Insulin resistance (IR) is a risk factor for cardiovascular diseases and type 2 diabetes. Associations between DNA methylation (DNAm) and IR have been less studied in African ancestry (AA) populations than those of European ancestry (EA). We aimed to identify associations between whole blood DNAm and IR in up to 1,811 AA and 964 EA participants from the Atherosclerosis Risk in Communities (ARIC) study. We quantified IR using three surrogate measures: the homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride-glucose index (TyG), and the triglyceride glucose-body mass index (TyG-BMI). We used ancestry-stratified linear regression models to conduct epigenome-wide association studies of IR, adjusting for batch effects and relevant covariates. Among 484,436 tested CpG sites, 39 were significantly associated with IR, of which 31% (10 in AA and two in EA) were associated with TyG-BMI and not previously reported for IR or related traits. These include a positive association at cg18335991-SEMA7A in AA. SEMA7A inhibits adipogenesis of preadipocytes and lipogenesis of mature adipocytes. DNAm levels at cg18335991 have been reported to be negatively associated with SEMA7A expression in blood. After additionally adjusting for smoking and drinking status, 15 of the 39 significant CpG sites remained significant or suggestive. Our study identified novel IR-associated CpG sites, contributing to a broader understanding of the epigenetic mechanisms underlying IR in diverse populations.

Controversy remains as to which obesity measures better predict type 2 diabetes (T2D) risk in overweight or obese individuals. The objective of this study is to determine which commonly used obesity measures better reflect beta cell function and predict T2D risk in participants with overweight or obesity and to validate the findings using prospective cohort data.

Cross-sectional data from the Obesity Clinic of the Xiangya Hospital of the Central South University and prospective cohort from UK Biobank. BMI, waist circumference (WC), waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR) were measured. Primary outcomes included beta cell function indices in the cross-sectional study and the occurrence of diabetes obtained from UK Biobank data.

One thousand four hundred and ninety-seven participants with overweight or obesity (median age 29 years, 41% males) and 322,023 UK Biobank participants without diabetes at baseline (mean age 56.83 years, 50.4% males) were studied. WHpR had a stronger association with beta cell function and central body fat distribution than the other three obesity measures irrespective of glucometabolic states. WHpR associated positively with diabetes risk in participants using the hazard ratio scale (HR per SD increase of WHpR, 2.311, 95% CI 2.250-2.374).

WHpR is a superior index in reflecting central body obesity, estimating beta cell function, and predicting T2D risk in people with overweight or obesity compared to BMI, WC, and WHtR.

Insulin resistance (IR) is an early marker of cardiometabolic deterioration which may develop heterogeneously in key metabolic organs, including the liver (LIR) and skeletal muscle (MIR). This tissue-specific IR is characterized by distinct metabolic signatures, but the role of the gut microbiota in its etiology remains unclear. Here, we profiled the gut microbiota, its metabolites and the plasma metabolome in individuals with either a LIR or MIR phenotype (n = 233). We observed distinct microbial community structures LIR and MIR, and higher short-chain fatty acid (SCFA) producing bacteria, fecal SCFAs and branched-chain fatty acids and a higher postprandial plasma glucagon-like-peptide-1 response in LIR. In addition, we found variations in metabolome profiles and phenotype-specific associations between microbial taxa and functional metabolite groups. Overall, our study highlights association between gut microbiota and its metabolites composition with IR heterogeneity that can be targeted in precision-based strategies to improve cardiometabolic health. Clinicaltrials.gov registration: NCT03708419.

Burnout is caused by long term psychosocial stress and has, besides the fatigue and mental health burden, been associated with increased risk of adverse physical health, such as for example type 2 diabetes. This study aims to investigate the glucose and insulin levels in individuals with stress related burnout, by assessing these metabolic markers in response to a standard oral glucose tolerance test (OGTT). 38 cases with burnout (13 men and 25 women) and 35 healthy controls (13 men and 22 women) in the age 24-55 were included in the study. The burnout group overall did not differ from healthy controls in glucose or insulin levels during the OGTT. However, the burnout cases who reported more severe burnout symptoms exhibited significantly higher levels of both glucose and insulin levels during the OGTT compared to burnout cases reporting lower severity of symptoms. Furthermore, the group of burnout cases who reported symptoms of depression exhibited higher insulin levels during OGTT compared to the burnout cases without depressive symptoms. The observed higher levels in the burnout cases with most severe symptoms indicate an increased diabetic risk in these patients and it may be of importance to follow glucose and insulin levels in individuals with more severe symptoms of burnout i.e. to perform an OGTT.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biologically inert cleavage product of a peptide formed in response to myocardial wall stress and can be used to screen for subclinical cardiovascular disease in adults. However, associations between NT-proBNP and demographic, lifestyle, and cardiometabolic factors in youth are poorly characterized.

We conducted a cross-sectional analysis of youth ages <20 years old in the nationally representative National Health and Nutrition Examination Survey 1999 to 2004 and measured NT-proBNP in stored serum specimens. We calculated age-and-sex-specific distributions of NT-proBNP and evaluated the associations between NT-proBNP and cardiometabolic risk factors. We found that NT-proBNP was inversely associated with BMI and most cardiometabolic risk factors in the general US population of children and adolescents.

The differences in NT-proBNP by age, sex, and race or ethnicity in younger persons mirror those seen in adults. These results suggest that as in adults, levels of NT-proBNP should be interpreted in children and adolescents based on these demographic and clinical factors.

Pedalium murex commonly known as (large caltrops, bara gokhru) is a medicinal plant with potential therapeutic benefits. Hyperglycemia, a hallmark of diabetes, affects millions worldwide. Research on its leaf ethanol extract demonstrates potential for managing hyperglycemia in vitro and in vivo. Phytochemical analysis revealed secondary metabolites, including tannins, alkaloids, saponins, flavonoids, and polyphenols, with high levels of total flavonoids (287.5 ± 17.3 μg QEq./mg) and polyphenols (327.5 ± 17.2 μg QEq./mg). Scanning electron microscopy (SEM) confirmed the granular nature of synthesized silver nanoparticles (AgNPs) with a size range of 20-40 nm, while transmission electron microscopy (TEM) showed spherical AgNPs (20-50 nm). Energy-dispersive X-ray spectroscopy (EDX) identified silver (66.75 %), carbon (22.02 %), and oxygen (11.23 %) as the primary components. The extract effectively neutralized DPPH-free radicals (39.57 ± 4.77 %), while the AgNPs showed greater efficacy (68.23 ± 5.37 %). Superoxide radical (O2•-) reduction was significant for both the extract (59.33 ± 0.17 %) and AgNPs (38.73 ± 0.21 %), highlighting potent antioxidant properties. Hydroxyl radical (●OH) scavenging was higher for the extract (63.72 ± 0.17 %) than for AgNPs alone (36.71 ± 0.29 %). The AgNPs showed significant antimicrobial activity, with inhibition zones of 16.27 ± 0.18 mm against Staphylococcus aureus and 11.23 ± 0.17 mm against Candida albicans at 80 μg/mL. In toxicity studies, P. murex-AgNPs were well tolerated in mice. In hyperlipidemic mice, treatment with P. murex-AgNPs (350 mg/kg and 700 mg/kg) significantly reduced cholesterol, triglycerides, and LDL-c levels without affecting HDL-c. These findings provide valuable insights into the therapeutic potential of P. murex-AgNPs for the treatment of hyperlipidemia and diabetes.

We aimed to determine the optimal cut-off points for metabolic health indicators, including insulin resistance (IR), glucose, insulin, BMI, and waist circumference, in middle-aged nondiabetic people to predict future type 2 diabetes mellitus (T2DM).

The data came from 12,543 Atherosclerosis Risk Communities Study participants, including 5758 men and 6785 women. They did not have diabetes at baseline and were followed for incident T2DM within 3, 6, and 9 years. IR was estimated using four IR metrics: HOMA-IR, METS-IR, TyG index, and TG/HDL-C. We used the Youden index to determine the optimal cut-off values. In females, the cut-off points for glucose to predict incident T2DM ranged from 96 to 102 mg/dL, with Area Under the Curve (AUC) values of 0.64-0.85. In males, the cut-off points ranged from 102 to 106 mg/dL, with AUC values of 0.60-0.83. For HOMA-IR, the cut-off points in females varied from 2.4 to 3.2, with AUC values of 0.69-0.78, while they ranged from 2.8 to 3.2 in males. The optimal cut-off values for METS-IR, TyG index, TG/HDL-C, insulin, BMI, and waist circumference were 40-43, 8.6-8.9, 2.0-3.2, 9-15 μU/mL, 28-29 kg/m2, and 91-97 cm in women, and 44-45, 8.8-8.9, 2.9-3.2, 11-12 μU/mL, 27-29 kg/m2, and 99-103 cm in men.

The optimal threshold for each predictor's prediction of incident T2DM varied by sex. The eight predictors' order of predictive performance were fasting glucose, HOMA-IR, METS-IR, insulin, BMI, waist circumference, TyG index, and TG/HDL-C.

Empirical evidence suggests that the origins of obesity and metabolic dysfunction can be traced to stress-related exposures in prenatal life. The aim of the present study was to examine the prospective association of a composite, multi-system measure of maternal biological stress in pregnancy -- allostatic load (AL) -- with offspring adiposity and insulin resistance across infancy and early childhood.

In N = 55 mother-child dyads, maternal allostatic load was operationalized as a latent variable representing the following components: pre-pregnancy BMI, cortisol, interleukin-6, C-reactive protein, homeostasis model assessment of insulin resistance (HOMA-IR), free fatty acids, and systolic/diastolic blood pressure. Offspring percent total (%FM) and abdominal (%AbFM) fat were quantified with dual-energy X-ray absorptiometry at birth (newborn), 6-mo, and ∼5 yrs age, and HOMA-IR was quantified at ∼5 yrs age. Generalized estimating equation modeling was used to estimate effects of maternal AL on serial (repeated) measures of child adiposity, and linear regression was used to estimate effects on child HOMA-IR. A priori model covariates included maternal race and ethnicity, socioeconomic status, infant feeding practices, child age, and sex.

Maternal AL was positively associated with child %FM and %AbFM before as well as after adjustment for key maternal and offspring covariates (%FM: adjusted β=0.38, p = 0.0074; %AbFM: adjusted β=0.37, p = 0.0013). Maternal AL also was positively associated with child insulin resistance (adjusted β= 0.011, p = 0.0324).

Our findings suggest that exposure to a higher biological stress milieu during prenatal development predisposes towards elevated early life adiposity and insulin resistance in early childhood, a proximate cause of type 2 diabetes and cardiometabolic disease. Collectively, these results provide evidence that a multi-systems approach to quantify early life exposures is useful in prospectively predicting variation in childhood adiposity and metabolic function.

The advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) axis is a pro-inflammatory pathway promoting endothelial dysfunction and vascular remodelling. The soluble RAGE form (sRAGE), by blocking circulating AGE, protects against AGE-induced detrimental effects. We investigated the role of sRAGE as a marker of high blood pressure and hypertension risk in children.

sRAGE was quantified in 284 children/adolescents (mean age (SD) 11.1 (2.5); 52.1 % male) referred for high-normal blood pressure (systolic and/or diastolic values ≥ 90th, but both <95th percentile) or hypertension (systolic and/or diastolic blood pressure ≥95th percentile) and/or other cardiovascular risk factors (excess weight, dyslipidaemia and insulin resistance). In 22.2 % of the sample, systolic and/or diastolic blood pressure values were above the 90th percentile. The prevalence of excess weight (overweight/obesity), central obesity (waist-to-height-ratio >50%), and insulin resistance (HOMA-index ≥90th percentile) was high (82.7 %, 70.8 %, and 70.5 %, respectively). Few children had altered LDL cholesterol, triglyceride, and HDL cholesterol values (15.7 %, 15.4 %, and 13.6 %, respectively). The lowest sRAGE tertile was associated with the highest risk of having hypertension (p = 0.028), obesity (p < 0.001), central obesity (p = 0.007), and insulin resistance (p < 0.001). sRAGE levels were inversely associated with systolic blood pressure (p < 0.01) and BMI (p = 0.022) z-scores and waist-to-height-ratio (p = 0.001). sRAGE values were inversely associated with the presence of hypertension (p = 0.036) and obesity (p = 0.038).

The independent relationship between sRAGE, systolic blood pressure, and hypertension in children suggests that the AGE-RAGE axis may be altered early in life, and that sRAGE could be a compelling marker for pediatric cardiovascular risk stratification.

Diabetes often leads to neurodegenerative complications that complicate treatment. Exploring dietary components with neuroprotective properties could offer new therapeutic avenues. This study aimed to evaluate the neuroprotective potential of β-sitosterol against diabetes-associated neurodegenerative complications using a combined in silico and in vivo approach. β-Sitosterol exhibited significant neuroprotective effects in a diabetic neuropathy model. Compared to sitagliptin, β-sitosterol demonstrated stronger binding affinities to DPP4, acetylcholinesterase, and butyrylcholinesterase, along with more stable molecular dynamics profiles. In vivo, β-sitosterol treatment markedly improved glucose tolerance, insulin sensitivity, lipid profiles, and antioxidant capacity. Histological analysis revealed reduced neurodegenerative changes and enhanced neuronal integrity in the cortex and hippocampus. These findings suggest β-sitosterol as a promising therapeutic agent for managing diabetic neurodegeneration, warranting further research and potential clinical application.

What is the role of insulin resistance (IR), increased insulin secretion, and impaired insulin clearance, either alone or in combination, on metabolic features and androgen levels in women with PCOS?

IR, reduced insulin clearance and increased insulin secretion independently contribute to predicting hyperandrogenemia, whereas metabolic abnormalities may differ according to the mechanisms underlying hyperinsulinemia.

Hyperinsulinemia is a common finding in women with PCOS, and it is closely associated with the metabolic and endocrine alterations of these women. It is considered a compensatory mechanism to IR, and results from two separate mechanisms: increased secretion and/or reduced insulin clearance. The contribution of these two distinct adaptive processes may differ, and the implications of these differences are poorly understood.

Cross-sectional study of 355 women with PCOS recruited in the Verona 3P study from 2010 to 2021.

Women with PCOS, diagnosed by the Rotterdam criteria, underwent a hyperinsulinemic euglycemic clamp, to measure insulin sensitivity (M-clamp) and to calculate insulin clearance (MCRI). Insulin secretion was estimated by the HOMA β-index. Serum androgens were measured by LC/MS-MS and equilibrium dialysis.

Hyperinsulinemia was found in 65.4% women with PCOS. Insulin sensitivity was impaired in 69.6% subjects, MCRI was reduced in 57.2%, and HOMA β-index was increased in 60.0% women. Overall, 311 subjects (87.6%) had at least one of these insulin metabolism alterations. The combination of the three alterations was found in 127 (35.8%) women, whereas 98 (27.6%) had two alterations: 30 had IR and reduced MCRI, 47 had IR and increased HOMA β-index, 21 had reduced MCRI and increased HOMA β-index. Eighty-six (24.2%) women had only one alteration: 43 had IR, 25 had reduced MCRI, 18 had increased HOMA β-index; finally, 44 (12.4%) subjects showed no alterations. Anthropometric parameters, and fasting glucose and insulin, were progressively lower in women with 3, 2, 1, or 0 insulin metabolism alterations. Similar trends were observed for serum triglycerides, blood pressure, and androgens, whereas progressively increasing values were observed for high-density lipoprotein-cholesterol and sex hormone-binding globulin.In logistic regression analysis, after adjusting for age and fat mass, IR and increased insulin secretion were independent predictors of altered glucose tolerance, whereas IR and low MCRI were independent predictors of metabolic syndrome; in multivariable analysis, M-clamp, MCRI, and HOMA β-index were all independent predictors of serum free testosterone.

Insulin secretion was estimated by a validated surrogate index, whose performance may be suboptimal. This study was carried out in Caucasian women. Therefore, our findings may not be generalizable to other ethnic groups. Finally, the cross-sectional design of the study limits the causal inference of the results.

The presence of IR, reduced MCRI, and increased insulin secretion, especially when combined, worsens metabolic outcomes and androgen levels in women with PCOS. However, these factors may play a different role in determining altered glucose metabolism or metabolic syndrome, whereas all of them independently contribute to hyperandrogenemia.

Academic grants to P. Moghetti from the University of Verona (FUR 2010-2022). All authors declare no conflict of interest.

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The pivotal role of gut fungi (i.e., mycobiome) in host health is increasingly recognized. Diet is a critical determinant factor for both gut fungi and host metabolic health. This study aimed to investigate the associations of plasma n-3 polyunsaturated fatty acids (PUFAs), an important dietary lipid component, with gut mycobiome and explore the relationship of n-3 PUFA-related gut fungi with type 2 diabetes (T2D) and glycemic phenotypes. Here, we identified four fungal genera that were inversely associated with plasma total n-3 PUFA in the discovery cohort. Among these, Debaryomyces, Kodamaea, and Wickerhamomyces were consistently associated with total n-3 PUFA in the metaanalysis of 4 human cohorts (FDR-meta<0.1). We also found that Wickerhamomyces was positively associated with host fasting blood glucose and glycated hemoglobin (FDR<0.05). Moreover, we observed an interaction between n-3 PUFA and Kodamaea on T2D (P-interaction=0.02), which was confirmed in the mice study. In human and mice studies, the inverse associations between n-3 PUFA and glycemic phenotypes were only observed in the Kodamaea-free population. Additionally, the enrichment of specific primary bile acids, namely cholic acid and its conjugated forms, was associated with Kodamaea colonization. Our results indicate that n-3 PUFA is associated with specific gut fungal genera, which may, in turn, affect host glucose homeostasis.

The current study investigated the potential molecular mechanisms of telmisartan and vitamin D3 against the progression of skeletal muscle injury in a metabolic syndrome (MetS) rat model and the capacity of vitamin D3 to potentiate telmisartan effects.

This 12-week study comprised a 6-week induction phase to establish MetS, followed by a 6-week treatment phase. MetS was induced by supplementing drinking water with 10% fructose and providing a diet enriched with 24% fat and 3% NaCl. Following the induction phase and along with fructose/fat/NaCl feeding, MetS rats exhibiting weight gain, dysglycemia, atherogenic dyslipidemia, hyperuricemia, hypertension, and soleus muscle dysfunction were treated orally with telmisartan (5 mg/kg), vitamin D3 (10 μg/kg) or both daily for an additional 6 weeks before sacrifice.

MetS rats exhibited increased soleus muscle oxidative stress, inflammation, and insulin resistance, accompanied by functional decline and structural damages (interstitial edema, leukocytic infiltration, degenerative myopathy, and fibrosis). Telmisartan and vitamin D3 significantly mitigated these detrimental effects. While telmisartan demonstrated broad protective effects, it failed to combat the MetS-induced muscular fibrosis. Conversely, vitamin D3 played a prominent anti-fibrotic role, which significantly contributed to the observed functional and structural recovery of MetS-induced skeletal muscle damage.

Our data provide a molecular basis for treating MetS-induced skeletal muscle injury through the co-administration of vitamin D3 and telmisartan, a unique angiotensin II type 1 receptor (AT1 receptor) blocker and partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist. A new insight has been introduced into PPAR-γ/AT1 receptor/glucose transporter type 4 (GLUT4) axis.

The purpose of this study was to observe the relationship between youth obesity and metabolic syndrome (MetS) among middle-aged and elderly adults in the United States.

A retrospective study was conducted on United States adults aged ≥50 years. Data were extracted from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 cycles. The levels of height and weight at aged 25 years were obtained. Body mass index (BMI) at aged 25 years (BMI25) was calculated. Healthy weight, overweight and obesity at aged 25 years (healthy weight25, overweight25 and obesity25) were defined as BMI25 18.5 to <25 kg/m2, 25 to <30 kg/m2 and 30 kg/m2 or greater. MetS was defined According to the National Cholesterol Education Program's Adult Treatment Panel III report (ATP III).

The prevalences of MetS were 48.7 %, 63.5 %, and 71.4 % in adults with healthy weight25, overweight25, and obesity25 group. After control for confounding factors, the prevalences of MetS in overweight25 group and obesity25 group were 2.147 (95%CI: 1.892-2.436, P < 0.001) times and 2.878 (95%CI: 2.304-3.597, P < 0.001) times than that in healthy weight25 group. After further adjusted for BMI at the time of survey, the prevalences of MetS in adults with overweight25 group and obesity25 group were 1.193 (95%CI:1.035-1.375，P = 0.015) times and 1.222 (95%CI:0.959-1.557，P = 0.105) times than adults with healthy weight25 group.

The present study demonstrates that youth obesity was closely associated with an increased risk of MetS among middle-aged and elderly adults.

This study examined associations of cigarette smoking with appetite perceptions, appetite-related hormones, food preferences and eating traits. In a cross-sectional matched-pair cohort design, 25 participants who smoke cigarettes and 25 who do not were matched 1:1 by age, sex, ethnicity, and BMI. Across two visits, participants' food preferences (Leeds Food Preference Questionnaire), cravings (Control of Eating Questionnaire), and eating traits (Three-Factor Eating Questionnaire) were assessed. Fasting and postprandial appetite perceptions (visual analogue scales) were also assessed during a 4-h mixed-meal tolerance test (MM-TT), while fasting leptin and fasting and postprandial acylated ghrelin and total peptide-YY (PYY) were measured for 2 h postprandially. Group differences in study outcomes were analysed using generalised linear models. After adjustment (age and BMI), explicit liking and wanting for high-fat foods and cravings for savoury foods were higher in participants who smoke versus those who do not (P≤0.065; d≥0.52). Cognitive restraint was lower, while disinhibition was higher in participants who smoke compared to those who do not (P≤0.014; d≥0.69). Smoking was also associated with lower fasting acylated ghrelin and lower postprandial total PYY (P≤0.041; d≥0.58), whereas fasting leptin was similar between groups (P=0.821; d=0.06). Additionally, participants who smoke had higher fasting perceived fullness (P=0.021; d=0.65), while no other fasting or postprandial differences were identified for other appetite perceptions (hunger, prospective food consumption, satisfaction; P≥0.373; d≤0.25). In conclusion, cigarette smoking is associated with altered food preferences and less favourable eating traits, while more subtle differences may exist in appetite perceptions and appetite-related hormones.

Background: Hypovitaminosis D has become a warning sign for the development of gestational diabetes mellitus (GDM) with a lack of evidence related to pregnant mothers in Sri Lanka. Aim: This study was designed to compare serum 25(OH)D levels and selected biochemical parameters among a group of pregnant mothers in Sri Lanka. Methods: A total of 172 pregnant mothers (GDM-86 and non-GDM-86) were recruited to this case-control study from prenatal clinics at Colombo South Teaching Hospital, Sri Lanka. Serum 25(OH)D, fasting plasma glucose (FPG) and fasting serum insulin (FSI) were measured using overnight maternal fasting venous blood samples. Serum 25(OH)D level < 20 ng/mL was considered as "hypovitaminosis D". SPSS version 23.0 was used in data analysis. Results: During pregnancy, 44.2% (n = 38) of GDM and 38.4% (n = 33) of non-GDM mothers had received vitamin D supplements. Mean serum 25(OH)D concentrations between GDM and non-GDM mothers were 15.5 ± 4.5 ng/mL and 19.4 ± 5.9 ng/mL, respectively (P < 0.05). Among the participants, 84.9% of GDM and 60.5% of non-GDM mothers had serum 25(OH)D level < 20 ng/mL. FPG and HOMA-IR of GDM mothers were negatively correlated with serum 25(OH)D level (P < 0.05). Hypovitaminosis D was significantly associated with developing GDM after adjusting for family history of type 2 diabetes mellitus, maternal employment status, history of GDM, FPG, GWG at 24-28 weeks and HOMA-IR (aOR = 2.49; 95% CI: 1.083-5.762; P = 0.032). Conclusion: Future randomized controlled trials are recommended to determine whether adequate vitamin D supplementation can effectively reduce the incidence of developing GDM.

Metabolic syndrome (MetS) is a multifactorial condition linked to increased risk of cardiovascular disease and type 2 diabetes. The Single-Point Insulin Sensitivity Estimator (SPISE), a non-invasive index calculated via 600 × HDL-C^0.185 / (TG^0.2 × BMI^1.338), offers a practical alternative. This systematic review and meta-analysis aim to evaluate the accuracy of SPISE as an indicator for MetS.

We conducted a systematic review and meta-analysis following PRISMA guidelines. We searched databases such as MEDLINE, Scopus, Web of Science, and Embase, focusing on studies evaluating SPISE's screening accuracy for MetS. Eligible studies were observational, reporting mean SPISE values and its predictive performance. Meta-analyses were performed using Hedges' g standardized mean differences (SMD) and pooled area under the curve (AUC) estimates.

Seven studies comprising 12,919 participants were included, with an age range of 9.2 ± 2.1 to 52.4 ± 11.0. Individuals with MetS had significantly lower SPISE scores than controls (SMD = -0.94, 95% CI: -1.25 to -0.63). The pooled AUC for SPISE as a predictor of MetS was 0.86 (95% CI: 0.83 to 0.90), surpassing other insulin resistance indices like HOMA-IR and the triglyceride/HDL-C ratio. Meta-regression showed that systolic and diastolic blood pressure were potential sources of heterogeneity and age, gender, BMI, waist circumference, fasting blood glucose, triglyceride, and HDL did not contribute to heterogeneity.

SPISE is a highly accurate and non-invasive tool for predicting MetS, potentially outperforming traditional indices like HOMA-IR. Its ease of use and precision make it a valuable clinical screening tool, especially in diverse populations.

Background/Objectives: Obesity during pregnancy is strongly related to increased insulin resistance, and subsequent development of metabolic syndrome-like disorders, such as glucose intolerance, pre-eclampsia, as well as preterm birth, and cesarean delivery. Nutrition can influence the evolution of glycemic response and may help improve adverse pregnancy outcomes and long-term complications. The main objective of the Nutritional Intervention during Gestation and Offspring Health (NIGOHealth) randomized clinical trial (ClinicalTrials.gov Identifier: NCT02285764) was to investigate the potential effects of a low glycemic index/slow digesting (LGI/SD) carbohydrate product on maternal glycemia (glucose AUC at 27+0-28+6 weeks; maternal fasting blood glucose (MFBG) at 34+0-36+0 weeks), and neonatal body composition. Methods: Obese pregnant women were randomized: 230 in the intervention group (IG), who consumed two servings of an LGI/SD study product daily from 15 weeks of pregnancy until delivery, and 102 participants in the Standard of Care (SOC) group. Results: When analyzing baseline characteristics, significant differences were found in glucose metabolic parameters with higher values for IG than for the SOC group, compromising the group's comparability. Despite this, a statistical analysis was conducted (intention-to-treat analysis/evaluable cohort): no differences were detected regarding maternal blood glucose AUC at 27+0-28+6 weeks, nor for MFBG at 34+0-36+0 weeks. Nonetheless, HbA1c (%) at 34+0-36+0 weeks was significantly lower in the IG vs. the SOC group (5.26 ± 0.03, 5.31 ± 0.04, p = 0.007) after adjusting for baseline conditions. Conclusion: This result might suggest a potential effect of the intervention on Evaluable participants. However, it should be taken with caution, due to the limitations of the study. More RCTs should be carried out to explore the effects of LGI/SD products on glycemic response in obese pregnant women.

Diabetes mellitus (DM) is a chronic metabolic disorder that can lead to serious complications, including testicular dysfunction. This dysfunction is considered a significant cause of male infertility. Quercetin (Que), a naturally existing flavonoid with versatile biological functions, has limited water solubility and low bioavailability. The current study was designed to develop a bioavailable formulation of Que. via encapsulating it in PEGylated liposomes (Que-PEG-Lip) and determine whether this formulation is effective in the treatment of alloxan-induced testicular injury via targeting Kisspeptin/Neurokinin B/Dynorphin/steroidogenesis signaling pathway. Thirty-two male Sprague Dawley rats were randomly divided into four groups: Control, alloxan-induced diabetes with testicular dysfunction (ALX), ALX + metformin (MET) and ALX + Que-PEG-Lip. The results showed that treatment of ALX group with Que-PEG-Lip significantly improved the alteration of glycemic index, serum reproductive hormones, testicular antioxidant status, testicular Kiss-1, androgen receptor (AR), and proliferation marker protein (ki67) immunoexpression in compared to ALX group. Moreover, the treatment of ALX group with Que-PEG-Lip regulated the Kisspeptin/Neurokinin B/Dynorphin/steroidogenesis pathway gene expression. Interestingly, the outcomes of the molecular docking analysis revealed a strong agonistic effect of Que. on the kisspeptin, neurokinin, and dynorphin receptors. In conclusion, Que-PEG-Lip mitigated the testicular dysfunction in alloxan-induced diabetic rats via regulation of hypothalamic-pituitary-gonadal axis signaling pathway and alleviation the testicular oxidative stress.

Cardiometabolic traits are heritable, and some display parent-of-origin effects, which indicates preferential inheritance from one parent or parental bias. Most studies of these phenomena have focused on adult populations. We aimed to investigate the heritability and parent-of-origin effects on cardiometabolic traits in a birth cohort with serial measurements to determine whether these patterns emerged early in life.

The Pune Maternal Nutrition Study comprises a birth cohort in which offspring and parents were studied from birth and followed up for 24 years. We investigated parent-of-origin effects on cardiometabolic traits cross-sectionally at available timepoints using linear regression, and longitudinally across the life course using mixed-effect regression. Maternal and paternal effects on offspring phenotype were modelled after adjusting for age, sex and BMI. Parent-of-origin effects were calculated based on the difference between maternal and paternal effects. We also investigated these effects in another birth cohort, that of the Pune Children's Study. Genetic parent-of-origin effects were assessed using generalised estimating equations after taking the parental origin of the alleles into account.

Birthweight showed a maternal parent-of-origin effect. At 24 years, maternal bias was seen for some obesity-related traits for daughters, while paternal bias was seen for WHR in sons. A shift from paternal bias at 6 years to maternal bias at 24 years for the skinfold thickness was observed in daughters. Fasting glucose and lipids showed maternal bias at 6, 12 and 24 years. For fasting insulin and HOMA2-S, a negative maternal effect at 6 years transitioned to a positive one at 12 years. For HOMA2-B, a paternal effect at 6 years transitioned to a maternal one at 12 years, and this remained so at 24 years. Some of these findings were also observed in the cohort from the Pune Children's Study. Longitudinal modelling revealed stronger paternal effects over time for fasting insulin and HOMA indices but maternal effects for glucose and lipids, reflecting their cumulative effect over time. Genetic variants at the KCNQ1 locus showed a maternal parent-of-origin effect on birthweight, on HOMA2-B at 12 years, and on lipids at 6 and 12 years.

Our study provides proof of concept of the existence of parent-of-origin effects on cardiometabolic traits from birth, through childhood and puberty, until adult age. Our results indicate a predominantly maternal influence on intrauterine, pubertal and reproductive-age metabolism in the offspring. While the longitudinal analysis indicated a maternal bias for the macronutrients (glucose and lipids), and a paternal bias for glucose-insulin metabolism, the cross-sectional analysis revealed a transition between parental influence across physiological stages. This dynamic relationship may have its origins in the life-history theory of evolution, and could inform strategies for primordial prevention aimed at curbing the rising burden of cardiometabolic disease. Further studies are needed to determine the mechanisms underlying such effects.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly correlated with the severity of obesity, and the extent of liver fibrosis is associated with a higher risk of liver-related complications, cardiovascular events, and overall mortality. Leptin circulating levels are directly correlated with the amount of adipose tissue. Aims: In the present study, we investigated the association between circulating leptin levels and liver steatosis and fibrosis. Methods: Eighty-six patients (41.7 ± 12.6 yrs, 35 men, 41%), naïve to medications, who attended the Nutrition Center for the Research and Care of Obesity and Metabolic Diseases at the National Institute of Gastroenterology "Saverio de Bellis" for weight management, were cross-sectionally evaluated. Demographic, anthropometric, clinical, and laboratory data were collected and analyzed. All patients underwent liver ultrasonographic assessment by FibroScan to diagnose liver steatosis (controlled attenuation parameter, CAP > 275 dBm) and fibrosis (liver stiffness measurement, LSM > 8.2 kPa). Results: Sixty-three individuals (73.3%) had liver steatosis, and 17 (19.8%) had liver fibrosis. The mean leptin levels were 22.3 ± 14.1 ng/mL, while the BMI and waist circumference were 36.7 ± 7.2 kg/m2 and 114.5 ± 16.4 cm, respectively. CAP values exhibited no correlation with leptin (r = 0.09, p = 0.436), while a significant connection was seen between leptin and LSM (β = 0.065; p = 0.038). Specifically, for each unit increase in leptin, LSM values were varied by +0.065 units (p = 0.038). This association was independent of gender, age, insulin resistance, adiponectin, RBP4, and visfatin. This is the first study showing these results by using FibroScan assessment in patients naïve to medications. Conclusions: Circulating leptin concentrations are independently correlated with hepatic fibrosis in individuals with a BMI ≥ 25 kg/m2. These findings indicate a function for leptin in promoting liver fibrosis; however, longitudinal studies are required to elucidate the causal nature of this interaction.

Reliable biomarkers capturing immunometabolic processes in insulin resistance (IR) remain limited. IgG N-glycosylation modulates immune responses and reflects metabolic disorders, yet its role in IR remains unclear. This study investigated its potential for early detection, risk stratification, and targeted prevention within the framework of predictive, preventive, and personalised medicine (PPPM/3PM).

A total of 313 participants were categorized into three groups based on the homeostatic model assessment for insulin resistance (HOMA-IR): insulin-sensitive (HOMA-IR < 2.69 without diabetes, n = 75), mild IR (HOMA-IR ≥ 2.69 without diabetes, n = 155), and severe IR (HOMA-IR ≥ 2.69 with type 2 diabetes, n = 83). Canonical correlation analysis was conducted to explore the overall relationship between IgG N-glycosylation and IR-related inflammation, indicated by tumour necrosis factor-α, interleukin- 6, C-reactive protein, and adiponectin. Mediation analysis was performed to evaluate the effect of IgG N-glycans on IR. Ordinal logistic regression was used to assess the association between IgG N-glycans and IR severity, with discriminative power evaluated using receiver operating characteristic curves.

Pro-inflammatory IgG N-glycoforms, characterized by reduced sialylation and galactosylation, along with increased bisecting N-acetylglucosamine, were observed as IR severity increased. IgG N-glycosylation significantly correlated with inflammatory markers in the insulin-sensitive (r = 0.599, p < 0.05), mild (r = 0.461, p < 0.05), and severe (r = 0.666, p < 0.01) IR groups. IgG N-glycosylation significantly influenced IR (β = 0.406) partially via modulation of inflammation. Increased glycoforms FA2[6]G1 (OR: 0.86, 95% CI: 0.78-0.96) and A2G2S2 (OR: 0.88, 95% CI: 0.82-0.94) were associated with a lower IR risk, with respective area under the curves (AUCs) of 0.752, 0.683, and 0.764 for the insulin sensitive, mild, and severe IR groups.

IgG N-glycosylation contributes to IR by modulating inflammatory responses. Glycoforms FA2[6]G1 and A2G2S2 emerge as protective biomarkers, offering potential for predicting and preventing IR through primary prevention strategies within the PPPM framework.

The online version contains supplementary material available at 10.1007/s13167-025-00410-x.

C-reactive protein (CRP) appears to improve the ability to detect cardiometabolic risk in young and middle-aged adults with mild-to-moderate obstructive sleep apnea (mmOSA). The aim of this study is to assess utility of CRP in identifying the risk of hypertension and insulin resistance across a wide age range including older patients with mmOSA. Adults (n = 216) of a wide age range (28-90 years old, mean age 52.64 ± 12.74) with mmOSA (5 ≤ AHI < 30) completed in-lab polysomnography or home sleep apnea testing, physical examination including blood pressure (BP) measures, structured medical history questionnaire, and blood draw for CRP and fasting glucose and insulin levels. In adults < 60 years, lnCRP but not the apnea-hypopnea index (AHI) was associated with greater odds for hypertension (odds ratio [OR] = 2.40, 95% CI = 1.20-4.84, p = 0.01; OR = 1.00, 95% CI = 0.92-1.08, p = 0.92, respectively) and with higher average systolic and diastolic BP. Also, in adults < 60 years lnCRP but not AHI, was associated with higher lnHOMA values. In contrast, in adults > 60 years neither lnCRP nor AHI were associated with greater odds for hypertension, average systolic and diastolic BP, and lnHOMA. Receiver-operating characteristics curves revealed that adding CRP to standard clinical factors (age, sex, and BMI) yielded moderately good risk models for hypertension in patients < 60 years (AUC = 0.721). In conclusion, CRP improves the ability to detect cardiometabolic risk in young and middle-aged, but not older adults with mmOSA, suggesting that inflammation may be a primary pathogenetic mechanism in younger patients with OSA.

Prediabetes (preD) carries increased risk of cardiovascular (CV) events than normal-glucose-tolerance (NGT). Insulin resistance, a hallmark of preD, is closely linked to CV-risk, making its assessment crucial. Triglycerides-to-high-density-lipoprotein-cholesterol-ratio (TG/HDL) and triglycerides-and-glucose-product (TyG) have emerged as surrogate of insulin resistance. We aimed to evaluate the association of these indexes with CV-risk assessed through arterial stiffness in preD.

377 individuals without diagnosis of diabetes underwent: (1) complete biochemistry and oral-glucose-tolerance-test; (2) CV-risk assessment through arterial stiffness (pulsed-wave-velocity - PWV - and augmentation-index - AugI) and intima-media-thickness (IMT). Participants were split according to current guidelines: NGT (n = 100), preD (n = 216), and newly-diagnosed-type-2-diabetes (ND-T2D) (n = 61).

TG/HDL and TyG were higher in preD than NGT, with no difference between preD and ND-T2D regarding TG/HDL. PreD showed higher PWV, AugI, and IMT than NGT. In preD group, after adjusting for major confounders, PWV was correlated with TG/HDL (β = 0.16; P = 0.03), but not with TyG, and there was a trend of association with HOMA-IR (β = 0.19, P = 0.07). In logistic regression, being in the higher tertile of TG/HDL was associated with higher PWV (odds-ratio 2.51, 95 %CI 1.01-6.29, P = 0.048).

In preD, TG/HDL was independently associated with PWV, suggesting its possible role as a simple, cost-effective tool for assessing CV risk.

Numerous physiological responses to exercise are observed in humans, yet the effects of long-term exercise and varying intensities on the diversity and composition of human fecal microbiota remain unclear. We investigated the effect of a 24-week supervised concurrent exercise intervention, at moderate and vigorous intensities, on fecal microbiota diversity and composition in young adults.

This ancillary study was based on data from the ACTIBATE randomized controlled trial (ClinicalTrials.gov ID: NCT02365129), and included adults (aged 18-25 years, 70 % female) that were randomized to (i) a control group (CON: no exercise, n = 20), (ii) a moderate-intensity exercise group (MOD-EX, n = 21), and (iii) a vigorous-intensity exercise group (VIG-EX, n = 20). Fecal samples were collected before and after the 24-week exercise intervention, and the diversity and composition of the fecal microbiota were analyzed by 16S rRNA sequencing. Inferential functional profiling of the fecal microbiota was performed and correlations between microbial changes and cardiometabolic outcomes were assessed.

Exercise did not modify beta or alpha diversities regardless of the intensity (all P ≥ 0.062). The relative abundance of the Erysipelotrichaceae family (Bacillota phylum) (-0.3 ± 1.2 %; P = 0.031) was however reduced in the VIG-EX group. Coprococcus was the only genus showed a significant difference between MOD-EX and VIG-EX after the intervention, with its relative abundance increasing in MOD-EX (+0.4 ± 0.6 %; P = 0.005). None of these changes were related to the exercise-induced cardiometabolic benefits (all P ≥ 0.05).

In young adults, a 24-week supervised concurrent exercise program, at moderate and vigorous intensities, resulted in minor changes in fecal microbiota composition, while neither alpha nor beta diversities were affected.

ClinicalTrials.gov ID: NCT02365129.

Patients with type 2 diabetes mellitus (T2DM) duration ≥ 10 years often have significant β-cell failure. This study aimed to explore predictors of diabetes remission after bariatric surgery in these patients.

Patients with T2DM duration ≥ 10 years who underwent bariatric surgery were retrospective included and followed up. Remission of diabetes was defined as an HbA1c < 6.5 % (48 mmol/mol) at least 3 months after the discontinuation of hypoglycemic drugs. An intravenous glucose tolerance test (IVGTT) was performed in patients with diabetes remission.

203 patients with T2DM duration ≥ 10 years were included, 59.6 % were treated with insulin before bariatric surgery. One-, two- and three-year post-surgery remission rates were 65.6 %, 53.8 % and 41.9 %, respectively (∼10 % decrease/year). Cox regression analysis revealed that the odds of remission at one-year post-bariatric surgery were most strongly associated with β-cell function (HR 1.20, 95 % CI 1.03-1.40) and percentage of total weight loss (%TWL) (HR 1.04, 95 % CI 1.01-1.07). The first-phase insulin secretion peak was approximately 5-8 folds of the fasting insulin level in 50 patients with diabetes remission.

%TWL and β-cell function are significantly associated with diabetes remission after bariatric surgery in long-duration T2DM patients, with restored first-phase insulin secretion still observed.

Previous studies demonstrate that GDF15 and its related signaling activators may be affected by exercise training, leading to the suppression of inflammatory factors and the promotion of immune-metabolic balance. Therefore, the purpose of the study was to evaluate the effect of high-intensity interval training (HIIT) on amelioration of inter-organ crosstalk between liver and hypothalamus of the high-fat diet (HFD)-induced metabolic dysfunction-associated fatty liver disease (MAFLD) rats in a two-phase study. In this regard, rats were initially divided into two groups, the normal diet-inactive (NS) and the HFD groups. HFD course lasted 12 weeks to induce MAFLD in the latter group. After ensuring the induction of MAFLD, 25 rats were divided into three groups: the HFD-inactive group (HS), the HFD-HIIT group (HH), as well as the HFD-aerobic group (HA). The training interventions were consistently applied over a period of eight weeks, five days a week, with each session lasting 40-60 min, and the duration of the whole research was 21 weeks. The results of this study displayed that HIIT intervention promotes hypothalamic Gdf15 gene expression and there were similar alterations in genes expression of Foxo1 and Akt2. Moreover, our results confirmed that HIIT ameliorated hypothalamic NFKB gene expression and there was a similar trend in genes expression of Tnfa and Il1b following both HIIT as well as aerobic training protocols. Taking these findings together, it is concluded that interventions, particularly exercise training, uniquely contribute to the reduction of hypothalamic-associated inflammatory responses that result in prolonged and chronic increases in GDF15.

Energy-restricted (ER) diets promote weight loss and improve body composition and glycaemic control. Nut consumption also improves these parameters. However, less is known about the combined benefit of these two strategies. This scoping review implemented a systematic search of Medline, Embase and Scopus to identify randomised controlled trials evaluating the effect of ER diets with or without nuts on body mass, body composition and glycaemic control in adults. After reviewing titles and abstracts, twenty-nine full-text articles were screened, resulting in seven studies reported in eight papers that met the inclusion criteria. Energy restriction was achieved by prescribing a set energy target or reducing intake by 1000-4200 kJ from daily energy requirements. Interventions ranged from 4 to 52 weeks in duration and contained 42-84 g/d of almonds, peanuts, pistachios or walnuts. While all studies reported that energy restriction resulted in significant weight loss, the addition of nuts to ER diets demonstrated significantly greater weight loss in only approximately half of the included studies (4/7 studies). There was limited evidence to support additional benefits from nuts for body composition measures or glycaemic control. Although improvements in weight loss and glycaemia were not consistent when nuts were included in ER diets, no study revealed an adverse effect of nut consumption on health outcomes. Future studies could explore the effect of consuming different types and amounts of nuts, combined with various levels of energy restriction on weight, body composition and glycaemic control.

The International Diabetes Federation recently endorsed a 1-h oral glucose tolerance test (OGTT) as more convenient than the conventional 2-h OGTT. In practice, women with hyperglycemia in pregnancy are advised to undergo a 2-h OGTT within 6 months after delivery, but this test is often not completed, partly owing to its inconvenience for busy mothers. Recognizing the potential advantage of the 1-h OGTT in this setting, we sought to compare 1-h and 2-h OGTT glucose measurements at 3 months postpartum as predictors of dysglycemia (prediabetes/diabetes) over the first 5 years postpartum.

A total of 369 women across a range of glucose tolerance in pregnancy (from normoglycemia to gestational diabetes [GDM]) underwent multisample 2-h 75-g OGTTs at 3 months, 1 year, 3 years, and 5 years postpartum. Glucose measurements from the 3-month OGTT were ranked as predictors of dysglycemia (both criteria) by change in concordance index (CCI) of Cox proportional hazard regression models.

At the 3-month OGTT, 1-h glucose identified all but 10 of 70 women concurrently diagnosed with dysglycemia by 2-h glucose, while diagnosing an additional 96 women. The cumulative incidence of dysglycemia progressively increased over 5 years by tertile of 1-h glucose on the 3-month OGTT (P < 0.0001). On regression analyses, the strongest predictor of dysglycemia was 1-h glucose (change in CCI: 16.1%), followed by 2-h glucose (14.9%). In women with GDM, 1-h glucose again emerged as strongest predictor of dysglycemia (13.0%), followed by 2-h glucose (12.8%).

The 1-h OGTT may offer a strategy for increasing rates of postpartum reclassification following hyperglycemia in pregnancy.

The dietary inflammatory index (DII) has been associated with obesity and cardiovascular risk factors (CVRF) in the general population. We hypothesized that in kidney transplant recipients (KTR), a positive relationship between DII, body adiposity and CVRF would also be observed. To test this hypothesis, we conducted a cross-sectional study with adult KTR. Body mass index (BMI), body adiposity index (BAI) and waist circumference (WC) were assessed. Total fat mass (FM), trunk FM, and load-capacity index (LCI) were evaluated using dual-energy X-ray absorptiometry. Energy-adjusted DII (E-DII) was estimated based on three 24-h recalls and stratified as anti-inflammatory (E-DII<0) and pro-inflammatory (E-DII>0). CVRF included hypertension, diabetes, dyslipidemia, and metabolic syndrome. A total of 170 KTR, 59% male, with 49.5 (42-57) years and E-DII from -2.89 to 4.78 were evaluated. KTR with E-DII>0, compared to those with E-DII<0, exhibited significantly higher values of BAI, total FM (kg), and LCI. In multiple adjusted linear regression, E-DII was significantly associated with WC, total FM (kg), and trunk FM (kg). Logistic regression analysis indicated that E-DII>0 was significantly associated with obesity, as assessed by BAI. E-DII was not associated with CVRF. The present study suggests that a pro-inflammatory diet is associated with higher total and central body adiposity in KTR. Interventions targeting an anti-inflammatory diet may contribute to reducing excessive body adiposity in this population.

Glycaemic traits such as high fasting glucose levels and insulin resistance are positively associated with the risk of type 2 diabetes and other cardiometabolic diseases. Genetic association studies have identified hundreds of associations for each glycaemic trait, yet very few studies have involved continental African populations. We report the results of genome-wide association studies (GWASs) in a pan-African cohort for four glycaemic traits, namely fasting glucose, fasting insulin, insulin resistance (HOMA-IR) and beta cell function (HOMA-B), which are quantitative variables that affect the risk of developing type 2 diabetes.

GWASs for the four traits were conducted in approximately 10,000 individuals from the Africa Wits-INDEPTH Partnership for Genomics Studies (AWI-Gen) cohort, with participants from Burkina Faso, Ghana, Kenya and South Africa. Association testing was performed using linear mixed models implemented in BOLT-LMM, with age, sex, BMI and principal components as covariates. Replication, fine mapping and functional annotation were performed using standard approaches.

We identified a novel signal (rs574173815) in the intron of the ankyrin repeat domain 33B (ANKRD33B) gene associated with fasting glucose, and a novel signal (rs114029796) in the intronic region of the WD repeat domain 7 (WDR7) gene associated with fasting insulin. SNPs in WDR7 have been shown to be associated with type 2 diabetes. A variant (rs74806991) in the intron of ADAM metallopeptidase with thrombospondin type 1 motif 16 (ADAMTS16) and another variant (rs6506934) in the β-1,4-galactosyltransferase 6 gene (B4GALT6) are associated with HOMA-IR. Both ADAMTS16 and B4GALT6 are implicated in the development of type 2 diabetes. In addition, our study replicated several well-established fasting glucose signals in the GCK-YTK6, SLC2A2 and THORLNC gene regions.

Our findings highlight the importance of performing GWASs for glycaemic traits in under-represented populations, especially continental African populations, to discover novel associated variants and broaden our knowledge of the genetic aetiology of glycaemic traits. The limited replication of well-known signals in this study hints at the possibility of a unique genetic architecture of these traits in African populations.

The dataset used in this study is available in the European Genome-Phenome Archive (EGA) database ( https://ega-archive.org/ ) under study accession code EGAS00001002482. The phenotype dataset accession code is EGAD00001006425 and the genotype dataset accession code is EGAD00010001996. The availability of these datasets is subject to controlled access by the Data and Biospecimen Access Committee of the H3Africa Consortium. GWAS summary statistics are accessible through the NHGRI-EBI GWAS Catalog ( https://www.ebi.ac.uk/gwas/ ).