Publications by authors named "Jaakko Tuomilehto"

661 Publications

REPRINT OF: CLASSIFICATION OF DIABETES MELLITUS.

Diabetes Res Clin Pract 2021 Jul 31:108972. Epub 2021 Jul 31.

Boden Institute, University of Sydney, Australia.

Executive Summary This document updates the 1999 World Health Organization (WHO) classification of diabetes. It prioritizes clinical care and guides health professionals in choosing appropriate treatments at the time of diabetes diagnosis, and provides practical guidance to clinicians in assigning a type of diabetes to individuals at the time of diagnosis. It is a compromise between clinical and aetiological classification because there remain gaps in knowledge of the aetiology and pathophysiology of diabetes. While acknowledging the progress that is being made towards a more precise categorization of diabetes subtypes, the aim of this document is to recommend a classification that is feasible to implement in different settings throughout the world. The revised classification is presented in Table 1. Unlike the previous classification, this classification does not recognize subtypes of type 1 diabetes and type 2 diabetes and includes new types of diabetes ("hybrid types of diabetes" and "unclassified diabetes").
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http://dx.doi.org/10.1016/j.diabres.2021.108972DOI Listing
July 2021

Urocortin 3 overexpression reduces ER stress and heat shock response in 3T3-L1 adipocytes.

Sci Rep 2021 Aug 2;11(1):15666. Epub 2021 Aug 2.

Biochemistry and Molecular Biology Department, Research Division, Dasman Diabetes Institute, P.O. Box 1180, 15462, Dasman, Kuwait.

The neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1α) and attenuated inflammation (TNFα) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 μM of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis.
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http://dx.doi.org/10.1038/s41598-021-95175-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329193PMC
August 2021

Influence of COVID-19 pandemic and related quarantine procedures on metabolic risk.

Prim Care Diabetes 2021 10 19;15(5):745-750. Epub 2021 Jul 19.

Department of Public Health, University of Helsinki, Helsinki, Finland; Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has changed the lives of many people across the globe. In addition to the effect of the virus on the biological functions in those infected individuals, many countries have launched government policy with additional impact of these quarantine procedures on the metabolic health of many people worldwide. This mini-review aimed to highlight current evidence regarding the influence of metabolic health due to these quarantine procedures including decrease in physical activity, changes in unhealthy eating habits, increase in stress, and provide recommendations of healthy lifestyle during COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.pcd.2021.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286866PMC
October 2021

Validation of the Finnish Type 2 Diabetes Risk Score (FINDRISC) with the OGTT in Health Care Practices in Europe.

Diabetes Res Clin Pract 2021 Aug 22;178:108976. Epub 2021 Jul 22.

World Community for Prevention of Diabetes (WCPD) Foundation, Madrid, Spain; Javeriana University, Bogota, Colombia; San Ignacio University, Bogota, Colombia.

Aims: /hypothesis. To determine the best cut-off threshold value of the Finnish Diabetes Risk Score (FINDRISC) for the detection of diabetes and non-diabetic hyperglycaemia in people 35 years or older at primary health care settings in Europe.

Methods: Cross-sectional study in 11,444 adults from primary health care centres using community and opportunistic screening approaches. All participants completed the FINDRISC questionnaire and underwent a 2-hour oral glucose tolerance test (OGTT). The FINDRISC performance was assessed by the area under the curve (AUC) using receiver operating characteristics (ROC) analysis. The sensitivity, specificity, Youdeńs index, positive and negative prediction values for different FINDRISC cut-offs were calculated.

Results: The optimal FINDRISC value for detecting both diabetes or glucose impairment in the community - screened sample was 14 point with the associated AUC 0.75,5 (95 %CI 0.73,7-0.77,3). The optimal score in the opportunistic screening sample was 16 with the associated AUC only 0.60,4 (95% CI 0.56, 4-0.64, 4).

Conclusions/interpretation: The FINDRISC is a non-invasive tool useful for detecting people with unknown diabetes and glucose impairment in people visiting primary health centres in Europe.
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http://dx.doi.org/10.1016/j.diabres.2021.108976DOI Listing
August 2021

Effect of a Multidomain Lifestyle Intervention on Estimated Dementia Risk.

J Alzheimers Dis 2021 ;82(4):1461-1466

Karolinska Institutet, NVS, Division of Clinical Geriatrics, Solna, Stockholm, Sweden.

We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60-77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was -0.16 (95 %CI -0.31 to 0.00) (p = 0.013), corresponding to a relative dementia risk reduction between 6.04-6.50%. This could be interpreted as a reflection of the prevention potential of the intervention.
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http://dx.doi.org/10.3233/JAD-210331DOI Listing
January 2021

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat Commun 2021 06 9;12(1):3505. Epub 2021 Jun 9.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
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http://dx.doi.org/10.1038/s41467-021-23556-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190084PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Ferritinophagy and ferroptosis in the management of metabolic diseases.

Trends Endocrinol Metab 2021 07 15;32(7):444-462. Epub 2021 May 15.

Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Ferroptosis is a form of regulated cell death modality associated with disturbed iron-homeostasis and unrestricted lipid peroxidation. Ample evidence has depicted an essential role for ferroptosis as either the cause or consequence for human diseases, denoting the likely therapeutic promises for targeting ferroptosis in the preservation of human health. Ferritinophagy, a selective form of autophagy, contributes to the initiation of ferroptosis through degradation of ferritin, which triggers labile iron overload (IO), lipid peroxidation, membrane damage, and cell death. In this review, we will delineate the role of ferritinophagy in ferroptosis, and its underlying regulatory mechanisms, to unveil the therapeutic value of ferritinophagy as a target in the combat of ferroptosis to manage metabolic diseases.
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http://dx.doi.org/10.1016/j.tem.2021.04.010DOI Listing
July 2021

Change in CAIDE Dementia Risk Score and Neuroimaging Biomarkers During a 2-Year Multidomain Lifestyle Randomized Controlled Trial: Results of a Post-Hoc Subgroup Analysis.

J Gerontol A Biol Sci Med Sci 2021 Jul;76(8):1407-1414

Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.

The CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Risk Score is a validated tool estimating dementia risk. It was previously associated with imaging biomarkers. However, associations between dementia risk scores (including CAIDE) and dementia-related biomarkers have not been studied in the context of an intervention. This study investigated associations between change in CAIDE score and change in neuroimaging biomarkers (brain magnetic resonance imaging [MRI] and Pittsburgh Compound B-positron emission tomography [PiB-PET] measures) during the 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (post-hoc analyses). FINGER targeted at-risk older adults, aged 60-77 years, from the general population. Participants were randomized to either multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice). Neuroimaging (MRI and PiB-PET) data from baseline and 2-year visits were used. A toal of 112 participants had repeated brain MRI measures (hippocampal, total gray matter, and white matter lesion volumes, and Alzheimer's disease signature cortical thickness). Repeated PiB-PET scans were available for 39 participants. Reduction in CAIDE score (indicating lower dementia risk) during the intervention was associated with less decline in hippocampus volume in the intervention group, but not the control group (Randomization group × CAIDE change interaction β coefficient = -0.40, p = .02). Associations for other neuroimaging measures were not significant. The intervention may have benefits on hippocampal volume in individuals who succeed in improving their overall risk level as indicated by a reduction in CAIDE score. This exploratory finding requires further testing and validation in larger studies.
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http://dx.doi.org/10.1093/gerona/glab130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277089PMC
July 2021

Long-term outcomes of lifestyle intervention to prevent type 2 diabetes in people at high risk in primary health care.

Prim Care Diabetes 2021 06 23;15(3):444-450. Epub 2021 Mar 23.

Department of Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland.

Aims: The Finnish National Diabetes Prevention Program (FIN-D2D) was the first large-scale diabetes prevention program in a primary health care setting in the world. The risk reduction of type 2 diabetes was 69% after one-year intervention in high-risk individuals who were able to lose 5% of their weight. We investigated long-term effects of one-year weight change on the incidence of type 2 diabetes, cardiovascular events, and all-cause mortality.

Methods: A total of 10,149 high-risk individuals for type 2 diabetes were identified in primary health care centers and they were offered lifestyle intervention to prevent diabetes. Of these individuals who participated in the baseline screening, 8353 had an oral glucose tolerance test (OGTT). Complete follow-up data during one-year intervention were available for 2730 individuals and those were included in the follow-up analysis. The long-term outcome events were collected from national health registers after the median follow-up of 7.4 years.

Results: Among individuals who lost weight 2.5-4.9% and 5% or more during the first year, the hazard ratio for the incidence of drug-treated diabetes was 0.63 (95% CI 0.49-0.81, p = 0.0001), and 0.71 (95% CI 0.56-0.90, p = 0.004), respectively, compared with those with stable weight. There were no significant differences in cardiovascular events or all-cause mortality among study participants according to one-year weight changes.

Conclusions: High-risk individuals for type 2 diabetes who achieved a moderate weight loss by one-year lifestyle counseling in primary health care had a long-term reduction in the incidence of drug-treated type 2 diabetes. The observed moderate weight loss was not associated with a reduction in cardiovascular events.
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http://dx.doi.org/10.1016/j.pcd.2021.03.002DOI Listing
June 2021

Exercise, diet, and cognition in a 4-year randomized controlled trial: Dose-Responses to Exercise Training (DR's EXTRA).

Am J Clin Nutr 2021 06;113(6):1428-1439

Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.

Background: Evidence for the effects of exercise and dietary interventions on cognition from long-term randomized controlled trials (RCTs) in large general populations remains insufficient.

Objective: The objective of our study was to investigate the independent and combined effects of resistance and aerobic exercise and dietary interventions on cognition in a population sample of middle-aged and older individuals.

Methods: We conducted a 4-y RCT in 1401 men and women aged 57-78 y at baseline. The participants were randomly assigned to the resistance exercise, aerobic exercise, diet, combined resistance exercise and diet, combined aerobic exercise and diet, or control group. Exercise goals were at least moderate-intensity resistance exercise ≥2 times/wk and at least moderate-intensity aerobic exercise ≥5 times/wk. Dietary goals were ≥400 g/d of vegetables, fruit, and berries; ≥2 servings of fish/wk; ≥14 g fiber/1000 kcal; and ≤10% of energy of daily energy intake from SFAs. The primary outcome was the change in global cognition measured by the total score of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological tests [CERAD total score (CERAD-TS)]. The data were analyzed using the intention-to-treat principle and linear mixed-effects models.

Results: There was a trend toward improved CERAD-TS over 4 y in the combined aerobic exercise and diet group compared with the control group (net increase: 1.4 points; 95% CI: 0.1, 2.7; P = 0.06) adjusted for age, sex, years of education, symptoms of depression, and waist circumference at baseline. No other differences in CERAD-TS changes were found across the 6 study groups. Diet did not potentiate the effect of aerobic or resistance exercise on CERAD-TS.

Conclusions: A combination of at least moderate-intensity aerobic exercise and a healthy diet may improve cognition in older individuals over 4 y, but there was no effect of either of these interventions alone, resistance training alone, or resistance exercise with a healthy diet on cognition.
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http://dx.doi.org/10.1093/ajcn/nqab018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244125PMC
June 2021

Accuracy of 1-Hour Plasma Glucose During the Oral Glucose Tolerance Test in Diagnosis of Type 2 Diabetes in Adults: A Meta-analysis.

Diabetes Care 2021 04;44(4):1062-1069

Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland.

Objective: One-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard.

Research Design And Methods: We included 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA. We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG ≥11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3).

Results: Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%.

Conclusions: The 1-h PG of ≥11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes. Prescreening with a diabetes-specific risk calculator to identify high-risk individuals is suggested to decrease the proportion of false-positive cases. Studies including other ethnic groups and assessing complication risk are warranted.
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http://dx.doi.org/10.2337/dc20-1688DOI Listing
April 2021

Editorial: Diabetes in the Middle East.

Front Endocrinol (Lausanne) 2021 19;12:638653. Epub 2021 Feb 19.

Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman, Kuwait.

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http://dx.doi.org/10.3389/fendo.2021.638653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945692PMC
February 2021

Predicting the risk of developing type 2 diabetes in Chinese people who have coronary heart disease and impaired glucose tolerance.

J Diabetes 2021 Oct 17;13(10):817-826. Epub 2021 Mar 17.

Diabetes Trials Unit, University of Oxford, Oxford, UK.

Aims: Robust diabetes risk estimates in Asian patients with impaired glucose tolerance (IGT) and coronary heart disease (CHD) are lacking. We developed a Chinese type 2 diabetes risk calculator using Acarbose Cardiovascular Evaluation (ACE) trial data.

Methods: There were 3105 placebo-treated ACE participants with requisite data for model development. Clinically relevant variables, and those showing nominal univariate association with new-onset diabetes (P < .10), were entered into BASIC (clinical variables only), EXTENDED (clinical variables plus routinely available laboratory results), and FULL (all candidate variables) logistic regression models. External validation was performed using the Luzhou prospective cohort of 1088 Chinese patients with IGT.

Results: Over median 5.0 years, 493 (15.9%) ACE participants developed diabetes. Lower age, higher body mass index, and use of corticosteroids or thiazide diuretics were associated with higher diabetes risk. C-statistics for the BASIC (using these variables), EXTENDED (adding male sex, fasting plasma glucose, 2-hour glucose, and HbA1c), and FULL models were 0.610, 0.757, and 0.761 respectively. The EXTENDED model predicted a lower 13.9% 5-year diabetes risk in the Luzhou cohort than observed (35.2%, 95% confidence interval 31.3%-39.5%, C-statistic 0.643).

Conclusion: A risk prediction model using routinely available clinical variables can be used to estimate diabetes risk in Chinese people with CHD and IGT.
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http://dx.doi.org/10.1111/1753-0407.13175DOI Listing
October 2021

n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies.

Diabetes Care 2021 05 3;44(5):1133-1142. Epub 2021 Mar 3.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis.

Research Design And Methods: For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis.

Results: A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all < 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses.

Conclusions: Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.
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http://dx.doi.org/10.2337/dc20-2426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132316PMC
May 2021

Gender differences in screening for glucose perturbations, cardiovascular risk factor management and prognosis in patients with dysglycaemia and coronary artery disease: results from the ESC-EORP EUROASPIRE surveys.

Cardiovasc Diabetol 2021 02 11;20(1):38. Epub 2021 Feb 11.

Cardiology Unit, Department of Medicine K2, Karolinska Institutet, Solnavägen 1, 17177, Stockholm, Sweden.

Background: Gender disparities in the management of dysglycaemia, defined as either impaired glucose tolerance (IGT) or type 2 diabetes (T2DM), in coronary artery disease (CAD) patients are a medical challenge. Recent data from two nationwide cohorts of patients suggested no gender difference as regards the risk for diabetes-related CV complications but indicated the presence of a gender disparity in risk factor management. The aim of this study was to investigate gender differences in screening for dysglycaemia, cardiovascular risk factor management and prognosis in dysglycemic CAD patients.

Methods: The study population (n = 16,259; 4077 women) included 7998 patients from the ESC-EORP EUROASPIRE IV (EAIV: 2012-2013, 79 centres in 24 countries) and 8261 patients from the ESC-EORP EUROASPIRE V (EAV: 2016-2017, 131 centres in 27 countries) cross-sectional surveys. In each centre, patients were investigated with standardised methods by centrally trained staff and those without known diabetes were offered an oral glucose tolerance test (OGTT). The first of CV death or hospitalisation for non-fatal myocardial infarction, stroke, heart failure or revascularization served as endpoint. Median follow-up time was 1.7 years. The association between gender and time to the occurrence of the endpoint was evaluated using Cox survival modelling, adjusting for age.

Results: Known diabetes was more common among women (32.9%) than men (28.4%, p < 0.0001). OGTT (n = 8655) disclosed IGT in 17.2% of women vs. 15.1% of men (p = 0.004) and diabetes in 13.4% of women vs. 14.6% of men (p = 0.078). In both known diabetes and newly detected dysglycaemia groups, women were older, with higher proportions of hypertension, dyslipidaemia and obesity. HbA1c was higher in women with known diabetes. Recommended targets of physical activity, blood pressure and cholesterol were achieved by significantly lower proportions of women than men. Women with known diabetes had higher risk for the endpoint than men (age-adjusted HR 1.22; 95% CI 1.04-1.43).

Conclusions: Guideline-recommended risk factor control is poorer in dysglycemic women than men. This may contribute to the worse prognosis in CAD women with known diabetes.
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http://dx.doi.org/10.1186/s12933-021-01233-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879645PMC
February 2021

A diabetes risk score for Qatar utilizing a novel mathematical modeling approach to identify individuals at high risk for diabetes.

Sci Rep 2021 01 19;11(1):1811. Epub 2021 Jan 19.

Infectious Disease Epidemiology Group, Weill Cornell Medicine - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar.

We developed a diabetes risk score using a novel analytical approach and tested its diagnostic performance to detect individuals at high risk of diabetes, by applying it to the Qatari population. A representative random sample of 5,000 Qataris selected at different time points was simulated using a diabetes mathematical model. Logistic regression was used to derive the score using age, sex, obesity, smoking, and physical inactivity as predictive variables. Performance diagnostics, validity, and potential yields of a diabetes testing program were evaluated. In 2020, the area under the curve (AUC) was 0.79 and sensitivity and specificity were 79.0% and 66.8%, respectively. Positive and negative predictive values (PPV and NPV) were 36.1% and 93.0%, with 42.0% of Qataris being at high diabetes risk. In 2030, projected AUC was 0.78 and sensitivity and specificity were 77.5% and 65.8%. PPV and NPV were 36.8% and 92.0%, with 43.0% of Qataris being at high diabetes risk. In 2050, AUC was 0.76 and sensitivity and specificity were 74.4% and 64.5%. PPV and NPV were 40.4% and 88.7%, with 45.0% of Qataris being at high diabetes risk. This model-based score demonstrated comparable performance to a data-derived score. The derived self-complete risk score provides an effective tool for initial diabetes screening, and for targeted lifestyle counselling and prevention programs.
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http://dx.doi.org/10.1038/s41598-021-81385-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815783PMC
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

Cardiovascular health metrics from mid- to late-life and risk of dementia: A population-based cohort study in Finland.

PLoS Med 2020 12 15;17(12):e1003474. Epub 2020 Dec 15.

Aging Research Center & Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden.

Background: Very few studies have explored the patterns of cardiovascular health (CVH) metrics in midlife and late life in relation to risk of dementia. We examined the associations of composite CVH metrics from midlife to late life with risk of incident dementia.

Methods And Findings: This cohort study included 1,449 participants from the Finnish Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study, who were followed from midlife (baseline from1972 to 1987; mean age 50.4 years; 62.1% female) to late life (1998), and then 744 dementia-free survivors were followed further into late life (2005 to 2008). We defined and scored global CVH metrics based on 6 of the 7 components (i.e., smoking, physical activity, and body mass index [BMI] as behavioral CVH metrics; fasting plasma glucose, total cholesterol, and blood pressure as biological CVH metrics) following the modified American Heart Association (AHA)'s recommendations. Then, the composite global, behavioral, and biological CVH metrics were categorized into poor, intermediate, and ideal levels. Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Data were analyzed with Cox proportional hazards and the Fine and Gray competing risk regression models. During the follow-up examinations, dementia was diagnosed in 61 persons in 1998 and additional 47 persons in 2005 to 2008. The fully adjusted hazard ratio (HR) of dementia was 0.71 (95% confidence interval [CI]: 0.43, 1.16; p = 0.174) and 0.52 (0.29, 0.93; p = 0.027) for midlife intermediate and ideal levels (versus poor level) of global CVH metrics, respectively; the corresponding figures for late-life global CVH metrics were 0.60 (0.22, 1.69; p = 0.338) and 0.91 (0.34, 2.41; p = 0.850). Compared with poor global CVH metrics in both midlife and late life, the fully adjusted HR of dementia was 0.25 (95% CI: 0.08, 0.86; p = 0.028) for people with intermediate global CVH metrics in both midlife and late life and 0.14 (0.02, 0.76; p = 0.024) for those with midlife ideal and late-life intermediate global CVH metrics. Having an intermediate or ideal level of behavioral CVH in both midlife and late life (versus poor level in both midlife and late life) was significantly associated with a lower dementia risk (HR range: 0.03 to 0.26; p < 0.05), whereas people with midlife intermediate and late-life ideal biological CVH metrics had a significantly increased risk of dementia (p = 0.031). Major limitations of this study include the lack of data on diet and midlife plasma glucose, high rate of attrition, as well as the limited power for certain subgroup analyses.

Conclusions: In this study, we observed that having the ideal CVH metrics, and ideal behavioral CVH metrics in particular, from midlife onwards is associated with a reduced risk of dementia as compared with people having poor CVH metrics. Maintaining life-long health behaviors may be crucial to reduce late-life risk of dementia.
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http://dx.doi.org/10.1371/journal.pmed.1003474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737898PMC
December 2020

Variables associated with insulin production in persons with type 2 diabetes treated with multiple daily insulin injections.

Prim Care Diabetes 2021 06 7;15(3):607-613. Epub 2020 Dec 7.

Department of Medicine, NU-Hospital Group, Trollhättan/Uddevalla, Sweden; Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.

From the MDI-liraglutide study, we evaluated variables associated with endogenous insulin production in persons with multiple daily insulin injections-treated type 2 diabetes by relating C-peptide, proinsulin and proinsulin/C-peptide ratio at baseline to baseline variables. Lower insulin production was related to longer diabetes duration, shorter abdominal sagittal diameter and more glycaemic variability.
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http://dx.doi.org/10.1016/j.pcd.2020.11.005DOI Listing
June 2021

Comparison of oral glucose tolerance test and HbA1c in detection of disorders of glucose metabolism in patients with acute stroke.

Cardiovasc Diabetol 2020 12 5;19(1):204. Epub 2020 Dec 5.

Department for Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria.

Background: Diabetes is an increasingly important risk factor for ischemic stroke and worsens stroke prognosis. Yet a large proportion of stroke patients who are eventually diabetic are undiagnosed. Therefore, it is important to have sensitive assessment of unrecognized hyperglycaemia in stroke patients.

Design: Secondary outcome analysis of a randomized controlled trial focussing on parameters of glucose metabolism and detection of diabetes and prediabetes in patients with acute ischemic stroke (AIS).

Methods: A total of 130 consecutively admitted patients with AIS without previously known type 2 diabetes mellitus (T2DM) were screened for diabetes or prediabetes as part of secondary outcome analysis of a randomized controlled trial that tested lifestyle intervention to prevent post-stroke cognitive decline. Patients had the oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) measurements in the second week after stroke onset and after 1 year. The detection rates of diabetes and prediabetes based on the OGTT or HbA1c values were compared.

Results: By any of the applied tests at the second week after stroke onset 62 of 130 patients (48%) had prediabetes or T2DM. Seventy-five patients had results from both tests available, the OGTT and HbA1c; according to the OGTT 40 (53.3%) patients had normal glucose metabolism, 33 (44%) had prediabetes, two (2.7%) T2DM. In 50 (66.7%) patients the HbA1c results were normal, 24 (32%) in the prediabetic and one (1.3%) in the diabetic range. The detection rate for disorders of glucose metabolism was 10% higher (absolute difference; relative difference 29%) with the OGTT compared with HbA1c. After 1 year the detection rate for prediabetes or T2DM was 7% higher with the OGTT (26% relative difference). The study intervention led to a more favourable evolution of glycemic status after 1 year.

Conclusion: The OGTT is a more sensitive screening tool than HbA1c for the detection of previously unrecognized glycemic disorders in patients with acute stroke with an at least a 25% relative difference in detection rate. Therefore, an OGTT should be performed in all patients with stroke with no history of diabetes. Trial registration http://clinicaltrials.gov . Unique identifier: NCT01109836.
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http://dx.doi.org/10.1186/s12933-020-01182-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719250PMC
December 2020

The Finnish Diabetes Risk Score (FINDRISC), incident diabetes and low-grade inflammation.

Diabetes Res Clin Pract 2021 Jan 23;171:108558. Epub 2020 Nov 23.

Hospital Israelita Albert Einstein, São Paulo, SP, Brazil; Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil.

Aims: The FINDRISC was created to predict the development of type 2 diabetes mellitus (T2DM). Since T2DM associates with inflammation we evaluated if the FINDRISC could predict either current or incident T2DM, and elevated high sensitivity C-reactive protein (hs-CRP).

Methods: 41,880 people (age 41.9 ± 9.7 years; 31% female) evaluated between 2008 and 2016 were included. First, the cross-sectional association between the FINDRISC with presence of either T2DM or hs-CRP ≥ 2.0 mg/L was tested. After a 5 ± 3 years follow-up we tested the score predictive value for incident T2DM and inflammation in respectively 10,559 individuals without diabetes and in a subset of 2,816 individuals having no elevated hs-CRP at baseline.

Results: In the cross sectional analysis the FINDRISC was associated with both T2DM (OR 1.24, 95% CI: 1.23-1.26, P < 0.001) and inflammation (OR 1.10, 95% CI: 1.09-1.11, P < 0.001) per FINDRISC unit, as well as in longitudinal analyses (OR 1.17, 95% CI: 1.14-1.20, P < 0.001; and OR 1.04, 95% CI: 1.02-1.07, P < 0.001; respectively, per FINDRISC unit). The C-statistic for incident T2DM and inflammation was 0.79 (95% CI 0.77-0.82) and 0.55 (95% CI 0.53-0.58), respectively.

Conclusion: The FINDRISC shows good discrimination for incident T2DM but less for inflammation.
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http://dx.doi.org/10.1016/j.diabres.2020.108558DOI Listing
January 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline: A Randomized Clinical Trial.

J Gerontol A Biol Sci Med Sci 2021 02;76(3):491-498

Division of Clinical Geriatrics, Centre for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.

Background: Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia, has not been investigated in randomized controlled trials (RCTs).

Methods: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability is a 2-year RCT enrolling 1260 participants at risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. The primary outcome was cognitive change (Neuropsychological Test Battery z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction (trial registration: NCT01041989).

Results: This exploratory LTL substudy included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. The mean annual LTL change (SD) was -0.016 (0.19) in the intervention group and -0.023 (0.17) in the control group. Between-group difference was nonsignificant (unstandardized β-coefficient 0.007, 95% CI -0.015 to 0.030). Interaction analyses indicated better LTL maintenance among apolipoprotein E (APOE)-ε4 carriers versus noncarriers: 0.054 (95% CI 0.007 to 0.102); younger versus older participants: -0.005 (95% CI -0.010 to -0.001); and those with more versus less healthy lifestyle changes: 0.047 (95% CI 0.005 to 0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95% CI 0.057 to 0.396) and long-term memory (0.257, 95% CI 0.024 to 0.489), with a similar trend for Neuropsychological Test Battery total score (0.127, 95% CI -0.011 to 0.264).

Conclusions: This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among subgroups of older people at risk for dementia, including APOE-ε4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits.

Clinical Trials Registration Number: NCT01041989.
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http://dx.doi.org/10.1093/gerona/glaa279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907495PMC
February 2021

Correlation Profile of Suppression of Tumorigenicity 2 and/or Interleukin-33 with Biomarkers in the Adipose Tissue of Individuals with Different Metabolic States.

Diabetes Metab Syndr Obes 2020 20;13:3839-3859. Epub 2020 Oct 20.

Department of Immunology and Microbiology, Dasman Diabetes Institute, Kuwait City, Kuwait.

Purpose: The suppression of tumorigenicity 2 (ST2) has two main splice variants including a membrane bound (ST2) form, which activates the myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway, and a secreted soluble form (sST2), which acts as a decoy receptor for ST2 ligand, interleukin (IL)-33. The IL-33/ST2 axis is protective against obesity, insulin resistance, and type 2 diabetes (T2D). In humans, adipose tissue IL-33 displays distinct correlation profiles with glycated hemoglobin, ST2, and other immunometabolic mediators, depending on the glycemic health of the individuals. We determined whether adipose tissue ST2 displays distinct correlation profiles with immunometabolic mediators and whether ST2 and/or IL-33 are correlated with intracellular signaling molecules.

Patients And Methods: A total of 91 adults with normal glycemia, prediabetes, and T2D were included. After measuring their anthropometric and biochemical parameters, subcutaneous adipose tissues were isolated and mRNA expression of biomarkers was measured.

Results: In individuals with normal glycemia, adipose tissue ST2 was directly correlated with chemokine (C-C motif) ligand (CCL)-2, CCL5, IL-12, fibrinogen-like protein 2 (FGL2) and interferon regulatory factor (IRF)-4, but inversely correlated with cytochrome C oxidase subunit 7A1. IL-33 and ST2 were directly correlated with tumor necrosis factor receptor-associated factor 6 (TRAF6), NF-κB, and nuclear factor of activated T-cells 5 (NFAT5). In individuals with prediabetes, ST2 was inversely correlated with IL-5, whereas IL-33 but not ST2 was directly correlated with MyD88 and NF-κB. In individuals with T2D, ST2 was directly correlated with CCL2, IL-1β, and IRF5. IL-33 and ST2 were directly correlated with MyD88, TRAF6, and NF-κB.

Conclusion: Adipose tissue ST2 and IL-33 show different correlation profiles with various immunometabolic biomarkers depending on the metabolic state of the individuals. Therefore, targeting the IL-33/ST2 axis might form the basis for novel therapies to combat metabolic disorders.
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http://dx.doi.org/10.2147/DMSO.S251978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586022PMC
October 2020

The Association Between Dietary Habits and Other Lifestyle Indicators and Dysglycemia in Saudi Adults Free of Previous Diagnosis of Diabetes.

Nutr Metab Insights 2020 15;13:1178638820965258. Epub 2020 Oct 15.

Saudi Diabetes Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Objective: Study the association of dietary habits and other indicators of lifestyle with dysglycemia in Saudi adults.

Methods: In a cross-sectional design, data were obtained from 1403 Saudi adults (⩾20 years), not previously diagnosed with diabetes. Demographics, lifestyle variables and dietary habits were obtained using a predesigned questionnaire. Fasting plasma glucose, glycated hemoglobin and 1-hour oral glucose tolerance test were used to identify dysglycemia. Regression analysis was performed to determine the associations of dietary factors and other indicators of lifestyle with dysglycemia.

Results: A total 1075 adults (596 men, and 479 women) had normoglycemia, and 328 (195 men, and 133 women) had dysglycemia. Following adjustment for age, BMI and waist circumference, in men the weekly intake of 5 portions or more of red meat and Turkish coffee were associated with decreased odds of having dysglycemia odds ratio (OR) 0.444 (95% CI: 0.223, 0.881;  = .02) and 0.387 (95% CI: 0.202, 0.74;  = .004), respectively. In women, the intake of fresh juice 1 to 4 portions per week and 5 portions or more were associated with OR 0.603 (95% CI: 0.369, 0.985;  = .043) and OR 0.511 (95% CI: 0.279, 0.935;  = .029) decreased odds of having dysglycemia, respectively compared with women who did not drink fresh juice. The intake of 5 times or more per week of hibiscus drink was associated with increased odds of having dysglycemia, OR 5.551 (95% CI: 1.576, 19.55,  = .008) compared with women not using such a drink. Other lifestyle factors were not associated with dysglycemia.

Conclusion: Dietary practices by studied Saudis have some impact on risk of dysglycemia, with obvious sex differences.
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http://dx.doi.org/10.1177/1178638820965258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570793PMC
October 2020

Adult Diabetes and Prediabetes Prevalence in Kuwait: Data from the Cross-Sectional Kuwait Diabetes Epidemiology Program.

J Clin Med 2020 Oct 25;9(11). Epub 2020 Oct 25.

Dasman Diabetes Institute, Kuwait City 15462, Kuwait.

Background: This study aimed to estimate the prevalence of diabetes and prediabetes in adults in Kuwait.

Methods: The Kuwait Diabetes Epidemiology Program was a nationally representative, cross-sectional study of diabetes and obesity in Kuwait conducted between 2011 and 2014. The survey sampled 4937 adults in Kuwait aged 20 years or more and recorded participants' demographics, behaviours, medical history, physical measurements and blood biochemical measurements. Prediabetes was defined as fasting plasma glucose between 6.1 and 6.9 mmol/L or HbA1c between 6 and 6.4% (42-47 mmol/mol). Diabetes was defined as self-reported history with prescribed glucose-lowering medication or FPG ≥7mmol/L or HbA1c level ≥6.5% (≥48 mmol/mol).

Results: The overall adjusted prevalence of diabetes was 19.1%. The overall adjusted prevalence of prediabetes was 13.5%. Diabetes prevalence was 5.4%, 14.2%, 38.7% and 64.8% in adults aged 20-29, 30-44, 45-59 and 60 years or more, respectively. Diabetes prevalence was 22.4% in men and 14.4% in women. Prediabetes prevalence was 14.8% in men and 11.5% in women. In Kuwaitis, diabetes and prediabetes prevalence was 21.8% and 11.1%, respectively, while prevalence in non-Kuwaitis was 18.2% for diabetes and 14.3% for prediabetes.

Conclusion: These findings illustrate the severe public health challenge posed by diabetes in Kuwait.
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http://dx.doi.org/10.3390/jcm9113420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694112PMC
October 2020
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