Genetic and Metabolite Variability in One-Carbon Metabolism Applied to an Insulin Resistance Model in Patients With Schizophrenia Receiving Atypical Antipsychotics

Background: Patients with schizophrenia are at high risk of pre-mature mortality due to cardiovascular disease (CVD). Our group has completed studies in pharmacogenomics and metabolomics that have independently identified perturbations in one-carbon metabolism as associated with risk factors for CVD in this patient population. Therefore, this study aimed to use genetic and metabolomic data to determine the relationship between folate pharmacogenomics, one-carbon metabolites, and insulin resistance as measured using the homeostatic model assessment for insulin resistance (HOMA-IR) as a marker of CVD.Methods: Participants in this pilot analysis were on a stable atypical antipsychotic regimen for at least 6 months, with no diabetes diagnosis or use of antidiabetic medications. Participant samples were genotyped for MTHFR variants rs1801131 (MTHFR A1298C) and rs1801133 (MTHFR C677T). Serum metabolite concentrations were obtained with NMR. A least squares regression model was used to predict log(HOMA-IR) values based on the following independent variables: serum glutamate, glycine, betaine, serine, and threonine concentrations, and carrier status of the variant alleles for the selected genotypes.Results: A total of 67 participants were included, with a median age of 47 years old (IQR 42–52), 39% were female, and the median BMI was 30.3 (IQR 26.3–37.1). Overall, the model demonstrated an ability to predict log(HOMA-IR) values with an adjusted R2 of 0.44 and a p-value of < 0.001. Glutamate, threonine, and carrier status of the MTHFR 1298 C or MTHFR 677 T allele were positively correlated with log(HOMA-IR), whereas glycine, serine, and betaine concentrations trended inversely with log(HOMA-IR). All factors included in this final model were considered as having a possible effect on predicting log(HOMA-IR) as measured with a p-value < 0.1.Conclusions: Presence of pharmacogenomic variants that decrease the functional capacity of the MTHFR enzyme are associated with increased risk for cardiovascular disease, as measured in this instance by log(HOMA-IR). Furthermore, serine, glycine, and betaine concentrations trended inversely with HOMA-IR, suggesting that increased presence of methyl-donating groups is associated with lower measures of insulin resistance. Ultimately, these results will need to be replicated in a significantly larger population.

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Metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis

European Journal of Pediatrics ◽

10.1007/s00431-020-03924-w ◽

2021 ◽

Author(s):

Francesca Caroppo ◽

Alfonso Galderisi ◽

Laura Ventura ◽

Anna Belloni Fortina

Keyword(s):

Metabolic Disease ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Model Assessment ◽

Limited Data ◽

Single Center ◽

Increased Risk ◽

High Prevalence ◽

Homeostatic Model Assessment ◽

Homeostatic Model

AbstractPsoriasis in adults is associated with an increased risk of metabolic disease. Various cardiometabolic comorbidities have been reported in childhood psoriasis, but only a few studies have analyzed the prevalence of metabolic syndrome. We performed a single-center prospective study investigating the prevalence of metabolic syndrome and insulin resistance in children with psoriasis. The prevalence of metabolic syndrome was evaluated in 60 pre-pubertal children with psoriasis (age: 3–10 years), accordingly to recently established criteria for the diagnosis of metabolic syndrome in children. Insulin resistance was considered altered when the homeostatic model assessment (HOMA-IR) for insulin resistance was ≥ 90th sex- and age-specific percentile and HOMA 2-IR was > 1.8. Eighteen (30%) children with psoriasis were found to have metabolic syndrome. Sixteen (27%) children were found to have insulin resistance.Conclusion: Our data underline the importance of assessing metabolic syndrome not only in adults and adolescents but also in young children with psoriasis. What is Known:• Psoriasis in adults is strongly associated with metabolic disease and insulin resistance.• Very limited data are available on the prevalence of metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis. What is New:• This study reports that in pre-pubertal children with psoriasis, there is a high prevalence of metabolic syndrome and insulin resistance.• In children with psoriasis metabolic syndrome risk factors should be assessed.

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PCOS without hyperandrogenism is associated with higher plasma Trimethylamine N-oxide levels

BMC Endocrine Disorders ◽

10.1186/s12902-019-0486-9 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 2

Author(s):

Jiayu Huang ◽

Lin Liu ◽

Chunyan Chen ◽

Ying Gao

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary ◽

Predictive Biomarker ◽

Normal Weight ◽

Inflammatory Factors ◽

Low Grade ◽

Model Assessment ◽

Increased Risk ◽

Homeostatic Model Assessment ◽

Low Grade Inflammation

Abstract Background Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder, and its pathogenesis is still under debate. Trimethylamine-N-oxide (TMAO) is a small, organic compound generated by the gut microbiome with a hypothesized relation to insulin resistance (IR) and low-grade inflammation in PCOS. By comparing plasma TMAO levels in non-PCOS participants and PCOS patients without hyperandrogenism (HA), we aimed to determine whether plasma TMAO levels correlate with PCOS without HA and to analyze their relationship with low-grade inflammation and IR. Methods A total of 27 PCOS patients without HA and 23 non-PCOS participants were enrolled in this study and subdivided into “nonobese” and “obese” arms for each group. Levels of plasma TMAO were quantified, and basic clinical characteristics and plasma biomarkers of inflammation were assessed. Results First, plasma TMAO levels, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values were higher in PCOS patients without HA, especially in the obese subgroup. Second, the levels of the inflammatory factors interleukin (IL)-17A, IL-18 and interferon gamma (IFN-γ) were significantly increased in obese PCOS patients without HA. Third, plasma TMAO levels were associated with body mass index (BMI) in the normal-weight groups, and the obese groups had higher fasting plasma insulin (FINS) and HOMA-IR values. Finally, logistic regression showed that the plasma levels of TMAO and luteinizing hormone/follicle-stimulating hormone (LH/FSH) were independent predictors of PCOS and indicated an increased risk of PCOS. Conclusions Elevated plasma TMAO levels may be associated with the pathogenesis of PCOS without HA and correlated with increased systemic inflammation. Further studies are needed to determine the suitability of TMAO as a predictive biomarker and to identify possible therapies for PCOS.

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Depression and cardiovascular risk—association among Beck Depression Inventory, PCSK9 levels and insulin resistance

Cardiovascular Diabetology ◽

10.1186/s12933-020-01158-6 ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

C. Macchi ◽

C. Favero ◽

A. Ceresa ◽

L. Vigna ◽

D. M. Conti ◽

...

Keyword(s):

Insulin Resistance ◽

Risk Factor ◽

Beck Depression Inventory ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Model Assessment ◽

Cvd Risk ◽

Assessment Index ◽

Increased Risk ◽

Homeostatic Model Assessment

Abstract Background Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk. Results In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9. Conclusions This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.

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The Insulin Sensitivity Mcauley Index (Mcai) is Associated with 40-Year Cancer Mortality in a Cohort of Men and Women Free of Diabetes at Baseline

10.21203/rs.3.rs-1011207/v1 ◽

2021 ◽

Author(s):

Yonatan Moshkovits ◽

David Rott ◽

Angela Chetrit ◽

Rachel Dankner

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Cancer Mortality ◽

Model Assessment ◽

Cancer Death ◽

Men And Women ◽

Adult Men ◽

Sensitivity Indices ◽

Increased Risk ◽

Homeostatic Model Assessment

Abstract Background:The association between insulin resistance and cancer mortality is not fully explored. We investigated the association between several insulin sensitivity indices (ISIs) and cancer mortality in a cohort of adult men and women free of diabetes. We hypothesized that higher insulin resistance (Q1 of the Mcauley index (MCAi), calculated by fasting insulin and triglycerides, and Q4 of the Homeostatic Model Assessment (HOMA), calculated by fasting plasma glucose and insulin) will be associated with greater cancer mortality risk.Methods: A cohort of 1612 men and women free of diabetes during baseline were followed since 1979 through 2016 for cause specific mortality as part of the Israel study on Glucose Intolerance, Obesity and Hypertension (GOH). Results: Mean age at baseline was 51.5 ± 8.0 years, 804 (49.9%) were males, and 871 (54.0%) had prediabetes. Mean follow-up was 36.7±0.2 years and 47,191 person years were accrued. Cumulative incidence analysis using Cox proportional hazard model and competing risks analysis adjusted for age, sex, country of origin, BMI, blood pressure, total cholesterol, smoking and glycemic status (table 2), revealed an increased risk for cancer death, sub-distribution HR=1.4 (95% CI: 1.1-1.9, p=0.02) for individuals in the lower quartile of MCAi (Q1), denoting higher insulin resistance, compared with the upper quartiles (Q2-4). No statistically significant association was observed between the other insulin resistance surrogates and cancer death.Conclusion: The MCAi was found to independently associate with an increased risk for cancer mortality in adult men and women free of diabetes. The MCAi may be considered as a long-term prognostic biomarker in diabetes-free adults.

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Depression and Cardiovascular Risk - Association Among Beck Depression Inventory, PCSK9 Levels and Insulin Resistance

10.21203/rs.3.rs-56070/v2 ◽

2020 ◽

Author(s):

Chiara Macchi ◽

Chiara Favero ◽

Alessandro Ceresa ◽

Luisella Vigna ◽

Diana Misaela Conti ◽

...

Keyword(s):

Insulin Resistance ◽

Risk Factor ◽

Beck Depression Inventory ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Model Assessment ◽

Cvd Risk ◽

Assessment Index ◽

Increased Risk ◽

Homeostatic Model Assessment

Abstract Background. Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether in a population of obese subjects, more susceptible to depressive symptoms, the presence of depression could affect PCSK9 levels and how these changes may mediate a pre-diabetic risk. Results. In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9. Conclusions. This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.

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Nuclear Magnetic Resonance Derived Biomarkers for Evaluating Cardiometabolic Risk in Youth and Young Adults Across the Spectrum of Glucose Tolerance

Frontiers in Endocrinology ◽

10.3389/fendo.2021.665292 ◽

2021 ◽

Vol 12 ◽

Author(s):

Stephanie T. Chung ◽

Samantha T. Matta ◽

Abby G. Meyers ◽

Celeste K. Cravalho ◽

Alfredo Villalobos-Perez ◽

...

Keyword(s):

Insulin Resistance ◽

Cardiometabolic Risk ◽

Resistance Index ◽

Model Assessment ◽

Predictive Tool ◽

Clinical Trial Registration ◽

Increased Risk ◽

Homeostatic Model Assessment ◽

Normal Glucose ◽

Lipid Testing

Youth with obesity have an increased risk for cardiometabolic disease, but identifying those at highest risk remains a challenge. Four biomarkers that might serve this purpose are “by products” of clinical NMR LipoProfile® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance and type 2 diabetes (T2DM) in adults (glycine inversely) and are independent of biological and methodological variations in insulin assays. However, their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 186 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT, 23 with prediabetes (PreDM), and 33 with T2DM. All four biomarkers were associated with obesity and glycemia in youth. LPIR and GlycA were highest in youth with PreDM and T2DM, whereas glycine was lowest in youth with T2DM. While all four were correlated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LPIR had the strongest correlation (LPIR: r = 0.6; GlycA: r = 0.4, glycine: r = −0.4, BCAA: r = 0.2, all P < 0.01). All four markers correlated with HbA1c (LPIR, GlycA, BCAA: r ≥ 0.3 and glycine: r = −0.3, all P < 0.001). In multi-variable regression models, LPIR, GlycA, and glycine were independently associated with HOMA-IR (Adjusted R2 = 0.473, P < 0.001) and LPIR, glycine, and BCAA were independently associated with HbA1c (Adjusted R2 = 0.33, P < 0.001). An LPIR index of >44 was associated with elevated blood pressure, BMI, and dyslipidemia. Plasma NMR-derived markers were related to adverse markers of cardiometabolic risk in youth. LPIR, either alone or in combination with GlycA, should be explored as a non-insulin dependent predictive tool for development of insulin resistance and diabetes in youth.Clinical Trial RegistrationClinicaltrials.gov, identifier NCT:02960659

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Risk Assessment and Determination of Factors That Cause the Development of Hyperinsulinemia in School-Age Adolescents

Medicina ◽

10.3390/medicina58010009 ◽

2021 ◽

Vol 58 (1) ◽

pp. 9

Author(s):

Igor Lukic ◽

Nikola Savic ◽

Maja Simic ◽

Nevena Rankovic ◽

Dragica Rankovic ◽

...

Keyword(s):

Insulin Resistance ◽

Risk Assessment ◽

At Risk ◽

Statistical Tests ◽

Cross Sectional Study ◽

Model Assessment ◽

Cross Sectional ◽

Increased Risk ◽

Significant Difference ◽

Homeostatic Model Assessment

Background and Objectives: Hyperinsulinemia and insulin resistance are not synonymous; if the risk of developing insulin resistance in adolescents is monitored, they do not necessarily have hyperinsulinemia. It is considered a condition of pre-diabetes and represents a condition of increased risk of developing DM (diabetes mellitus); it can exist for many years without people having the appropriate symptoms. This study aims to determine the risk of developing hyperinsulinemia at an early age in adolescents by examining which factors are crucial for its occurrence. Materials and Methods: The cross-sectional study lasting from 2019 to 2021 (2 years) was realized at the school children’s department in the Valjevo Health Center, which included a total of 822 respondents (392 male and 430 female) children and adolescents aged 12 to 17. All respondents underwent a regular, systematic examination scheduled for school children. BMI is a criterion according to which respondents are divided into three groups. Results: After summary analyzes of OGTT test respondents and calculated values of HOMA-IR (homeostatic model assessment for insulin resistance), the study showed that a large percentage of respondents, a total of 12.7%, are at risk for hyperinsulinemia. The research described in this paper aimed to use the most popular AI (artificial intelligence) model, ANN (artificial neural network), to show that 13.1% of adolescents are at risk, i.e., the risk is higher by 0.4%, which was shown by statistical tests as a significant difference. Conclusions: It is estimated that a model using three different ANN architectures, based on Taguchi’s orthogonal vector plans, gives more precise and accurate results with much less error. In addition to monitoring changes in each individual’s risk, the risk assessment of the entire monitored group is updated without having to analyze all data.

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Depression And Cardiovascular Risk – Association Among Beck Depression Inventory, PCSK9 Levels And Insulin Resistance

10.21203/rs.3.rs-56070/v1 ◽

2020 ◽

Author(s):

Chiara Macchi ◽

Chiara Favero ◽

Alessandro Ceresa ◽

Luisella Vigna ◽

Diana Misaela Conti ◽

...

Keyword(s):

Insulin Resistance ◽

Beck Depression Inventory ◽

Model Assessment ◽

Assessment Index ◽

Increased Risk ◽

Common Causes ◽

Homeostatic Model Assessment ◽

Obese Subjects ◽

Behavioral Mechanisms ◽

Risk Association

Abstract Background. Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. The association of depression with CV outcomes is likely via behavioral mechanisms, e.g. sedentary lifestyle and obesity, this last being more frequently linked to the occurrence of depressive symptoms. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been related to a large number of CV risk factors, e.g. insulin resistance. Aim of this study was to investigate whether in a population of obese subjects, depression could affect PCSK9 levels and how these changes may mediate potentially associated pre-diabetic risk. Results. In 389 obese individuals, mainly women, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels, i.e. for every unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL and with the homeostatic model assessment index of insulin resistance (HOMA-IR). Mediation analysis suggested that PCSK9 levels partially mediates by 11% the effect of BDI-II on HOMA-IR. Conclusions. This study proposes a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence on a role for PCSK9.

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Diets with Higher Insulinemic Potential Are Associated with Increased Risk of Overall and Cardiovascular Disease-specific Mortality

British Journal Of Nutrition ◽

10.1017/s0007114521004815 ◽

2021 ◽

pp. 1-26

Author(s):

Yingying Wang ◽

Bo Chen ◽

Jiawei Zhang ◽

Hairong Li ◽

Xufen Zeng ◽

...

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Dietary Patterns ◽

Cox Regression ◽

Insulin Response ◽

Dietary Factors ◽

Model Assessment ◽

Increased Risk ◽

Specific Mortality ◽

Cvd Mortality

Abstract Hyperinsulinemia and insulin resistance have been proposed to be associated with mortality risk, and diet can modulate insulin response. However, whether dietary patterns with high insulinemic potential are associated with mortality remains unknown. We prospectively examined the associations between hyperinsulinemic diets and the risk of total and cause-specific mortality in a large nationally representative population. Dietary factors were assessed by 24-hour recalls. Two empirical dietary indices for hyperinsulinemia (EDIH) and insulin resistance (EDIR) were developed to identify food groups most predictive of biomarkers for hyperinsulinemia (C-peptide and insulin) and insulin resistance (homeostatic model assessment for insulin resistance), respectively. Deaths from date of the first dietary interview until December 31, 2015 were identified by the National Death Index. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models. During a median follow-up of 7.8 years, 4,904 deaths were documented among 40,074 participants. For EDIH, the multivariable-adjusted HRs (comparing extreme quintiles) were 1.20 (95% CI: 1.09-1.32, P-trend<0.001) for overall mortality, and 1.41 (95% CI: 1.15-1.74, P-trend=0.002) for cardiovascular disease (CVD) mortality. Similar associations were observed for EDIR with HRs of 1.18 (95% CI: 1.07-1.29, P-trend<0.001) for total and 1.35 (95% CI: 1.09-1.67, P-trend=0.005) for CVD mortality. After further adjustments for body mass index and diabetes, these positive associations were somewhat attenuated, but most remained statistically significant. Our findings suggested that diets with higher insulinemic potential are associated with increased risk of overall and CVD-specific mortality. Strategies to avoid hyperinsulinemic dietary patterns may potentially promote health and longevity.

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