, Kieren J.; Barrett-Connor, Elizabeth; Davis, Jaclyn; Florez, Jose C.; Wang, Thomas J.; Department of Medicine, IU School of MedicineAIMS/HYPOTHESIS: We aimed to study the relationship between measures of adiposity, insulin sensitivity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the Diabetes Prevention Program (DPP). METHODS: The DPP is a completed clinical trial. Using stored samples from this resource, we measured BMI, waist circumference (WC), an insulin sensitivity index (ISI; [1/HOMA-IR]) and NT-proBNP at baseline and at 2 years of follow-up in participants randomised to placebo (n = 692), intensive lifestyle intervention (n = 832) or metformin (n = 887). RESULTS: At baseline, log NT-proBNP did not differ between treatment arms and was correlated with baseline log ISI (p < 0.0001) and WC (p = 0.0003) but not with BMI (p = 0.39). After 2 years of treatment, BMI decreased in the lifestyle and metformin groups (both p < 0.0001); WC decreased in all three groups (p < 0.05 for all); and log ISI increased in the lifestyle and metformin groups (both p < 0.001). The change in log NT-proBNP did not differ in the lifestyle or metformin group vs the placebo group (p > 0.05 for both). In regression models, the change in log NT-proBNP was positively associated with the change in log ISI (p < 0.005) in all three study groups after adjusting for changes in BMI and WC, but was not associated with the change in BMI or WC after adjusting for changes in log ISI. CONCLUSION/INTERPRETATION: Circulating NT-proBNP was associated with a measure of insulin sensitivity before and during preventive interventions for type 2 diabetes in the DPP. This relationship persisted after adjustment for measures of adiposity and was consistent regardless of whether a participant was treated with placebo, intensive lifestyle intervention or metformin.Item Hepatic Fat in Participants With and Without Incident Diabetes in the Diabetes Prevention Program Outcome Study(The Endocrine Society, 2021) Goldberg, Ronald B.; Tripputi, Mark T.; Boyko, Edward J.; Budoff, Matthew; Chen, Zsu-Zsu; Clark, Jeanne M.; Dabelea, Dana M.; Edelstein, Sharon L.; Gerszten, Robert E.; Horton, Edward; Mather, Kieren J.; Perreault, Leigh; Temprosa, Marinella; Wallia, Amisha; Watson, Karol; Irfan, Zeb; Medicine, School of MedicineContext: There is little information about fatty liver in prediabetes as it transitions to early diabetes. Objective: This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP). Methods: We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed. Results: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence. Conclusion: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted.Item Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the diabetes prevention program except in those who develop diabetes(American Diabetes Association, 2014-08) Goldberg, Ronald B.; Temprosa, Marinella G.; Mather, Kieren J.; Orchard, Trevor J.; Kitabchi, Abbas E.; Watson, Karol E.; Diabetes Prevention Program Research Group; Department of Medicine, IU School of MedicineOBJECTIVE: We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes. RESEARCH DESIGN AND METHODS: The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were randomized to lifestyle, metformin, or placebo interventions for 3.4 years. Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing. In addition to baseline testing, anthropometry was performed every 6 months; fasting insulin yearly; and hs-CRP, tissue plasminogen activator (tPA), and fibrinogen at 1 year and end of study (EOS). RESULTS: CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS. These reductions were not seen in those who developed diabetes over the course of the study despite intervention. Fibrinogen was lower at 1 year in the lifestyle group. Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group, but only partly in the placebo and metformin groups. Weight, insulin sensitivity, and hyperglycemia differences each accounted for the influence of diabetes on the tPA response. CONCLUSIONS: Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA. Incident diabetes prevented these improvements, and this was accounted for by differences in weight, insulin resistance, and glucose levels.Item Metabolic syndrome components and their response to lifestyle and metformin interventions are associated with differences in diabetes risk in persons with impaired glucose tolerance(Wiley Blackwell (Blackwell Publishing), 2014-04) Florez, Hermes; Temprosa, Marinella G.; Orchard, Trevor J.; Mather, Kieren J.; Marcovina, Santica M.; Barrett-Connor, Elizabeth; Horton, Edward; Saudek, Christopher; Pi-Sunyer, Xavier F.; Ratner, Robert E.; Goldberg, Ronald B.; Department of Medicine, IU School of MedicineAIMS: To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence. METHODS: We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years. RESULTS: In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3-2.3), 1.7 (1.2-2.3) and 2.0 (1.3-3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk. CONCLUSIONS: MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence.Item Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions(Springer Verlag, 2018-10-17) Goldberg, Ronald B.; Bray, George A.; Marcovina, Santica M.; Mather, Kieren J.; Orchard, Trevor J.; Perreault, Leigh; Temprosa, Marinella; Medicine, School of MedicineWe compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes. METHODS: The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these. RESULTS: E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]). CONCLUSIONS/INTERPRETATION: These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.Item Predictive utilities of lipid traits, lipoprotein subfractions and other risk factors for incident diabetes: a machine learning approach in the Diabetes Prevention Program(BMJ, 2021-03) Varga, Tibor V.; Liu, Jinxi; Goldberg, Ronald B.; Chen, Guannan; Dagogo-Jack, Samuel; Lorenzo, Carlos; Mather, Kieren J.; Pi-Sunyer, Xavier; Brunak, Søren; Temprosa, Marinella; Medicine, School of MedicineIntroduction: Although various lipid and non-lipid analytes measured by nuclear magnetic resonance (NMR) spectroscopy have been associated with type 2 diabetes, a structured comparison of the ability of NMR-derived biomarkers and standard lipids to predict individual diabetes risk has not been undertaken in larger studies nor among individuals at high risk of diabetes. Research design and methods: Cumulative discriminative utilities of various groups of biomarkers including NMR lipoproteins, related non-lipid biomarkers, standard lipids, and demographic and glycemic traits were compared for short-term (3.2 years) and long-term (15 years) diabetes development in the Diabetes Prevention Program, a multiethnic, placebo-controlled, randomized controlled trial of individuals with pre-diabetes in the USA (N=2590). Logistic regression, Cox proportional hazards model and six different hyperparameter-tuned machine learning algorithms were compared. The Matthews Correlation Coefficient (MCC) was used as the primary measure of discriminative utility. Results: Models with baseline NMR analytes and their changes did not improve the discriminative utility of simpler models including standard lipids or demographic and glycemic traits. Across all algorithms, models with baseline 2-hour glucose performed the best (max MCC=0.36). Sophisticated machine learning algorithms performed similarly to logistic regression in this study. Conclusions: NMR lipoproteins and related non-lipid biomarkers were associated but did not augment discrimination of diabetes risk beyond traditional diabetes risk factors except for 2-hour glucose. Machine learning algorithms provided no meaningful improvement for discrimination compared with logistic regression, which suggests a lack of influential latent interactions among the analytes assessed in this study.