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Type 2 diabetes mellitus (T2DM) is a pivotal chronic disease with an increasing prevalence. Recent studies have found associations between T2DM and the development of central nervous system (CNS) tumours, a special class of solid tumours with an unclear pathogenesis. In this study, we aimed to explore the relationship between T2DM and certain glycaemic factors with common CNS tumours by using genetic data to conduct Mendelian randomization (MR) and co-localisation analysis. We found a causal relationship between T2DM and glioblastoma, fasting glucose and spinal cord tumours, glycated haemoglobin and spinal cord tumours, and insulin-like growth factor-1 and spinal cord tumours, pituitary tumours, and craniopharyngiomas. These results clarify the relationship between T2DM, glucose-related factors, and common CNS tumours, and they provide valuable insight into further clinical and basic research on CNS tumours, as well as new ideas for their diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: The risks of heart disease, resistance of insulin, and diabetes mellitus type II are increased in individuals diagnosed with metabolic syndrome. Furthermore, there is an increase in the vascular and neurological effects. This study aimed to assess the isolated independent impact of hepatitis C virus (HCV) on metabolic syndrome, excluding obesity and diabetes mellitus as common risks, this impact was assessed using the metabolic syndrome Severity Z-score (MetS Z-Score) which was initially designed to assess metabolic disease severity itself. Fifty-one HCV patients non-obese and non-diabetic who visited the Tropical Medicine Department from July 2023 to June 2024 were included in our prospective cross sectional study. Results: After calculation of MetS Z-Score, strong correlations were observed between MetS Z-score and the following data: HDL, fasting insulin, fasting blood sugar, HOMA-IR and hypertension (P value < 0.05). Moreover, The MetS Z-Score was found to have higher values in hypertensive patients. Jaundice shows a near to significance correlation with the MetS Z-Score. Anemia, hypoalbuminemia and thrombocytopenia were observed in the included HCV patients. Low density lipoprotein, alanine aminotransferase, aspartate aminotransferase, cholesterol and triglycerides have shown higher levels than normal in the included HCV patients. Conclusion: The MetS Z-score can be used for determining the severity of metabolic abnormalities in HCV patients who are neither diabetic nor obese. [ABSTRACT FROM AUTHOR]

Context Insulin sensitivity (IS) is an important factor in type 2 diabetes (T2D) and can be estimated by many different indices. Objective We aimed to compare the genetic components underlying IS indices obtained from fasting and oral glucose-stimulated plasma glucose and serum insulin levels. Methods We computed 21 IS indices, classified as fasting, OGTT0,120, and OGTT0,30,120 indices, using fasting and oral glucose tolerance test (OGTT) data in 2 cohorts. We used data from a family cohort (n = 313) to estimate the heritability and the genetic and phenotypic correlations of IS indices. The population cohort, Inter99 (n = 5343), was used to test for associations between IS indices and 426 genetic variants known to be associated with T2D. Results Heritability estimates of IS indices ranged between 19% and 38%. Fasting and OGTT0,30,120 indices had high genetic (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 variant was associated only with fasting indices and PIK3R rs4976033 only with OGTT0,30,120 indices. The variants in FAM63A/MINDY1 , GCK , C2CD4A/B , and FTO loci were associated only with OGTT0,120 indices. Conclusion Even though the IS indices mostly share a common genetic background, notable differences emerged between OGTT0,120 indices. The fasting and OGTT-based indices have distinct associations with T2D risk variants. This work provides a basis for future large-scale genetic investigations into the differences between IS indices. [ABSTRACT FROM AUTHOR]

Abstract Background The risks of heart disease, resistance of insulin, and diabetes mellitus type II are increased in individuals diagnosed with metabolic syndrome. Furthermore, there is an increase in the vascular and neurological effects. This study aimed to assess the isolated independent impact of hepatitis C virus (HCV) on metabolic syndrome, excluding obesity and diabetes mellitus as common risks, this impact was assessed using the metabolic syndrome Severity Z-score (MetS Z-Score) which was initially designed to assess metabolic disease severity itself. Fifty-one HCV patients non-obese and non-diabetic who visited the Tropical Medicine Department from July 2023 to June 2024 were included in our prospective cross sectional study. Results After calculation of MetS Z-Score, strong correlations were observed between MetS Z-score and the following data: HDL, fasting insulin, fasting blood sugar, HOMA-IR and hypertension (P value

Abstract Dietary intake of live microbes may benefit human health, but less is known about the role in insulin resistance. This study was developed with the goal of evaluating potential relationships between IR and dietary live microbes. The National Health and Nutrition Examination Survey (NHANES) dataset was leveraged to collect data from 6,333 subjects 18 + years of age. The Sanders system for the classification of dietary live microbe intake (containing Low ( 107 CFU/g) levels of live microbes) was then used to separate these patients into three groups (low, medium, or high). Fasting blood glucose and insulin levels were used to approximate IR based on the homeostasis model of insulin resistance (HOMA-IR). Weighted linear regressions were used to assess the relationship between IR and live microbe intake. After fully adjusting for confounding factors, subjects in the groups exhibiting medium and high levels of live microbe intake exhibited HOMA-IR scores that were below those of subjects in the low group. The relationship between live microbe intake and HOMA-IR scores was also potentially impacted by ethnicity. In summary, a negative correlation was detected between dietary live microbe intake and HOMA-IR values.

Background: This study aimed to investigate the effects of hemoglobin A1c (HbA1c), fasting blood glucose (FBG), 2-hours postprandial blood glucose (2hPBG), and fasting insulin (FINS) levels on pregnancy outcomes and their predictive value in patients with gestational diabetes mellitus (GDM). Methods: A total of 109 pregnant women with GDM (GDM group) were included and assayed for serum FBG, 2hPBG, HbA1c, and FINS levels. The incidence of adverse pregnancy outcomes was recorded. GDM patients were divided into the poor pregnancy outcome group and the favorable pregnancy outcome group and analyzed for HbA1c, FBG, 2hPBG, and FINS. The predictive value of serum index combined detection on GDM pregnancy outcome was assessed, and the effect of serum indices on pregnancy outcome was evaluated in GDM patients with logistic regression. Results: In the GDM group, there were 8 cases of premature membranes breaking (7.34%), 6 cases of premature delivery (5.50%), 3 cases of hyperamniotic fluid (2.75%), 2 cases of neonatal asphyxia (1.83%), 5 cases of fetal growth restriction (4.59%), and 3 cases of low-birth-weight infants (2.75%). The total incidence of adverse pregnancy outcomes was 24.77% (27/109). HbA1c, FBG, 2hPBG, and FINS in the poor pregnancy outcome group were higher than those in the favorable pregnancy outcome group. The AUC value of blood biochemical indicators combined detection in predicting pregnancy outcome in GDM patients was higher than of HbA1c, FBG, 2hPBG, and FINS alone detection. HbA1c ≥ 6.94%, FBG ≥ 7.18 mmol/L, 2hPBG ≥ 9.36 mmol/L, and FINS ≥ 13.07 U/L were the risk factors affecting pregnancy outcomes in GDM patients. Conclusions: The changes of HbA1c, FBG, 2hPBG, and FINS levels in GDM patients are associated with adverse pregnancy outcomes, and the combined detection of serum indicators has predictive value for pregnancy outcomes in GDM patients. [ABSTRACT FROM AUTHOR]

Dietary intake of live microbes may benefit human health, but less is known about the role in insulin resistance. This study was developed with the goal of evaluating potential relationships between IR and dietary live microbes. The National Health and Nutrition Examination Survey (NHANES) dataset was leveraged to collect data from 6,333 subjects 18 + years of age. The Sanders system for the classification of dietary live microbe intake (containing Low (< 104 CFU/g), Medium (104–107 CFU/g), or High (> 107 CFU/g) levels of live microbes) was then used to separate these patients into three groups (low, medium, or high). Fasting blood glucose and insulin levels were used to approximate IR based on the homeostasis model of insulin resistance (HOMA-IR). Weighted linear regressions were used to assess the relationship between IR and live microbe intake. After fully adjusting for confounding factors, subjects in the groups exhibiting medium and high levels of live microbe intake exhibited HOMA-IR scores that were below those of subjects in the low group. The relationship between live microbe intake and HOMA-IR scores was also potentially impacted by ethnicity. In summary, a negative correlation was detected between dietary live microbe intake and HOMA-IR values. [ABSTRACT FROM AUTHOR]

Background: This study examined the effects of a single all-out bout of 30-s sprint-cycle performed daily for 5 consecutive days per week for 6 weeks, on aerobic fitness, muscle strength and metabolic-health markers in physically active young males and females. Methods: Healthy, physically active 20–28 year olds, were randomly assigned to either experimental (EXP, N = 11) or non-training control (CON, N = 8) group. With supervision, the EXP group performed one bout of 30-s sprint-cycle daily, Mondays to Fridays over 6 weeks, while CON group continued with their usual lifestyle. The followings were measured at pre- and post-intervention: maximal aerobic power, peak torque of knee extensors and flexors at velocities 30° s−1 and 300° s−1, resting heart rate, resting blood pressure, body fat percentage, fasting lipid profile, fasting blood glucose, and fasting insulin levels. Results: There were no significant improvements in the EXP group for all the measured variables (all P > 0.05); except for significant interaction effects in peak torque of knee extensors at 30° s−1 (P = 0.044) and low-density lipoprotein-cholesterol (P = 0.046). Post hoc test indicate that CON group showed decline in their low-density lipo-proteins levels (P = 0.024). Conclusion: Six weeks of one all-out bout of 30-s sprint-cycle per day, for 5 consecutive days per week, was ineffective in improving cardiovascular fitness, maximal strength, and most health markers in physically active young adults. The present results when combined with the previous literature suggest that there is a possibility of a minimum threshold for a number of sprint-cycle bouts needed to be performed before any form of cardio-metabolic-health benefit is accrued. [ABSTRACT FROM AUTHOR]

Meat intake, particularly from oily fish, has been associated with various chronic diseases. However, its relationship with acne has always been controversial. Therefore, we have adopted Mendelian randomization (MR) analysis to investigate the causal relationship between different types of meat intake and acne. The exposure and outcome datasets for this study were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS project. Seven datasets on meat intake were included, which consisted of non‐oily fish, oily fish, lamb/mutton, poultry, pork, beef, and processed meat. The main methods used for MR analysis were inverse variance weighted, weighted median, and MR‐egger. To ensure the accuracy of the results, heterogeneity, pleiotropy, and Mendelian randomization pleiotropy residual sum and outlier (MR‐PRESSO) analyses were conducted. Additionally, an analysis of four risk factors (fasting insulin, insulin resistance, total testosterone level, and estradiol level) was performed to investigate the underlying mechanisms linking statistically significant meat intake to acne. Oily fish intake was found to be a protective factor for acne (OR: 0.22, 95% CI: 0.10–0.49, p <.001), and it was also observed that oily fish intake can reduce the level of fasting insulin by the IVW method (OR: 0.89, 95% CI: 0.81–0.98, p =.02). No causal relationship was identified between other types of meat intake and acne. The intake of oily fish reduces the risk of acne by lowering fasting insulin levels. [ABSTRACT FROM AUTHOR]

This article discusses a study conducted in a semi-urban area of North India that examined the relationship between vitamin D deficiency and insulin resistance in individuals with type 2 diabetes. The study found a significant negative correlation between vitamin D levels and fasting insulin, as well as other markers of insulin resistance. The findings suggest that vitamin D deficiency may contribute to insulin resistance in type 2 diabetes and that vitamin D supplementation could potentially improve glycemic control. However, more research is needed to fully understand this relationship. [Extracted from the article]

STUDY QUESTION Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility? SUMMARY ANSWER Genetic instruments suggest that higher fasting insulin may increase infertility in women. WHAT IS KNOWN ALREADY Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. STUDY DESIGN, SIZE, DURATION This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study. PARTICIPANTS/MATERIALS, SETTING, METHODS There were 68 882 women (average age 30, involved in 81 682 pregnancies) and 47 474 of their male partners (average age 33, 55 744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P -value < 0.00625). MAIN RESULTS AND THE ROLE OF CHANCE In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P -value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P -value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility. LIMITATIONS, REASONS FOR CAUTION We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry. WIDER IMPLICATIONS OF THE FINDINGS Treatments for lower fasting insulin levels may reduce the risk of infertility in women. STUDY FUNDING/COMPETING INTEREST(S) The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This work was supported by the European Research Council [grant numbers 947684, 101071773, 293574, 101021566], the Research Council of Norway [grant numbers 262700, 320656, 274611], the South-Eastern Norway Regional Health Authority [grant numbers 2020022, 2021045], and the British Heart Foundation [grant numbers CH/F/20/90003, AA/18/1/34219]. Open Access funding was provided by the Norwegian Institute of Public Health. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. D.A.L. has received research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. O.A.A. has been a consultant to HealthLytix. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

The causal relationship between type 2 diabetes (T2D) and frozen shoulder is unclear. This study aims to explore the genetic causal association between T2D and glycemic traits (fasting glucose [FG], fasting insulin [FI], glycated hemoglobin [HbA 1c ], and 2-hour postprandial glucose [2hGlu]) on frozen shoulder. Using 2-sample Mendelian randomization (MR), we analyzed nonconfounded estimates of the effects of T2D and glycemic traits on frozen shoulder. Single-nucleotide polymorphisms (SNPs) strongly associated (P < 5 × 10–8) with exposures from genome-wide association studies (GWAS) were identified. We employed fixed effect mode inverse variance weighting (IVW-FE), random effect mode IVW (IVW-MRE), MR-Egger, and weighted median to assess the association of exposures and outcome. Sensitivity analysis was conducted to test for heterogeneity and multidirectionality bias in MR. We found a significant genetic causal correlation between T2D (IVW-MRE P =.007, odds ratio [OR] 1.093, 95% confidence interval [CI] 1.03-1.16), FG (IVW-FE P <.001, OR 1.455, 95% CI 1.173-1.806), and frozen shoulder, but no evidence for causal correlation between FI, HbA 1c , and 2hGlu and frozen shoulder. Although there was certain heterogeneity, sensitivity analysis reveals no deviation from the MR assumptions. This study supports a genetic causal relationship between T2D and FG and frozen shoulder. [ABSTRACT FROM AUTHOR]

Background: Zinc is an essential micronutrient, a vital stabiliser and a cofactor in many enzymes such as superoxide dismutase and phospholipase C and also acts as an antioxidant by protecting the sulfhydryl groups of different proteins and enzymes against free radicals. It is unclear if serum zinc levels are correlated with polycystic ovary syndrome (PCOS) and its pathophysiology, although relation between diabetes and insulin resistance has been established. Aims: This study aimed to investigate circulating serum zinc levels in PCOS subjects compared with non‑PCOS subjects. Settings and Design: In this cohort study, PCOS subjects were compared with normal subjects aged between 18 and 35. Materials and Methods: All the included subjects underwent measurement of anthropometric parameters, fasting insulin, luteinising hormone, follicle‑stimulating hormone, thyroid‑stimulating hormone, prolactin, progesterone, oestrogen and serum zinc levels. These values were taken on days 2–5 of the menstrual cycle. Statistical Analysis Used: Univariate analysis and linear regression were performed for serum zinc levels and fasting insulin levels in PCOS subjects and non‑PCOS subjects using SPSS (version 21) and Microsoft Excel (2019). Results: Serum zinc levels in the PCOS group were lower than in the control group (P = 0.012). Fasting insulin levels in the PCOS group were higher than in non‑PCOS subjects (P = 0.001). We found a negative correlation between zinc and fasting insulin (r = −0.580, P < 0.0001) in the normal group and (r = −0.332, P = 0.019) in the PCOS group. A positive correlation was found between body mass index (BMI) and fasting insulin levels in both the PCOS group (r = 0.227, P = 0.112) and normals (r = 0.612, P < 0.0001). A negative statistically significant correlation between BMI and zinc in both the PCOS group (r = −0.378, P = 0.007) and the non‑PCOS group (r = −0.7452, P < 0.0001) was seen. Conclusion: The data suggest that serum zinc levels were found to be lower in PCOS subjects as compared to normal controls and evaluation of these levels may indicate that zinc has a vital role in PCOS pathophysiology. [ABSTRACT FROM AUTHOR]

Abstract Background Previous studies have created plant-based diet indices to assess the health effects of specific dietary patterns. Objective To examine the association between the plant-based content of diet and fasting insulin in adults from the NHANES 2017–2018 database. Methods Demographic, dietary, lab and clinical data and fasting insulin were obtained from the NHANES 2017–2018 database. From two 24-h dietary recalls, we created a plant-based diet index (PDI) and a healthy plant-based diet index (hPDI). A high PDI score indicated more plants were consumed versus animal foods. A high hPDI score indicated healthier, plant materials (whole grains, whole fruits, vegetables, legumes, vegetable oils, seeds and nuts) were consumed. The relationships between the natural log of fasting insulin, PDI, and hPDI were analyzed using multiple linear regression adjusting for body mass index (BMI) and alanine aminotransferase (ALT). Results Analyses were based on 1,714 participants, 897 women and 817 men with a median age of 52 years. In this sample, 610 (35.6%) were white, 407 (23.8%) were black, 231 (13.5%) were Mexican, 207 (12.1%) were Asian, 157 (9.2%) were other Hispanic, and 102 (6%) were other or mixed race. Median fasting insulin was 9.74 μU/mL (IQR: 6.2, 15.56). For every 1 unit increase in PDI, the natural log of fasting insulin decreased 0.0068 ± 0.003 μU/mL (CI: -0.00097, -0.013) (p = 0.02). After adjusting for BMI and ALT, the PDI did not significantly predict fasting insulin as the association was not robust due to multicollinearity. The hPDI was inversely and significantly associated with the natural log of fasting insulin (-0.0027 ± 0.00134, CI: -0.000087, -0.0053) (p = 0.043) in a multivariable model including BMI and ALT. Conclusion A healthy plant-based diet is associated with a decrease in fasting insulin levels. Healthfulness of the diet is an important factor when considering the benefit of a plant-based diet.

Purpose: Asthma is a chronic disease that causes frequent hospital admissions, medication use and impaired quality of life. The purpose of this study was to investigate the effect on insulin resistance of ICS in children with asthma using ICS in the prepubertal period. Materials and Methods: Asthmatic children receiving at least one month of maintenance asthma treatment and healthy children were included in the study. Patients’ fasting glucose, fasting insulin, BMI, and homeostasis model assessment insulin resistance (HOMA-IR) values were compared. Results: Two hundred twenty individuals were included in the study, 117 asthmatic and 103 healthy children. The children with asthma were divided into two groups depending on the maintenance treatment received-ICS (n=60) and montelukast (n=57). The median total cumulative inhaled corticosteroid doses were 40 mg (7.75-1090) in the ICS group and 3.75 mg (0-50) in the montelukast group (p

Background: Previous studies have created plant-based diet indices to assess the health effects of specific dietary patterns. Objective: To examine the association between the plant-based content of diet and fasting insulin in adults from the NHANES 2017–2018 database. Methods: Demographic, dietary, lab and clinical data and fasting insulin were obtained from the NHANES 2017–2018 database. From two 24-h dietary recalls, we created a plant-based diet index (PDI) and a healthy plant-based diet index (hPDI). A high PDI score indicated more plants were consumed versus animal foods. A high hPDI score indicated healthier, plant materials (whole grains, whole fruits, vegetables, legumes, vegetable oils, seeds and nuts) were consumed. The relationships between the natural log of fasting insulin, PDI, and hPDI were analyzed using multiple linear regression adjusting for body mass index (BMI) and alanine aminotransferase (ALT). Results: Analyses were based on 1,714 participants, 897 women and 817 men with a median age of 52 years. In this sample, 610 (35.6%) were white, 407 (23.8%) were black, 231 (13.5%) were Mexican, 207 (12.1%) were Asian, 157 (9.2%) were other Hispanic, and 102 (6%) were other or mixed race. Median fasting insulin was 9.74 μU/mL (IQR: 6.2, 15.56). For every 1 unit increase in PDI, the natural log of fasting insulin decreased 0.0068 ± 0.003 μU/mL (CI: -0.00097, -0.013) (p = 0.02). After adjusting for BMI and ALT, the PDI did not significantly predict fasting insulin as the association was not robust due to multicollinearity. The hPDI was inversely and significantly associated with the natural log of fasting insulin (-0.0027 ± 0.00134, CI: -0.000087, -0.0053) (p = 0.043) in a multivariable model including BMI and ALT. Conclusion: A healthy plant-based diet is associated with a decrease in fasting insulin levels. Healthfulness of the diet is an important factor when considering the benefit of a plant-based diet. [ABSTRACT FROM AUTHOR]

Background: Unexplained recurrent pregnancy loss (RPL) accounts for >50% of the patients with RPL. Insulin resistance (IR) is a potential cause of unexplained RPL. Objectives: To evaluate the relationship between insulin resistance (IR) and unexplained RPL among Saudi women. Methods: This is a single-center, case–control study conducted at a tertiary hospital in the Eastern Province of Saudi Arabia. The study group comprised Saudi women with unexplained RPL, while the control group had Saudi women with at least one live birth and no RPL. Blood samples were taken to determine the fasting glucose (FG) and fasting insulin (FI) levels. Women with diabetes mellitus and polycystic ovarian syndrome were excluded. A homeostatic model assessment of insulin resistance index (HOMA-IR) value ≥3 was considered as IR. Results: The study and control groups comprised 43 and 56 women, respectively. Between the groups, there was a significant difference in the mean age (case: 37.9 ± 5.4 years; control: 32.2 ± 5.9 years; P ˂ 0.0001) and the mean BMI (case: 31.5 ± 6.0; control: 26.1 ± 2.8; P ˂ 0.0001). FG level was slightly higher in the control group (90.9 mg/dL vs 88.7 mg/dL; P = 0.068). FI level was significantly higher in the study group (16.33 μU/mL vs. 6.17 μU/mL; P ˂ 0.0001). HOMA-IR of ≥3 was significantly more common in the study group (n = 22; 51.2%) than the control group (4; 7.1%) (P < 0.0001). After adjusting for age and BMI, IR ≥3 was found to be independently associated with unexplained RPL (aOR: 13.2; 95% CI: 3.77–46.36). Conclusions: This study showed that Saudi women with unexplained RPL had significantly higher levels of fasting insulin and insulin resistance than those without a history of RPL. Therefore, it is recommended to assess IR in women with RPL. [ABSTRACT FROM AUTHOR]

Abstract Background Observational studies have reported an inverse association of type 2 diabetes (T2D) with thoracic aortic aneurysm (TAA). However, the causality of the association has not been established yet. The present study aims to clarify the causal relationship between T2D and TAA via a Mendelian randomization (MR) approach. Methods Causality of associations were assessed using a two-sample MR framework. Genome-wide association study (GWAS) summary statistics were obtained for T2D, glycated hemoglobin (HbA1c), fasting glucose (FG) and fasting insulin (FI) as exposures, and TAA, ascending aortic diameter (AAoD) and descending aortic diameter (DAoD) as outcomes. Four different methods (inverse variance weighted [IVW], weight median, MR-Egger and MR-PRESSO) were used to calculate causal estimates. Heterogeneity and horizontal pleiotropy were assessed using Cochran Q test and MR-Egger regression intercept, respectively. Results Genetically predicted T2D was inversely associated with the risk of TAA (OR: 0.931, 95% CI 0.870 to 0.997, p = 0.040, IVW method) and AAoD (Beta: -0.065, 95%CI −0.099 to − 0.031, p = 1.7e−04, IVW method), but not with DAoD (p > 0.05). Genetically predicted FG level was inversely associated with AAoD (Beta: −0.273, 95% CI −0.396 to –0.150, p = 1.41e−05, IVW method) and DAoD (Beta: −0.166, 95% CI −0.281 to −0.051, p = 0.005, IVW method), but not with TAA (p > 0.05). The effect of genetically predicted HbA1c and FI on TAA, AAoD and DAoD did not reach statistical significance (p > 0.05). Conclusions Genetic predisposition to T2D decreases the risk of TAA. Genetically predicted T2D is inversely associated with AAoD, but not with DAoD. Genetically predicted FG level was inversely associated with AAoD and DAoD.

Observational studies suggested a close link between type 2 diabetes (T2D), metabolic factors and depression, while the causal relationships remained poorly understood. To determine the causality between T2D and depression, and to investigate the roles of metabolic factors in mediating the relationship between T2D and depression in East Asians. Using summary statistics from the largest and most up-to-date genome-wide association studies of depression (12,588 cases and 85,914 controls) and T2D (36,614 cases and 155,150 controls) among East Asians, two-step and two-sample MR analyses were performed to estimate the causal mediation effects of metabolic factors including lipid profiles, blood pressure (BP) and fasting insulin (FI) on the relationship between T2D and depression. Genetically predicted T2D was significantly associated with depression (OR [95 % CI]:1.06 [1.01, 1.11], P = 0.043), but not vice versa. T2D was causally associated with lower levels of HDL-C and higher levels of LDL-C, triglycerides (TG), BP and FI. Furthermore, the causal effects of T2D on depression were significantly mediated by LDL-C (β [95 % CI]: −0.003 [−0.005, −0.001], P = 0.007), and suggestively mediated by TG (0.001 [0.001, 0.003], P = 0.049) and FI (0.006 [0.001, 0.012], P = 0.049). First, depression was defined by several methods, like symptom questionnaires or self-completed surveys. Second, two-sample MR approach is unable to detect the non-linear causal relationships. Third, independent data sets were not available for replication of our findings. T2D was causally associated with the risk of depression, and LDL-C, TG, and FI were potential causal mediators of the effect of T2D on depression. Understanding the causality among T2D, metabolic factors and depression is crucial for identifying potential targets for early intervention. [Display omitted] • Using the MR to dissect the roles of metabolic factors in mediating the causality between T2D and depression in East Asians. • T2D was causally associated with an increased risk of depression, but not vice versa. • T2D was causally associated with lower levels of HDL-C and higher LDL-C, triglycerides, blood pressure and fasting insulin. • LDL-C, triglycerides, and fasting insulin were potential causal mediators of the effect of T2D on depression. [ABSTRACT FROM AUTHOR]

Objectives: To determine the correlation of subclinical hypothyroidism (SCH) with polycystic ovarian syndrome (PCOS) and to assess its impact on the clinical, biochemical and hormonal features in polycystic ovarian syndrome. Background: PCOS is one of the most common endocrinopathies seen in women of the reproductive age group with a prevalence ranging from [Formula: see text] to [Formula: see text] globally (Joshi et al., 2014) and [Formula: see text] to [Formula: see text] (Malik et al., 2014) in the Indian population. Thyroid disorders are quite commonly seen in PCOS patients, SCH are seen in up to [Formula: see text] of this population (de Medeiros et al., 2018). Its association with PCOS has been insufficiently explored and therefore this study was designed to better understand the correlation. Methodology: This was a cross-sectional study conducted from November 2019 to 2021 in the Department of Obstetrics and Gynecology of Jawaharlal Nehru Medical College and Hospital, Aligarh, India, on 150 PCOS women in the age bracket of 18–35 years. They were divided in two groups: one with normal thyroid levels and the other with SCH. Measurement of clinical, anthropometrical, biochemical and hormonal profile was made in both groups and comparison was made using appropriately matched tests of significance and coefficient of correlations. Results: Notable findings included a positive and statistically significant correlation between SCH and menstrual cycle irregularities ([Formula: see text], [Formula: see text]), infertility ([Formula: see text], [Formula: see text]), body mass index ([Formula: see text], [Formula: see text]), waist to hip ratio ([Formula: see text], [Formula: see text]), testosterone([Formula: see text], [Formula: see text]), total cholesterol ([Formula: see text], [Formula: see text]), triglyceride values ([Formula: see text], [Formula: see text]), fasting insulin ([Formula: see text], [Formula: see text]) and HOMA-IR ([Formula: see text], [Formula: see text]). A positive but statistically insignificant correlation was found with hirsutism ([Formula: see text], [Formula: see text]), luteinizing hormone ([Formula: see text], [Formula: see text]), follicle-stimulating hormone ([Formula: see text], [Formula: see text]), prolactin levels ([Formula: see text], [Formula: see text]), high-density lipoprotein ([Formula: see text], [Formula: see text]), low-density lipoprotein ([Formula: see text], [Formula: see text]) and fasting blood sugar values ([Formula: see text], [Formula: see text]). No statistical significance with systolic blood pressure ([Formula: see text], [Formula: see text]) and diastolic blood pressure ([Formula: see text], [Formula: see text]) was found. Conclusion: The study showed a significant correlation between SCH and multiple variables in PCOS and thereby necessitating thyroid screen in PCOS population.

Abstract Background Recent studies found associations between non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS), but the causal nature of this association is still uncertain. Methods We performed a bidirectional two-sample Mendelian randomization (MR) analysis to test for the causal association between NAFLD and PCOS using data from a large-scale biopsy-confirmed NAFLD genome-wide association study (GWAS) (1483 cases and 17,781 controls) and PCOS GWAS (10,074 cases and 103,164 controls) in European ancestries. Data from glycemic-related traits GWAS (in up to 200,622 individuals) and sex hormones GWAS (in 189,473 women) in the UK Biobank (UKB) were used in the MR mediation analysis to assess potential mediating roles of these molecules in the causal pathway between NAFLD and PCOS. Replication analysis was conducted using two independent datasets from NAFLD and PCOS GWASs in the UKB and a meta-analysis of data from FinnGen and the Estonian Biobank, respectively. A linkage disequilibrium score regression was conducted to assess genetic correlations between NAFLD, PCOS, glycemic-related traits, and sex hormones using full summary statistics. Results Individuals with higher genetic liability to NAFLD were more likely to develop PCOS (OR per one-unit log odds increase in NAFLD: 1.10, 95% CI: 1.02–1.18; P = 0.013). Indirect causal effects of NAFLD on PCOS via fasting insulin only (OR: 1.02, 95% CI: 1.01–1.03; P = 0.004) and further a suggestive indirect causal effect via fasting insulin in concert with androgen levels were revealed in MR mediation analyses. However, the conditional F statistics of NAFLD and fasting insulin were less than 10, suggesting likely weak instrument bias in the MVMR and MR mediation analyses. Conclusions Our study suggests that genetically predicted NAFLD was associated with a higher risk of developing PCOS but less evidence for vice versa. Fasting insulin and sex hormones might mediate the link between NAFLD and PCOS.

Background: Unexplained recurrent pregnancy loss (RPL) accounts for >50% of the patients with RPL. Insulin resistance (IR) is a potential cause of unexplained RPL. Objectives: To evaluate the relationship between insulin resistance (IR) and unexplained RPL among Saudi women. Methods: This is a single-center, case–control study conducted at a tertiary hospital in the Eastern Province of Saudi Arabia. The study group comprised Saudi women with unexplained RPL, while the control group had Saudi women with at least one live birth and no RPL. Blood samples were taken to determine the fasting glucose (FG) and fasting insulin (FI) levels. Women with diabetes mellitus and polycystic ovarian syndrome were excluded. A homeostatic model assessment of insulin resistance index (HOMA-IR) value ≥3 was considered as IR. Results: The study and control groups comprised 43 and 56 women, respectively. Between the groups, there was a significant difference in the mean age (case: 37.9 ± 5.4 years; control: 32.2 ± 5.9 years; P ˂ 0.0001) and the mean BMI (case: 31.5 ± 6.0; control: 26.1 ± 2.8; P ˂ 0.0001). FG level was slightly higher in the control group (90.9 mg/dL vs 88.7 mg/dL; P = 0.068). FI level was significantly higher in the study group (16.33 μU/mL vs. 6.17 μU/mL; P ˂ 0.0001). HOMA-IR of ≥3 was significantly more common in the study group (n = 22; 51.2%) than the control group (4; 7.1%) (P < 0.0001). After adjusting for age and BMI, IR ≥3 was found to be independently associated with unexplained RPL (aOR: 13.2; 95% CI: 3.77–46.36). Conclusions: This study showed that Saudi women with unexplained RPL had significantly higher levels of fasting insulin and insulin resistance than those without a history of RPL. Therefore, it is recommended to assess IR in women with RPL.

Background: Metabolic syndrome (MetS) is a state of inflammatory condition carrying several risk factors that lead to insulin resistance (IR), atherosclerotic events, and related complications. Serum ferritin is an acute phase reactant. As an acute phase, serum ferritin increases inflammatory condition which can contribute for IR and MetS. Gamma-glutamyl transferase (GGT) is a pro-inflammatory marker, which participates in various pathophysiological processes such as oxidative stress and lipid peroxidation which are important in the pathogenesis of IR and MetS. This study was undertaken to understand the association of serum ferritin and GGT levels with IR and MetS. Methodology: A comparative, descriptive cross-sectional study was conducted including 50 MetS cases and 50 matched healthy controls. Clinical examination was followed by laboratory investigations of GGT, ferritin, insulin, lipid profile, glycated hemoglobin (HbA1c), and IR were calculated by homeostasis model assessment-IR (HOMA-IR). Results: In the MetS patients' group, IR (HOMA-IR) was found to have significant positive correlations with serum GGT, ferritin, insulin, and high-sensitivity C-reactive protein (HsCRP). It was also found that body mass index, fasting blood sugar, postprandial blood sugar, and HbA1c were significant risk factors of IR. Conclusion: The present study suggests that fasting insulin, HsCRP, GGT, and ferritin levels were found to be significantly associated with HOMA-IR. GGT and ferritin play a significant role toward the increasing oxidant stress and inflammatory load which predisposes to MetS. Hence, these parameters could be used as markers for the early diagnosis of MetS.

Background: Elevated levels of uric acid are the end product of purine metabolism. Uric acid levels are regulated by xanthine oxidase enzyme. Increased xanthine oxidase activity results in the generation of free radicals. Hence, elevated uric acid levels are the manifestations of oxidative stress. Meanwhile, raised uric acid can trigger release of inflammatory mediatory and create the inflammatory state. Thus, inflammation and oxidative stress are the important events in the pathogenesis of metabolic syndrome. This study aimed to find the association of uric acid levels with metabolic syndrome and the individual components of metabolic syndrome. Methodology: A comparative, descriptive, cross-sectional study was conducted among 50 metabolic syndrome cases and 50 controls. Clinical examination followed by laboratory investigations for the estimation of serum uric acid, fasting blood sugar, postprandial blood sugar, glycated hemoglobin, high sensitivity C-reactive protein (Hs-CRP), fasting insulin, and lipid profile. Insulin resistance (IR) was calculated by homeostatic model assessment-IR (HOMA-IR). Results: In the metabolic syndrome patients' group, serum uric acid was found to have strong positive correlation with body mass index, blood pressure, glycemic indices, IR, lipid profile, and Hs-CRP. It was found that there was 2.5 times higher risk of development of metabolic syndrome with every unit increase in serum uric acid levels and this association was found to be statistically significant. Conclusion: Uric acid can be used as the marker for the early identification of metabolic syndrome or as a prognostic marker in the diagnosed cases of metabolic syndrome.

Background: Observational studies have reported an inverse association of type 2 diabetes (T2D) with thoracic aortic aneurysm (TAA). However, the causality of the association has not been established yet. The present study aims to clarify the causal relationship between T2D and TAA via a Mendelian randomization (MR) approach. Methods: Causality of associations were assessed using a two-sample MR framework. Genome-wide association study (GWAS) summary statistics were obtained for T2D, glycated hemoglobin (HbA1c), fasting glucose (FG) and fasting insulin (FI) as exposures, and TAA, ascending aortic diameter (AAoD) and descending aortic diameter (DAoD) as outcomes. Four different methods (inverse variance weighted [IVW], weight median, MR-Egger and MR-PRESSO) were used to calculate causal estimates. Heterogeneity and horizontal pleiotropy were assessed using Cochran Q test and MR-Egger regression intercept, respectively. Results: Genetically predicted T2D was inversely associated with the risk of TAA (OR: 0.931, 95% CI 0.870 to 0.997, p = 0.040, IVW method) and AAoD (Beta: -0.065, 95%CI −0.099 to − 0.031, p = 1.7e−04, IVW method), but not with DAoD (p > 0.05). Genetically predicted FG level was inversely associated with AAoD (Beta: −0.273, 95% CI −0.396 to –0.150, p = 1.41e−05, IVW method) and DAoD (Beta: −0.166, 95% CI −0.281 to −0.051, p = 0.005, IVW method), but not with TAA (p > 0.05). The effect of genetically predicted HbA1c and FI on TAA, AAoD and DAoD did not reach statistical significance (p > 0.05). Conclusions: Genetic predisposition to T2D decreases the risk of TAA. Genetically predicted T2D is inversely associated with AAoD, but not with DAoD. Genetically predicted FG level was inversely associated with AAoD and DAoD. [ABSTRACT FROM AUTHOR]

Context: Hyperinsulinemia and adiposity are associated with one another, but the directionality of this relation is debated. Objective: Here, we tested the direction of the causal effects of fasting insulin (FI) levels and body fat accumulation/distribution using 2-sample bidirectional Mendelian randomization (MR). Methods: We included summary statistics from large-scale genome-wide association studies for body mass index (BMI, n=806 834), waist to hip ratio adjusted for BMI (WHRadjBMI, n=694 649), abdominal subcutaneous, visceral and gluteofemoral adipose tissue (n=38 965), FI levels (n=98 210), pancreatic islets gene expression (n=420), and hypothalamus gene expression (n= 155). We used inverse variance-weighted and robust MR methods that relied on statistically and biologically driven genetic instruments. Results: Both BMI and WHRadjBMI were positively associated with FI. Results were consistent across all robust MR methods and when variants mapped to the hypothalamus (presumably associated with food behavior) were included. In multivariable MR analyses, when waist circumference and BMI were mutually adjusted, the direct effect of waist circumference on FI was 2.43 times larger than the effect of BMI on FI. FI was not associated with adiposity. By contrast, using genetic instruments mapped to gene expression in pancreatic islets (presumably more specific to insulin secretion), insulin was positively associated with BMI and abdominal subcutaneous and gluteofemoral adipose tissue, but not with visceral adipose tissue. Conclusion: Although these results will need to be supported by experimental investigations, results of this MR study suggest that abdominal adiposity may be a key determinant of circulating insulin levels. Alternatively, insulin secretion may promote peripheral adipose tissue accumulation. [ABSTRACT FROM AUTHOR]

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Aims: Type 2 diabetes is a major public health problem for the global community. Having a family history of diabetes significantly increases risk for diabetes development and understanding how family history contributes to diabetes risk could lead to more effective prevention efforts for at-risk individuals. In a previous study, we showed family history of diabetes is a significant predictor of fasting insulin in healthy weight children. The present study aimed to use the National Health and Nutrition Examination Survey (NHANES 2017) to apply similar multiple regression models to a population of healthy weight adults to determine if family history is a significant predictor of fasting glucose and fasting insulin. Methods: Fasting glucose (mg/dL) and fasting insulin (pmol/L) were used as dependent variables in each model, respectively, with family history of diabetes as the independent variable. Covariates for each model included age, gender, race/ethnicity, waist circumference, and macronutrient intake. Results: The model significantly predicted the variance of fasting glucose [(F(11,364) = 34.80, p < 0.001, R2 = 0.2342] and fasting insulin [F(11,343) = 17.58, p < 0.001, R2 = 0.1162]. After adjusting for covariates, family history was a significant predicator of fasting glucose (p = 0.0193) as well as age, gender, non-Hispanic black ethnicity, waist circumference, and fat intake. Significant predictors of fasting insulin included gender and waist circumference, but not family history (p = 0.8264). In addition, fasting glucose was higher in individuals with a family history of diabetes (p = 0.033). Conclusions: These results add to the understanding of how family history influences the biomarkers that contribute to diabetes development. Knowledge of how family history of diabetes relates to fasting insulin and fasting glucose activity in healthy weight individuals can be used to design personalized screening and early prevention strategies. [ABSTRACT FROM AUTHOR]

Background: Recent studies found associations between non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS), but the causal nature of this association is still uncertain. Methods: We performed a bidirectional two-sample Mendelian randomization (MR) analysis to test for the causal association between NAFLD and PCOS using data from a large-scale biopsy-confirmed NAFLD genome-wide association study (GWAS) (1483 cases and 17,781 controls) and PCOS GWAS (10,074 cases and 103,164 controls) in European ancestries. Data from glycemic-related traits GWAS (in up to 200,622 individuals) and sex hormones GWAS (in 189,473 women) in the UK Biobank (UKB) were used in the MR mediation analysis to assess potential mediating roles of these molecules in the causal pathway between NAFLD and PCOS. Replication analysis was conducted using two independent datasets from NAFLD and PCOS GWASs in the UKB and a meta-analysis of data from FinnGen and the Estonian Biobank, respectively. A linkage disequilibrium score regression was conducted to assess genetic correlations between NAFLD, PCOS, glycemic-related traits, and sex hormones using full summary statistics. Results: Individuals with higher genetic liability to NAFLD were more likely to develop PCOS (OR per one-unit log odds increase in NAFLD: 1.10, 95% CI: 1.02–1.18; P = 0.013). Indirect causal effects of NAFLD on PCOS via fasting insulin only (OR: 1.02, 95% CI: 1.01–1.03; P = 0.004) and further a suggestive indirect causal effect via fasting insulin in concert with androgen levels were revealed in MR mediation analyses. However, the conditional F statistics of NAFLD and fasting insulin were less than 10, suggesting likely weak instrument bias in the MVMR and MR mediation analyses. Conclusions: Our study suggests that genetically predicted NAFLD was associated with a higher risk of developing PCOS but less evidence for vice versa. Fasting insulin and sex hormones might mediate the link between NAFLD and PCOS. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is a state of inflammatory condition carrying several risk factors that lead to insulin resistance (IR), atherosclerotic events, and related complications. Serum ferritin is an acute phase reactant. As an acute phase, serum ferritin increases inflammatory condition which can contribute for IR and MetS. Gamma-glutamyl transferase (GGT) is a pro-inflammatory marker, which participates in various pathophysiological processes such as oxidative stress and lipid peroxidation which are important in the pathogenesis of IR and MetS. This study was undertaken to understand the association of serum ferritin and GGT levels with IR and MetS. Methodology: A comparative, descriptive cross-sectional study was conducted including 50 MetS cases and 50 matched healthy controls. Clinical examination was followed by laboratory investigations of GGT, ferritin, insulin, lipid profile, glycated hemoglobin (HbA1c), and IR were calculated by homeostasis model assessment-IR (HOMA-IR). Results: In the MetS patients' group, IR (HOMA-IR) was found to have significant positive correlations with serum GGT, ferritin, insulin, and high-sensitivity C-reactive protein (HsCRP). It was also found that body mass index, fasting blood sugar, postprandial blood sugar, and HbA1c were significant risk factors of IR. Conclusion: The present study suggests that fasting insulin, HsCRP, GGT, and ferritin levels were found to be significantly associated with HOMA-IR. GGT and ferritin play a significant role toward the increasing oxidant stress and inflammatory load which predisposes to MetS. Hence, these parameters could be used as markers for the early diagnosis of MetS. [ABSTRACT FROM AUTHOR]

Background: Elevated levels of uric acid are the end product of purine metabolism. Uric acid levels are regulated by xanthine oxidase enzyme. Increased xanthine oxidase activity results in the generation of free radicals. Hence, elevated uric acid levels are the manifestations of oxidative stress. Meanwhile, raised uric acid can trigger release of inflammatory mediatory and create the inflammatory state. Thus, inflammation and oxidative stress are the important events in the pathogenesis of metabolic syndrome. This study aimed to find the association of uric acid levels with metabolic syndrome and the individual components of metabolic syndrome. Methodology: A comparative, descriptive, cross-sectional study was conducted among 50 metabolic syndrome cases and 50 controls. Clinical examination followed by laboratory investigations for the estimation of serum uric acid, fasting blood sugar, postprandial blood sugar, glycated hemoglobin, high sensitivity C-reactive protein (Hs-CRP), fasting insulin, and lipid profile. Insulin resistance (IR) was calculated by homeostatic model assessment-IR (HOMA-IR). Results: In the metabolic syndrome patients' group, serum uric acid was found to have strong positive correlation with body mass index, blood pressure, glycemic indices, IR, lipid profile, and Hs-CRP. It was found that there was 2.5 times higher risk of development of metabolic syndrome with every unit increase in serum uric acid levels and this association was found to be statistically significant. Conclusion: Uric acid can be used as the marker for the early identification of metabolic syndrome or as a prognostic marker in the diagnosed cases of metabolic syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. Methods Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10−8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. Results In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10−31), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10−12), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10−9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10−7) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10−4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10−2) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10−3), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10−8) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10−2) in the relationship between BMI and endometrial cancer risk. Conclusions Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

Diabetes is a group of metabolic disorder effecting health of wide number of population and cause neuropsychological decline. In the present study, effect of AI leaves extract on neuropsychological behaviors was observed in diabetic rat's model. Rats were divided into 4 groups as control (saline treated healthy rats), positive control (pioglitazone treated diabetic rats), diabetic control (untreated diabetic rats) and AI leaves extract treated diabetic rats. Diabetes was induced by giving 35% fructose for 6 weeks and a single dose of Streptozotocin (40 mg/kg). After 3 weeks of treatment behavioral and biochemical analysis were done. Behavioral results revealed that induction of type 2 diabetes produced anxiety, depression, decreased motor activity and impaired recognition memory in rats. Treatment with AI leaves extract in diabetic rats significantly decreased anxiety, depression, increased motor activity, enhanced recognition memory. Biochemical investigation revealed that AI leaves extract treat diabetes via improving the levels of fasting insulin and HbA1c and a significant decrease in CK and SGPT levels were observed in AI leaves treated diabetic rats. So, AI besides treating diabetes, helps in lowering the risk of co-occurring diabetic diseases and found effective in lowering neuropsychological decline observed in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Previous research suggests a correlation between nontoxic goitre and type 2 diabetes mellitus (T2DM). However, the causality was vulnerable to confounding variables. Therefore, there is an urgent need for a more rigorous research approach to examine the causal connection between nontoxic goitre and T2DM., Design: Multiple exposures and outcomes two-sample Mendelian randomization (MR) study was carried out in two stages: nontoxic goitre traits (including nontoxic diffuse goitre, NDG; nontoxic multinodular goitre, NMG; and other/unspecified nontoxic goitre, OUNG) were investigated as exposure while T2DM was investigated as an outcome in the first step, whereas the second step was reversed. The GWAS summary data for nontoxic goitre traits and T2DM were collected from the Finngen database. The summary data for fasting glucose, fasting insulin, and HbA1c were obtained from the open GWAS database established by the MRC Integrated Epidemiology Unit (IEU). The inverse-variance weighted (IVW) approach was used to obtain MR estimates, and various sensitivity analysis was also performed., Results: NDG had a potential protective causal relationship with T2DM (OR = 0.978; 95% CI: 0.957-0.998; p = 0.034) and fasting glucose (OR = 0.995; 95% CI: 0.990-0.999; p = 0.011), while NMG had a potential protective causal relationship with T2DM (OR = 0.941; 95% CI: 0.902-0.982; p = 0.008) and HbA1c (OR = 0.992; 95% CI: 0.986-0.998; p = 0.015). OUNG was found to decrease the odds of T2DM by 4.4% (OR = 0.966; 95% CI: 0.938-0.995, p = 0.023). T2DM had a potential causal relationship with NDG (OR = 1.239; 95% CI: 1.020-1.504; p = 0.031), and a potential protective effect against NMG (OR = 0.669; 95% CI: 0.566-0.792; p < 0.001) and OUNG (OR = 0.694; 95% CI: 0.545-0.883; p = 0.004). There was no evidence of a positive association between glycemic traits and nontoxic goitre traits (p > 0.05)., Conclusions: Our findings indicate a potential causal relationship between nontoxic goitre traits and T2DM. Specifically, our study addresses that NMG and T2DM may have a significant causal effect on each other in both directions., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

Elevated blood glucose concentration due to food intake will trigger insulin secretion from the dorsal pancreas has been extensively studied. This increased intracellular insulin level can stimulate glucagon release from intra-islets. However, the interaction between glucagon and insulin under a fasting state is unknown. To explore the relationship, we partially removed the ventral and dorsal pancreas on wild-type adult rats. The glucose tolerance test was conducted to measure influence of the surgery on the integrity function of the pancreas. The fasting insulin/glucagon level before and after surgery were measured by the ELISA kit. The statistical analyses indicated that the ventral removal of the pancreas had higher fasting glucose than that of dorsal removal. And only the ventral removal group showed significantly increased basal insulin and basal glucagon levels. Our findings showed differential role of the ventral pancreas in response to a glucose-free stimulus and also provided the possible in vitro target for developing the anti-hyperglycemic drugs. [ABSTRACT FROM AUTHOR]

Background: Evidence on the effects of dietary interventions on inflammatory markers in individuals with obesity and type 2 diabetes mellitus (T2DM) is scarce. Our study evaluated the effects of extra-virgin olive oil alone and in combination with a traditional Brazilian diet on inflammatory markers and glycemic profiles in adults with both T2DM and class II/III obesity. Methods: Adults aged 18-64 years with T2DM and class II/III obesity were randomized into two intervention groups: 1) extra-virgin olive oil only and 2) extra-virgin olive oil + a traditional Brazilian diet (OliveOil+DietBra). Data on sociodemographic characteristics, lifestyle, anthropometry, biochemical markers and inflammatory markers were collected. The primary outcomes were glycemic parameters and inflammatory markers. The body mass index (BMI) and weight were the secondary outcomes. Results: Forty individuals with T2DM and class II/III obesity were enrolled, and 34 (85%) completed the intervention course. The intake of olive oil was 37.88 ± 12.50 mL/day in the olive oil group and 37.71 ± 12.23 mL/day in the OliveOil+DietBra group, with no significant difference between groups (p = 0.484). Compared to the olive oil only group, the OliveOil+DietBra group had significantly lower levels of fasting insulin (p = 0.047) at the end of the intervention, whereas the other glycemic parameters were not altered. In the OliveOil+DietBra group, serum levels of inflammatory cytokines, IL-1α (p = 0.006) and adiponectin (p = 0.049) were lower and those of TNFα were higher (p = 0.037). There was a significant reduction in BMI and weight compared to the baseline values in the OliveOil+DietBra group (p = 0.015). Conclusions: The intervention with OliveOil+DietBra effectively decreased the levels of fasting insulin, IL-1α and adiponectin, suggesting its beneficial role in improving the inflammatory profiles and fasting insulin levels in adults with class II/III obesity and T2DM. Clinical Trial Registration: ClinicalTrials.gov , identifier: NCT02463435 [ABSTRACT FROM AUTHOR]

Objective: Whether fasting insulin (FI) plays a role in cancer risk remains unclear. This study aimed to investigate the association between FI and cancer risk and to explore its potential mediator role in the association between type 2 diabetes mellitus (T2DM) and cancer. Methods: Two-sample Mendelian randomization (TSMR) analysis was performed to evaluate the effect of FI on overall and 14 site-specific cancers using genome-wide association study (GWAS) summary-level data from Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) and consortia of 14 site-specific cancers. The primary MR approach was conducted by using the random-effect inverse-variance weighted (IVW) method, and sensitivity analyses were implemented by adopting weighted-median, weighted-mode, MR-Egger, and MR-PRESSO tests. Polygenic risk score analysis was executed by using individual-level data from UK Biobank to validate the findings from TSMR analyses. Multivariable Mendelian randomization (MVMR) was carried out to estimate the mediation effect of FI on the association between T2DM and cancer. Results: TSMR study suggested that genetically determined high FI levels were associated with increased risk of colorectal cancer (odds ratio (OR) = 1.87, 95% CI: 1.23–2.84, p = 0.003) and endometrial cancer (OR = 1.89, 95% CI: 1.08–3.01, p = 0.008), but not associated with overall cancer risk or the other 12 studied cancer sites. Polygenic risk score analysis successfully replicated the association between genetic liability to high FI levels and the increased risk of colorectal and endometrial cancers. MVMR and MR mediation analyses detected an intermediary effect of FI and quantified that FI mediated 21.3% of the association between T2DM and endometrial cancer. Conclusions: This study demonstrated that FI levels are associated with the risk of colorectal and endometrial cancers, and FI was found to play an intermediary role in the association between T2DM and endometrial cancer. The associations between FI and other cancers need to be further studied. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR.Methods: Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10-8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR.Results: In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10-31), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10-12), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10-9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10-7) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10-4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10-2) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10-3), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10-8) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10-2) in the relationship between BMI and endometrial cancer risk.Conclusions: Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer. [ABSTRACT FROM AUTHOR]

BackgroundSleep deprivation and poor sleep quality contribute to increases in oxidative stress, antioxidant imbalance, and a pro-inflammatory state which may predispose to a higher risk of diabetes. Our objective was to estimate the contributions of C-reactive protein (CRP), gamma glutamyl transferase (GGT), and micronutrient antioxidants (bilirubin, carotenoids, uric acid, vitamins A, C–E?) to the relationships between sleep-fasting insulin concentration and -glycosylated hemoglobin (HbA1c).MethodsData from the 2005/06 US National Health and Nutritional Examination Survey were used (N = 1,946; 20 y+). Sleep quality and quantity was assessed by the Sleep Disorders Questionnaire, and fasting blood was collected to quantify CRP, GGT, antioxidant micronutrients, insulin concentration, and HbA1c. The bootstrap method was used to estimate the amount of mediation or contribution of these mediators to the sleep–insulin concentration and -HbA1c relationships, which were quantified as large (≥0.25) or moderate (≥0.09).ResultsThe sleep duration–fasting insulin relationship was mediated by GGT, carotenoids, uric acid, and vitamins C and D, whereas CRP and bilirubin were non-significant mediators of a moderate effect size. Similarly, the sleep quality–fasting insulin relationship was mediated by CRP, bilirubin and vitamin C, whereas GGT, carotenoids, uric acid, and vitamin D were non-significant large-to-moderate mediators. To a lesser degree, these micronutrients mediated for the relationship between sleep-HbA1c levels.ConclusionSeveral factors related to inflammation, oxidative stress, and antioxidant status were found to lie on the pathway of the sleep–insulin and –glycemic control relationships. Sleep hygiene, reduced systemic inflammation/oxidative stress, and optimal antioxidants intake are potentially beneficial targets for managing diabetes risk.

BackgroundEvidence on the effects of dietary interventions on inflammatory markers in individuals with obesity and type 2 diabetes mellitus (T2DM) is scarce. Our study evaluated the effects of extra-virgin olive oil alone and in combination with a traditional Brazilian diet on inflammatory markers and glycemic profiles in adults with both T2DM and class II/III obesity.MethodsAdults aged 18-64 years with T2DM and class II/III obesity were randomized into two intervention groups: 1) extra-virgin olive oil only and 2) extra-virgin olive oil + a traditional Brazilian diet (OliveOil+DietBra). Data on sociodemographic characteristics, lifestyle, anthropometry, biochemical markers and inflammatory markers were collected. The primary outcomes were glycemic parameters and inflammatory markers. The body mass index (BMI) and weight were the secondary outcomes.ResultsForty individuals with T2DM and class II/III obesity were enrolled, and 34 (85%) completed the intervention course. The intake of olive oil was 37.88 ± 12.50 mL/day in the olive oil group and 37.71 ± 12.23 mL/day in the OliveOil+DietBra group, with no significant difference between groups (p = 0.484). Compared to the olive oil only group, the OliveOil+DietBra group had significantly lower levels of fasting insulin (p = 0.047) at the end of the intervention, whereas the other glycemic parameters were not altered. In the OliveOil+DietBra group, serum levels of inflammatory cytokines, IL-1α (p = 0.006) and adiponectin (p = 0.049) were lower and those of TNFα were higher (p = 0.037). There was a significant reduction in BMI and weight compared to the baseline values in the OliveOil+DietBra group (p = 0.015).ConclusionsThe intervention with OliveOil+DietBra effectively decreased the levels of fasting insulin, IL-1α and adiponectin, suggesting its beneficial role in improving the inflammatory profiles and fasting insulin levels in adults with class II/III obesity and T2DM.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT02463435

ObjectiveWhether fasting insulin (FI) plays a role in cancer risk remains unclear. This study aimed to investigate the association between FI and cancer risk and to explore its potential mediator role in the association between type 2 diabetes mellitus (T2DM) and cancer.MethodsTwo-sample Mendelian randomization (TSMR) analysis was performed to evaluate the effect of FI on overall and 14 site-specific cancers using genome-wide association study (GWAS) summary-level data from Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) and consortia of 14 site-specific cancers. The primary MR approach was conducted by using the random-effect inverse-variance weighted (IVW) method, and sensitivity analyses were implemented by adopting weighted-median, weighted-mode, MR-Egger, and MR-PRESSO tests. Polygenic risk score analysis was executed by using individual-level data from UK Biobank to validate the findings from TSMR analyses. Multivariable Mendelian randomization (MVMR) was carried out to estimate the mediation effect of FI on the association between T2DM and cancer.ResultsTSMR study suggested that genetically determined high FI levels were associated with increased risk of colorectal cancer (odds ratio (OR) = 1.87, 95% CI: 1.23–2.84, p = 0.003) and endometrial cancer (OR = 1.89, 95% CI: 1.08–3.01, p = 0.008), but not associated with overall cancer risk or the other 12 studied cancer sites. Polygenic risk score analysis successfully replicated the association between genetic liability to high FI levels and the increased risk of colorectal and endometrial cancers. MVMR and MR mediation analyses detected an intermediary effect of FI and quantified that FI mediated 21.3% of the association between T2DM and endometrial cancer.ConclusionsThis study demonstrated that FI levels are associated with the risk of colorectal and endometrial cancers, and FI was found to play an intermediary role in the association between T2DM and endometrial cancer. The associations between FI and other cancers need to be further studied.

Background: Obesity increase the risk for type 2 diabetes through induction of insulin resistance. Diagnosis of diabetes were based on blood glucose level. However, insulin resistance may had happened far before diagnosis itself. This study aimed to compare fasting insulin level, insulin resistance, and blood glucose pattern during oral glucose load in healthy obese and non-obese subject. Methods: This semi-experimental study was conducted at Department of Internal Medicine, Sanglah Hospital, Denpasar. Sixteen subjects in each obese and non-obese group were matched by age and sex. Obesity was defined based on body mass index (BMI) of ≥25kg/m2 and waist circumference (WC) ≥80cm (female) or ≥90cm (male). The non-obese group was defined by BMI of 18-25kg/m2 and WC

Sesame, with an oily seed containing oil, lignans, and proteins, is a popular plant that has demonstrated health benefits such as antioxidative, antiobesity, and antiinflammatory effects. In this systematic review and meta‐analysis, we aimed to summarize the effect of sesame seeds and their consumption compared to a control group on blood glucose and insulin resistance in human adults. PubMed/MEDLINE, SCOPUS, Web of Science, Google Scholar, and EMBASE were searched to identify eligible controlled clinical trials up to February 2021. Finally, eight clinical trials were included in this study. Sesame products used in these trials were sesame oil, sesamin, and tahini, and the duration of the intervention varied from 45 days to 9 weeks. Our results showed the significant positive effects of sesame and its products on fasting blood glucose FBG (weighted mean difference, WMD: −21.31 mg/dl, 95% CI: −41.23, −1.39, p =.036) and HbA1c (WMD: −0.75, 95% CI: −1.16, −0.34, p <.001) levels but results about fasting serum insulin (WMD: 5.51 μU/ml, 95% CI: −2.31, 13.33, p =.167) and HOMA‐IR (WMD: −0.07, 95% CI: −0.33, 0.20, p =.617) were not meaningful. Sesame may be considered a beneficial agent for human glucose metabolism and can be a part of glucose‐lowering diets. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is an age-related and skeletal muscle disorder involving the loss of muscle mass or strength, and physiological function. Although the diagnostic indicators used in the different guidelines are for muscle mass, strength and physical performance, there are currently no uniform diagnostic criteria. Therefore, we aimed to explore the relationship between a series of biomarkers with sarcopenia in southwest China. Methods: We included 4302 patients from West China Health and Aging Trend (WCHAT) study. Sarcopenia was defined according to the Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. Thyroxine、albumin、total protein、prealbumin、albumin to globulin ratio (A/G)、25(OH)VD、fasting insulin、adrenal cortisol、triglyceride、high-density lipoprotein、hemoglobin and aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT) were measured. The receiver operating characteristic curves (ROC) were established to describe the predictive value for sarcopenia and we also used multivariate logistic regression analysis to identify risk factors of the disease. Results: In terms of protein state, patients with sarcopenia had lower value in total protein, albumin, prealbumin, A/G than the control (P <0.001). Patients had lower value in triglyceride but higher value in high-density lipoprotein compared with the healthy in the indicators of lipid metabolism (P <0.001). In the aspect of hormone state, patients had lower free triiodothyronine, fasting insulin but higher free tetraiodothyronine and adrenal cortisol than the healthy (P <0.001). The fasting insulin level (AUC=0.686) and the AST/ALT ratio (AUC=0.682) were the best predictors of sarcopenia among biomarkers. The diagnostic performance of fasting insulin combined with the AST/ALT ratio (AUC=0.720) is equal to multiple indicators (AUC=0.742). Conclusion: The fasting insulin combined with the AST/ALT ratio exhibits good diagnostic performance for sarcopenia. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children. Methods: We included 312 normal-weight youth exposed or unexposed to overnutrition in utero (maternal BMI ≥25 kg/m2 or gestational diabetes). Fasting insulin, glucose and body composition were measured at age ~10 years (baseline) and ~16 years (follow-up). We examined associations of overnutrition in utero with baseline fasting insulin, followed by associations of baseline fasting insulin with adiposity (BMI z score [BMIZ], subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT]), insulin resistance (HOMA-IR) and fasting glucose during follow-up. Results: >All participants were normal weight at baseline (BMIZ −0.32 ± 0.88), with no difference in BMIZ for exposed vs unexposed youth (p = 0.14). Of the study population, 47.8% were female sex and 47.4% were of white ethnicity. Overnutrition in utero corresponded with 14% higher baseline fasting insulin (geometric mean ratio 1.14 [95% CI 1.01, 1.29]), even after controlling for VAT/SAT ratio. Higher baseline fasting insulin corresponded with higher BMIZ (0.41 [95% CI 0.26, 0.55]), SAT (13.9 [95% CI 2.4, 25.4] mm2), VAT (2.0 [95% CI 0.1, 3.8] mm2), HOMA-IR (0.87 [95% CI 0.68, 1.07]) and fasting glucose (0.23 [95% CI 0.09, 0.38] SD). Conclusions/interpretation: Overnutrition in utero may result in hyperinsulinaemia during childhood, preceding development of adiposity. However, our study started at age 10 years, so earlier metabolic changes in response to overnutrition were not taken into account. Longitudinal studies in normal-weight youth starting earlier in life, and with repeated measurements of body weight, fat distribution, insulin sensitivity, beta cell function and blood glucose levels, are needed to clarify the sequence of metabolic changes linking early-life exposures to adiposity and dysglycaemia. [ABSTRACT FROM AUTHOR]

BackgroundSarcopenia is an age-related and skeletal muscle disorder involving the loss of muscle mass or strength, and physiological function. Although the diagnostic indicators used in the different guidelines are for muscle mass, strength and physical performance, there are currently no uniform diagnostic criteria. Therefore, we aimed to explore the relationship between a series of biomarkers with sarcopenia in southwest China.MethodsWe included 4302 patients from West China Health and Aging Trend (WCHAT) study. Sarcopenia was defined according to the Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. Thyroxine、albumin、total protein、prealbumin、albumin to globulin ratio (A/G)、25(OH)VD、fasting insulin、adrenal cortisol、triglyceride、high-density lipoprotein、hemoglobin and aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT) were measured. The receiver operating characteristic curves (ROC) were established to describe the predictive value for sarcopenia and we also used multivariate logistic regression analysis to identify risk factors of the disease.ResultsIn terms of protein state, patients with sarcopenia had lower value in total protein, albumin, prealbumin, A/G than the control (P

While the co-morbidity between metabolic and psychiatric behaviors is well-established, the mechanisms are poorly understood, and exposure to early life adversity (ELA) is a common developmental risk factor. ELA is associated with altered insulin sensitivity and poor behavioral inhibition throughout life, which seems to contribute to the development of metabolic and psychiatric disturbances in the long term. We hypothesize that a genetic background associated with higher fasting insulin interacts with ELA to influence the development of executive functions (e.g., impulsivity in young children). We calculated the polygenic risk scores (PRSs) from the genome-wide association study (GWAS) of fasting insulin at different thresholds and identified the subset of single nucleotide polymorphisms (SNPs) that best predicted peripheral insulin levels in children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort [N = 467; pt– initial = 0.24 (10,296 SNPs), pt– refined = 0.05 (57 SNPs)]. We then calculated the refined PRS (rPRS) for fasting insulin at this specific threshold in the children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort and investigated its interaction effect with adversity on an impulsivity task applied at 36 months. We found a significant effect of interaction between fasting insulin rPRS and adversity exposure predicting impulsivity measured by the Snack Delay Task at 36 months [β = −0.329, p = 0.024], such that higher PRS [β = −0.551, p = 0.009] was linked to more impulsivity in individuals exposed to more adversity. Enrichment analysis (MetaCoreTM) of the SNPs that compose the fasting insulin rPRS at this threshold was significant for certain nervous system development processes including dopamine D2 receptor signaling. Additional enrichment analysis (FUMA) of the genes mapped from the SNPs in the fasting insulin rPRS showed enrichment with the accelerated cognitive decline GWAS. Therefore, the genetic background associated with risk for adult higher fasting insulin moderates the impact of early adversity on childhood impulsivity.

While the co-morbidity between metabolic and psychiatric behaviors is well-established, the mechanisms are poorly understood, and exposure to early life adversity (ELA) is a common developmental risk factor. ELA is associated with altered insulin sensitivity and poor behavioral inhibition throughout life, which seems to contribute to the development of metabolic and psychiatric disturbances in the long term. We hypothesize that a genetic background associated with higher fasting insulin interacts with ELA to influence the development of executive functions (e.g., impulsivity in young children). We calculated the polygenic risk scores (PRSs) from the genome-wide association study (GWAS) of fasting insulin at different thresholds and identified the subset of single nucleotide polymorphisms (SNPs) that best predicted peripheral insulin levels in children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort [ N = 467; p t – initial = 0.24 (10,296 SNPs), p t – refined = 0.05 (57 SNPs)]. We then calculated the refined PRS (rPRS) for fasting insulin at this specific threshold in the children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort and investigated its interaction effect with adversity on an impulsivity task applied at 36 months. We found a significant effect of interaction between fasting insulin rPRS and adversity exposure predicting impulsivity measured by the Snack Delay Task at 36 months [β = −0.329, p = 0.024], such that higher PRS [β = −0.551, p = 0.009] was linked to more impulsivity in individuals exposed to more adversity. Enrichment analysis (MetaCoreTM) of the SNPs that compose the fasting insulin rPRS at this threshold was significant for certain nervous system development processes including dopamine D2 receptor signaling. Additional enrichment analysis (FUMA) of the genes mapped from the SNPs in the fasting insulin rPRS showed enrichment with the accelerated cognitive decline GWAS. Therefore, the genetic background associated with risk for adult higher fasting insulin moderates the impact of early adversity on childhood impulsivity. [ABSTRACT FROM AUTHOR]