Clinical and metabolomic predictors of regression to normoglycemia in a population at intermediate cardiometabolic risk.

BACKGROUND: Impaired fasting glucose (IFG) is a prevalent and potentially reversible intermediate stage leading to type 2 diabetes that increases risk for cardiometabolic complications. The identification of clinical and molecular factors associated with the reversal, or regression, from IFG to a normoglycemia state would enable more efficient cardiovascular risk reduction strategies. The aim of this study was to identify clinical and biological predictors of regression to normoglycemia in a non-European population characterized by high rates of type 2 diabetes. METHODS: We conducted a prospective, population-based study among 9637 Mexican individuals using clinical features and plasma metabolites. Among them, 491 subjects were classified as IFG, defined as fasting glucose between 100 and 125 mg/dL at baseline. Regression to normoglycemia was defined by fasting glucose less than 100 mg/dL in the follow-up visit. Plasma metabolites were profiled by Nuclear Magnetic Resonance. Multivariable cox regression models were used to examine the associations of clinical and metabolomic factors with regression to normoglycemia. We assessed the predictive capability of models that included clinical factors alone and models that included clinical factors and prioritized metabolites. RESULTS: During a median follow-up period of 2.5 years, 22.6% of participants (n = 111) regressed to normoglycemia, and 29.5% progressed to type 2 diabetes (n = 145). The multivariate adjusted relative risk of regression to normoglycemia was 1.10 (95% confidence interval [CI] 1.25 to 1.32) per 10 years of age increase, 0.94 (95% CI 0.91-0.98) per 1 SD increase in BMI, and 0.91 (95% CI 0.88-0.95) per 1 SD increase in fasting glucose. A model including information from age, fasting glucose, and BMI showed a good prediction of regression to normoglycemia (AUC = 0.73 (95% CI 0.66-0.78). The improvement after adding information from prioritized metabolites (TG in large HDL, albumin, and citrate) was non-significant (AUC = 0.74 (95% CI 0.68-0.80), p value = 0.485). CONCLUSION: In individuals with IFG, information from three clinical variables easily obtained in the clinical setting showed a good prediction of regression to normoglycemia beyond metabolomic features. Our findings can serve to inform and design future cardiovascular prevention strategies.

Identification of a threshold to discriminate fasting hypertriglyceridemia with postprandial values.

BACKGROUND: Postprandial lipemia is an important cardiovascular risk factor. The assessment of postprandial lipid metabolism is a newly trend that several consortiums and countries have adopted. The aim of the study is to determine a postprandial triglyceride concentration cut-off point that accurately discriminate individuals with fasting normal triglyceride concentrations from those with fasting hypertriglyceridemia. METHODS: Cross sectional population-based study. A total of 212 subjects underwent an eight hours' oral fat tolerance test. Samples were taken fasting, three, four, five, six and eight hours after the meal. The area under the receiver operating characteristic curve (c-statistic) was computed using postprandial triglycerides concentrations as independent predictor, and fasting hypertriglyceridemia as dependent variable. RESULTS: The best threshold of postprandial lipemia to discriminate fasting hypertriglyceridemia was 280 mg/dL at any hour area under the curve 0.816 (95% confidence interval 0.753-0.866), bootstrap-corrected c-statistic = 0.733 (95% confidence interval 0.68-0.86). The same value was compared with apolipoprotein B concentrations (>90th percentile) having a good performance: area under the curve 0.687 95% confidence interval 0.624-0.751). Likewise, subjects with high postprandial lipemia have higher Globo risk scores. CONCLUSION: The 280 mg/dL cut-off point value of postprandial triglycerides concentration any time after a test meal discriminate subjects with fasting hypertriglyceridemia. This threshold has a good performance in a heterogeneous population and has a good concordance with cardiovascular risk surrogates.

Diagnostic performance of questionnaires to identify individuals with impaired fasting glucose in Mexican adult population.

AIMS: To evaluate the diagnostic performance of five questionnaires to identify impaired fasting glucose (IFG) in Mexican adult population. METHODS: The study included 23,311 subjects from five cohorts, three composed of individuals who sought medical advice in their first level clinics or participated in research studies and two representative surveys of the Mexican population. The reference standard was IFG which was defined as a fasting glucose ≥ 100 mg/dL. Diagnostic performance was evaluated with specificity, sensitivity, positive and negative predictive values, area under the curve, and the proportion of correctly classified individuals. RESULTS: The prevalence of IFG ranged from 14.4 to 48.1 % across the cohorts. Diagnostic performance of the questionnaires varied in each cohort depending on IFG prevalence. The questionnaires designed by Rojas, American Diabetes Association and International Diabetes Federation had the best performance considering the correct classification (>66.0 %) of subjects in all cohorts. However, Rojas' questionnaire had the best balance between sensitivity and specificity across the cohorts. CONCLUSION: In the Mexican population, considering different scenarios, the Rojas' questionnaire had the best diagnostic performance. The implementation of questionnaires for the identification of prediabetes and undiagnosed diabetes requires further study in specific populations.

Metabolomic markers of glucose regulation after a lifestyle intervention in prediabetes.

INTRODUCTION: Disentangling the specific factors that regulate glycemia from prediabetes to normoglycemia could improve type 2 diabetes prevention strategies. Metabolomics provides substantial insights into the biological understanding of environmental factors such as diet. This study aimed to identify metabolomic markers of regression to normoglycemia in the context of a lifestyle intervention (LSI) in individuals with prediabetes. RESEARCH DESIGN AND METHODS: We conducted a single-arm intervention study with 24 weeks of follow-up. Eligible study participants had at least one prediabetes criteria according to the American Diabetes Association guidelines, and body mass index between 25 and 45 kg/m2. LSI refers to a hypocaloric diet and >150 min of physical activity per week. Regression to normoglycemia (RNGR) was defined as achieving hemoglobin A1c (HbA1c) <5.5% in the final visit. Baseline and postintervention plasma metabolomic profiles were measured using liquid chromatography-tandem mass spectrometry. To select metabolites associated with RNGR, we conducted the least absolute shrinkage and selection operator-penalized regressions. RESULTS: The final sample was composed of 82 study participants. Changes in three metabolites were significantly associated with regression to normoglycemia; N-acetyl-D-galactosamine (OR=0.54; 95% CI 0.32 to 0.82), putrescine (OR=0.90, 95% CI 0.81 to 0.98), and 7-methylguanine (OR=1.06; 95% CI 1.02 to 1.17), independent of HbA1c and weight loss. In addition, metabolomic perturbations due to LSI displayed enrichment of taurine and hypotaurine metabolism pathway (p=0.03) compatible with biomarkers of protein consumption, lower red meat and animal fats and higher seafood and vegetables. CONCLUSIONS: Evidence from this study suggests that specific metabolomic markers have an influence on glucose regulation in individuals with prediabetes after 24 weeks of LSI independently of other treatment effects such as weight loss.

Evaluation of a Web Platform to Record Lifestyle Habits in Subjects at Risk of Developing Type 2 Diabetes in a Middle-Income Population: Prospective Interventional Study.

BACKGROUND: Lifestyle is the focus of type 2 diabetes (T2D) prevention strategies. Prevention strategies using mobile health (mHealth)-based therapy have shown positive results for T2D prevention in high-income settings, but little is known about their effectiveness in low- and middle-income populations where the burden of T2D is substantial. "Vida Sana" is a web platform designed to record lifestyle habits and medication use within a lifestyle change program. OBJECTIVE: We sought to identify the barriers, feasibility, usability, and effectiveness of Vida Sana to record lifestyle habits in subjects at risk of developing T2D in a middle-income setting. METHODS: This was a 3-month prospective interventional study in Mexican individuals. A total of 77 subjects at risk of T2D (with prediabetes and BMI between 24 and 40 kg/m2) were selected. Feasibility was assessed by study retention. Usability was evaluated with the System Usability Scale (SUS). Effectiveness measures included changes in weight, body composition, BMI, glycated hemoglobin A1c (HbA1c), and fasting blood glucose from baseline to 3 months. Linear regression models were used to account for covariates. RESULTS: The feasibility of Vida Sana was 42%, with 33 subjects using the platform, and the usability was 48.7 (SD 14.24). Reported barriers to platform usage were; difficulty in accessing the platform from difficulty of use (12 subjects, 36%), lack of time to record their habits (11 subjects, 34%), lack of interest to record their habits (6 subjects, 18%), and lack of resources (4 subjects, 11%). The platform was effective for lowering glucose in fasting (-3.1 mg/dL vs -0.11 [SD 8.08] mg/dL; P=.038) and at 2 hours (-16.9 mg/dL vs 2.5 [SD 26.1] mg/dL; P=.045), body fat percentage (-1.3 [-2.2 to -0.7] vs -1.02 [-1.9 to -0.3]; P=.02), and waist circumference (-3.2 [SD 5.1] cm vs -1.7 [SD 5.0] cm; P=.02) independent of their age, sex, treatment, and education level. CONCLUSIONS: The use of the web platform was effective for improving glycemic and anthropometric parameters in a population at risk of developing diabetes. Improving accessibility and ease of navigation could improve the acceptance of digital health solutions in a middle-income population.

Gene-Environment Interaction Analysis Incorporating Sex, Cardiometabolic Diseases, and Multiple Deprivation Index Reveals Novel Genetic Associations With COVID-19 Severity.

Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors [obesity and type 2 diabetes (T2D), tested jointly], and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the placental growth factor (PGF) gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.

Spanish Version of the System Usability Scale for the Assessment of Electronic Tools: Development and Validation.

BACKGROUND: The System Usability Scale (SUS) is a common metric used to assess the usability of a system, and it was initially developed in English. The implementation of electronic systems for clinical counseling (eHealth and mobile health) is increasing worldwide. Therefore, tools are needed to evaluate these applications in the languages and regional contexts in which the electronic tools are developed. OBJECTIVE: This study aims to translate, culturally adapt, and validate the original English version of the SUS into a Spanish version. METHODS: The translation process included forward and backward translation. Forward translations were made by 2 native Spanish speakers who spoke English as their second language, and a backward translation was made by a native English speaker. The Spanish SUS questionnaire was validated by 10 experts in mobile app development. The face validity of the questionnaire was tested with 10 mobile phone users, and the reliability testing was conducted among 88 electronic application users. RESULTS: The content validity index of the new Spanish SUS was good, as indicated by a rating of 0.92 for the relevance of the items. The questionnaire was easy to understand, based on a face validity index of 0.94. The Cronbach α was .812 (95% CI 0.748-0.866; P<.001). CONCLUSIONS: The new Spanish SUS questionnaire is a valid and reliable tool to assess the usability of electronic tools among Spanish-speaking users.

METS-IR, a novel score to evaluate insulin sensitivity, is predictive of visceral adiposity and incident type 2 diabetes.

OBJECTIVE: We developed a novel non-insulin-based fasting score to evaluate insulin sensitivity validated against the euglycemic-hyperinsulinemic clamp (EHC). We also evaluated its correlation with ectopic fact accumulation and its capacity to predict incident type 2 diabetes mellitus (T2D). DESIGN AND METHODS: The discovery sample was composed by 125 subjects (57 without and 68 with T2D) that underwent an EHC. We defined METS-IR as Ln((2*G0)+TG0)*BMI)/(Ln(HDL-c)) (G0: fasting glucose, TG0: fasting triglycerides, BMI: body mass index, HDL-c: high-density lipoprotein cholesterol), and compared its diagnostic performance against the M-value adjusted by fat-free mass (MFFM) obtained by an EHC. METS-IR was validated in a sample with EHC data, a sample with modified frequently sampled intravenous glucose tolerance test (FSIVGTT) data and a large cohort against HOMA-IR. We evaluated the correlation of the score with intrahepatic and intrapancreatic fat measured using magnetic resonance spectroscopy. Subsequently, we evaluated its ability to predict incident T2D cases in a prospective validation cohort of 6144 subjects. RESULTS: METS-IR demonstrated the better correlation with the MFFM (ρ = -0.622, P < 0.001) and diagnostic performance to detect impaired insulin sensitivity compared to both EHC (AUC: 0.84, 95% CI: 0.78-0.90) and the SI index obtained from the FSIVGTT (AUC: 0.67, 95% CI: 0.53-0.81). METS-IR significantly correlated with intravisceral, intrahepatic and intrapancreatic fat and fasting insulin levels (P < 0.001). After a two-year follow-up, subjects with METS-IR in the highest quartile (>50.39) had the highest adjusted risk to develop T2D (HR: 3.91, 95% CI: 2.25-6.81). Furthermore, subjects with incident T2D had higher baseline METS-IR compared to healthy controls (50.2 ± 10.2 vs 44.7 ± 9.2, P < 0.001). CONCLUSION: METS-IR is a novel score to evaluate cardiometabolic risk in healthy and at-risk subjects and a promising tool for screening of insulin sensitivity.

Interaction Between Depression, Obesity, and Type 2 Diabetes: A Complex Picture.

Depression plays an important role in the pathogenesis and treatment of obesity and type 2 diabetes (T2D). However, its relevance is frequently unrecognized by clinicians and researchers. The purpose of this review is to present a critical analysis of the evidence linking depression and metabolic disorders and to highlight the practical implications of this complex relationship. Evidence obtained from epidemiological, basic, clinical and controlled studies demonstrate that the association goes beyond a random phenomenon. Epidemiological studies have rendered controversial results due to the lack of control of the confounding variables and the bidirectional relationship that exists between the outcomes and the conditions that modulate the association (i.e. socioeconomic status). Animal and human studies have been useful to define the anatomic substrates and physiologic processes that participate in the association, but, the evidence is preliminary in many areas (i.e gene × environmental interactions). Controlled studies have shown the strong impact that treatment of depression has on body weight and the large effect that has the correction of excess body weight on the depression-related symptoms. Practical implications of the depression-obesity duet include the training of the health providers to assess and treat these conditions in a concomitant manner, the need for translational medicine projects and the application the systems biology approach to fill the existing gaps of knowledge.