Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium

Abstract/SummaryBackground and aims:Understanding the aetiology, clinical presentation and prognosis of type 2 diabetes (T2D) and optimizing its treatment might be facilitated by biomarkers that help predict a person’s susceptibility to the risk factors that cause diabetes or its complications, or response to treatment. The IMI DIRECT (Diabetes Research on Patient Stratification) Study is a European Union (EU) Innovative Medicines Initiative (IMI) project that seeks to test these hypotheses in two recently established epidemiological cohorts. Here, we describe the characteristics of these cohorts at baseline and at the first main follow-up examination (18-months).Materials and methods:From a sampling-frame of 24,682 European-ancestry adults in whom detailed health information was available, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm and enrolled into a prospective cohort study (n=2127) undertaken at four study centres across Europe (Cohort 1: prediabetes). We also recruited people from clinical registries with recently diagnosed T2D (n=789) into a second cohort study (Cohort 2: diabetes). The two cohorts were studied in parallel with matched protocols. Endogenous insulin secretion and insulin sensitivity were modelled from frequently sampled 75g oral glucose tolerance (OGTT) in Cohort 1 and with mixed-meal tolerance tests (MMTT) in Cohort 2. Additional metabolic biochemistry was determined using blood samples taken when fasted and during the tolerance tests. Body composition was assessed using MRI and lifestyle measures through self-report and objective methods.Results:Using ADA-2011 glycaemic categories, 33% (n=693) of Cohort 1 (prediabetes) had normal glucose regulation (NGR), and 67% (n=1419) had impaired glucose regulation (IGR). 76% of the cohort was male, age=62(6.2) years; BMI=27.9(4.0) kg/m2; fasting glucose=5.7(0.6) mmol/l; 2-hr glucose=5.9(1.6) mmol/l [mean(SD)]. At follow-up, 18.6(1.4) months after baseline, fasting glucose=5.8(0.6) mmol/l; 2-hr OGTT glucose=6.1(1.7) mmol/l [mean(SD)]. In Cohort 2 (diabetes): 65% (n=508) were lifestyle treated (LS) and 35% (n=271) were lifestyle + metformin treated (LS+MET). 58% of the cohort was male, age=62(8.1) years; BMI=30.5(5.0) kg/m2; fasting glucose=7.2(1.4)mmol/l; 2-hr glucose=8.6(2.8) mmol/l [mean(SD)]. At follow-up, 18.2(0.6) months after baseline, fasting glucose=7.8(1.8) mmol/l; 2-hr MMTT glucose=9.5(3.3) mmol/l [mean(SD)].Conclusion:The epidemiological IMI DIRECT cohorts are the most intensely characterised prospective studies of glycaemic deterioration to date. Data from these cohorts help illustrate the heterogeneous characteristics of people at risk of or with T2D, highlighting the rationale for biomarker stratification of the disease - the primary objective of the IMI DIRECT consortium.Abbreviations:ASATAbdominal subcutaneous adipose tissueDIRECTDiabetes Research on Patient StratificationEUEuropean UnionMMTTMixed-meal tolerance testMRIMagnetic resonance imaginghpfVMHigh-pass filtered vector magnitudeIAATIntra-abdominal adipose tissueIGRImpaired glucose regulationIMIInnovative Medicines InitiativeMEmultiechoNGRNormal glucose regulationOGTTOral glucose tolerance testPAPhysical activityTAATTotal abdominal adipose tissueT2DType 2 Diabetes

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Evaluation of insulin release and insulin sensitivity through oral glucose tolerance test: differences between NGT, IFG, IGT, and type 2 diabetes mellitus. A cross-sectional and follow-up study

Acta Diabetologica ◽

10.1007/s00592-004-0147-x ◽

2004 ◽

Vol 41 (2) ◽

Cited By ~ 16

Author(s):

A.E. Pontiroli ◽

P. Pizzocri ◽

A. Caumo ◽

G. Perseghin ◽

L. Luzi

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Cross Sectional ◽

Follow Up Study

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Genetic Polymorphisms of Alcohol Dehydrogenase and Aldehyde Dehydrogenase: Alcohol Use and Type 2 Diabetes in Japanese Men

Epidemiology Research International ◽

10.1155/2011/583682 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8

Author(s):

Guang Yin ◽

Keizo Ohnaka ◽

Makiko Morita ◽

Shinji Tabata ◽

Osamu Tajima ◽

...

Keyword(s):

Type 2 Diabetes ◽

Alcohol Consumption ◽

Glucose Tolerance ◽

Positive Association ◽

Tolerance Test ◽

Normal Glucose Tolerance ◽

Oral Glucose ◽

Normal Glucose ◽

Glucose Tolerance Status

This study investigated the association of ADH1B (rs1229984) and ALDH2 (rs671) polymorphisms with glucose tolerance status, as determined by a 75-g oral glucose tolerance test, and effect modification of these polymorphisms on the association between alcohol consumption and glucose intolerance in male officials of the Self-Defense Forces. The study subjects included 1520 men with normal glucose tolerance, 553 with prediabetic condition (impaired fasting glucose and impaired glucose tolerance), and 235 men with type 2 diabetes. There was an evident interaction between alcohol consumption and ADH1B polymorphism in relation to type 2 diabetes (interaction P=.03). The ALDH2487Lys allele was associated with a decreased prevalence odds of type 2 diabetes regardless of alcohol consumption. In conclusion, the ADH1B polymorphism modified the association between alcohol consumption and type 2 diabetes. A positive association between alcohol consumption and type 2 diabetes was confounded by ALDH2 polymorphism.

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Serum Uromodulin Is Associated With But Does Not Predict Type 2 Diabetes in Elderly KORA F4/FF4 Study Participants

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-02557 ◽

2019 ◽

Vol 104 (9) ◽

pp. 3795-3802 ◽

Cited By ~ 4

Author(s):

Cornelia Then ◽

Holger Then ◽

Christa Meisinger ◽

Margit Heier ◽

Annette Peters ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Tolerance ◽

Tolerance Test ◽

Population Based ◽

Oral Glucose ◽

Linear Regression Models ◽

Glucose Tolerance Status ◽

Study Participants

AbstractAimsSerum uromodulin has recently emerged as promising biomarker for kidney function and was suggested to be associated with type 2 diabetes (T2D) in patients with coronary heart disease. Here, we analyzed the association of serum uromodulin with T2D in the population-based KORA F4/FF4 study.MethodsIn 1119 participants of the KORA F4 study aged 62 to 81 years, serum uromodulin was measured, and the association of serum uromodulin with T2D was assessed using logistic and linear regression models stratified for sex. After a mean follow-up time of 6.5 years, 635 participants where re-evaluated. Glucose tolerance status was determined by oral glucose tolerance test at baseline and at the follow-up examination except in cases of known T2D.ResultsSerum uromodulin was inversely associated with T2D in the crude analysis and after adjustment for age and body mass index in men (P < 0.001) and in women (P < 0.05). After further adjustment for estimated glomerular filtration rate, serum uromodulin was significantly inversely associated with T2D in men (P < 0.001) but not in women. Serum uromodulin was not associated with prediabetes after multivariate adjustment and did not predict T2D in men or in women after the follow-up time of 6.5 ± 0.3 years.ConclusionsIn participants of the KORA F4 study, serum uromodulin is independently associated with T2D in men but is not a predictor of future development of T2D.

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Vitamin D and Incidence of Prediabetes or Type 2 Diabetes: A Four-Year Follow-Up Community-Based Study

Disease Markers ◽

10.1155/2018/1926308 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Yun Gao ◽

Tianpeng Zheng ◽

Xingwu Ran ◽

Yan Ren ◽

Tao Chen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Linear Regression Analysis ◽

Multiple Linear Regression Analysis ◽

Tolerance Test ◽

Oral Glucose ◽

Community Based ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D

Aim. To examine whether the baseline 25-hydroxyvitamin D [25(OH)D] level was predictive of the onset of prediabetes or type 2 diabetes (T2DM) in the Chinese population. Methods. This was a 4-year follow-up study that was conducted in the Chengdu region of China as part of the China National Diabetes and Metabolic Disorders Study. The study included 490 participants that were free of prediabetes and type 2 diabetes mellitus (T2DM) at baseline and had complete data by follow-up examinations. Glucose, insulin, and 25(OH)D levels were measured at baseline and at 4 years later. Prediabetes and T2DM were defined by results obtained from an oral glucose tolerance test. Results. Over a 4-year follow-up, 95 (48.5‰) developed prediabetes and 31 (15.8‰) individuals developed diabetes. Low 25(OH)D status was significantly associated with the risk of developing prediabetes [OR 3.01 (95% CI: 1.50–6.06), P=0.002] and T2DM [OR 5.61 (95% CI: 1.73–18.27), P=0.004] after adjustment for multiple potential confounders. In a multiple linear regression analysis, low baseline levels of 25(OH)D were an independent predictor of increased insulin resistance over a 4-year period (P<0.05). Conclusions. The current prospective study suggests that low 25(OH)D levels might have contributed to the incidence of prediabetes or T2DM in Chinese individuals. This trial is registered with TR-CCH-ChiCTR-OCS-09000361.

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Impaired succinate response to a mixed meal in obesity and type 2 diabetes is normalized after metabolic surgery

10.2337/figshare.12621884 ◽

2020 ◽

Author(s):

Brenno Astiarraga ◽

Laia Martínez ◽

Victoria Ceperuelo-Mallafré ◽

Gemma Llauradó ◽

Margarida Terrón-Puig ◽

...

Keyword(s):

Type 2 Diabetes ◽

Metabolic Surgery ◽

Healthy Subjects ◽

Area Under The Curve ◽

Tolerance Test ◽

Glucose Sensing ◽

Oral Glucose ◽

One Year

<div>Objective To explore the meal response of circulating succinate in patients with obesity and type 2 diabetes undergoing bariatric surgery, and to examine the role of gastrointestinal glucose sensing in succinate dynamics in healthy subjects. </div><div>Research Design and Methods Cohort I comprised 45 patients with morbid obesity and type 2 diabetes (BMI 39.4±1.9 kg/m2) undergoing metabolic surgery. Cohort II was a confirmatory cohort of 13 patients (BMI 39.3±1.4 kg/m2) undergoing gastric bypass surgery. Cohort III comprised 15 healthy subjects (BMI 26.4±0.5 kg/m2). Cohorts I and II completed a 2-hour meal tolerance test (MTT) before the intervention and at one-year of follow-up, and cohort II also completed a 3-hour lipid test (LT). Cohort III underwent a 3-hour oral glucose tolerance test (OGTT) and an isoglycemic variable glucose infusion (ISO) study. </div> Results In cohort I, succinate response to MTT at follow-up was greater than before the intervention (p<0.0001). This response was confirmed in cohort II with a greater increase after one year of surgery (p=0.009). By contrast, LT did not elicit a succinate response. Changes in succinate response were associated with changes in the area under the curve of glucose (r=0.417, p<0.0001) and insulin (r=0.204, p=0.002). In cohort III, glycemia per se stimulated a plasma succinate response (p=0.0004), but its response was greater in the OGTT (p=0.02; OGTT versus ISO). Conclusions The meal-related response of circulating succinate in patients with obesity and type 2 diabetes is recovered after metabolic surgery.

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Variability, mean, and baseline values of metabolic parameters in predicting the risk of type 2 diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgac017 ◽

2022 ◽

Author(s):

Duong Duc Pham ◽

Jaekyung Song ◽

Yunwan Jeon ◽

Ibrahimi Hajar ◽

Chae Hun Leem

Keyword(s):

Type 2 Diabetes ◽

Density Lipoprotein ◽

Tolerance Test ◽

Metabolic Parameters ◽

Sensitivity Analyses ◽

Oral Glucose ◽

Average Value ◽

Hazard Ratios

Abstract Context Impact of baseline and alteration of metabolic parameters (MPs), including plasma glucose (PGs) testing, insulin resistance surrogates, and lipid profile and their mutual interactions on the development of type 2 diabetes (T2DM) has not been investigated systematically. Objective To access the association of the past variability (V), past mean (M), and the baseline (B) values of various MPs and their mutual interaction with the risk of T2DM. Design Longitudinal analysis from the Korean Genome and Epidemiology Study. Setting Community-based Participants 3829 non-diabetic participants with completed MPs measurements during three biannually visits were followed up over the next 10 years. Outcomes Incidence of T2DM during the follow up. Results Among predictors, PG concentrations measured during the oral glucose tolerance test were the most prominent T2DM determinants, in which the M of the average value of fasting PG, 1-h, and 2-h PGs had the strongest discriminative power (hazard ratios and 95% CI for an increment of SD: 3.00 (2.5–3.26), AUC: 0.82). The M values of MPs were superior to their B and V values in predicting T2DM, especially among post-load PGs. Various mutual interactions between indices and among MPs were found. The most consistent interactants were the M values of high-density lipoprotein cholesterol and the M and V values of fasting PG. The findings were similar in normal tolerance glucose participants and were confirmed by sensitivity analyses. Conclusion The post-load PGs, past alteration of measurements, and mutual interactions among indices of MPs are important risk factors for T2DM development.

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Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes

Acta Endocrinologica ◽

10.1530/eje-13-0286 ◽

2013 ◽

Vol 169 (3) ◽

pp. 291-297 ◽

Cited By ~ 66

Author(s):

Hanna Huopio ◽

Henna Cederberg ◽

Jagadish Vangipurapu ◽

Heidi Hakkarainen ◽

Mirja Pääkkönen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Gestational Diabetes ◽

Glucose Tolerance ◽

Tolerance Test ◽

Oral Glucose ◽

Nucleotide Polymorphisms ◽

Risk Variants

ObjectiveThe aim of this study was to investigate the association of risk variants for type 2 diabetes (T2D) and hyperglycemia with gestational diabetes (GDM).Design and methodsFive hundred and thirty-three Finnish women who were diagnosed with GDM and 407 controls with normal glucose tolerance during the pregnancy were genotyped for 69 single-nucleotide polymorphisms (SNPs) which have been previously verified as susceptibility risk variants for T2D and hyperglycemia. All participants underwent an oral glucose tolerance test at the follow-up study after the index pregnancy.ResultsRisk variants rs10830963 and rs1387153 ofMTNR1Bwere significantly associated with GDM (odds ratio (OR)=1.62 (95% CI 1.34–1.96),P=4.5×10−7and 1.38 (1.14–1.66),P=7.6×10−4respectively). Both SNPs ofMTNR1Bwere also significantly associated with elevated fasting glucose level and reduced insulin secretion at follow-up. Additionally, risk variants rs9939609 ofFTO, rs2796441 ofTLE1, rs560887 ofG6PC2, rs780094 ofGCKR, rs7903146 ofTCF7L2and rs11708067 ofADCY5showed nominally significant associations with GDM (OR range from 1.25 to 1.30).ConclusionsOur study suggests that GDM and T2D share a similar genetic background. Our findings also provide further evidence that risk variants ofMTNR1Bare associated with GDM by increasing fasting plasma glucose and decreasing insulin secretion.

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Relationship Between Insulin Resistance and β-Cell Dysfunction in Subphenotypes of Prediabetes and Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-2853 ◽

2015 ◽

Vol 100 (2) ◽

pp. 707-716 ◽

Cited By ~ 21

Author(s):

Kristine Færch ◽

Nanna B. Johansen ◽

Daniel R. Witte ◽

Torsten Lauritzen ◽

Marit E. Jørgensen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Tolerance Test ◽

Fasting Glucose ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Β Cell

Abstract Context: There is little overlap between diabetes diagnosed by glycated hemoglobin (HbA1c) and blood glucose, and it is unclear which pathophysiological defects are captured when using HbA1c for diagnosis. Objective: We examined and compared the relationship between insulin sensitivity and β-cell function in different subphenotypes of prediabetes and type 2 diabetes (T2D). Design, Setting, and Participants: A cross-sectional analysis of the Danish ADDITION-PRO study was performed (n = 1713). Participants without known diabetes were classified into subgroups of prediabetes and T2D based on fasting or 2-hour glucose criteria or HbA1c. Insulin sensitivity and insulin release were determined from glucose and insulin concentrations during the oral glucose tolerance test, and disposition indices were calculated. Results: Individuals with prediabetes or T2D diagnosed by fasting glucose had lower absolute insulin release (P ≤ .01) and higher insulin sensitivity in response to glucose intake (P ≤ .01) but a similar disposition index (P ≥ .36), compared with individuals with elevated 2-hour glucose concentrations. Individuals with HbA1c-defined T2D or prediabetes had a mixture of the pathophysiological defects observed in the glucose-defined subgroups, and individuals with normoglycemia by HbA1c had worse pathophysiological abnormalities than individuals with normoglycemia by the glucose criteria. Conclusions: On average, the diagnostic HbA1c criteria for diabetes and prediabetes identified individuals with a mixture of the pathophysiological characteristics found when using the glucose criteria, but the diversity and pathophysiology captured by the oral glucose tolerance test cannot be captured when applying the more simple HbA1c criteria. Whether the disease progression and prognosis will differ in individuals diagnosed by fasting glucose, 2-hour glucose, or HbA1c should be examined in longitudinal studies.

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Incidence of type 2 diabetes in Mexico. Results of The Mexico City Diabetes Study after 18 years of follow-up

Salud Pública de México ◽

10.21149/spm.v56i1.7318 ◽

2014 ◽

Vol 56 (1) ◽

pp. 11 ◽

Cited By ~ 19

Author(s):

Clicerio González-Villalpando ◽

Claudio Alberto Dávila-Cervantes ◽

Mireya Zamora-Macorra ◽

Belem Trejo-Valdivia ◽

María Elena González-Villalpando

Keyword(s):

Type 2 Diabetes ◽

Tolerance Test ◽

Population Based ◽

Mexican Population ◽

Oral Glucose ◽

The Mean ◽

Incident Cases

Objective. To estimate the incidence of type 2 diabetes (T2D) in Mexican population. Materials and methods. Population based prospective study. At baseline (1990), the population at risk (1939 non-diabetic adults 35-64 years) was evaluated with oral glucose tolerance test. Subsequent similar evaluations were done (1994, 1998, 2008). American Diabetes Association diagnostic criteria were applied. Results. The period of observation was 27842 person-years, the cumulative incidence of T2D was 14.4 and 13.7 per 1000 person-years for men and women, respectively. Incidence was 15.8, 15.7 and 12.7 per 1 000 person-years for the second (1994), third (1998) and fourth (2008) follow-up phases, respectively. The mean age at diagnosis was 44 years for prevalent cases and 56 years for incident cases. Conclusions. This is the first estimate of long-term incidence of T2D in Mexican population. The incidence is among the highest reported worldwide. It remained with few changes throughout the study period.

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