The relationship between dietary intake of live microbes and insulin resistance among healthy adults in the US: a cross-sectional study from NHANES 2003-2020.

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.

Oily fish reduces the risk of acne by lowering fasting insulin levels: A Mendelian randomization study.

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.

Serum Zinc Levels in Women with Polycystic Ovarian Syndrome are Lower as Compared to Those without Polycystic Ovarian Syndrome: A Cohort Study.

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.

Genetic underpinnings of fasting and oral glucose-stimulated based insulin sensitivity indices.

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 two 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=5,343), 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 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.

Glucose Metabolism and Sex Hormones in Male Patients with Medication-naïve First-episode Schizophrenia: A Large-scale Cross-sectional Study.

BACKGROUND: Schizophrenia (SCZ) usually begins in early adult life. The underlying molecular mechanisms of SCZ remain unclear. There is evidence for the involvement of abnormalities in metabolic and endocrine systems in SCZ, even in drug-naïve first-episode schizophrenia patients (DNFES). However, the association between impaired regulation of glucose metabolism and sex hormones was not studied in SCZ. This study aimed to evaluate the interrelationship between sex hormones and high fasting glucose levels in male DNFES patients. METHODS: A total of 99 patients with SCZ were recruited, and fasting glucose, fasting insulin, the insulin resistance index (HOMA-IR), and sex hormones were measured. RESULTS: We found that some male patients with SCZ had abnormal levels in glucose metabolism parameters and gonadal hormones that were not within the normal range. Linear regression analysis adjusted for age, waist circumference, and body mass index showed that testosterone levels were negatively associated with fasting insulin in male patients (ß = -0.21, t = -2.2, p = 0.03). CONCLUSION: Our findings confirm the abnormalities in glucose metabolism parameters and gonadal hormones at the onset of the illness in male DNFES patients with SCZ. In addition, there was an interaction effect between abnormal glucose metabolism and sex hormones in male patients.

A single all-out bout of 30-s sprint-cycle performed on 5 consecutive days per week over 6 weeks does not enhance cardiovascular fitness, maximal strength, and clinical health markers in physically active young adults.

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.

Sex- and time-specific associations of obesity with glycaemic traits: A two-step multivariate Mendelian randomization study.

AIM: To assess the sex- and time-specific causal effects of obesity-related anthropometric traits on glycaemic traits. MATERIALS AND METHODS: We used univariate and multivariate Mendelian randomization to assess the causal associations of anthropometric traits (gestational variables, birth weight, childhood body mass index [BMI], BMI, waist-to-hip ratio [WHR], BMI-adjusted WHR [WHRadj BMI]) with fasting glucose and insulin in Europeans from the Early Growth Genetics Consortium (n ≤ 298 142), the UK Biobank, the Genetic Investigation of Anthropometric Traits Consortium (n ≤ 697 734; females: n ≤ 434 794; males: n ≤ 374 754) and the Meta-Analyses of Glucose and Insulin-related traits Consortium (n ≤ 151 188; females: n ≤ 73 089; males: n ≤ 67 506), adjusting for maternal genetic effects, smoking, alcohol consumption, and age at menarche. RESULTS: We observed a null association for gestational variables, a negative association for birth weight, and positive associations for childhood BMI and adult traits (BMI, WHR, and WHRadj BMI). In female participants, increased birth weight causally decreased fasting insulin (betaIVW , -0.07, 95% confidence interval [CI] -0.11 to -0.03; p = 1.92 × 10-3 ), but not glucose levels, which was annulled by adjusting for age at menarche. In male participants, increased birth weight causally decreased fasting glucose (betainverse-variance-weighted (IVW) , -0.07, 95% CI -0.11 to -0.03; p = 3.22 × 10-4 ), but not insulin levels. In time-specific analyses, independent effects of birth weight were absent in female participants, and were more pronounced in male participants. Independent effects of childhood BMI were attenuated in both sexes; independent effects of adult traits differed by sex. CONCLUSIONS: Our findings provide evidence for causal and independent effects of sex- and time-specific anthropometric traits on glycaemic variables, and highlight the importance of considering multiple obesity exposures at different time points in the life course.

Type 2 diabetes and fasting glycemic traits are causal factors of frozen shoulder: a 2-sample Mendelian randomization analysis.

BACKGROUND: 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 [HbA1c], and 2-hour postprandial glucose [2hGlu]) on frozen shoulder. METHODS: 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. RESULTS: 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, HbA1c, and 2hGlu and frozen shoulder. Although there was certain heterogeneity, sensitivity analysis reveals no deviation from the MR assumptions. CONCLUSION: This study supports a genetic causal relationship between T2D and FG and frozen shoulder.

Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study.

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.

Association between suicidal behavior and impaired glucose metabolism in first-episode drug-naïve patients with schizophrenia.

BACKGROUND: Schizophrenia (SZ) patients have been reported to have comorbid suicidal behavior (SB) and impaired glucose metabolism in early psychosis, but it is unclear whether impaired glucose metabolism plays a role in the occurrence of SB in patients with first-episode drug-naïve (FEDN) SZ. Therefore, our main aim was to examine the relationship between SB and glucose metabolism in FEDN SZ patients. METHODS: We recruited 319 FEDN SZ patients and collected information on their sociodemographic characteristics, clinical data, and glucose metabolism parameters. Participants' psychotic and depressive symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HAMD), respectively. Fasting plasma glucose and insulin levels were also measured. RESULTS: The percentage of FEDN SZ patients with SB was 45.5% (145/319). Compared to SZ patients without SB, SZ patients with SB exhibited higher scores on HAMD, PANSS positive subscale, as well as higher levels of fasting plasma glucose, fasting plasma insulin, and homeostasis model assessment of insulin resistance index (all p<0.05). Logistic regression analysis indicated that increased levels of insulin resistance (adjusted OR = 1.920), body mass index (adjusted OR = 0.931), and PANSS general psychopathology (adjusted OR = 1.041) were independently associated with SB. The Receiver Operating Characteristic Curve showed an Area Under Curve value of 0.732 for the combination of three factors in regression model to distinguish between SB and non-SB. CONCLUSIONS: Our results indicate that fasting glucose, fasting insulin, and insulin resistance are strongly associated with SB in FEDN SZ patients, suggesting that glucose metabolism abnormalities may be potential biomarkers of SB in SZ patients. Regular monitoring of glucose metabolism variables is essential for suicide prevention.

Predictors of controlled attenuation parameter in metabolic dysfunction.

BACKGROUND & AIMS: Hepatic fat content can be non-invasively estimated by controlled attenuation parameter (CAP) during transient elastography. The aim of this study was to examine the determinants and predictors of CAP values in individuals with metabolic dysfunction. METHODS: We enrolled 1230 consecutive apparently healthy individuals (Liver-Bible-2022 cohort) with ≥3 metabolic dysfunction features. CAP was measured by Fibroscan. CAP determinants and predictors were identified using backward stepwise analysis and introduced in generalized linear models. RESULTS: Participants were predominantly males (82.9%), mean age was 53.8 ± 6.4 years, 600 (48.8%) had steatosis (CAP ≥ 275 dB/m), and 27 had liver stiffness measurement (LSM) ≥ 8 kPa. CAP values correlated with LSM (p < 10-22). In multivariable analysis, fasting insulin and abdominal circumference (AC) were the main determinants of CAP (p < 10-6), together with body mass index (BMI; p < 10-4), age, diabetes, triglycerides, ferritin, and lower HDL and thyroid stimulating hormone (TSH; p < 0.05 for all). In a subset of 592 participants with thyroid hormone measurement, we found an association between higher free triiodothyronine levels, correlating with lower TSH, and CAP values, independent of TSH and of levothyroxine treatment (p = 0.0025). A clinical CAP score based on age, BMI, AC, HbA1c, ALT, and HDL predicted CAP ≥ 275 dB/m with moderate accuracy (AUROC = 0.73), which was better than that of the Fatty Liver Index and of ALT (AUROC = 0.70/0.61, respectively) and validated it in multiple cohorts. CONCLUSION: Abdominal adiposity and insulin resistance severity were the main determinants of CAP in individuals with metabolic dysfunction and may improve steatotic liver disease risk stratification. CAP values were modulated by the hypophysis-thyroid axis.

High blood pressure mediated the effect of fasting insulin level on nonalcoholic fatty liver disease risk: A Mendelian randomization study.

Objective: The interactions between fasting insulin levels, high blood pressure and nonalcoholic fatty liver disease (NAFLD) are still unclear. We examined the causal mechanisms between these three cardiometabolic traits using Mendelian randomization (MR) approach by utilizing genetic instruments. Methods: Three different genome-wide association studies resources of European ancestry were utilized for the present study. Two-sample MRs were used to assess causal effects between fasting insulin levels, high blood pressure and NAFLD. Multivariate MR was used to calculate the mediating effect. The inverse variance-weighted method was used as the main analysis method. Results: Our study confirmed a causal effect of fasting insulin levels (IVW-OR = 9.54, P = 0.001) and high blood pressure (IVW-OR = 3.926, P = 0.005) on NAFLD risk. And fasting insulin level was positively casually associated with high blood pressure risk (IVW-OR = 1.170, P < 0.001). However, the impact of high blood pressure on fasting insulin levels was still uncertain because of the presence of horizontal pleiotropy. Reverse MR showed NAFLD had a positive correlation with fasting insulin levels (IVW-OR = 1.010, P < 0.001) and a negative causal effect on high blood pressure risk (IVW-OR = 0.997, P = 0.037). Combined the multivariate MR result revealed high blood pressure partially mediated the contribution of fasting insulin level to NAFLD risk (proportion mediated: 9.091%). Conclusions: Our study suggests there is a bidirectional causal relationship between fasting insulin levels and NAFLD. High blood pressure seems to play a mediating role in the development of NAFLD caused by changes in fasting insulin levels. However, it is uncertain whether high blood pressure is a mediator between NAFLD and the risk of fasting insulin level.

Plant-based dietary patterns and fasting insulin: a cross-sectional study from NHANES 2017-2018.

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.

High Insulin Resistance in Saudi Women with Unexplained Recurrent Pregnancy Loss: A Case-control Study.

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.

The clinical implications of fasting serum insulin levels in patients with insulin-treated type 2 diabetes: a cross-sectional survey.

Objective: This study aimed to investigate the clinical implications of fasting serum insulin (FINS) levels in subjects with type 2 diabetes who were receiving insulin therapy. Methods: A total of 1,553 subjects with type 2 diabetes [774 subjects who had never received insulin treatment (N-INS) and 779 subjects who were receiving insulin therapy (constant insulin treatment, C-INS)] admitted to the Department of Endocrinology and Metabolism of Peking University People's Hospital were enrolled in this study. Their FINS levels were measured and those with hyperinsulinemia were identified. The underlying mechanisms of hyperinsulinemia were revealed by measuring insulin antibodies (IAs) and analyzing changes in FINS levels before and after polyethylene glycol (PEG) precipitation. In addition, the clinical characteristics of patients with different types of hyperinsulinemia were compared. Results: Higher FINS levels and a higher incidence (43.8%, 341/779) of hyperinsulinemia (FINS > 15µIU/mL) were observed in subjects with C-INS than in subjects with N-INS. Among subjects with C-INS and hyperinsulinemia, 66.9% (228/341) were IAs positive, and the incidence of IAs was found to be positively associated with FINS level. By performing PEG precipitation, we found that all subjects without IAs (i.e., those with real hyperinsulinemia) and 31.1% of subjects (71/228) with IAs (i.e., those with both real and IAs-related hyperinsulinemia) still had hyperinsulinemia after PEG precipitation, whereas FINS levels in the other 68.9% of subjects (157/228) with IAs were normal (IAs-related hyperinsulinemia) after PEG precipitation. Comparisons between the groups showed that subjects with real hyperinsulinemia showed more obvious insulin resistance characteristics, including higher lipid levels, BMIs, and homoeostasis model assessment2-estimated insulin resistance (HOMA2-IR) index, and were more likely to have hypertension, obesity, and metabolic syndromes (p < 0.05). However, the risk of hypoglycemia and glucose variability increased significantly in subjects with IAs compared with those without IAs. A cutoff of FINS to serum C-peptide ratio (≥ 9.3µIU/ng) could be used to screen IAs in clinical practice with 83.3% sensitivity and 70% specificity. Conclusions: It is necessary to measure FINS in subjects with C-INS to distinguish between types of hyperinsulinemia, which should help to tailor treatment regimens.

Type 2 diabetes has a protective causal association with thoracic aortic aneurysm: a Mendelian randomization study.

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.

Effects of combined treatment of probiotics and metformin in management of type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Lifestyle changes and dietary intervention, including the use of probiotics, can modulate dysbiosis of gut microbiome and contribute to the management of type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aim to assess the efficacy of metformin plus probiotics versus metformin alone on outcomes in patients with T2DM. METHODS: We searched MEDLINE and EMBASE from inception to February 2023 to identify all randomized controlled trials (RCTs), which compared the use of metformin plus probiotics versus metformin alone in adult patients with T2DM. Data were summarized as mean differences (MD) with 95 % confidence interval (CI) and pooled under the random effects model. FINDINGS: Fourteen RCTs (17 comparisons, 1009 patients) were included in this systematic review. Pooled results show a significant decrease in fasting glucose (FG) (MD = -0.64, 95 % CI = -1.06, -0.22) and HbA1c (MD = -0.29, 95 % CI = -0.47, -0.10) levels in patients with T2DM treated with metformin plus probiotics versus metformin alone. The addition of probiotics to metformin resulted in lower odds of gastrointestinal adverse events (Odds ratio = 0.18, 95 % CI = 0.09, 0.3.8; I2 = 0 %). CONCLUSIONS: The addition of probiotics to metformin therapy is associated with improvement in T2DM outcomes. However, high-quality and adequately reported RCTs are needed in the future to confirm our findings.

Effects of metabolic factors in mediating the relationship between Type 2 diabetes and depression in East Asian populations: A two-step, two-sample Mendelian randomization study.

BACKGROUND: Observational studies suggested a close link between type 2 diabetes (T2D), metabolic factors and depression, while the causal relationships remained poorly understood. OBJECTIVE: 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. METHODS: 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. RESULTS: 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 (ß [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). LIMITATIONS: 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. CONCLUSION: 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.

Maternal hair cortisol concentrations and its association with increased insulin resistance in midpregnancy.

PURPOSE: Stress and elevated maternal glycemia have negative effects on pregnancy. We evaluated the association of hair cortisol concentrations (HCC), a marker of chronic stress, with insulin resistance and gestational diabetes (GDM). METHODS: In total, 527 women from Lima, Peru, provided a hair sample in the second trimester of their pregnancy to measure HCC using liquid chromatography-tandem mass spectrometry. Each 6 cm of hair captured HCC in early (T1=1-12 weeks) and midpregnancy (T2 = 13-24 weeks). GDM diagnosis was conducted in midpregnancy. Multivariable regression models adjusted for putative risk factorsincluding maternal sociodemographic factors, diabetes history, and hair characteristics, were used to estimate the association of HCC with GDM and various glycemic traits. RESULTS: GDM was diagnosed in 122 (23%) women. Mean HCC across pregnancy was T1 = 3.7 (±3.4) pg/mg and T2 = 4.8 (±3.4) pg/mg. HCC was associated with increased log-transformed units of fasting insulin (T1 = 0.15 [0.03, 0.27], T2 = 0.17 [0.04, 0.30]), homeostasis model assessment for insulin resistance (T1 = 0.14 [0.01, 0.26], T2 = 0.17 [0.03, 0.30]), and homeostasis model assessment for ß-cell function (T1 = 0.20 [0.05, 0.34], T2 = 0.20 [0.04, 0.36]), but not with GDM (T1 = 0.95 [0.63, 1.40], T2 = 1.11 [0.74, 1.67]). CONCLUSIONS: Elevated maternal HCC was associated with abnormal insulin homeostasis in pregnancy. Dysregulation of the hypothalamic-pituitary-adrenal axis, as reflected by high HCC, may also contribute to insulin resistance syndrome in pregnancy.