Insulin resistance and cardiovascular outcomes in the <scp>ORIGIN</scp> trial

Gerstein, Hertzel C.; Ferrannini, Ele; Riddle, Matthew C.; Yusuf, Salim; Investigators, Origin Trial

doi:10.1111/dom.13112

Cited by 11 publications

(9 citation statements)

References 27 publications

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“…Insulin resistance is always claimed when insulin fails to elicit a normal physiological response that is presented by hyperglycemia in face of normal or even higher insulin levels [31] , which is confirmed by monitoring elevated (HOMA-IR) value [5] .…”

Section: Discussionmentioning

confidence: 99%

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Effect of Vitamin D on Serum Fibroblast Growth Factor-23 and Cardiac Tissue Hydroxyproline Levels in Experimentally Induced Insulin Resistance Associated with Left Ventricular Hypertrophy in Rats

Ibrahim¹,

Almeligy

2019

The Medical Journal of Cairo University

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Background: Insulin resistance cardiomyopathy refers to functional and structural changes at the level of myocardium; independent of hypertension, coronary artery disease, or any other known cardiac diseases, leading to HF, with LVH as the main structural hall mark for it. Several factors have been documented in its pathogenesis; in obese insulin resistant FGF-23 a bone derived hormone can be involved .The role of vitamin D, has gained much attention over the last years as a potential therapeutic agent for prevention of insulin resistance and its protective role against ventricular hypertrophy. Aim of Study: Was to evaluate the potential effect of vitamin D as a protective factor against the development of LVH in experimentally induced insulin resistance in rats using the level of FGF-23 as a predictor and cardiac tissue hydroxyproline as a biomarker for cardiac affection. Material and Methods: This study was conducted on 60 male albino rats divided randomly into four equal groups as follow group I (normal control group), group II (vitamin D treated control group), group III (high sucrose subjected group) and group IV (vitamin D co-treated high sucrose subjected group). In order to induce insulin resistance and cardiomyopathy both third and fourth groups were allowed to get free access to 35% sucrose as their drinking water for 16 weeks, during induction of insulin resistance cardiomyopathy by sucrose in the fourth group rats were co-treated by giving vitamin D orally in a dose (1000IU/kg) dissolved in 1 ml olive oil, given every other day by gavage for 12 weeks. At the end of the experiment blood samples were collected by cardiac puncture after ether anesthesia, chest and abdomen were opened and the heart was extracted. All groups were subjected to estimation of: Serum measurement of fasting glucose level using colorimetric assay and fasting insulin level by rat insulin ELISA kit to asses insulin resistance using (HOMA-IR index). Also, serum FGF-23 by rat FGF-23 ELISA kit as well as left ventricular tissue hydroxyproline content using colorimetric assay. Histopathological examination of the left ventricle specimens was done.

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Section: Discussionmentioning

confidence: 99%

“…Insulin resistance associated with many health problems, of which its hazards to the cardiovascular system including stroke, coronary artery disease and cardiomyopathy [5] .…”

Section: Introductionmentioning

confidence: 99%

Effect of Vitamin D on Serum Fibroblast Growth Factor-23 and Cardiac Tissue Hydroxyproline Levels in Experimentally Induced Insulin Resistance Associated with Left Ventricular Hypertrophy in Rats

Ibrahim¹,

Almeligy

2019

The Medical Journal of Cairo University

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“…Insulin resistance was measured as defined previously, using the insulin res in the ORIGIN trial to achieve normoglycemia. 33 Models assessing local ancestry associations demonstrated that the African local estimate associated with increased C-peptide at rs4149261 was also associated with increased risk of T2D (OR ¼ 6.07 per SD, 95% CI 1.44 to 25.56, p ¼ 0.01) and median dose of insulin used (per kg of fat-free mass, log transformed) (b ¼ 0.54 per SD, 95% CI 0.16 to 0.92, p ¼ 0.005). However, African local estimates at rs3769050 were not associated with T2D or insulin resistance (p > 0.05).…”

Section: Evaluation Of the Role Of C-peptide In Disparities In T2d Risk Among Ethnic Groupsmentioning

confidence: 99%

Influence of Genetic Ancestry on Human Serum Proteome

Sjaarda

Gerstein

Kutalik

et al. 2020

The American Journal of Human Genetics

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Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. We developed a variance component model in order to determine the proportion of variance explained by inter-ancestry differences, and we applied it to the biomarker panel. Multivariable linear regression was used to identify and localize genetic loci affecting biomarker variability between ethnicities. Variance component analysis revealed that 5% of biomarkers were significantly impacted by genetic admixture (p < 0.05/237), including C-peptide, apolipoprotein-E, and intercellular adhesion molecule 1. We also identified 46 regional associations across 40 different biomarkers (p < 1.13 3 10 À6 ). An independent analysis revealed that 34 of these 46 regions were associated at genome-wide significance (p < 5 3 10 À8 ) with their respective biomarker in either Europeans or Latin populations. Additional analyses revealed that an admixture mapping signal associated with increased C-peptide levels was also associated with an increase in diabetes risk (odds ratio [OR] ¼ 6.07 per SD, 95% confidence interval [CI] 1.44 to 25.56, p ¼ 0.01) and surrogate measures of insulin resistance. Our results demonstrate the impact of ancestry on biomarker levels, suggesting that some of the observed differences in disease prevalence have a biological basis, and that reference intervals for those biomarkers should be tailored to ancestry. Specifically, our results point to a strong role of ancestry in insulin resistance and diabetes risk.

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“…In this study, we used the motivating example that intensification of metformin therapy with insulin versus with sulfonylurea was associated with increased risk of mortality to explore whether substantial residual confounding due to unmeasured frailty may have affected this comparison (1,20). While a large randomized controlled trial has shown neutral effect of insulin on the risk of cardiovascular events, in this study, we sought to examine the potential influence of frailty as a confounder, an unmeasured effect that may influence both the exposure and outcomes, in observational studies (21). To estimate the potential confounding by frailty, we estimated the hazard ratio of death between two FI values corresponding to the mean FI for patients on metformin plus insulin and for patients on metformin plus sulfonylurea.…”

Section: Motivating Example: Estimation Of Residual Confounding Due Tmentioning

confidence: 99%

Evaluation of Frailty as an Unmeasured Confounder in Observational Studies of Antidiabetic Medications

Presley

Chipman

Min

et al. 2018

The Journals of Gerontology: Series A

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Background It is unknown whether observational studies evaluating the association between antidiabetic medications and mortality adequately account for frailty. Our objectives were to evaluate if frailty was a potential confounder in the relationship between antidiabetic medication regimen and mortality and how well administrative and clinical electronic health record (EHR) data account for frailty. Methods We conducted a retrospective cohort study in a single Veterans Health Administration (VHA) healthcare system of 500 hospitalizations—the majority due to heart failure—of Veterans who received regular VHA care and initiated type 2 diabetes treatment from 2001 to 2008. We measured frailty using a modified frailty index (FI, >0.21 frail). We obtained antidiabetic medication regimen and time-to-death from administrative sources. We compared FI among patients on different antidiabetic regimens. Stepwise Cox proportional hazards regression estimated time-to-death by demographic, administrative, clinical EHR, and FI data. Results Median FI was 0.22 (interquartile range 0.18, 0.27). Frailty differed across antidiabetic regimens (p < .001). An FI increase of 0.05 was associated with an increased risk of death (hazard ratio 1.45, 95% confidence interval 1.32, 1.60). Cox proportional hazards model for time-to-death including demographic, administrative, and clinical EHR data had a c-statistic of 0.70; adding FI showed marginal improvement (c-statistic 0.72). Conclusions Frailty was associated with antidiabetic regimen and death, and may confound that relationship. Demographic, administrative, and clinical EHR data, commonly used to balance differences among exposure groups, performed moderately well in assessing risk of death, with minimal gain from adding frailty. Study design and analytic techniques can help minimize potential confounding by frailty in observational studies.

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Insulin resistance and cardiovascular outcomes in the ORIGIN trial

Abstract: Insulin resistance may not promote cardiovascular outcomes in individuals with dysglycaemia.

Cited by 11 publications

References 27 publications

Effect of Vitamin D on Serum Fibroblast Growth Factor-23 and Cardiac Tissue Hydroxyproline Levels in Experimentally Induced Insulin Resistance Associated with Left Ventricular Hypertrophy in Rats

Effect of Vitamin D on Serum Fibroblast Growth Factor-23 and Cardiac Tissue Hydroxyproline Levels in Experimentally Induced Insulin Resistance Associated with Left Ventricular Hypertrophy in Rats

Influence of Genetic Ancestry on Human Serum Proteome

Evaluation of Frailty as an Unmeasured Confounder in Observational Studies of Antidiabetic Medications

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