Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 143
Filtrar
1.
Nat Med ; 25(11): 1733-1738, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31700171

RESUMO

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.

2.
Mol Metab ; 29: 182-196, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31668389

RESUMO

OBJECTIVE: Prokineticin 2 (PROK2) is a hypothalamic neuropeptide that plays a critical role in the rhythmicity of physiological functions and inhibits food intake. PROK2 is also expressed in the main olfactory bulb (MOB) as an essential factor for neuro-and morphogenesis. Since the MOB was shown to be strongly involved in eating behavior, we hypothesized that PROK2 could be a new target in the regulation of food intake and energy homeostasis, through its effects in the MOB. We also asked whether PROK2 could be associated with the pathophysiology of obesity, the metabolic syndrome (MetS), and type 2 diabetes (T2D) in humans. METHODS: We assessed in wild type mice whether the expression of Prok2 in the MOB is dependent on the nutritional status. We measured the effect of human recombinant PROK2 (rPROK2) acute injection in the MOB on food intake and olfactory behavior. Then, using a lentivirus expressing Prok2-shRNA, we studied the effects of Prok2 underexpression in the MOB on feeding behavior and glucose metabolism. Metabolic parameters and meal pattern were determined using calorimetric cages. In vivo 2-deoxyglucose uptake measurements were performed in mice after intraperitoneally insulin injection. Plasmatic PROK2 dosages and genetic associations studies were carried out respectively on 148 and more than 4000 participants from the D.E.S.I.R. (Data from an Epidemiologic Study on the Insulin Resistance Syndrome) cohort. RESULTS: Our findings showed that fasting in mice reduced Prok2 expression in the MOB. Acute injection of rPROK2 in the MOB significantly decreased food intake whereas Prok2-shRNA injection resulted in a higher dietary consumption characterized by increased feeding frequency and decreased meal size. Additionally, Prok2 underexpression in the MOB induced insulin resistance compared to scrambled shRNA-injected mice. In the human D.E.S.I.R. cohort, we found a significantly lower mean concentration of plasma PROK2 in people with T2D than in those with normoglycemia. Interestingly, this decrease was no longer significant when adjusted for Body Mass Index (BMI) or calorie intake, suggesting that the association between plasma PROK2 and diabetes is mediated, at least partly, by BMI and feeding behavior in humans. Moreover, common Single Nucleotide Polymorphisms (SNPs) in PROK2 gene were genotyped and associated with incident T2D or impaired fasting glycemia (IFG), MetS, and obesity. CONCLUSIONS: Our data highlight PROK2 as a new target in the MOB that links olfaction with eating behavior and energy homeostasis. In humans, plasma PROK2 is negatively correlated with T2D, BMI, and energy intake, and PROK2 genetic variants are associated with incident hyperglycemia (T2D/IFG), the MetS and obesity.

3.
Environ Health Perspect ; 127(10): 107013, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31663775

RESUMO

BACKGROUND: The question of whether exposure to bisphenol A (BPA) contributes to the development of type 2 diabetes is still unresolved. Most epidemiological evidence on the association between BPA and diabetes is from cross-sectional studies or longitudinal studies with single urinary measurements. No prospective study has examined exposure to BPA analogs such as bisphenol S (BPS) in relation to incident type 2 diabetes. OBJECTIVES: We aimed to investigate whether exposure to BPA and BPS, assessed at up to two time points, was associated with the incidence of type 2 diabetes. METHODS: We performed a case-cohort study on 755 participants without diabetes at baseline and followed-up over 9 y as part of the French prospective cohort Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.). BPA-glucuronide (BPA-G) and BPS-glucuronide (BPS-G) were assessed in fasting spot urine samples collected during the health examinations at baseline and 3 y later. Associations with incident diabetes were examined using Prentice-weighted Cox regression models adjusted for potential confounders. RESULTS: A total of 201 incident cases of type 2 diabetes were diagnosed over the follow-up, including 30 in the subcohort. Compared with participants with the lowest average BPA exposure (below the first quartile), participants in the second, third, and fourth quartile groups of exposure had a near doubling of the risk of type 2 diabetes, with a hazard ratio (HR) = 2.56 (95% CI: 1.16, 5.65), 2.35 (95% CI: 1.07, 5.15), and 1.56 (95% CI: 0.68, 3.55), respectively. The detection of BPS-G in urine at one or both time points was associated with incident diabetes, with an HR = 2.81 (95% CI: 1.74, 4.53). DISCUSSION: This study shows positive associations between exposure to BPA and BPS and the incidence of type 2 diabetes, independent of traditional diabetes risk factors. Our results should be confirmed by recent, population-based observational studies in different populations and settings. Overall, these findings raise concerns about using BPS as a BPA substitute. Further research on BPA analogs is warranted. https://doi.org/10.1289/EHP5159.

4.
Diabetes Care ; 42(12): 2290-2297, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31582427

RESUMO

OBJECTIVE: Diabetes is the leading cause of nontraumatic lower-extremity amputations (LEAs). Identification of patients with foot ulcers at risk for amputation remains clinically challenging. Plasma copeptin, a surrogate marker of vasopressin, is associated with the risk of cardiovascular and renal complications in diabetes. RESEARCH DESIGN AND METHODS: We assessed the association between baseline plasma copeptin and risk of LEA during follow-up in four cohorts of people with type 1 (GENESIS, n = 503, and GENEDIAB, n = 207) or type 2 diabetes (DIABHYCAR, n = 3,101, and SURDIAGENE, n = 1,452) with a median duration of follow-up between 5 and 10 years. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay. RESULTS: In the pooled cohorts with type 1 diabetes (n = 710), the cumulative incidence of LEA during follow-up by increasing tertiles (tertile 1 [TER1], TER2, and TER3) of baseline plasma copeptin was 3.9% (TER1), 3.3% (TER2), and 10.0% (TER3) (P = 0.002). Cox regression analyses confirmed the association of copeptin with LEA: hazard ratio (HR) for 1 SD increment of log[copeptin] was 1.89 (95% CI 1.28-2.82), P = 0.002. In the pooled cohorts of type 2 diabetes (n = 4,553), the cumulative incidence of LEA was 1.1% (TER1), 2.9% (TER2), and 3.6% (TER3) (P < 0.0001). In Cox regression analyses, baseline plasma copeptin was significantly associated with LEA: HR for 1 SD increment of log[copeptin] was 1.42 (1.15-1.74), P = 0.001. Similar results were observed in the cohort with type 2 diabetes for lower-limb revascularization (HR 1.20 [95% CI 1.03-1.39], P = 0.02). CONCLUSIONS: Baseline plasma copeptin is associated with cumulative incidence of LEA in cohorts of people with both type 1 and type 2 diabetes and may help to identify patients at risk for LEA.

5.
Int J Obes (Lond) ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388097

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 250 loci associated with body mass index (BMI) and obesity. However, post-GWAS functional genomic investigations have been inadequate for understanding how these genetic loci physiologically impact disease development. METHODS: We performed a PCR-free expression assay targeting genes located nearby the GWAS-identified SNPs associated with BMI/obesity in a large panel of human tissues. Furthermore, we analyzed several genetic risk scores (GRS) summing GWAS-identified alleles associated with increased BMI in 4236 individuals. RESULTS: We found that the expression of BMI/obesity susceptibility genes was strongly enriched in the brain, especially in the insula (p = 4.7 × 10-9) and substantia nigra (p = 6.8 × 10-7), which are two brain regions involved in addiction and reward. Inversely, we found that top obesity/BMI-associated loci, including FTO, showed the strongest gene expression enrichment in the two brain regions. CONCLUSIONS: Our data suggest for the first time that the susceptibility genes for common obesity may have an effect on eating addiction and reward behaviors through their high expression in substantia nigra and insula, i.e., a different pattern from monogenic obesity genes that act in the hypothalamus and cause hyperphagia. Further epidemiological studies with relevant food behavior phenotypes are necessary to confirm these findings.

6.
Sci Rep ; 9(1): 9439, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

8.
Diabetes Ther ; 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30767173

RESUMO

INTRODUCTION: The LIGHTNING study applied conventional and advanced analytic approaches to model, predict, and compare hypoglycemia rates of people with type 2 diabetes (T2DM) on insulin glargine 300 U/ml (Gla-300) with those on first-generation (insulin glargine 100 U/ml [Gla-100]; insulin detemir [IDet]) or second-generation (insulin degludec [IDeg]) basal-insulin (BI) analogs, utilizing a large real-world database. METHODS: Data were collected between 1 January 2007 and 31 March 2017 from the Optum Humedica US electronic health records [EHR] database. Patient-treatments, the period during which a patient used a specific BI, were analyzed for patients who switched from a prior BI or those who newly initiated BI therapy. Data were analyzed using two approaches: propensity score matching (PSM) and a predictive modeling approach using machine learning. RESULTS: A total of 831,456 patients with T2DM receiving BI were included from the EHR data set. Following selection, 198,198 patient-treatments were available for predictive modeling. The analysis showed that rates of severe hypoglycemia (using a modified definition) were approximately 50% lower with Gla-300 than with Gla-100 or IDet in insulin-naïve individuals, and 30% lower versus IDet in BI switchers (all p < 0.05). Similar rates of severe hypoglycemia were predicted for Gla-300 and IDeg, regardless of prior insulin experience. Similar results to those observed in the overall cohorts were seen in analyses across subgroups at a particularly high risk of hypoglycemia. PSM (performed on 157,573 patient-treatments) revealed comparable reductions in HbA1c with Gla-300 versus first- and second-generation BI analogs, alongside lower rates of severe hypoglycemia with Gla-300 versus first-generation BI analogs (p < 0.05) and similar rates versus IDeg in insulin-naïve and BI-switcher cohorts. CONCLUSIONS: Based on real-world data, predicted rates of severe hypoglycemia with Gla-300 tended to be lower versus first-generation BI analogs and similar versus IDeg in a wide spectrum of patients with T2DM. FUNDING: Sanofi, Paris, France.

9.
Diabetologia ; 62(6): 939-947, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30809716

RESUMO

AIMS/HYPOTHESIS: Recently, safety data signalled an increased risk of amputations in people taking canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. If this side effect is due to drug-induced hypovolaemia, diuretics should also increase that risk. The aim of this study was to analyse the association between diuretic use and the risk of lower limb events (LLEs) in people with type 2 diabetes. METHODS: SURDIAGENE (SUivi Rénal, DIAbète de type 2 et GENEtique) is a prospective observational cohort that includes people with type 2 diabetes enrolled from 2002 to 2012 and followed-up until onset of LLE, death or 31 December 2015, whichever came first. Primary outcome was the first occurrence of LLE, a composite of lower limb amputation (LLA) and lower limb revascularisation (LLR). The rates of primary outcome were compared between participants taking and not taking diuretics at baseline in a Cox-adjusted model. RESULTS: At baseline, of the 1459 participants included, 670 were taking diuretics. In participants with and without diuretics, the mean ages were 67.1 and 62.9 years and 55.8% and 59.8% were men, respectively. During a median follow-up of 7.1 years, the incidence of LLE was 1.80 per 100 patient-years in diuretic users vs 1.00 in non-users (p < 0.001). The HR for LLE in users vs non-users was 2.08 (95% CI 1.49, 2.93), p < 0.001. This association remained significant in a multivariable-adjusted model (1.49 [1.01, 2.19]; p = 0.04) and similar after considering death as a competing risk (subhazard ratio 1.89 [1.35, 2.64]; p < 0.001). When separated, LLA but not LLR, was associated with the use of diuretics: 2.01 (1.14, 3.54), p = 0.02 and 1.05 (0.67, 1.64), p = 0.84, respectively, in the multivariable-adjusted model. CONCLUSIONS/INTERPRETATION: Among people with type 2 diabetes treated with diuretics, there was a significant increase in the risk of LLE, predominantly in the risk of LLA.

10.
Obes Surg ; 29(5): 1514-1520, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30685835

RESUMO

BACKGROUND: Obesity is a risk factor for chronic kidney disease (CKD) and a relative contraindication for renal transplantation. Bariatric surgery (BS) is an option to address this issue but we hypothesize that severe CKD is associated with a loss of efficacy of BS which could justify recommending it at an earlier stage of the CKD. METHODS: A retrospective study (n = 101 patients) to test primarily for differences in weight loss at 6 and 12 months according to estimated glomerular filtration rate categories (eGFR < 30 including patients on dialysis, 30-60, 60-90, and ≥ 90 ml/min/1.73 m2) was performed with multivariate analysis adjusted for sex, age, BMI, surgical procedure, and diabetes. We used a second method to confirm our hypothesis comparing weight loss in patients with stage 4-5 CKD (eGFR < 30 ml/min/1.73 m2, n = 17), and matched controls with eGFR ≥ 90 ml/min/1.73 m2. RESULTS: In the first comparison, the multivariate analysis showed a significant positive association between eGFR and weight loss. However, after exclusion of the subgroup of patients with eGFR < 30 ml/min/1.73 m2, the difference between groups was no more significant. In addition, percent total weight loss (%TWL) was significantly lower in patients with severe CKD compared to controls: - 15% vs - 23% at 6 months (p < 0.01); - 17% vs - 27% at 12 months (p < 0.01). The percent excess weight loss at 1 year reached 47% in patients with stage 4-5 CKD and 68% in controls subjects (p < 0.01). Surgery was a success at 12 months (weight loss > 50% of excess weight) in 38% of advanced CKD and 88% of controls (p < 0.01). CONCLUSION: The efficacy of BS was reduced in patients with advanced CKD. These results support early BS in patients with early-to-moderate CKD.

12.
J Nucl Cardiol ; 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30574676

RESUMO

BACKGROUND: The aim of this study was to compare the diagnostic performances for the detection of myocardial ischemia of 82-Rb-PET-MPS and 99m-Tc-SPECT-MPS in overweight individuals and women. METHODS AND RESULTS: Men with BMI ≥ 25 and women referred for MPS were considered for inclusion. All individuals underwent 99m-Tc-SPECT-MPS with CZT cameras and 82-Rb-PET-MPS in 3D-mode. Individuals with at least one positive MPS were referred for coronary angiography (CA) with FFR measurements. A criterion for positivity was a composite endpoint including significant stenosis on CA or, in the absence of CA, the occurrence of acute coronary event during the following year. 313 patients (46% women) with mean BMI of 31.8 ± 6.5 were included. Sensitivity for the detection of myocardial ischemia was higher with 82-Rb-PET-MPS compared with 99m-Tc-SPECT-MPS (85% vs. 57%, P < .05); specificity was equally high with both imaging techniques (93% vs. 94%, P > .05). 82-Rb-PET allowed for a more accurate detection of patients with a high-risk coronary artery disease (HR-CAD) than 99m-Tc-SPECT-MPS (AUC = 0.86 vs. 0.75, respectively; P = .04). CONCLUSIONS: In women and overweight individuals, 82-Rb-PET-MPS provides higher sensitivity for the detection of myocardial ischemia than 99m-Tc-SPECT-MPS thanks to a better image quality and an improved detection of HR-CAD.

13.
Diabetes Obes Metab ; 2018 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-30393950

RESUMO

AIMS: To compare the effects of continuing vs. discontinuing sitagliptin when initiating and intensively titrating insulin glargine. MATERIALS AND METHODS: Eligible patients had inadequately controlled type 2 diabetes on metformin (≥1500 mg/day) in combination with a dipeptidyl peptidase-4 inhibitor (DPP-4i) and/or a sulfonylurea. Those on metformin + sitagliptin were directly randomized; all others were switched to metformin + sitagliptin (discontinuing other DPP-4is and sulfonylureas) and stabilized during a run-in period. At randomization, patients were allocated to continuing sitagliptin or discontinuing sitagliptin, with both groups initiating insulin glargine and titrating to a target fasting glucose of 4.0-5.6 mmol/L. RESULTS: A total of 743 participants (mean HbA1c 8.8% [72.6 mmol/mol], disease duration 10.8 years), were treated. After 30 weeks, the mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 6.85% (51.4 mmol/mol) and -1.88% (-20.5 mmol/mol) in the sitagliptin group and 7.31% (56.4 mmol/mol) and -1.42% (-15.5 mmol/mol) in the placebo group; the difference in LS mean changes from baseline HbA1c was -0.46% (-5.0 mmol/mol) (p<0.001). The percentage of participants with HbA1c <7.0% was higher (54% vs. 35%) and the mean daily insulin dose was lower (53 units vs. 61 units) in the sitagliptin group. Despite lower HbA1c, event rates and incidences of hypoglycemia were not higher in the sitagliptin group. Adverse events overall and changes from baseline in body weight were similar between the two treatment groups. CONCLUSION: When initiating insulin glargine therapy, continuation of sitagliptin, compared with discontinuation, resulted in a clinically meaningful greater reduction in HbA1c without an increase in hypoglycemia. This article is protected by copyright. All rights reserved.

14.
Cardiovasc Diabetol ; 17(1): 138, 2018 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-30352589

RESUMO

Lower-extremity arterial disease (LEAD) is a major endemic disease with an alarming increased prevalence worldwide. It is a common and severe condition with excess risk of major cardiovascular events and death. It also leads to a high rate of lower-limb adverse events and non-traumatic amputation. The American Diabetes Association recommends a widespread medical history and clinical examination to screen for LEAD. The ankle brachial index (ABI) is the first non-invasive tool recommended to diagnose LEAD although its variable performance in patients with diabetes. The performance of ABI is particularly affected by the presence of peripheral neuropathy, medial arterial calcification, and incompressible arteries. There is no strong evidence today to support an alternative test for LEAD diagnosis in these conditions. The management of LEAD requires a strict control of cardiovascular risk factors including diabetes, hypertension, and dyslipidaemia. The benefit of intensive versus standard glucose control on the risk of LEAD has not been clearly established. Antihypertensive, lipid-lowering, and antiplatelet agents are obviously worthfull to reduce major cardiovascular adverse events, but few randomised controlled trials (RCTs) have evaluated the benefits of these treatments in terms of LEAD and its related adverse events. Smoking cessation, physical activity, supervised walking rehabilitation and healthy diet are also crucial in LEAD management. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in LEAD management. The revascularization strategy should take into account several factors including anatomical localizations of lesions, medical history of each patients and operator experience. Further studies, especially RCTs, are needed to evaluate the interest of different therapeutic strategies on the occurrence and progression of LEAD and its related adverse events in patients with diabetes.

15.
Cell Rep ; 24(11): 2957-2971.e6, 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30208320

RESUMO

Hypertrophic white adipose tissue (WAT) represents a maladaptive mechanism linked to the risk for developing type 2 diabetes in humans. However, the molecular events that predispose WAT to hypertrophy are poorly defined. Here, we demonstrate that adipocyte hypertrophy is triggered by loss of the corepressor GPS2 during obesity. Adipocyte-specific GPS2 deficiency in mice (GPS2 AKO) causes adipocyte hypertrophy, inflammation, and mitochondrial dysfunction during surplus energy. This phenotype is driven by HIF1A activation that orchestrates inadequate WAT remodeling and disrupts mitochondrial activity, which can be reversed by pharmacological or genetic HIF1A inhibition. Correlation analysis of gene expression in human adipose tissue reveals a negative relationship between GPS2 and HIF1A, adipocyte hypertrophy, and insulin resistance. We propose therefore that the obesity-associated loss of GPS2 in adipocytes predisposes for a maladaptive WAT expansion and a pro-diabetic status in mice and humans.

16.
Diabetologia ; 61(12): 2643-2653, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30232509

RESUMO

AIMS/HYPOTHESIS: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes. METHODS: Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation. RESULTS: We included 1438 participants (age 65 ± 11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (adjHR [95%CI] 1.83 [1.51, 2.21] and 2.20 [1.86, 2.61], respectively, per 1 SD log10 increment, both p < 0.001). MR-proADM contributed significant supplementary information to the prognosis of heart failure when we considered the clinical risk factors (integrated discrimination improvement [IDI, mean ± SEM] 0.021 ± 0.007, p = 0.001) (Table 3). Inclusion of NT-proBNP in the multivariable model including MR-proADM contributed significant complementary information on prediction of heart failure (IDI [mean ± SEM] 0.028 ± 0.008, p < 0.001). By contrast, MR-proADM did not contribute supplementary information on prediction of heart failure in a model including NT-proBNP (IDI [mean ± SEM] 0.003 ± 0.003, p = 0.27), with similar results for heart failure with reduced ejection fraction and preserved ejection fraction. CONCLUSIONS/INTERPRETATION: MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.

17.
Cardiovasc Diabetol ; 17(1): 110, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30071874

RESUMO

BACKGROUND: Cardiovascular disease and kidney damage are tightly associated in people with type 2 diabetes. Experimental evidence supports a causal role for vasopressin (or antidiuretic hormone) in the development of diabetic kidney disease (DKD). Plasma copeptin, the COOH-terminal portion of pre-provasopressin and a surrogate marker of vasopressin, was shown to be positively associated with the development and progression of DKD. Here we assessed the association of plasma copeptin with the risk of cardiovascular events during follow-up in two prospective cohorts of type 2 diabetic patients, and we examined if this association could be mediated by deleterious effects of vasopressin on the kidney. METHODS: We studied 3098 and 1407 type 2 diabetic patients from the French cohorts DIABHYCAR and SURDIAGENE, respectively. We considered the incidence during follow-up (median: 5 years) of a combined end point composed of myocardial infarction, coronary revascularization, hospitalization for congestive heart failure, or cardiovascular death. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay. RESULTS: The cumulative incidence of cardiovascular events during follow-up by sex-specific tertiles of baseline plasma copeptin was 15.6% (T1), 18.7% (T2) and 21.7% (T3) in DIABHYCAR (p = 0.002), and 27.7% (T1), 34.1% (T2) and 47.6% (T3) in SURDIAGENE (p < 0.0001). Cox proportional hazards survival regression analyses confirmed the association of copeptin with cardiovascular events in both cohorts: hazard ratio with 95% confidence interval for T3 vs. T1 was 1.29 (1.04-1.59), p = 0.02 (DIABHYCAR), and 1.58 (1.23-2.04), p = 0.0004 (SURDIAGENE), adjusted for sex, age, BMI, duration of diabetes, systolic blood pressure, arterial hypertension, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, estimated glomerular filtration rate (eGFR), urinary albumin concentration (UAC), active tobacco smoking, and previous history of myocardial infarction at baseline. No interaction was observed between plasma copeptin and eGFR (p = 0.40) or UAC (p = 0.61) categories on the risk of cardiovascular events in analyses of pooled cohorts. CONCLUSIONS: Plasma copeptin was positively associated with major cardiovascular events in people with type 2 diabetes. This association cannot be solely accounted for by the association of copeptin with kidney-related traits.

18.
Diabetes Care ; 41(10): 2162-2169, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30072406

RESUMO

OBJECTIVE: Inflammation and oxidative stress play an important role in the pathogenesis of lower-extremity artery disease (LEAD). We assessed the prognostic values of inflammatory and redox status biomarkers on the risk of LEAD in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Plasma concentrations of tumor necrosis factor-α receptor 1 (TNFR1), angiopoietin-like 2, ischemia-modified albumin (IMA), fluorescent advanced glycation end products, protein carbonyls, and total reductive capacity of plasma were measured at baseline in the SURDIAGENE (Survie, Diabete de type 2 et Genetique) cohort. Major LEAD was defined as the occurrence during follow-up of peripheral revascularization or lower-limb amputation. RESULTS: Among 1,412 participants at baseline (men 58.2%, mean [SD] age 64.7 [10.6] years), 112 (7.9%) developed major LEAD during 5.6 years of follow-up. High plasma concentrations of TNFR1 (hazard ratio [95% CI] for second vs. first tertile 1.12 [0.62-2.03; P = 0.71] and third vs. first tertile 2.16 [1.19-3.92; P = 0.01]) and of IMA (2.42 [1.38-4.23; P = 0.002] and 2.04 [1.17-3.57; P = 0.01], respectively) were independently associated with an increased risk of major LEAD. Plasma concentrations of TNFR1 but not IMA yielded incremental information, over traditional risk factors, for the risk of major LEAD as follows: C-statistic change (0.036 [95% CI 0.013-0.059]; P = 0.002), integrated discrimination improvement (0.012 [0.005-0.022]; P < 0.001), continuous net reclassification improvement (NRI) (0.583 [0.294-0.847]; P < 0.001), and categorical NRI (0.171 [0.027-0.317]; P = 0.02). CONCLUSIONS: Independent associations exist between high plasma TNFR1 or IMA concentrations and increased 5.6-year risk of major LEAD in people with type 2 diabetes. TNFR1 allows incremental prognostic information, suggesting its use as a biomarker for LEAD.

19.
Diabetes Care ; 41(10): 2147-2154, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30104294

RESUMO

OBJECTIVE: To compare insulin glargine 300 units/mL (Gla-300) versus insulin degludec 100 units/mL (IDeg-100) in this first head-to-head randomized controlled trial. RESEARCH DESIGN AND METHODS: BRIGHT (NCT02738151) was a multicenter, open-label, active-controlled, two-arm, parallel-group, 24-week, noninferiority study in insulin-naive patients with uncontrolled type 2 diabetes. Participants were randomized 1:1 to evening dosing with Gla-300 (N = 466) or IDeg-100 (N = 463), titrated to fasting self-monitored plasma glucose of 80-100 mg/dL. The primary end point was HbA1c change from baseline to week 24. Safety end points included incidence and event rates of hypoglycemia. RESULTS: At week 24, HbA1c improved similarly from baseline values of 8.7% (72 mmol/mol) in the Gla-300 group and 8.6% (70 mmol/mol) in the IDeg-100 group to 7.0% (53 mmol/mol)-least squares mean difference -0.05% (95% CI -0.15 to 0.05) (-0.6 mmol/mol [-1.7 to 0.6])-demonstrating noninferiority of Gla-300 versus IDeg-100 (P < 0.0001). Hypoglycemia incidence and event rates over 24 weeks were comparable with both insulins, whereas during the active titration period (0-12 weeks) the incidence and rate of anytime (24-h) confirmed hypoglycemia (≤70 and <54 mg/dL) were lower with Gla-300. Both insulins were properly titrated and exhibited no specific safety concerns. CONCLUSIONS: Gla-300 and IDeg-100 provided similar glycemic control improvements with relatively low hypoglycemia risk. Hypoglycemia incidence and rates were comparable with both insulins during the full study period but lower in favor of Gla-300 during the titration period. The choice between these longer-acting basal insulins may be determined by factors such as access and cost, alongside clinical considerations.

20.
JCI Insight ; 3(13)2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-29997293

RESUMO

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS: The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS: High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING: INSERM and Danone Research Centre for Specialized Nutrition.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA