Higher HOMA-IR Research Articles

Liver magnetic resonance imaging, non-alcoholic fatty liver disease and metabolic syndrome risk in pre-pubertal Mexican boys.

Rising global pediatric obesity rates, increase non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) prevalence, with MetS being a NAFLD risk factor. NAFLD can be asymptomatic, with liver function tests insensitive to mild disease, and liver biopsy, risking complications. Thus, we investigated multiparametric MRI (mpMRI) metrics of liver fat (proton density fat fraction, PDFF) and disease activity (fibro-inflammation; iron-corrected T1, cT1), in a Hispanic pre-pubertal pediatric cohort, with increased risk of NAFLD. Pre-pubertal boys (n = 81) of varying Body-Mass Index (BMI) were recruited in Mexico City. Most children (81%) had normal liver transaminase levels, 38% had high BMI, and 14% had ≥ 3 MetS risk factors. Applying mpMRI thresholds, 12%, 7% and 4% of the cohort had NAFLD, NASH and high-risk NASH respectively. Participants with ≥ 3 MetS risk factors had higher cT1 (834ms vs. 737ms, p = 0.004) and PDFF (8.7% vs. 2.2%, p < 0.001) compared to those without risk factors. Those with elevated cT1 tended to have high BMI and high insulin (p = 0.005), HOMA-IR (p = 0.005) and leptin (p < 0.001). The significant association of increased risk of MetS with abnormal mpMRI, particularly cT1, proposes the potential of using mpMRI for routine pediatric NAFLD screening of high-risk (high BMI, high MetS risk score) populations.

7718 Dysregulated BCAA catabolism and insulin secretory response in the early stages of insulin resistance in mature adolescents

Abstract Disclosure: A. Basin: None. Q. Wang: None. H. Hong: None. O. Ilkayeva: None. M. Muehlbauer: None. D. Hsia: None. D.A. D'Alessio: None. C.B. Newgard: None. M. Freemark: None. P. Gumus Balikcioglu: None. Objective: We recently showed that surrogate markers of insulin resistance (IR) and insulin secretion are differentially associated with branched-chain amino acids (BCAAs) and their catabolites the branched-chain ketoacids (BCKAs). In this longitudinal study, we determined if baseline levels of BCAAs, BCKAs or the BCKA/BCAA ratio are associated with changes in IR, insulin secretion, and insulin secretion adjusted for IR after a one year follow up in adolescents aged 18-21 yr without Type 2 diabetes. Methods: We performed frequently sampled oral glucose tolerance tests (OGTT) at baseline and one year follow up in 10 adolescents with normal weight and 10 adolescents without Type 2 diabetes but with overweight/obesity and mild IR. After an overnight fast of 8-12 hours, participants had fasting blood samples drawn and consumed 1.75 g/kg, to a maximum of 75 g glucose solution as the initiation of an OGTT. Glucose (G) and insulin (I) were measured at times -15, 0, 10, 15, 30, 45, 60, 90, 120, and 180 minutes. Plasma metabolomic profiles were obtained at time 0. HOMA-IR, Matsuda Index, AUC glucose, AUC insulin, insulinogenic index (IGI) and disposition index (DI) at 15 and 30 min were calculated. % Body fat was measured by TANITA. Results: At one year follow up groups were comparable in age, sex, race, ethnicity and pubertal status. Participants with overweight/obesity had higher BMI (22.5±1.3 vs 36.2±9.7), BF% (16.8±8.4 vs 37.9±10.2), leptin, and diastolic blood pressure than lean participants. They were also more insulin resistant as evidenced by higher HOMA-IR . AUC glucose,AUC insulin, and IGI were comparable across groups, as were fasting BCAA levels and BCKA/BCAA ratio. As with baseline levels, follow-up BCAA levels correlated positively with AUC insulin, HOMA-IR, and IGI at 30 min and negatively with totaland HMW-adiponectin, and Matsuda Index, but did not correlate with BMI or % body fat. Likewise at follow up, BCKAs correlated negatively with total and HMW-adiponectin and did not correlate with Matsuda Index, or HOMA-IR. In association models adjusted for baseline age, sex, and BMI, higher baseline levels of the BCKA, α-keto-β-methylvalerate (KMV, isoleucine catabolite), and a higher BCKA/BCAA ratio were associated with a relative reduction in acute insulin secretion as reflected in a reduction in 15 min IGI at 1 year follow up. Conclusions: In this cohort of adolescents without Type 2 diabetes and with varying degrees of adiposity and insulin sensitivity, we identified KMV as a marker associated with a subsequent reduction in acute glucose-stimulated insulin secretion at one year follow up.These findings suggest that dysregulated BCAA catabolism is associated with loss of compensatory insulin secretion in the face of IR and may play a role in progression to impaired glucose tolerance and development of Type 2 diabetes. Presentation: 6/1/2024

A-073 Is there a relationship of FIB 4 with weight and insulin resistance in subjects without type 2 diabetes and with normal transaminases?

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common hepatic disease, affecting 20-30% of the world's population, and is more frequent in subjects with cardiometabolic diseases. The Fibrosis-4 Index (FIB-4) is a non-invasive scoring system that helps estimate the risk of hepatic fibrosis in MASLD. It is based on age, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelets (PLT). MASLD is associated with high risk of insulin resistance (IR) and type 2 diabetes (DM2), and subjects with overweight or obesity are more likely to have both. In such cases the association of FIB-4 with IR and weight are evident. It is questioned whether, even in subjects without DM2 and with normal transaminases, FIB-4 could be associated with the body mass index (BMI) and the homeostasis model assessment of insulin resistance index HOMA-IR, which is the index usually used to assess IR. The objective of this study was to evaluate how FIB-4 would behave in subjects without DM2 and with normal transaminases and whether there was a correlation between FIB-4 with HOMA-IR and BMI in these subjects. Methods Authors studied the distribution of FIB-4 results and correlation of HOMA-IR and BMI with FIB-4 using the database of a clinical laboratory. We included patients aged 20-65 years, both gender, who measured fasting glucose and insulin, in the same visit, and transaminases and platelets within up to one year before or later. Were excluded hospitalized subjects, those using medications to treat DM2, dyslipidemia, subjects with blood glucose over 200 mg/dL, and AST and/or ALT above the reference range for gender and age. The methods and reference intervals were: transaminases: UVKinetic, AST &amp;lt; 40 U/L for men and &amp;lt; 32 U/L for women, ALT &amp;lt; 41 for men and &amp;lt; 33 for women; PLT: automated method, 150000-450000/µL. Glucose: hexokinase, 70 - 99 mg/dL; Insulin: electrochemiluminescence, 2-12 mcU/mL. HOMA-IR index was calculated using the equation: glucose (mg/dL) x insulin (mcIU/mL) / 405 and FIB-4 using the equation: age (years) × TGO (U/L) / [(platelets (µL) ÷1000) x √TGP (U/L))]. Shapiro Wilk test was performed to assess whether the analytes had normal distribution. To evaluate the correlation with HOMA-IR, Spearman's non-parametric correlation test was used. Results After applying the exclusion criteria and subtracting outliers 270,135 records were selected, 75% female, with 39,9 ± 10.1 years. As the parameters did not present Gaussian distribution, the results are shown in median and 25th and 75th percentiles: AST=18.9 (16-22); ALT=17.2 (13-23.3); PLT=266000 (229000-308000); glucose = 89.3 (84.2-95); insulin = 8.17 (5.52-12.8); HOMA-IR=1.81 (1.19-2.75); IMC=26.53 (23.80-29.91); FIB-4 = 0.65 (0.5 - 0.86). A weak and surprisingly negative correlation between HOMA-IR and BMI with FIB-4 was found. (HOMA-IR: r=- 0.2, p&amp;lt;0.001; BMI: r=- 0.1, p&amp;lt;0.01). Conclusions Our study showed that in a population with normal transaminases, FIB-4 had results compatible with low risk of fibrosis in subjects without DM2 even in cases with high HOMA-IR or BMI. The negative correlation was surprising and perhaps indicates that FIB-4 may not be a good predictor of liver fibrosis for this population profile.

Betaine and B12 Intake, Glutathione Concentration, and MTHFR, PEMT, and MTHFD1 Genotypes Are Associated with Diabetes-Related Parameters in Polish Adults

BackgroundThere is a growing body of evidence on associations between one-carbon metabolism (OCM) and diabetes-related parameters. For this reason, we aimed to examine the associations of plasma choline, betaine, trimethylamine N-oxide (TMAO), glutathione (GSH), serum folate, vitamin B12, dihydrofolate reductase (rs70991108) genotype, methylenetetrahydrofolate reductase (MTHFR) (rs180113) genotype, methylenetetrahydrofolate dehydrogenase (MTHFD1) (rs2236225) genotype, and phosphatidylethanolamine N-methyltransferase (rs7946 and rs12325817) genotype with fasting glucose level, insulin level, and diabetes-related indices. MethodsThe study group consisted of 421 Polish adults aged 20–40 y. Food intake was assessed using a 3-d food diary. Plasma concentrations of choline, betaine, and TMAO were determined by ultra-high-performance liquid chromatography-electrospray ionization mass spectrometry. The total plasma GSH level was measured by high-performance liquid chromatography. Insulin, folate, and vitamin B12 concentrations were estimated by enzyme-linked immunosorbent assay method. Genotyping was performed with TaqMan probes. ResultsGSH level was negatively associated with insulin (β = −0.11, P < 0.05) and gamma-glutamyl transferase (GGTP) (β = −0.12, P < 0.05), and positively associated with fasting glucose (β = 0.11, P < 0.05). Betaine intake was negatively associated with serum insulin concentration (β = −0.13, P < 0.05) and HOMA-IR (β = −0.12, P < 0.05). Choline intake was negatively associated with insulin (β = −0.17, P < 0.01). Serum folate level was negatively associated with GGTP (β = −0.11; P < 0.05). The methylenetetrahydrofolate reductase (MTHFR) CC genotype was associated with higher serum insulin levels (β = 0.15; P < 0.01) and higher HOMA-IR (β = 0.15, P < 0.01), whereas the MTHFD1 AA genotype was negatively associated with Quantitative Insulin Sensitivity Check Index (β = −0.11, P < 0.05). ConclusionsOur findings suggest that higher GSHL and higher intake of betaine, B12, and choline, as well as the TT genotype of MTHFR and the AA genotype of MTHFD1, are associated with lower diabetes-related parameters among adults.

Thyroid Dysfunction In Metabolic Syndrome In Patients: An Observational Study

Objective: To assess the clinico-demographic profile thyroid dysfunction (TD in patients with metabolic syndrome (MetS). Methods: Research was done at the Medical Department. We included 200 MetS patients in this investigation. Demographics, anthropometric measurements, significant medical (including FPG, serum TG, and HDL-C values from patients' medical records) and surgical history, family history, lifestyle parameters, history of obesogenic medicine use, vital signs, and physical examination details were collected in case report forms at the screening visit. Results: We included 200 MetS patients in this investigation. The baseline demographics of these patients are presented. Of the recruited patients, 60 (30%) had TD, with women being more likely than males. Overt hypothyroidism was detected in 36 of 200 MetS patients and hyperthyroidism in 4. High waist circumference, lowered HDL-C, elevated HOMA-IR, systolic and diastolic blood pressure, fasting hyperglycemia, and TG were seen in TD patients in this research. More women than men had waist circumferences exceeding 80 cm. Conclusion: Metabolic syndrome complications include thyroid problems. High frequency of TD in MetS patients suggests a thyroid-MetS interaction. This investigation will help link TD and MetS in Indian patients. Early identification of TD in MetS may help change disease course with lifestyle modifications.

Does insulin resistance predict prostate cancer? Results from the Reduction by Dutasteride of Prostate Cancer (REDUCE) Trial.

Prior studies testing the association between insulin resistance (IR) and prostate cancer (PC) risk are inconsistent. We examined the association between Homeostatic Assessment of Insulin Resistance (HOMA-IR; calculated from fasting baseline insulin and glucose) and PC in REDUCE, a 4-year randomized trial of dutasteride vs. placebo for PC prevention. All patients had prestudy negative biopsies and underwent study mandated biopsies at 2 and 4 years regardless of prostate-specific antigen. Multivariable logistic regression models were used to investigate the associations between log-transformed or categorized HOMA-IR scores and PC risk. Multinominal regression was used to assess associations between HOMA-IR scores and tumor grade (low grade [grade group 1]; high-grade [grade groups 2-5]). Among 5430 REDUCE participants (1212 with PC; 856 low- and 356 high-grade), higher HOMA-IR was associated with lower PC risk (log-HOMA-IR: OR,0.89; 95% CI,0.80-0.99; p=.03; categorized HOMA-IR: p-trend=.04). When stratified by grade, HOMA-IR was significantly associated with reduced low-grade PC risk (log-HOMA-IR: OR,0.84; 95% CI,0.74-0.94; p=.003; categorized HOMA-IR: p-trend=.002) but was unrelated to high-grade PC (log-HOMA-IR: OR,1.02; 95% CI,0.86-1.21; p=.81; categorized HOMA-IR: p-trend=.26). Results were similar in placebo and treatment arms. In summary, higher HOMA-IR was associated with a reduced risk of low-grade PC but was not associated with high-grade disease. The mechanisms to explain these findings are unclear.

Impact of blood glucose on cognitive function in insulin resistance: novel insights from ambulatory assessment

Background/objectivesInsulin resistance (IR)-related disorders and cognitive impairment lead to reduced quality of life and cause a significant strain on individuals and the public health system. Thus, we investigated the effects of insulin resistance (IR), and blood glucose fluctuations on cognitive function under laboratory and free-living conditions, using ecological momentary assessment (EMA).Subjects/methodsBaseline assessments included neuropsychological tests and blood analysis. Individuals were classified as either insulin-sensitive (<2) or insulin-resistant (≥2), based on their Homeostatic Model Assessment (HOMA-IR) values. Continuous glucose monitoring (CGM) using a percutaneous sensor was performed for 1 week. Using multiple linear regression, we examined the effects of HOMA-IR and CGM metrics on cognitive domains. Working memory (WM) performance, which was assessed using EMA, 4 times a day for 3 consecutive days, was matched to short-term pre-task CGM metrics. Multilevel analysis was used to map the within-day associations of HOMA-IR, short-term CGM metrics, and WM.ResultsAnalyses included 110 individuals (mean age 48.7 ± 14.3 years, 59% female, n = 53 insulin-resistant). IR was associated with lower global cognitive function (b = −0.267, P = 0.027), and WM (b = −0.316; P = 0.029), but not with executive function (b = −0.216; P = 0.154) during baseline. EMA showed that higher HOMA-IR was associated with lower within-day WM performance (β = −0.20, 95% CI −0.40 to −0.00). CGM metrics were not associated with cognitive performance.ConclusionsThe results confirm the association between IR and decrements in global cognitive functioning and WM, while no effects of CGM metrics were observed, making IR a crucial time point for intervention. Targeting underlying mechanisms (e.g., inflammation) in addition to glycemia could be promising to minimize adverse cognitive effects. Registered under https://drks.de/register/de identifier no. DRKS00022774.

Effects of ibuprofen in the ZDF rat model of type 2 diabetes.

We aimed to investigate the therapeutic potential of ibuprofen against type 2 diabetes (T2D) using obese Zucker diabetic fatty (ZDF) rats as type 2 diabetes model. ZDF rats were hyperglycemic, dyslipidemic and expressed proinflammatory markers in contrast to lean controls, thus reflecting the relationship between obesity and chronic inflammation promoting T2D. Chronic treatment with ibuprofen (2-(4-Isobutylphenyl)propanoic acid) was used to study the impact on pathological T2D conditions as compared to metformin (1,1-dimethylbiguanide) treated ZDF as well as lean controls. Ibuprofen decreased A1c but induced a high insulin release with improved glucose tolerance only after early time points (i.g., 15 and 30 min) resulting in a non-significant decline of AUC values and translating into a high HOMA-IR. In addition, ibuprofen significantly lowered cholesterol, free fatty acids and HDL-C. Some of these effects by ibuprofen might be based on its anti-inflammatory effects through inhibition of cytokine/chemokine signaling (i.g., COX-2, ICAM-1 and TNF-α) as measured in whole blood and epididymal adipose tissue by TaqMan and/or upregulation of anti-inflammatory cytokines (i.g., IL-4 and IL-13) by ELISA analysis in blood. In conclusion, our ZDF animal study showed positive effects of ibuprofen against diabetic complications such as inflammation and dyslipidemia but also demonstrated the risk of causing insulin resistance.

The effect of statin treatment on glucose homeostasis in prediabetic individuals: A prospective, randomized, controlled trial.

This study aimed to evaluate the effects of rosuvastatin and pravastatin on glucose homeostasis and other biomarkers in individuals at high risk of developing diabetes. This prospective, randomized, open-labeled, and controlled trial included prediabetic individuals with impaired fasting glucose and impaired glucose tolerance. The participants were randomized into three groups: rosuvastatin (10 mg), pravastatin (40 mg), or control. Biomarkers of diabetes and glucose and insulin responses to oral glucose tolerance tests were assessed at baseline and after 6 months of treatment. The primary outcomes were comparisons of glucose homeostasis and biomarkers of diabetes among groups at baseline and after 6 months of treatment. A total of 141 subjects with impaired fasting glucose (IFG) were screened and 41 participants were recruited. Twenty-two subjects were randomized to either the rosuvastatin or pravastatin group and 19 subjects were assigned to the control group. After 6 months of treatment, all groups had similar cholesterol and triglyceride levels. Likewise, HbA1c levels, glucose, and insulin excursions during oral glucose tolerance test, were similar among the three groups. However, compared to the other groups, the rosuvastatin group had higher homeostasis model assessment for insulin resistance (HOMA-IR) (insulin resistance) and a lower Matsuda index (insulin sensitivity). Among prediabetic individuals with IFG, rosuvastatin treatment was associated with increased insulin resistance and decreased insulin sensitivity compared to pravastatin and control groups. Further research is needed to elucidate the underlying mechanisms and clinical implications of these findings.

Heterogeneity and high prevalence of bone manifestations, and bone mineral density in congenital generalized lipodystrophy subtypes 1 and 2.

Congenital Generalized Lipodystrophy (CGL) is a rare autosomal recessive disease caused by mutations in genes responsible for the formation and development of adipocytes. Bone abnormalities are described. However, there is a scarcity of data. To describe bone characteristics in a large CGL1 and 2 case series. Cross-sectional study that assessed bone radiological features of CGL patients of a reference hospital in Fortaleza (CE), Brazil. Patients underwent clinical and bone mineral metabolism evaluation, radiographs of the axial and appendicular skeleton and bone mineral density (BMD) assessment by DEXA (dual energy X-ray absorptiometry). Nineteen patients were included, fourteen were CGL1 and 5, CGL2. Median age was 20 years (8-42) and 58% were women. Median BMI and percentage of body fat were, respectively, 21 Kg/m² (16-24), and 10.5% (7.6-15). The median leptin concentration was 1 ng/mL (0.1-3.3). Diabetes mellitus and dyslipidemia were present in 79% and 63% of patients, respectively. Median calcium and phosphate were normal in almost all patients (95%). Median parathyroid hormone and 25-OH-vitamin D were 23 pg/mL (7-75) and 28 ng/mL (18-43). Osteolytic lesions, osteosclerosis and pseudo-osteopoikylosis, were present in 74%, 42% and 32% of patients, respectively. Lytic lesions were found predominantly in the extremities of long bones, bilaterally and symmetrically, spine was spared. Osteosclerosis was present in axial and appendicular skeleton. Pseudo-osteopoikilosis was found symmetrically in epiphyses of femur and humerus, in addition to the pelvis. BMD Z-score greater than +2.5 SD was observed in 13 patients (68.4%). BMD was higher in CGL1 compared to CGL2 in lumbar spine and total body in adults. No associations were found between high BMD and HOMA-IR (p=0.686), DM (p=0.750), osteosclerosis (p=0.127) or pseudo-osteopoikilosis (p=0.342), and, between pain and bone lesions. Fractures were found in 3 patients. Bone manifestations are prevalent, heterogeneous, and silent in CGL1 and CGL2. Osteolytic lesions are the most common, followed by osteosclerosis and pseudo-osteopoikilosis. Bone mass is high in most cases. There was no pain complaint related to bone lesions. Thus, systematic assessment of bone manifestations in CGL is essential. Studies are needed to better understand its pathogenesis and clinical consequences.

The effect of β-cell dysfunction on reproductive outcomes of PCOS undergoing IVF or ICSI embryo transfer cycles: a retrospective cohort study.

To investigate the effects of β-cell dysfunction on IVF outcomes in women with PCOS. This retrospective cohort study includes 1,212 women with PCOS undergoing their first IVF cycle between September 2010 and December 2019. Beta-cell dysfunction was measured by homeostasis model assessment of β-cell function (HOMA-β) index. In quartiles of HOMA-β, the incidence of miscarriage dramatically increased from 10.2% (Q1) to 31.1% (Q4) (P for trend <0.001). Likewise, the incidence of miscarriage in quartiles of HOMA-β also showed a similar trend (P for trend <0.001). After adjusting for confounding factors, logistic regression analyses showed that high HOMA-IR values were independently associated with a high risk of miscarriage, with the odds ratios (OR) and 95% confidence intervals for quartiles 2-4 versus quartile 1 were 1.30 (0.69-2.46), 1.82 (0.97-3.43), and 3.57 (1.86-6.85), respectively (P for trend <0.001). When analyzed jointly, women in the highest HOMA-IR and highest HOMA-β group exhibited the highest risk for miscarriage compared with all other groups. Furthermore, higher HOMA-IR values were associated with higher risks of miscarriage among PCOS women regardless of HOMA-β values. β-cell dysfunction is independently associated with increased miscarriage rate and decreased live birth rate in women with PCOS. It also plays a synergistic role with IR in terms of the reproductive outcomes, while the influence of IR overweighs that of β-cell dysfunction.

Association between a polygenic lipodystrophy genetic risk score and diabetes risk in the high prevalence Maltese population.

Type 2 diabetes (T2DM) is genetically heterogenous, driven by beta cell dysfunction and insulin resistance. Insulin resistance drives the development of cardiometabolic complications and is typically associated with obesity. A group of common variants at eleven loci are associated with insulin resistance and risk of both type 2 diabetes and coronary artery disease. These variants describe a polygenic correlate of lipodystrophy, with a high metabolic disease risk despite a low BMI. In this cross-sectional study, we sought to investigate the association of a polygenic risk score composed of eleven lipodystrophy variants with anthropometric, glycaemic and metabolic traits in an island population characterised by a high prevalence of both obesity and type 2 diabetes. 814 unrelated adults (n = 477 controls and n = 337 T2DM cases) of Maltese-Caucasian ethnicity were genotyped and associations with phenotypes explored. A higher polygenic lipodystrophy risk score was correlated with lower adiposity indices (lower waist circumference and body mass index measurements) and higher HOMA-IR, atherogenic dyslipidaemia and visceral fat dysfunction as assessed by the visceral adiposity index in the DM group. In crude and covariate-adjusted models, individuals in the top quartile of polygenic risk had a higher T2DM risk relative to individuals in the first quartile of the risk score distribution. This study consolidates the association between polygenic lipodystrophy risk alleles, metabolic syndrome parameters and T2DM risk particularly in normal-weight individuals. Our findings demonstrate that polygenic lipodystrophy risk alleles drive insulin resistance and diabetes risk independent of an increased BMI.

Additive interactions between obesity and insulin resistance on hypertension in a Chinese rural population

BackgroundAdiposity and insulin resistance (IR) are closely associated with hypertension; however, the role of interactions between obesity phenotypes and IR in hypertension is unclear. This study aimed to evaluate the interactions of body mass index (BMI), waist circumference (WC), and body fat percentage (BF%) with IR on hypertension risk.MethodsWe analyzed data from 4888 participants (mean age 57 years, 41.2% men) in the China Northwest Natural Population Cohort, Ningxia Project. BMI, WC, and BF% were determined using bioelectrical impedance analysis devices. IR was estimated using a homeostasis model assessment index (HOMA-IR). Multivariable-adjusted logistic regression was used to evaluate the association between HOMA-IR and hypertension risk. We calculated the relative excess risk and attributable proportion with their 95% confidence intervals (CIs) to assess whether adiposity phenotypes modified the effect of HOMA-IR on hypertension risk.ResultsThe crude prevalence of hypertension was 52.2%. The multivariable-adjusted odds ratio of HOMA-IR was 1.80 (95% CI: 1.23–2.65) for the risk of hypertension in the highest versus the lowest quartiles, but this association became marginal in models further adjusting for BMI, WC, and BF% (P for trend = 0.056). Relative excess risk and attributable proportion for interaction between high HOMA-IR and high BF% were 0.32 (0.04–0.59) and 0.33 (0.06–0.60), respectively. Additionally, high truncal and leg BF% and high HOMA-IR accounted for the hypertension risk in women, but not in men. We did not observe any significant interactions between BMI or WC and HOMA-IR on hypertension.ConclusionBF% modified the association between IR and increased risk of hypertension in women with high truncal and leg BF%, but not in men.

Association between the homeostasis model assessment of insulin resistance and coronary artery calcification: a meta-analysis of observational studies.

Insulin resistance (IR), a risk factor for cardiovascular diseases, has garnered significant attention in scientific research. Several studies have investigated the correlation between IR and coronary artery calcification (CAC), yielding varying results. In light of this, we conducted a systematic review to investigate the association between IR as evaluated by the homeostasis model assessment (HOMA-IR) and CAC. A comprehensive search was conducted to identify relevant studies in PubMed, Embase, Scopus, and Web of Science databases. In addition, preprint servers such as Research Square, BioRxiv, and MedRxiv were manually searched. The collected data were analyzed using either fixed or random effects models, depending on the heterogeneity observed among the studies. The assessment of the body of evidence was performed using the GRADE approach to determine its quality. The current research incorporated 15 studies with 60,649 subjects. The analysis revealed that a higher category of HOMA-IR was associated with a greater prevalence of CAC in comparison to the lowest HOMA-IR category, with an OR of 1.13 (95% CI: 1.06-1.20, I2=29%, P < 0.001). A similar result was reached when HOMA-IR was analyzed as a continuous variable (OR: 1.27, 95% CI: 1.14-1.41, I2=54%, P < 0.001). In terms of CAC progression, a pooled analysis of two cohort studies disclosed a significant association between increased HOMA-IR levels and CAC progression, with an OR of 1.44 (95% CI: 1.04-2.01, I2=21%, P < 0.05). It is important to note that the strength of the evidence was rated as low for the prevalence of CAC and very low for the progression of CAC. There is evidence to suggest that a relatively high HOMA-IR may be linked with an increased prevalence and progression of CAC.

Assessment HOMA as a predictor for new onset diabetes mellitus and diabetic complications in non-diabetic adults: a KoGES prospective cohort study

BackgroundHomeostasis model assessment for insulin resistance (HOMA-IR) is a biomarker for type 2 diabetes mellitus (T2DM). However, the role of HOMA-IR in the non-diabetic is unclear. This study aimed to determine whether IR measured HOMA-IR value is associated with new onset diabetes as well as vascular disease and can be used as an early predictor for diabetes and vascular diseases in non-diabetic participants.MethodsFrom a prospective community-based cohort of 10,030 individuals, 4314 individuals younger than 65 years and without diabetes were enrolled and divided into three groups by baseline HOMA-IR tertiles: low (n = 1454), moderate (n = 1414), and high (n = 1446). The primary outcome was new onset T2DM. Secondary outcomes were chronic kidney disease (CKD) and a composite of coronary artery disease, myocardial infarction, and stroke as macrovascular events.ResultsThe mean age was 51 years. The prevalence of hypertension and cholesterol and HbA1c were higher in the high HOMA-IR group. New onset T2DM (5.8%) and CKD (12.2%) incidence in the high HOMA-IR group was higher than that in the others. The prevalence of macrovascular events did not differ among groups. High-HOMA-IR was an independent risk factor for new onset T2DM (odds ratio 1.86 [1.17–2.96]; p = 0.01) and CKD (1.49 [1.12–1.98]; p = 0.01).ConclusionsHigh HOMA-IR was an early predictor of new onset T2DM and CKD, regardless of HbA1c in non-diabetic individuals. Further research on the specific cut off value will be needed.

Relationship of vitamin D level with HOMA IR and LH in PCOS patients

Background: the most prevalent endocrine disorder in young women is polycystic ovary syndrome (PCOS). In many patients, vitamin D insufficiency aggravates the condition. Early diagnosis of insulin resistance and vitamin D insufficiency will simplify management and reduce morbidity in the future. This study analyzes the relationship between vitamin D levels and HOMA IR and LH in PCOS patients and compares the levels of LH and HOMA IR between obese and non-obese PCOS. Method: This study used a cross-sectional study on 48 women of reproductive age who were diagnosed with PCOS according to the Rotterdam criteria and who met the inclusion and exclusion criteria. Subjects were taken by consecutive sampling, measured levels of vitamin D, HOMA IR, and LH, then correlated and compared between obese and non-obese. Results: 48 samples were included in the study conducted within 3 months. A significant relationship was found between vitamin D and HOMA IR levels in PCOS patients with a p-value of 0.000. There was a significant relationship between vitamin D and LH levels in PCOS patients with a p-value of 0.000. There were significant differences in HOMA IR and LH levels in obese and non-obese PCOS patients, with higher HOMA IR in obese patients with a p-value of 0.001 and higher LH levels in non-obese PCOS patients with a p-value of 0.045. Conclusion: there was a significant relationship between vitamin D levels and HOMA IR and LH in PCOS patients and a significant difference in HOMA IR and LH in obese and non-obese PCOS patients.

Relation between waist circumference and the renal hemodynamic in healthy individuals

Background and aimsObesity has been shown to be an independent risk factor for the development of CKD. Little is known about pathways of interaction of visceral fat mass estimated by waist circumference (WC) and metabolic factors with the renal and intraglomerular hemodynamic profile in healthy, non-obese individuals. Methods and resultsThe study population of this post-hoc analysis in 80 healthy individuals, who participated in a randomized, controlled clinical trial (www.clinicaltrials.gov: NCT02783456) was divided into two groups based on median of WC (high WC and low WC group). Renal hemodynamic profiles were analyzed using steady state input clearance (infusion of para-amino-hippuric acid and inulin). Intraglomerular pressure (IGP) and resistances of the afferent (RA) and efferent (RE) arterioles were calculated (Gomez equation). The analysis included healthy, non-smoking individuals, aged 27 ± 9 years with median WC of 84.75 ± 9 cm. Glomerular filtration rate (GFR) (110 ± 15 vs. 127 ± 16 ml/min/m2, p < 0.001), renal plasma flow (RPF) (620 ± 109 vs. 700 ± 104 ml/min, p = 0.001) and IGP (36.7 ± 2.3 vs. 38.5 ± 3.1 mmHg, p = 0.003) were lower in the high WC compared to the low WC group. Patients in the high WC group showed higher renal vascular resistance (RVR) (85 ± 19 vs. 70 ± 12 mmHg/(ml/min), p < 0.001), higher RA (4034 ± 1177 vs. 3069 ± 786 dyn∗s/cm5, p < 0.001) and higher RE (2283 ± 339 vs. 2118 ± 280 dyn∗s/cm5, p = 0.021) compared to the low WC group. Individuals in the high WC group showed higher leptin levels (p = 0.003) and higher HOMA-IR (p = 0.024) compared to the low WC group. ConclusionIncreased WC in healthy young individuals was associated with reduced GFR and RPF likely mediated by increased RVR.

HOMA-IR and the Matsuda Index as predictors of progression to type 1 diabetes in autoantibody-positive relatives

Aim/hypothesisWe assessed whether HOMA-IR and the Matsuda Index are associated with transitions through stages of type 1 diabetes.MethodsAutoantibody (AAb)-positive relatives of individuals with type 1 diabetes (n=6256) from the TrialNet Pathway to Prevention were studied. Associations of indicators of insulin resistance (HOMA-IR) and insulin sensitivity (Matsuda Index) with BMI percentile (BMIp) and age were assessed with adjustments for measures of insulin secretion, Index60 and insulinogenic index (IGI). Cox regression was used to determine if tertiles of HOMA-IR and Matsuda Index predicted transitions from Not Staged (<2 AAbs) to Stage 1 (≥2 AAbs and normoglycaemia), from Stage 1 to Stage 2 (≥2 AAbs with dysglycaemia), and progression to Stage 3 (diabetes as defined by WHO/ADA criteria).ResultsThere were strong associations of HOMA-IR (positive) and Matsuda Index (inverse) with baseline age and BMIp (p<0.0001). After adjustments for Index60, transitioning from Stage 1 to Stage 2 was associated with higher HOMA-IR and lower Matsuda Index (HOMA-IR: HR=1.71, p<0.0001; Matsuda Index, HR=0.40, p<0.0001), as with progressing from Stages 1 or 2 to Stage 3 (HOMA-IR: HR=1.98, p<0.0001; Matsuda Index: HR=0.46, p<0.0001). Without adjustments, associations of progression to Stage 3 were inverse for HOMA-IR and positive for Matsuda Index, opposite in directionality with adjustments. When IGI was used in place of Index60, the findings were similar.Conclusions/interpretationProgression to Stages 2 and 3 of type 1 diabetes increases with HOMA-IR and decreases with the Matsuda Index after adjustments for insulin secretion. Indicators of insulin secretion appear helpful for interpreting associations of progression to type 1 diabetes with HOMA-IR or the Matsuda Index in AAb-positive relatives.Graphical

C-reactive protein during pregnancy and in the early postpartum predicts adverse metabolic health outcomes at 1 year postpartum in women with gestational diabetes

BackgroundWomen with gestational diabetes mellitus (GDM) have higher insulin resistance and/or reduced secretion, an increased risk of future diabetes and cardiovascular disease, which may be due to a pathological activation of the innate immune system. C-reactive protein (CRP) is induced by inflammatory cytokines and reflects innate immune activity. We investigated the prospective associations between CRP during the perinatal period with adverse metabolic outcomes at 1 year postpartum in women with previous GDM.MethodsWe analyzed data from the MySweetheart trial that included 211 women with GDM at 28–32 weeks gestational age (GA). CRP was measured during pregnancy at 28-32 weeks GA, at 6–8 weeks and at 1 year postpartum. Metabolic outcomes at 1 year postpartum included weight, total and central body fat, measures of insulin resistance and secretion and presence of the metabolic syndrome (MetS). A 75 g oral glucose tolerance test was performed to measure glucose and insulin values every 30 min over 2 h to calculate indices of insulin resistance (MATSUDA, HOMA-IR) and of absolute (AUCins/glu, HOMA-B) and insulin resistance-adjusted insulin secretion (ISSI-2).ResultsCRP during pregnancy and at 6–8 weeks postpartum predicted increased weight, body fat and visceral adipose tissue (VAT), insulin resistance (higher HOMA-IR, lower MATSUDA), absolute insulin secretion (HOMA-B, AUCins/glu), a reduced adjusted insulin secretion (ISSI-2) and a higher prevalence of the MetS at 1 year postpartum (all p ≤ 0.036). These relationships particularly those concerning CRP during pregnancy, were independent of weight ( for VAT, insulin resistance and secretion indices, MetS; all p ≤ 0.032) and of body fat ( for VAT, MATSUDA, MetS; all p ≤ 0.038). ConclusionCRP during pregnancy and in the early postpartum predicted an adverse cardio-metabolic profile in women with prior GDM at 1 year postpartum independent of weight. The prospective association of CRP with increased insulin resistance and reduced adjusted insulin secretion hint to the role of inflammation in the development of impaired metabolism after GDM and could be used as an early marker for risk stratification.

THU136 Insulin Resistance, Insulin Secretion, And Body Fat In Youth: Associations With Branched-chain Amino-acids (BCAA), Branched-chain Keto-acids (BCKAs), Glutamate/Glutamine (Glx), And Kynurenine (KYN)

Abstract Disclosure: K. Blew: None. Q. Wang: None. H. Hong: None. O. Ilkayeva: None. M. Muehlbauer: None. M. Crawford: Employee; Self; Laboratory Corporations of America. Stock Owner; Self; Laboratory Corporations of America. R.P. Grant: Employee; Self; Laboratory Corporations of America. Stock Owner; Self; Laboratory Corporations of America. D.S. Hsia: None. J.R. Bain: None. M. Freemark: None. P. Gumus Balikcioglu: None. Objective: We recently showed that insulin resistance (IR) and Type 2 diabetes (T2D) in youth with obesity are associated with disordered metabolism of BCAA and diversion of tryptophan (TRP) metabolism from the serotonin to the kynurenine (KYN) pathway. In this study we determined if BCAAs, BCKAs, Glx and KYN/TRP correlate with metrics of obesity, insulin sensitivity, and insulin secretion. Methods: We performed frequently sampled oral glucose tolerance tests (OGTT) in 16 youth with normal weight and 16 non-diabetic youth with overweight/obesity and mild-moderate IR ages 18-21 yo. After an overnight fast of 8-12 hours, subjects underwent a 3-hour (1.75 g/kg, max 75 g) frequently sampled OGTT. Glucose (G) and insulin (I) were measured at times -15, 0, 10, 15, 30, 45, 60, 90, 120, and 180 minutes. Plasma metabolomic profiles were obtained at time 0. HOMA-S, HOMA-B, HOMA-IR, Matsuda Index, AUC glucose, AUC insulin, insulinogenic index (IGI) and disposition index (DI) at 10, 15 and 30 min were calculated. % Body fat was measured by TANITA. Results: Groups were comparable in age (19±1.2 vs 19.6±1.1 years), sex, race, ethnicity and pubertal status. Overweight/obese participants had higher BMI (22±2.3 vs 33.7±8.1), BF% (19.6±7.2 vs 37±9.2), leptin, and CRP and were more insulin resistant as evidenced by higher HOMA-IR and HOMA-B and lower HOMA-S and Matsuda Index. Glucose at 120’, insulin at -15’,0’,15’ and 120’, and IGI at 15’ were higher among overweight/obese subjects. AUC glucose, AUC insulin and DI were comparable across groups, as were fasting BCAA, BCAA/BCKA ratio, TRP, KYN, Kynurenic acid, and the KYN/TRP ratio. BCKA levels trended lower (p=0.05) in the overweight/obese group. Glx levels were higher among overweight/obese subjects (p=0.03) and correlated positively with BMI, % body fat, and metrics of hepatic IR including HOMA IR and ALT. BCAA levels correlated positively with fasting KYN and negatively with DI at 15’ and HMW-adiponectin, a metric of insulin sensitivity, but did not correlate with BMI or % body fat. The ratio of BCAA to BCKA correlated positively with KYN, KYN/TRP ratio and BMI. In contrast, BCKAs correlated negatively with BMI and % body fat but did not correlate with metrics of insulin sensitivity. KIV, the α-keto-acid of valine, associated negatively with metrics of insulin secretion including DI and IGI at 15’ and AUC glucose. Conclusions: In this cohort of non-diabetic youth, the levels of Glx correlated strongly with body fat mass and metrics of hepatic insulin resistance. The levels of BCAA and the ratio of BCAA/BCKA associated positively with KYN and negatively with HMW-adiponectin, a metric of insulin sensitivity, but did not correlate with % body fat. In contrast, BCKAs correlated negatively with % body fat and insulin secretion but did not correlate with metrics of IR. These findings suggest complex effects of fat deposition and insulin sensitivity on BCAA and glutamate metabolism. Presentation: Thursday, June 15, 2023