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

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

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Identification of cutoff points for Homeostatic Model Assessment for Insulin Resistance index in adolescents: systematic review

Revista Paulista de Pediatria (English Edition) ◽

10.1016/j.rppede.2016.01.004 ◽

2016 ◽

Vol 34 (2) ◽

pp. 234-242 ◽

Cited By ~ 3

Author(s):

Maria Izabel Siqueira de Andrade ◽

Juliana Souza Oliveira ◽

Vanessa Sá Leal ◽

Niedja Maria Silva da Lima ◽

Emília Chagas Costa ◽

...

Keyword(s):

Systematic Review ◽

Insulin Resistance ◽

Resistance Index ◽

Model Assessment ◽

Insulin Resistance Index ◽

Cutoff Points ◽

Homeostatic Model Assessment ◽

Homeostatic Model

Download Full-text

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

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.623143 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kristen M. Ward ◽

Kyle Burghardt ◽

A. Zarina Kraal ◽

Andrew Jaeger ◽

Larisa Yeomans ◽

...

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Carbon Metabolism ◽

Carrier Status ◽

Diabetes Diagnosis ◽

Model Assessment ◽

Least Squares Regression ◽

Increased Risk ◽

Homeostatic Model Assessment ◽

One Carbon Metabolism

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.

Download Full-text

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.

Download Full-text

Interplay of Glycemic Index, Glycemic Load, and Dietary Antioxidant Capacity with Insulin Resistance in Subjects with a Cardiometabolic Risk Profile

International Journal of Molecular Sciences ◽

10.3390/ijms19113662 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3662 ◽

Cited By ~ 10

Author(s):

Cristina Galarregui ◽

María Zulet ◽

Irene Cantero ◽

Bertha Marín-Alejandre ◽

José Monreal ◽

...

Keyword(s):

Insulin Resistance ◽

Antioxidant Capacity ◽

Diet Quality ◽

Glycemic Index ◽

Cardiometabolic Risk ◽

Glycemic Load ◽

Risk Profile ◽

Model Assessment ◽

Susceptible Population ◽

Homeostatic Model Assessment

Background: Dietary total antioxidant capacity (TAC), glycemic index (GI), and glycemic load (GL) are accepted indicators of diet quality, which have an effect on diet–disease relationships. The aim of this study was to evaluate potential associations of dietary TAC, GI, and GL with variables related to nutritive status and insulin resistance (IR) risk in cardiometabolic subjects. Methods: A total of 112 overweight or obese adults (age: 50.8 ± 9 years old) were included in the trial. Dietary intake was assessed by a validated 137-item food frequency questionnaire (FFQ), which was also used to calculate the dietary TAC, GI, and GL. Anthropometrics, blood pressure, body composition by dual-energy X-ray absorptiometry (DXA), glycemic and lipid profiles, C-reactive protein (CRP), as well as fatty liver quantification by magnetic resonance imaging (MRI) were assessed. Results: Subjects with higher values of TAC had significantly lower circulating insulin concentration and homeostatic model assessment of insulin resistance (HOMA-IR). Participants with higher values of HOMA-IR showed significantly higher GI and GL. Correlation analyses showed relevant inverse associations of GI and GL with TAC. A regression model evidenced a relationship of HOMA-IR with TAC, GI, and GL. Conclusion: This data reinforces the concept that dietary TAC, GI, and GL are potential markers of diet quality, which have an impact on the susceptible population with a cardiometabolic risk profile.

Download Full-text

Resveratrol Attenuates Intermittent Hypoxia-Induced Macrophage Migration to Visceral White Adipose Tissue and Insulin Resistance in Male Mice

Endocrinology ◽

10.1210/en.2014-1706 ◽

2014 ◽

Vol 156 (2) ◽

pp. 437-443 ◽

Cited By ~ 40

Author(s):

Alba Carreras ◽

Shelley X. L. Zhang ◽

Isaac Almendros ◽

Yang Wang ◽

Eduard Peris ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Intermittent Hypoxia ◽

Resistance Index ◽

Model Assessment ◽

Male Mice ◽

Insulin Resistance Index ◽

Phosphorylated Akt ◽

Homeostatic Model Assessment ◽

Homeostatic Model

Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

Download Full-text

Plasma Osteopontin Increases After Bariatric Surgery and Correlates with Markers of Bone Turnover But Not with Insulin Resistance

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2383 ◽

2008 ◽

Vol 93 (6) ◽

pp. 2307-2312 ◽

Cited By ~ 43

Author(s):

Michaela Riedl ◽

Greisa Vila ◽

Christina Maier ◽

Ammon Handisurya ◽

Soheila Shakeri-Manesch ◽

...

Keyword(s):

Insulin Resistance ◽

Bariatric Surgery ◽

Resistance Index ◽

Model Assessment ◽

Obese Patients ◽

C Reactive Protein ◽

Reactive Protein ◽

Insulin Resistance Index ◽

Homeostatic Model Assessment ◽

Homeostatic Model

Abstract Context: Osteopontin (OPN) is a multifunctional protein involved in bone metabolism, cardiovascular disease, diabetes, and obesity. OPN levels are elevated in the plasma and adipose tissue of obese subjects, and are decreased with diet-induced weight loss. Objective: We investigated the effect of bariatric surgery on plasma OPN concentrations in morbidly obese patients. Setting: The study was performed at a university hospital. Subjects: We investigated 40 obese patients aged 43.1 ± 1.8 yr, scheduled to undergo bariatric surgery. Roux-en-Y gastric bypass (RYGB) was performed in 30 subjects (27 females, three males), and laparoscopic adjustable gastric banding (LAGB) in 10 subjects (eight females, two males). Study Design: All patients were studied before and 1 yr (10.3–14.8 months) after the intervention. Main Outcome Measures: OPN, leptin, C-reactive protein, insulin, the homeostatic model assessment insulin resistance index, calcium, 25-hydroxyvitamin D, C telopeptide, and osteocalcin were determined. Results: Both bariatric procedures significantly reduced body weight, body mass index, insulin, leptin, and C-reactive protein 1 yr after surgery. Plasma OPN increased from 31.4 ± 3.8 to 52.8 ± 3.7 ng/ml after RYGB (P < 0.001) and from 29.8 ± 6.9 to 46.4 ± 10.6 ng/ml after LAGB (P = 0.042). Preoperative OPN correlated with age, insulin, the homeostatic model assessment insulin resistance index, and postoperative OPN. Postoperative OPN correlated with C telopeptide and osteocalcin. Conclusions: One year after RYGB and LAGB, plasma OPN levels significantly increased and correlated with biomarkers of bone turnover. Unlike other proinflammatory cytokines, OPN does not normalize but increases further after bariatric surgery.

Download Full-text

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.

Download Full-text