Publications by authors named "Beverley Balkau"

299 Publications

HDL Containing Apolipoprotein C-III is Associated with Insulin Sensitivity: a Multi-Center Cohort Study.

J Clin Endocrinol Metab 2021 Apr 11. Epub 2021 Apr 11.

Department of Nutrition, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, United States of America.

Context: HDL in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects.

Objective: We investigated the prospective associations between HDL subspecies containing and lacking apoC-III at baseline and insulin sensitivity at year 3.

Design, Setting, And Participants: A prospective cohort study of 864 healthy volunteers drawn from the RISC study, a multi-center European clinical investigation, whose recruitment initiated in 2002 with a follow-up of 3 years.

Main Measures: Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT) at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich ELISA-based method.

Results: The two HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (p-heterogeneity=0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (p-trend=0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (p-trend=0.01), compared to the lowest quintile. No significant association was observed for total HDL, and VLDL and LDL containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III.

Conclusion: Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.
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http://dx.doi.org/10.1210/clinem/dgab234DOI Listing
April 2021

Exposure to persistent organic pollutants and the risk of type 2 diabetes: a case-cohort study.

Diabetes Metab 2021 Jan 27;47(5):101234. Epub 2021 Jan 27.

EPI-PHARE Scientific Interest Group in Epidemiology of Health Products, French National Agency for the Safety of Medicines and Health Products and the French National Health Insurance, Saint-Denis, Ile-de-France, France; IRSA, La Riche, France.

Aims: To explore exposure to 22 persistent organic pollutants (POPs) and incident type 2 diabetes in a population-based, prospective cohort.

Methods: This case-cohort study on 753 participants without type 2 diabetes at baseline, was followed-up over nine years, as part of the French D.E.S.I.R. cohort. We measured 22 POPs in fasting serum at baseline. The associations between baseline POP concentrations, pre-adjusted for lipids, BMI, age and sex, with incident type 2 diabetes, were assessed using Prentice-weighted Cox regression models (time scale: age), adjusted for traditional confounding factors. POPs were also modelled summed in functional groups: polychlorinated biphenyls (∑PCB) and organochlorines (∑OC) and also individually, after log-transformation, in adjusted Cox models.

Results: There were 200 incident diabetes cases over nine years. Pre-adjusted POP concentrations were not related to diabetes risk for any of the 22 POPs examined. The fully-adjusted hazard ratios (HRs) per interquartile range of the pre-adjusted POPs, ranged from 0.87 (95% CI: 0.64,1.19) to 1.22 (0.93,1.59,). For dichlorodiphenyldichloroethylene (p, p'-DDE) and dichlorodiphenyltrichloroethane (p, p'-DDT), the HRs were 1.09 (0.83,1.43) and 0.89 (0.70,1.13), respectively. The HRs for PeCB, HCB, β-HCH, γ-HCH, oxychlordane, trans-nonachlor were 0.98 (0.85,1.13), 1.06 (0.84,1.33), 1.22 (0.93,1.59), 1.13 (0.89,1.42), 1.00 (0.76,1.31), 0.86 (0.66,1.13), respectively. HRs for ∑PCB, ∑OC and for individual log-transformed POPs did not differ significantly from one.

Conclusion: We did not observe any relations between exposure to POPs and diabetes in this population-based cohort. These results do not support causal inferences reported in previous studies linking serum POP concentrations and diabetes risk.
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http://dx.doi.org/10.1016/j.diabet.2021.101234DOI Listing
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

The JUBILE cohort: Quality of life after more than 40 years with type 1 diabetes.

Diabet Med 2020 Nov 16:e14460. Epub 2020 Nov 16.

Service des urgences adultes, Assistance Publique-Hôpitaux de Paris, Hôpital Kremlin Bicêtre and Université Paris-Saclay, Paris, France.

Aim: The incidence of type 1 diabetes is increasing, and more people are going to live many years with the disease. Quality of life might become the most challenging long-term complication. The JUBILE study describes the quality of life of people living with type 1 diabetes for more than 40 years.

Methods: Patients were recruited from 35 French regional or university hospitals: patients and physicians completed questionnaires, validated by the Delphi method. From 1200 questionnaires circulated, 808 patients and their physicians returned questionnaires.

Results: The duration of type 1 diabetes was 49 ± 6 years (mean±SD), age at diagnosis 15 ± 10 years, HbA1c 7.4 ± 0.9% [58 ± 10 mmol/mol] and 52% were men. Macrovascular disease was present in 32%, 46% had no or only mild non proliferative retinopathy. Insulin pumps were used by 25% and insulin pen/syringe users injected 3.9 ± 2.1 times per day. Blood glucose was self monitored at least five times per day by 67% of patients. Men had 1.8 ± 1.2 children, women 1.4 ± 1.0. More than half (55%) of this population was working, 38% had a university degree. Patients still had a busy life, going out (59%), eating out (82%), playing sports (38%) and travelling (66%). No differences appeared based on age, duration of diabetes, demography or social features.

Conclusions: Living a long and pleasant life is possible with type 1 diabetes. Diabetes does not prevent people from having children, working at highly qualified jobs, travelling abroad: a message of hope that is comforting for patients, their family, relatives and the medical teams.
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http://dx.doi.org/10.1111/dme.14460DOI Listing
November 2020

Gonadal hormonal factors before menopause and incident type 2 diabetes in women: A 22-year follow-up of 83 799 women from the E3N cohort study.

J Diabetes 2021 Apr 22;13(4):330-338. Epub 2020 Nov 22.

Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP) "Health Across Generations" Team, Université Paris-Saclay, Gustave Roussy, Espace Maurice Tubiana, Villejuif, France.

Background: In many populations the incidence of type 2 diabetes is higher in men than in women. This may be explained by exposure to female gonadal hormones, but so far, there is no consensus on their role over the life course in type 2 diabetes etiology.

Methods: Data are from 83 799 French women from the E3N (Etude Épidémiologique de Femmes de la Mutuelle Générale de l'Education Nationale) cohort study, followed for 22 years. Multivariable Cox models including classical risk factors were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) between gonadal hormonal factors and incident type 2 diabetes.

Results: Older age at menarche, more menstrual cycles, older age at menopause, longer duration of exposure to gonadal hormones and breastfeeding were inversely associated with incident type 2 diabetes cases (n = 4806). While a longer duration of menstrual cycles (HR = 1.23 [95% CI: 1.07-1.41] comparing ≥32 vs ≤24 days) and use of contraceptive pills (HR = 1.33 [1.25-1.42]) were associated with a greater risk of type 2 diabetes.

Conclusions: In women, a longer exposure to endogenous gonadal hormones with a later menopause as well as breastfeeding were associated with a lower risk of developing type 2 diabetes, independently of classical diabetes risk factors. In contrast, the use of contraceptive agents was associated with incident diabetes, but the influence of each type of contraception and of exposure duration remain to be investigated.
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http://dx.doi.org/10.1111/1753-0407.13129DOI Listing
April 2021

Plasma total adiponectin and changes in renal function in a cohort from the community: the prospective Data from an Epidemiological Study on the Insulin Resistance Syndrome study.

Nephrol Dial Transplant 2020 Nov 3. Epub 2020 Nov 3.

Centre de Recherche des Cordeliers UMR-S 1138, Université de Paris, INSERM, Paris, France.

Background: High adiponectin levels are associated with diabetic nephropathy. Nevertheless, it is not known whether plasma adiponectin is associated with renal function decline in the general population. We evaluated whether adiponectin concentrations were associated with changes in renal function in a community cohort, the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study.

Methods: Plasma adiponectin concentrations were measured in a random sample of 3284 people from the DESIR study, a 9-year prospective cohort from the general population. Data were analysed for three endpoints during follow-up: incidence of Stage 3 chronic kidney disease (CKD); the Kidney Disease: Improving Global Outcomes (KDIGO) criterion 'certain drop in eGFR' and rapid kidney function decline [estimated glomerular filtration rate (eGFR) slope steeper than -3 mL/min/1.73 m2/year].

Results: After exclusion of participants with an eGFR <60 mL/min/1.73 m2 at baseline and those with type 2 diabetes or impaired fasting glycaemia at any time during follow-up (remaining n = 2174), there was a 113% higher risk for a rapid decline in kidney function in participants with adiponectin above the third tertile (T3) versus below the first tertile (T1) (Ptrend = 0.004) and a 53% higher risk for kidney function decline as defined by the KDIGO criterion (Ptrend = 0.04). In a cross-sectional analysis, adiponectin was positively associated with urinary albumin:creatinine ratio at baseline (P = 0.009).

Conclusions: In a healthy cohort from the general population, higher levels of plasma adiponectin were associated with decreased renal function at baseline and at follow-up. This result is similar to what is observed in people with diabetic nephropathy, in contrast with animal models of nephropathy.
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http://dx.doi.org/10.1093/ndt/gfaa228DOI Listing
November 2020

Pathogenic variants in actionable MODY genes are associated with type 2 diabetes.

Nat Metab 2020 10 12;2(10):1126-1134. Epub 2020 Oct 12.

Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Université de Lille, Institut Pasteur de Lille, Lille University Hospital, Lille, France.

Genome-wide association studies have identified 240 independent loci associated with type 2 diabetes (T2D) risk, but this knowledge has not advanced precision medicine. In contrast, the genetic diagnosis of monogenic forms of diabetes (including maturity-onset diabetes of the young (MODY)) are textbook cases of genomic medicine. Recent studies trying to bridge the gap between monogenic diabetes and T2D have been inconclusive. Here, we show a significant burden of pathogenic variants in genes linked with monogenic diabetes among people with common T2D, particularly in actionable MODY genes, thus implying that there should be a substantial change in care for carriers with T2D. We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. The carriers with T2D are leaner, which evidences a functional metabolic effect of these mutations. Pathogenic variants in actionable MODY genes are more frequent than was previously expected in common T2D. These results open avenues for future interventions assessing the clinical interest of these pathogenic mutations in precision medicine.
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http://dx.doi.org/10.1038/s42255-020-00294-3DOI Listing
October 2020

Serum sclerostin and glucose homeostasis: No association in healthy men. Cross-sectional and prospective data from the EGIR-RISC study.

Bone 2021 02 7;143:115681. Epub 2020 Oct 7.

Department of Endocrinology, Odense University Hospital, Odense, Denmark; Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark.

Introduction: Sclerostin, an inhibitor of bone formation, has emerged as a potential negative regulator of glucose homeostasis. We aimed to investigate if serum sclerostin associates with insulin sensitivity, beta cell function, prediabetes or metabolic syndrome in healthy men.

Materials And Methods: Serum sclerostin was measured in basal and insulin-stimulated samples from 526 men without diabetes from the RISC cohort study. An OGTT was performed at baseline and after 3 years. An IVGTT and a hyperinsulinaemic-euglycaemic clamp were performed at baseline. Insulin sensitivity was estimated by the oral glucose sensitivity index (OGIS) and the M-value relative to insulin levels. Beta cell function was assessed by the acute and total insulin secretion (ISR) and by beta cell glucose sensitivity.

Results: Serum sclerostin levels correlated positively with age but were similar in individuals with (n = 69) and without (n = 457) prediabetes or the metabolic syndrome. Serum sclerostin was associated with measures of neither insulin sensitivity nor beta cell function at baseline in age-adjusted analyses including all participants. However, baseline serum sclerostin correlated inversely with OGIS at follow-up in men without prediabetes (B: -0.29 (-0.57, -0.01) p = 0.045), and inversely with beta cell glucose sensitivity in men with prediabetes (B: -13.3 (-26.3, -0.2) p = 0.046). Associations between serum sclerostin and 3-year changes in measures of glucose homeostasis were not observed. Acute hyperinsulinemia suppressed serum sclerostin (p = 0.02), and this reduction correlated with OGIS and ISR.

Conclusions: Overall, serum sclerostin was not associated with prediabetes, insulin sensitivity or insulin secretion in healthy men. The inverse relationship between serum sclerostin and insulin sensitivity at follow-up was weak and likely not of clinical relevance. The ability of insulin to reduce sclerostin, possibly promoting bone formation, needs to be clarified.
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http://dx.doi.org/10.1016/j.bone.2020.115681DOI Listing
February 2021

Insulin pricing and other major diabetes-related concerns in the USA: a study of 46 407 tweets between 2017 and 2019.

BMJ Open Diabetes Res Care 2020 06;8(1)

Digital Epidemiology Hub, Department of Population Health, Luxembourg Institute of Health, Strassen, Luxembourg

Introduction: Little research has been done to systematically evaluate concerns of people living with diabetes through social media, which has been a powerful tool for social change and to better understand perceptions around health-related issues. This study aims to identify key diabetes-related concerns in the USA and primary emotions associated with those concerns using information shared on Twitter.

Research Design And Methods: A total of 11.7 million diabetes-related tweets in English were collected between April 2017 and July 2019. Machine learning methods were used to filter tweets with personal content, to geolocate (to the USA) and to identify clusters of tweets with emotional elements. A sentiment analysis was then applied to each cluster.

Results: We identified 46 407 tweets with emotional elements in the USA from which 30 clusters were identified; 5 clusters (18% of tweets) were related to insulin pricing with both positive emotions () referring to advocacy for affordable insulin and emotions related to the frustration of insulin prices, 5 clusters (12% of tweets) to solidarity and support with a majority of and emotions expressed. The most negative topics (10% of tweets) were related to diabetes distress (24% 27% , 21% elements), to diabetic and insulin shock (45% , 46% ) and comorbidities (40% ).

Conclusions: Using social media data, we have been able to describe key diabetes-related concerns and their associated emotions. More specifically, we were able to highlight the real-world concerns of insulin pricing and its negative impact on mood. Using such data can be a useful addition to current measures that inform public decision making around topics of concern and burden among people with diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2020-001190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282343PMC
June 2020

Complex interaction of fasting glucose, body mass index, age and sex on all-cause mortality: a cohort study in 15 million Korean adults.

Diabetologia 2020 08 19;63(8):1616-1625. Epub 2020 May 19.

Department of Preventive Medicine, School of Medicine, Konkuk University, Seoul, Republic of Korea.

Aims/hypothesis: The aim of this work was to examine whether synergistic associations with mortality exist for BMI and fasting blood glucose (FBG) and to identify FBG-BMI combined subgroups with higher mortality according to sex and age.

Methods: A total of 15,149,275 Korean adults participated in health examinations during 2003-2006 and were followed up until December 2018. Mortality HRs of 40 FBG-BMI combined groups were assessed by Cox proportional hazards models.

Results: During a mean 13.7 years of follow-up, 1,213,401 individuals died. A J-shaped association was seen between FBG and all-cause mortality for all BMI categories. Those with BMI <20 kg/m had the highest mortality for any given FBG level, followed by those with BMI 20-22.4 kg/m. The detrimental effect of elevated FBG was greater among leaner individuals than more corpulent individuals. Moreover, the synergistic adverse effects of hyperglycaemia and leanness was stronger in younger adults than in older adults. Compared with the reference group (overweight with normoglycaemia), age- and sex-adjusted HRs of the leanest with normoglycaemia (BMI <20 kg/m and FBG 4.4-5.2 mmol/l), overweight with diabetes (BMI 25-27.4 kg/m and FBG ≥10.0 mmol/l) and leanest with diabetes (BMI <20 kg/m and FBG ≥10.0 mmol/l) were 1.29, 2.59 and 11.18, respectively, in those aged 18-44 years and 1.56, 1.72 and 2.87, respectively, in those aged 75-99 years. The identification of BMI-FBG subgroups associated with higher mortality was not straightforward, illustrated by the group with FBG 6.1-6.9 mmol/l and BMI 20-22.4 kg/m having a similar or higher mortality compared with the group with FBG 7.0-9.9 mmol/l and BMI ≥22.5 kg/m. In women aged <45 years with FBG <6.9 mmol/l, those with BMI ≥27.5 kg/m had the highest mortality, whereas individuals with BMI <20 kg/m had the highest mortality for each given FBG level in other age and sex groups.

Conclusions/interpretation: Leanness and hyperglycaemia interact together to increase mortality in a supra-multiplicative manner, especially in younger adults; the interactions of BMI, FBG, sex and age with mortality are complex. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05160-1DOI Listing
August 2020

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.

Eur J Epidemiol 2020 Jul 7;35(7):685-697. Epub 2020 May 7.

Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 21741, Malmö, Sweden.

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.
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http://dx.doi.org/10.1007/s10654-020-00638-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867117PMC
July 2020

Higher mortality risk among kidney transplant recipients than among estimated glomerular filtration rate-matched patients with CKD-preliminary results.

Nephrol Dial Transplant 2021 01;36(1):176-184

Division of Nephrology, Ambroise Paré University Medical Center, APHP, Boulogne Billancourt, F-92100 Paris, France.

Background: Although kidney transplantation prolongs survival relative to dialysis, it is associated with a higher death rate than in the general population. The objective of the present study was to assess and compare the risk of mortality and frequency of non-lethal cardiovascular (CV) events in kidney transplant recipients (KTRs) beyond 1 year after successful transplantation versus patients with chronic kidney disease (CKD) using propensity score-matched analysis of estimated glomerular filtration rate (eGFR) and other parameters.

Methods: After propensity score matching, we studied 340 KTRs from the French Données Informatisées et Validées en Transplantation cohort and 605 non-transplant patients with CKD (CKDps) from the French Chronic Kidney Disease-Renal Epidemiology and Information Network cohort. The mean ± standard deviation eGFR was 42 ± 13 and 41 ± 12 mL/min/  1.73 m2, respectively (P = 0.649). Descriptive data were completed by a survival analysis with Cox regression models.

Results: After a median follow-up period of 2.8 years (KTRs 2.0 years, CKDp 2.9 years), 71 deaths were recorded (31 and 40 in the KTR and CKD groups, respectively). Univariate analysis showed that KTRs had a significantly greater risk of mortality than CKDps. In multivariable analysis, KTRs were found to have a 2.7-fold greater risk of mortality [hazard ratio 2.7 (95% confidence interval 1.6-4.7); P = 0.005]. There was no between-group difference concerning the risk of CV events (P = 0.448). CV death rates in KTRs (29.0%) approximated those of CKDps (22.5%), whereas death rates due to infections were higher in KTRs (19.4% versus 10.0%).

Conclusion: Beyond 1 year after transplantation, KTRs, who possibly had a longer CKD history, had a significantly greater mortality risk than eGFR-matched CKDps. The excess risk was not associated with CV events.
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http://dx.doi.org/10.1093/ndt/gfaa026DOI Listing
January 2021

General regression model: A "model-free" association test for quantitative traits allowing to test for the underlying genetic model.

Ann Hum Genet 2020 05 13;84(3):280-290. Epub 2019 Dec 13.

Mission Associations Recherche & Société - Inserm Siège, DISC, Paris, France.

Most genome-wide association studies used genetic-model-based tests assuming an additive mode of inheritance, leading to underpowered association tests in case of departure from additivity. The general regression model (GRM) association test proposed by Fisher and Wilson in 1980 makes no assumption on the genetic model. Interestingly, it also allows formal testing of the underlying genetic model. We conducted a simulation study of quantitative traits to compare the power of the GRM test to the classical linear regression tests, the maximum of the three statistics (MAX), and the allele-based (allelic) tests. Simulations were performed on two samples sizes, using a large panel of genetic models, varying genetic models, minor allele frequencies, and the percentage of explained variance. In case of departure from additivity, the GRM was more powerful than the additive regression tests (power gain reaching 80%) and had similar power when the true model is additive. GRM was also as or more powerful than the MAX or allelic tests. The true simulated model was mostly retained by the GRM test. Application of GRM to HbA1c illustrates its gain in power. To conclude, GRM increases power to detect association for quantitative traits, allows determining the genetic model and is easily applicable.
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http://dx.doi.org/10.1111/ahg.12372DOI Listing
May 2020

Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.

Nat Med 2019 11 7;25(11):1733-1738. Epub 2019 Nov 7.

CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, University of Lille, Lille, France.

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor. Although some MRAP2 mutations have been described in people with obesity, 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 tolerance. 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.
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http://dx.doi.org/10.1038/s41591-019-0622-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858878PMC
November 2019

New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans.

Mol Metab 2019 11 28;29:182-196. Epub 2019 Aug 28.

Université de Paris, Paris, France; Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR8251, Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.molmet.2019.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812023PMC
November 2019

Exposure to Bisphenol A and Bisphenol S and Incident Type 2 Diabetes: A Case-Cohort Study in the French Cohort D.E.S.I.R.

Environ Health Perspect 2019 10 30;127(10):107013. Epub 2019 Oct 30.

Institut inter-Régional pour la Santé (IRSA), La Riche, France.

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 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 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.
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http://dx.doi.org/10.1289/EHP5159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867193PMC
October 2019

Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study.

JAMA Netw Open 2019 09 4;2(9):e1910915. Epub 2019 Sep 4.

Division of Obstetrics and Gynaecology, School of Medicine, University of Western Australia, Crawley, Western Australia, Australia.

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations.

Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis.

Design, Setting, And Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included.

Main Outcomes And Measures: Type 2 diabetes and glycemic traits.

Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration.

Conclusions And Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.10915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755534PMC
September 2019

Dietary inflammatory index and type 2 diabetes risk in a prospective cohort of 70,991 women followed for 20 years: the mediating role of BMI.

Diabetologia 2019 12 9;62(12):2222-2232. Epub 2019 Aug 9.

Centre for Research in Epidemiology and Population Health (CESP), Inserm (Institut National de la Santé et de la Recherche Médicale) U1018, Generations and Health Across Generations, Gustave Roussy Institute, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France.

Aims/hypothesis: Diet is one of the main lifestyle-related factors that can modulate the inflammatory process. Surprisingly the dietary inflammatory index (DII) has been little investigated in relation to type 2 diabetes, and the role of BMI in this relationship is not well established. We studied this association and the role of BMI in the inflammatory process in a large population-based observational study.

Methods: A total of 70,991 women from the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort study were followed for 20 years. Incident type 2 diabetes cases were identified using diabetes-specific questionnaires and drug reimbursement insurance databases, and 3292 incident cases were validated. The DII was derived from a validated food frequency questionnaire. Multivariable Cox regression models estimated HRs and 95% CIs between DII and incident type 2 diabetes. Interactions were tested between DII and BMI on incident type 2 diabetes and a mediation analysis of BMI was performed.

Results: Higher DII scores, corresponding to a higher anti-inflammatory potential of the diet, were associated with a lower risk of type 2 diabetes. Compared with the 1st quintile group, women from the 2nd quintile group (HR 0.85 [95% CI 0.77, 0.94]) up to the 5th quintile group (HR 0.77 [95% CI 0.69, 0.85]) had a lower risk of type 2 diabetes before adjustment for BMI. There was an interaction between DII and BMI on type 2 diabetes risk (p < 0.0001). The overall association was partly mediated by BMI (58%).

Conclusions/interpretation: Our findings suggest that a higher anti-inflammatory potential of the diet is associated with a lower risk of type 2 diabetes, and the association may be mediated by BMI. These results may improve our understanding of the mechanisms underlying the role of diet-related anti-inflammation in the pathogenesis of type 2 diabetes in women. Further studies are warranted to validate our results and evaluate whether the results are similar in men.
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http://dx.doi.org/10.1007/s00125-019-04972-0DOI Listing
December 2019

The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward.

Int J Obes (Lond) 2020 02 6;44(2):539-543. Epub 2019 Aug 6.

CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France.

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) and substantia nigra (p = 6.8 × 10), 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.
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http://dx.doi.org/10.1038/s41366-019-0428-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002163PMC
February 2020

Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals.

Sci Rep 2019 07 1;9(1):9439. Epub 2019 Jul 1.

Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.

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) 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.
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http://dx.doi.org/10.1038/s41598-019-45823-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602949PMC
July 2019

Correction to: One hour post-load plasma glucose and 3 year risk of worsening fasting and 2 hour glucose tolerance in the RISC cohort.

Diabetologia 2019 05;62(5):874

CESP Centre for Research in Epidemiology and Population Health, Univ Paris-Saclay, Univ Paris Sud, Villejuif, France.

The affiliation details for Geltrude Mingrone are corrected below.
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http://dx.doi.org/10.1007/s00125-019-4846-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828079PMC
May 2019

Strong adherence to dietary and lifestyle recommendations is associated with decreased type 2 diabetes risk in the AusDiab cohort study.

Prev Med 2019 06 7;123:208-216. Epub 2019 Mar 7.

CESP, INSERM U1018, Univ. Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France; Gustave Roussy, Villejuif, France.

We aimed to determine whether adherence to the Australian dietary guidelines and an index of healthy behavior was associated with a lower risk of type 2 diabetes (T2D) and to provide estimates of the proportion of preventable cases. Participants of the AusDiab cohort study were followed for 12 years (n = 6242), starting from May 1999, during which T2D cases were identified. The associations between T2D risk and a score of adherence to the dietary guidelines, its components, and a score of adherence to an index of healthy behaviors, (which included smoking, recreational physical activity, waist circumference and adherence to the dietary guidelines), were estimated using Cox proportional hazards ratios (HR) and 95% confidence intervals. The proportion of preventable cases was estimated using the population attributable fraction (PAF). Strong adherence to the dietary guidelines was not associated with T2D risk (HR = 0.64 [95% CI 0.39-1.06]), unless moderate alcohol consumption was considered as beneficial instead of no alcohol consumption (HR = 0.59 [0.36-0.96]). However, strong adherence to the guidelines regarding fruit and dairy intake were both associated with decreased risk of T2D (HR = 0.68 [0.51-0.91]; 0.56 [0.38-0.84], respectively) and could have prevented 23-37% of cases (PAF = 23.3% [7.3-38.2]; 37.1% [14.6-56.0], respectively). Strong adherence to the index of healthy behaviors was associated with decreased risk of T2D (HR = 0.30 [0.17-0.51]) and estimated to prevent almost 60% of T2D (PAF = 59.4% [34.3-76.6]). More than half of T2D cases could be preventable in Australia through modifying health behavior. These results could serve as a basis for prevention programs based on lifestyle modification.
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http://dx.doi.org/10.1016/j.ypmed.2019.03.006DOI Listing
June 2019

Mentally tiring work and type 2 diabetes in women: a 22-year follow-up study.

Eur J Endocrinol 2019 Apr;180(4):257-263

Inserm U1018, Center for Research in Epidemiology and Population Health (CESP).

Hypothesis Previous work suggested no or inconsistent associations between components of work-related stress and type 2 diabetes risk, but suggested sex-specific differences should be further investigated, as women potentially had higher risks. Methods We analyzed data from 73 517 women, mostly teachers, from the E3N cohort study followed for 22 years (1992-2014), to study the association between mentally tiring work, used as a proxy of job demands, and type 2 diabetes risk. Univariate and multivariable Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Results A total of 4187 incident cases of type 2 diabetes cases were observed. There was a higher type 2 diabetes risk for women with a 'Very mentally tiring work' when compared to women with 'Little or not mentally tiring work' (HR = 1.21 (1.09-1.35)). This association was independent of unhealthy lifestyle and traditional metabolic factors. An interaction between mentally tiring work and BMI was detected (P < 0.0001), with a stronger association being observed in non-overweight women, HR = 1.26 (1.08-1.47) vs HR = 1.14 (0.98, 1.32), in overweight women. Conclusions We observed an increased risk of type 2 diabetes associated with mentally tiring work, used as a proxy of job demands. These observational results suggest the importance of taking into consideration the potential long-term metabolic impact of work-related stress for women working in a demanding environment. Increased support for such women should be investigated in intervention studies.
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http://dx.doi.org/10.1530/EJE-18-0804DOI Listing
April 2019

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

One hour post-load plasma glucose and 3 year risk of worsening fasting and 2 hour glucose tolerance in the RISC cohort.

Diabetologia 2019 03 29;62(3):544-548. Epub 2018 Dec 29.

CESP Centre for Research in Epidemiology and Population Health, Univ Paris-Saclay, Univ Paris Sud, Villejuif, France.

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http://dx.doi.org/10.1007/s00125-018-4798-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428784PMC
March 2019

Associations Between Migraine and Type 2 Diabetes in Women: Findings From the E3N Cohort Study.

JAMA Neurol 2019 03;76(3):257-263

Center for Research in Epidemiology and Population Health, UMR 1018, Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Paris-South Paris Saclay University, Gustave Roussy Institute, Villejuif, France.

Importance: Little is known about the associations between migraine and type 2 diabetes and the temporality of the association between these 2 diseases.

Objective: To evaluate the association between migraine and type 2 diabetes incidence as well as the evolution of the prevalence of active migraine before and after type 2 diabetes diagnosis.

Design, Setting, And Participants: We used data from the E3N cohort study, a French prospective population-based study initiated in 1990 on a cohort of women born between 1925 and 1950. The E3N study participants are insured by a health insurance plan that mostly covers teachers. From the eligible women in the E3N study, we included those who completed the 2002 follow-up questionnaire with information available on migraine. We then excluded prevalent cases of type 2 diabetes, leaving a final sample of women who were followed up between 2004 and 2014. All potential occurrences of type 2 diabetes were identified through a drug reimbursement database. Statistical analyses were performed in March 2018.

Exposures: Self-reported migraine occurrence.

Main Outcomes And Measures: Pharmacologically treated type 2 diabetes.

Results: From the 98 995 women in the study, 76 403 women completed the 2002 follow-up survey. Of these, 2156 were excluded because they had type 2 diabetes, leaving 74 247 women. Participants had a mean (SD) age of 61 (6) years at baseline, and all were free of type 2 diabetes. During 10 years of follow-up, 2372 incident type 2 diabetes cases occurred. A lower risk of type 2 diabetes was observed for women with active migraine compared with women with no migraine history (univariate hazard ratio, 0.80 [95% CI, 0.67-0.96], multivariable-adjusted hazard ratio, 0.70 [95% CI, 0.58-0.85]). We also observed a linear decrease in active migraine prevalence from 22% (95% CI, 16%-27%) to 11% (95% CI, 10%-12%) during the 24 years prior to diabetes diagnosis, after adjustment for potential type 2 diabetes risk factors. A plateau of migraine prevalence around 11% was then observed for 22 years after diagnosis.

Conclusions And Relevance: We observed a lower risk of developing type 2 diabetes for women with active migraine and a decrease in active migraine prevalence prior to diabetes diagnosis. Further targeted research should focus on understanding the mechanisms involved in explaining these findings.
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http://dx.doi.org/10.1001/jamaneurol.2018.3960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440234PMC
March 2019