Insulin Sensitivity Index Research Articles

Empagliflozin improves insulin sensitivity in patients with recent acute coronary syndrome and newly detected dysglycaemia

BackgroundEmpagliflozin reduces the risk of cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM) and high cardiovascular risk via mechanisms which have not been fully explained. The mechanisms of such benefit have not been fully understood, and whether empagliflozin can be safely administered as first-line treatment in patients with CVD at the initial stages of glycaemic perturbations remains to be established. We investigated the effects of empagliflozin on insulin resistance, insulin sensitivity and β-cell function indexes in patients with a recent acute coronary event and newly detected dysglycaemia, i.e., impaired glucose tolerance (IGT) or T2DM.MethodsForty-two patients (mean age 67.5 years, 19% females) with a recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected dysglycaemia were randomized to either empagliflozin 25 mg daily (n = 20) or placebo (n = 22). Patients were investigated with stress-perfusion cardiac magnetic resonance imaging before randomization, 7 months after the start of study drug and 3 months following its cessation. Indexes of insulin resistance, sensitivity and β-cell function were calculated based on glucose and insulin values from 2-hour oral glucose tolerance tests (OGTT) and fasting C-peptide. The differences in glucose, insulin, C-peptide, mannose levels and indexes between the two groups were computed by repeated measures ANOVA including an interaction term between the treatment allocation and the time of visit.ResultsAfter 7 months, empagliflozin significantly decreased glucose and insulin values during the OGTT, whereas C-peptide, mannose and HbA1c did not differ. Empagliflozin significantly improved insulin sensitivity indexes but did not impact insulin resistance and β-cell function. After cessation of the drug, all indexes returned to initial levels. Insulin sensitivity indexes were inversely correlated with left ventricular mass at baseline.ConclusionsEmpagliflozin improved insulin sensitivity indexes in patients with a recent coronary event and drug naïve dysglycaemia. These findings support the safe use of empagliflozin as first-line glucose-lowering treatment in patients at very high cardiovascular risk with newly diagnosed dysglycaemia.Trial registration numberEudraCT number 2015-004571-73.

Methods for estimating insulin resistance from untargeted metabolomics data

ContextInsulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming.ObjectiveDevelop estimation models for measures of insulin resistance, including insulin sensitivity index (SI) and homeostatic model assessment of insulin resistance (HOMA-IR) from metabolomics data.DesignInsulin Resistance Atherosclerosis Family Study (IRASFS).SettingCommunity based.ParticipantsMexican Americans (MA) and African Americans (AA).Main outcomeEstimation models for measures of insulin resistance, i.e. SI and HOMA-IR.ResultsLeast Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net regression were used to build insulin resistance estimation models from 1274 metabolites combined with clinical data, e.g. age, sex, body mass index (BMI). Metabolite data were transformed using three approaches, i.e. inverse normal transformation, standardization, and Box Cox transformation. The analysis was performed in one MA recruitment site (San Luis Valley, Colorado (SLV); N = 450) and tested in another MA recruitment site (San Antonio, Texas (SA); N = 473). In addition, the two MA recruitment sites were combined and estimation models tested in the AA recruitment sample (Los Angeles, California; N = 495). Estimated and empiric SI were correlated in the SA (r2 = 0.77) and AA (r2 = 0.74) testing datasets. Further, estimated and empiric SI were consistently associated with BMI, low-density lipoprotein cholesterol (LDL), and triglycerides. We applied similar approaches to estimate HOMA-IR with similar results.ConclusionsWe have developed a method for estimating insulin resistance with metabolomics data that has the potential for application to a wide range of biomedical studies and conditions.

The lncOb rs10487505 polymorphism impairs insulin sensitivity and glucose tolerance in children and adolescents with obesity.

Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity who were homozygous for the lncOb rs10487505 leptin lowering allele. Enrolled children underwent an anthropometrical evaluation, biochemical assessment, and genotyping for lncOb rs10487505. Plasma leptin levels were assessed in 150 participants. A total of 434 patients were included and divided into two groups according to rs10487505 recessive inheritance (CC vs. GG/GC). Children who were homozygous for the C allele showed higher fasting insulin (p = 0.01), homeostasis model assessment of insulin resistance (p = 0.01), lower whole-body insulin sensitivity index (p = 0.02), and lower disposition index (p = 0.03). Moreover, CC patients presented with a higher prevalence of prediabetes (9.3% vs. 3.4%, p = 0.04) and a 2.9-fold (95% CI: 1.1-7.9, p = 0.04) higher risk of prediabetes compared with G-carriers independently from confounders. Leptin plasma levels were significantly lower in the CC group (p = 0.002). Hormone levels correlated with BMI z score (r = 0.19, p = 0.04), fasting insulin (r = -0.34, p < 0.0001), homeostasis model assessment of insulin resistance (r = -0.33, p < 0.0001), and disposition index (r = 0.20, p = 0.04). The lncOb rs10487505 polymorphism affects leptin circulating levels, worsens insulin resistance, and heightens the risk of prediabetes in children and adolescents with obesity.

Prediabetes in rural adolescent girls from DERVAN cohort: data from the KONKAN region of the state of Maharashtra, India (DERVAN-4).

India is witnessing an epidemic of type 2 diabetes. Overweight/obesity, overnutrition, physical inactivity, and family history are well-known risk factors for diabetes. We investigated the role of undernutrition in the development of diabetes among rural adolescent girls. DERVAN cohort study was set up in the KONKAN region of the western Indian state of Maharashtra. It enrolled 1,520 adolescent girls (16-18 years old at the time of enrollment). We measured glycemic parameters (glucose, insulin, and HbA1C) and body size using anthropometry and body composition using bioimpedance. Prediabetes was diagnosed using the American Diabetic Association (ADA) criteria. We also calculated various HOMA indices for insulin resistance (HOMA-IR), β-cell function (HOMA-β), insulin sensitivity (HOMA-S), and compensatory β-cell response using a homeostasis model. BMI, body fat%, and waist circumferences were treated as exposures and all the glycemic parameters and indices as outcomes. The median age of the subjects was 16.6 years. The median weight, height, and BMI were 40.7 kg, 151.7 cm, and 17.5 kg/m2, respectively. Prevalence of underweight was 28.8%, and stunting was observed in 30.4%. Thinness and obesity using BMI were observed in 58.4% and 4.2%, respectively. The median body fat% was 22.5, and excess body fat (>35%) was observed in 5.7%. The prevalence of prediabetes was 39.4%. Fasting insulin concentrations, HOMA-IR, and HOMA-β showed a positive trend across body composition quartiles (p < 0.001). HOMA-S and compensatory β-cell response showed an inverse trend (p < 0.001). Compared with prediabetic girls in the overweight/obese group, girls most undernourished group had lower median insulin concentrations (8.1 μIU/ml vs. 17.1 μIU/ml), lower HOMA-IR (1.1 vs. 2.3), and lower HOMA-β (75.6 vs. 129.2) but higher sensitivity (87.4 vs. 43.7) (p < 0.001) for all. We have reported a high prevalence of prediabetes among rural adolescent girls with a very low prevalence of obesity. Prediabetes in obesity is driven by hyperinsulinemia and overworking of the pancreas while poor β-cell function and poor insulin secretion are major drivers in the undernourished group. The high-risk diabetes screening programs are much needed for the undernourished populations. Caution should be exercised for planning the interventions as overfeeding (or overnutrition) is likely to put the populations at risk of development of obesity and insulin resistance.

Ostarine does not enhance the metabolic effect of exercise in obese rats.

Overweight and obesity are associated with severe metabolic disorders and an increased risk of cardiovascular diseases. It is a known fact that physical activity has a positive effect on metabolic parameters, and also reduces the risk of diseases such as diabetes. Some products can enhance the rate of lipolysis and help in improving fat loss. One of these are selective androgen receptor modulators (SARMs) which act as anabolic agents and are also believed to aid in fat-burning. In this study, we investigated whether 30 days of ostarine administration could potentially improve metabolic parameters using the rat model of obesity combined with exercise. We assessed the levels of biochemical and hormonal parameters in serum samples as well as insulin sensitivity indices of tissues. There were significant changes in the metabolic parameters with exercise. However, we did not find any additive effects of ostarine and exercise on most of the parameters tested. Similar results were obtained from the analysis of gene expression and the concentration of leptin and adiponectin. Our results indicated that ostarine had a lowering effect on cholesterol concentration in the serum (P<0.05). Moreover, when combining ostarine and exercise, additive changes were only observed in the levels of total and HDL cholesterol. No significant change was observed in the metabolic parameters of obese rats with the use of ostarine at the dose of 0.4 mg/kg body weight. Since ostarine is known to enhance performance, further research on its effects is needed.

Glycemic and metabolic sub-classification of prediabetes and risk factors for cardiovascular disease in the D2d cohort

ObjectivesPrediabetes represents a spectrum of metabolic abnormalities, including insulin resistance and secretory impairment, that carries increased cardiovascular disease (CVD) risk. It is unclear whether specific glycemic and metabolic sub-classifications are associated with CVD risk. This cross-sectional analysis of 3946 participants from the Vitamin D and Type 2 Diabetes (D2d) study cohort aimed to determine the associations between various baseline CVD risk factors, glycemic sub-classifications of prediabetes (FPG, 2hPG, and HbA1c), and measures of insulin sensitivity and secretion from an OGTT. MethodsThe metabolic syndrome and atherosclerotic cardiovascular disease (ASCVD) risk scores were determined for tertiles of insulin sensitivity (HOMA2S) and insulinogenic index (IGI). Unadjusted analyses showed elevated CVD risk factors in the lowest tertile for both IGI and HOMA2S. ResultsAfter adjustment for age, gender, race, obesity, and smoking status, the association remained between HOMA2S and ASCVD score (r = -0.11, p< 0.001) but not for IGI. Those who met at least 2 diagnosic criteria for prediabetes had the largest proportion (> 40%) of participants with high ASCVD risk score >20. A higher percentage of individuals that met all 3 criteria for prediabetes had metabolic syndrome and ASCVD risk score >20 (87.2% and 15.3%, respectively) than those who only met 1 prediabetes criterion (51.6% and 7.1%, respectively). ConclusionsIn conclusion, multiple metabolic (HOMA2S, IGI) and glycemic criteria of prediabetes (FPG, 2hPG, & HbA1c) are needed to fully recognize the elevated CVD risk profile that can manifest in prediabetes.

Impact of saturated compared with unsaturated dietary fat on insulin sensitivity, pancreatic β-cell function and glucose tolerance: a systematic review and meta-analysis of randomized, controlled trials

BackgroundThe impact of the dietary fat type on type 2 diabetes (T2D) remains unclear. ObjectivesWe aimed to evaluate the effects of replacing dietary saturated fatty acids (SFA) with mono- or poly-unsaturated fatty acids (MUFA and PUFA, respectively) on insulin sensitivity, pancreatic β-cell function, and glucose tolerance, as surrogate endpoints for T2D. MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials that replaced ≥5% of total energy intake provided by SFA with MUFA or PUFA and reported indexes of insulin sensitivity, β-cell function, and/or glucose tolerance. We searched MEDLINE, Scopus, and the Cochrane Library (CENTRAL) up to 9 January, 2023. Eligible interventions had to be isocaloric, with no significant difference in other macronutrients. Data were synthesized using random-effects model meta-analysis. ResultsOf 6355 records identified, 10 parallel and 20 crossover trials with 1586 participants were included. The mean age of the participants was 42 years, 47% were male, mean body mass index (BMI; in kg/m2) was 26.8, median baseline fasting glucose was 5.13 mmol/L, and the median duration of interventions was 5 weeks. Replacing SFA with MUFA or PUFA had no significant effects on insulin sensitivity [standardized mean difference (SMD) SFA compared with MUFA: 0.01, 95% confidence interval (CI): −0.06 to 0.09, I2 = 0% and SMD SFA compared with PUFA: 0, 95% CI: −0.15 to 0.14, I2 = 0%]. Replacing SFA with MUFA did not significantly impact the β-cell function, evaluated by the disposition index (mean difference: −12, 95% CI: −158 to 133, I2=0%). Evidence on glucose tolerance (SFA compared with MUFA or PUFA) and on β-cell function when SFA were replaced with PUFA was scant. ConclusionsShort-term substitution of saturated with unsaturated fat does not significantly affect insulin sensitivity nor β-cell function (the latter in the SFA compared with MUFA comparison). Future studies are needed to elucidate longer term effects of dietary fat saturation on glucose homeostasis. This trial was registered at PROSPERO as CRD42020178382.

Sex Hormone Binding Globulin is an Independent Predictor for Insulin Resistance in Male Patients with Newly Diagnosed Type2 Diabetes Mellitus.

This study explored the correlation between sex hormones, sex hormone binding globulin (SHBG), and insulin resistance in male patients with newly diagnosed type2 diabetes mellitus (T2DM). A total of 48 male patients with newly diagnosed T2DM were enrolled in this study between March 2022 and December 2022. Clinical characteristics, sex hormones, and SHBG levels were collected. All enrolled subjects received intensive hypoglycemic treatment with insulin pump for 1week to achieve glycemic control, then the steady-state glucose infusion rate (GIR), an indicator of insulin sensitivity, was determined by the hyperinsulinemic-euglycemic clamp. Correlation analysis and multivariate logistic regression analysis were performed to explore the association of clinical characteristics, sex hormones, and SHBG with insulin sensitivity. The optimal cutoff value to predict insulin resistance was calculated using receiver operating characteristic (ROC) curve. According to the GIR cut-point value of 5.700mg/(kgmin), there were 40 patients with insulin resistance (IR group) and 8 patients without (non-IR group). The IR group exhibited lower testosterone and SHBG levels than the non-IR group (all p < 0.050). Correlation analysis showed that insulin sensitivity was positively associated with testosterone and SHBG, while negatively associated with body mass index, fasting blood glucose, alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride, and apolipoproteinB (all p < 0.050). Multivariate logistic regression analysis demonstrated that SHBG is an independent predictor for insulin resistance (p = 0.029). Further ROC curve analysis revealed that the optimal cutoff value of SHBG to predict insulin resistance is 17.200nmol/L, with the corresponding area under the curve (AUC) and its 95% confidence interval (CI) being 0.813 and 0.691-0.934. SHBG is an independent predictor for insulin resistance in male patients with newly diagnosed T2DM. KY20220314-01.

Severe COVID-19 associated hyperglycemia is caused by beta cell dysfunction: a prospective cohort study

BackgroundCOVID-19, an infectious disease caused by SARS-CoV-2, was shown to be associated with an increased risk of new-onset diabetes. Mechanisms contributing to the development of hyperglycemia are still unclear. We aimed to study whether hyperglycemia is related to insulin resistance and/or beta cell dysfunction.Materials and methodsSurvivors of severe COVID-19 but without a known history of diabetes were examined at baseline (T0) and after 3 (T3) and 6 (T6) months: corticosteroids use, indirect calorimetry, and OGTT. Insulin response and sensitivity (IS) were expressed as insulinogenic (IGI), disposition (DI), and Matsuda insulin sensitivity index (ISI). Resting energy expenditure (REE) and respiratory quotient (RQ) was calculated from the gas exchange and nitrogen losses.Results26 patients (out of 37) with complete outcome data were included in the analysis (age ~59.0 years; BMI ~ 30.4, 35% women). Patients were hypermetabolic at T0 (30.3 ± 4.0 kcal/kg lean mass/day, ~120% predicted) but REE declined over 6 months (ΔT6-T0 mean dif. T6-T0 (95% CI): −5.4 (−6.8, −4.1) kcal/kg FFM/day, p < 0.0001). 17 patients at T0 and 13 patients at T6 had hyperglycemia. None of the patients had positive islet autoantibodies. Insulin sensitivity in T0 was similarly low in hyperglycemic (H) and normoglycemic patients (N) (T0 ISIH = 3.12 ± 1.23, ISIN = 3.47 ± 1.78, p = 0.44), whereas insulin response was lower in the H group (DIH = 3.05 ± 1.79 vs DIN = 8.40 ± 5.42, p = 0.003). Over 6 months ISI (ΔT6-T0 mean dif. T6-T0 for ISI (95% CI): 1.84 (0.45, 3.24), p = 0.01)) increased in the H group only.ConclusionsPatients with severe COVID-19 had increased REE and insulin resistance during the acute phase due to the infection and corticosteroid use, but these effects do not persist during the follow-up period. Only patients with insufficient insulin response developed hyperglycemia, indicating that beta cell dysfunction, rather than insulin resistance, was responsible for its occurrence.

Patients with gestational diabetes mellitus may be treated in both early and late pregnancy, especially in patients with pre-pregnancy overweight: A cross-sectional study in Japan.

The significance of diagnosing gestational diabetes mellitus (GDM) in early pregnancy is controversial. We used the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria to investigate whether clinical background and neonatal outcomes differ depending on when GDM is diagnosed in early or late pregnancy. This was a single-center, observational study conducted between November 2012 and March 2020 at St. Marianna University Hospital (Kawasaki, Japan). We compared the background and perinatal outcomes of patients with GDM depending on the time of diagnosis (at < 24 gestational weeks or ≥ 24weeks). Insulin sensitivity index, homeostasis model assessment of insulin resistance, and β-cell function were calculated from a 75-g oral glucose tolerance test. Stratified analysis was performed by pre-pregnancy BMI in patients with early GDM. As a result, in the 507 patients, 89.9% gave birth at our hospital. The pre-pregnancy BMI was significantly higher in patients with early GDM than in those with late GDM (the median [interquartile range], 22.7 [20.3, 26.3] and 21.5 [19.3, 23.8] kg/m2, respectively; p = 0.001). Perinatal outcomes were not different between the two groups. However, in the subgroup analysis of patients with early GDM, the prevalence of large-for-gestational-age infants was significantly higher in the group with overweight (15.4% vs 2.1%, respectively; p = 0.008). In conclusion, patients with GDM using the IADPSG criteria in early pregnancy may be treated, especially in patients with pre-pregnancy overweight.

The acute effects of a DASH diet and whole food, plant-based diet on insulin requirements and related cardiometabolic markers in individuals with insulin-treated type 2 diabetes

AimsThere is limited research regarding insulin dosing changes following adoption of plant-based diets. We conducted a nonrandomized crossover trial utilizing two plant-based diets (Dietary Approaches to Stop Hypertension, or DASH, and Whole Food, Plant-Based, or WFPB) to assess acute changes in insulin requirements and associated markers among individuals with insulin-treated type 2 diabetes. MethodsParticipants (n = 15) enrolled in a 4-week trial with sequential, one-week phases: Baseline, DASH 1, WFPB, and DASH 2. Each diet was ad libitum and meals were provided. ResultsCompared to baseline, daily insulin usage was 24%, 39%, and 30% lower after DASH 1, WFPB, and DASH 2 weeks respectively (all p < 0.01). Insulin resistance (HOMA-IR) was 49% lower (p < 0.01) and the insulin sensitivity index was 38% higher (p < 0.01) at the end of the WFPB week before regressing toward baseline during DASH 2. Total, LDL, and HDL cholesterol, leptin, urinary glucose, and hsCRP decreased to a nadir at the end of the WFPB week before increasing during DASH 2. ConclusionsAdopting a DASH or WFPB diet can result in significant, rapid changes in insulin requirements, insulin sensitivity, and related markers among individuals with insulin-treated type 2 diabetes, with larger dietary changes producing larger benefits.

Arsenic metabolism, diabetes prevalence, and insulin resistance among Mexican Americans: A mendelian randomization approach.

Differences in arsenic metabolism capacity may influence risk for type 2 diabetes, but the mechanistic drivers are unclear. We evaluated the associations between arsenic metabolism with overall diabetes prevalence and with static and dynamic measures of insulin resistance among Mexican Americans living in Starr County, Texas. We utilized data from cross-sectional studies conducted in Starr County, Texas, from 2010-2014. A Mendelian randomization approach was utilized to evaluate the associations between arsenic metabolism and type 2 diabetes prevalence using the intronic variant in the arsenic methylating gene, rs9527, as the instrumental variable for arsenic metabolism. To further assess mechanisms for diabetes pathogenesis, proportions of the urinary arsenic metabolites were employed to assess the association between arsenic metabolism and insulin resistance among participants without diabetes. Urinary biomarkers of arsenic metabolites were modeled as individual proportions of the total. Arsenic metabolism was evaluated both with a static outcome of insulin resistance, homeostatic measure of assessment (HOMA-IR), and a dynamic measure of insulin sensitivity, Matsuda Index. Among 475 Mexican American participants from Starr County, higher metabolism capacity for arsenic is associated with higher diabetes prevalence driven by worse insulin resistance. Presence of the minor T allele of rs9527 is independently associated with an increase in the proportion of monomethylated arsenic (MMA%) and is associated with an odds ratio of 0.50 (95% CI: 0.24, 0.90) for type 2 diabetes. This association was conserved after potential covariate adjustment. Furthermore, among participants without type 2 diabetes, the highest quartile of MMA% was associated with 22% (95% CI: -33.5%, -9.07%) lower HOMA-IR and 56% (95% CI: 28.3%, 91.3%) higher Matsuda Index for insulin sensitivity. Arsenic metabolism capacity, indicated by a lower proportion of monomethylated arsenic, is associated with increased diabetes prevalence driven by an insulin resistant phenotype among Mexican Americans living in Starr County, Texas.

The effect of weight loss on whole-body and tissue-specific insulin sensitivity and hepatic lipid content and composition: SWEET substudy.

This study (1) investigated the effect of weight loss on whole-body and tissue-specific insulin sensitivity and on intrahepatic lipid (IHL) content and composition and (2) investigated the association between weight-loss-induced changes in insulin sensitivity and IHL content in individuals with overweight or obesity. In this secondary analysis of the European SWEET project, 50 adults (age 18-65 years) with overweight or obesity (BMI ≥ 25 kg/m2 ) followed a low-energy diet (LED) for 2 months. At baseline and after the LED, body composition (dual-energy x-ray absorptiometry), IHL content and composition (proton magnetic resonance spectroscopy), whole-body insulin sensitivity (Matsuda index), muscle insulin sensitivity index (MISI), and hepatic insulin resistance index (HIRI) were determined (7-point oral glucose tolerance test). The LED reduced body weight (p < 0.001). This was accompanied by increased Matsuda index and reduced HIRI (both p < 0.001) but no change in MISI (p = 0.260). Weight loss decreased IHL content (mean [SEM], 3.9% [0.7%] vs. 1.6% [0.5%], p < 0.001) and the hepatic saturated fatty acid fraction (41.0% [1.5%] vs. 36.6% [1.9%], p = 0.039). The reduced IHL content was associated with an improvement in HIRI (r = 0.402, p = 0.025). Weight loss decreased IHL content and the hepatic saturated fatty acid fraction. The decrease in IHL content was associated with weight-loss-induced improvement in hepatic insulin sensitivity in individuals with overweight or obesity.

Heterogeneity in the effect of marked weight loss on metabolic function in women with obesity.

BACKGROUNDThere is considerable heterogeneity in the effect of weight loss on metabolic function in people with obesity.METHODSWe evaluated muscle and liver insulin sensitivity, body composition, and circulating factors associated with insulin action before and after approximately 20% weight loss in women identified as "Responders" (n = 11) or "Non-responders" (n = 11), defined as the top (>75% increase) and bottom (<5% increase) quartiles of the weight loss-induced increase in glucose disposal rate (GDR) during a hyperinsulinemic-euglycemic clamp procedure, among 43 women with obesity (BMI: 44.1 ± 7.9 kg/m2).RESULTSAt baseline, GDR, which provides an index of muscle insulin sensitivity, and the hepatic insulin sensitivity index were more than 50% lower in Responders than Non-responders, but both increased much more after weight loss in Responders than Non-responders, which eliminated the differences between groups. Weight loss also caused greater decreases in intrahepatic triglyceride content and plasma adiponectin and PAI-1 concentrations in Responders than Non-responders and greater insulin-mediated suppression of plasma free fatty acids, branched-chain amino acids, and C3/C5 acylcarnitines in Non-responders than Responders, so that differences between groups at baseline were no longer present after weight loss. The effect of weight loss on total body fat mass, intra-abdominal adipose tissue volume, adipocyte size, and circulating inflammatory markers were not different between groups.CONCLUSIONThe results from our study demonstrate that the heterogeneity in the effects of marked weight loss on muscle and hepatic insulin sensitivity in people with obesity is determined by baseline insulin action, and reaches a ceiling when "normal" insulin action is achieved.TRIAL REGISTRATIONNCT00981500, NCT01299519, NCT02207777.FUNDINGNIH grants P30 DK056341, P30 DK020579, P30 DK052574, UL1 TR002345, and T32 HL13035, the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011), and the Atkins Philanthropic Trust.

251-LB: Association of Plasma Sphingolipids with Insulin Secretion and Insulin Sensitivity in Healthy Black and White Adults

Objective: Sphingolipid (SPL) are associated with glucose dysregulation. Here, we examined plasma SPL profiles in relation to insulin action and secretion in Black and White adults. Methods: Baseline plasma levels of 58 SPLs (ceramides {CER}, monohexosyl-ceramides {MHC}, sphingomyelins {SM}, sphingosine {SO} and dihydro-SO-1-phosphate {DHS1P}) were assayed using LC-MS/MS. Insulin sensitivity was assessed by euglycemic clamp (ISI) and HOMA-IR; insulin secretion by IVGTT (AIR), HOMA-B and disposition index (DI, i.e, AIR × ISI). Results: We enrolled healthy offspring of parents with T2DM (75 Black, 65 White; mean age 47.7 ± 9.01 y, BMI 30.4 ± 6.12 kg/m2, FPG 92.9 ± 6.86 mg/dl and 2-hrPG 130 ± 28.8 mg/dl. Total SPLs showed no association with ISI or HOMA-IR but was significantly associated with insulin secretion (AIR, r=0.19, P=0.031; DI r=0.21, P=0.038). There were differential associations between individual SPLs and insulin secretion/sensitivity, but 5 of 58 SPLs (SM C16:0, SM C28:0, SM C28:1, SM C30:1 and SM C34:0) showed concurrent associations with both measures (r=0.16-0.37, P=0.04-&amp;lt;0.0001). Four SPLs were significantly associated with insulin secretion corrected for insulin sensitivity: MHC C14:0 (r=0.24, P=0.016); MHC C26:0 (r=0.23, P=0.025); SM C22:0 (r=0.26, P=0.009); DHS1P (r=0.27, P=0.006). Very long chain SMs correlated with BMI, waist circumference, body fat and lean mass (r=0.19-0.25, P=0.03-0.0004). Plasma CERs and SMs showed significant associations with 2hrPG (r=0.17-0.25, P=0.04-0.003) but not FPG. Conclusion: Circulating SPLs associate differentially with indices of insulin sensitivity, secretion, and adiposity. Of the 58 individual SPLs assayed, MHC C14:0 and C26:0, SM C22:0 and DHS1P showed the strongest association with insulin secretion corrected for insulin sensitivity. Disclosure P. Asuzu: None. N. Mandal: None. J. Y. Wan: None. F. B. Stentz: None. S. Dagogo-jack: None.

68-LB: Early Pharmacological Intervention (EPIC) to Preserve Beta-Cell Function in Prediabetes (PreDM)

Beta cell failure is the key pathophysiologic determinant in progression from PreDM to type 2 diabetes (T2D). Lifestyle modifications frequently are insufficient to prevent T2D onset and drugs that modify disease progression by targeting pathophysiologic defects in PreDM may be required. Methods: EPIC seeks to answer whether a specific drug provides greater benefit to prevent PreDM progression and to assess the effect of two years of treatment with antidiabetic drugs in 200 individuals with IFG and/or IGT on insulin sensitivity (IS) and beta cell function (BCF). At baseline, participants received 2h-OGTT and two-step hyperglycemic clamp (HC) (+125 and +400 mg/dl) with GLP-1RA infusion. Subjects then were randomized to metformin (MET), pioglitazone (PIO), saxagliptin (SAXA) or dapagliflozin (DAPA). 55 participants have completed the intervention (35F/20M; age = 51 ± 3 ys) Matsuda Index of IS was quantitated from OGTT. Beta Cell Function (BCF) was quantitated: (i) from OGTT as (ΔC-Pep/ΔG) x (Matsuda) and (ii) from HC as ΔC-Pep (First Phase, AIR x Matsuda; ΔC-Pep (Second Phase, +400 mg/dL x Matsuda; and (Second Phase + Exenatide) x Matsuda. Results: A1c did not change significantly in any group, while FPG (106 ±4 to 100 ± 3 mg/dl) and 2h PG (150 ±8 to 141 ± 11) decreased significantly in all groups (p&amp;lt;0.05 for PIO &amp;gt; SAXA). Matsuda Index increased in all groups (p&amp;lt;0.01 for PIO vs all other groups). Weight increased significantly in PIO (+2.5kg p&amp;lt;0.05), did not change with SAXA, decreased with DAPA and MET (both p = NS). BCF during OGTT tended to increase in all groups (p&amp;lt;0.10 for trend). No significant changes in AIR, second phase (+400 mg/dl), and second phase (+400) + Exenatide were seen for MET, SAXA, DAPA, but significantly increased with PIO (AIR 7.1 to 22.8; 2ND STEP 10 to 45.4; 2nd STEP + Exenatide 19 to 79 (all p &amp;lt;0.01). Conclusion: Early drug intervention in prediabetes with pioglitazone preserves beta cell function and improves insulin sensitivity better than MET, SAXA, and DAPA. Disclosure A. Chavez: None. A. Merovci: None. S. Neppala: None. L. A. Cruz Moreno: None. G. Baskoy: None. F. M. Acosta: None. A. A. Hansis-Diarte: None. C. L. Puckett: None. J. M. Adams: None. M. Abdul-Ghani: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. E. Cersosimo: None. R. A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck &amp; Co., Inc. Funding National Institutes of Health (R01DK024092-3AZ, ISSDAPA0002)

223-LB: Associations between Genetic Risk for Insulin Resistance and Measured Insulin Sensitivity Are Impacted by Race and BMI Status

African Americans (AA) are at greater risk for type 2 Diabetes (T2D) compared to European Americans (EA). This greater risk may derive in part from genetic factors. The genetic risk for insulin resistance (IR) has been linked to the failure to expand adipose tissue and is reflected in a genetic risk score (GRS) that is inversely associated with adiposity. In this study, we investigated whether associations between the GRS and measured insulin sensitivity (IS) differ by BMI status and/or race in a sample of 107 EA and AA adults without diabetes. IS was measured with the euglycemic clamp with an insulin dose of 120 µU/m²/min/kg lean body mass. In addition, surrogate indices of IS were calculated using glucose and insulin values obtained from an oral glucose tolerance test. Participants were classified as “high” or “low” BMI using the sample median (25.9 kg/m^2) as the cut-point. GRS were derived from imputed genotypes and weighted for clamp-derived IS. Multiple linear regression models were used to assess interactions between BMI status and GRS on measures of IS. Models were stratified by race and adjusted for percent body fat, sex, and age. In EA, associations of GRS with HOMA-IR and Matsuda differed by BMI status (pint=0.024 and pint=0.007, respectively), where GRS was inversely associated with IS in the high BMI group only (p=0.027 and p=0.010, respectively), suggesting that genetic risk for IR in EA is driven by greater adiposity. Conversely in AA, associations of GRS with IS from the clamp differed by BMI status (pint=0.083), but an inverse association was observed only in the low BMI group (p=0.035), suggesting that in AA, genetic risk for IR is associated with lower adiposity. Our results indicate that obesity status may differentially impact the link between genetic risk for IR and measured IS within and between races. Further, these results suggest that with a larger sample, a distinct phenotype may exist in AA where higher adiposity permits greater IS. Disclosure M. L. Yurchishin: None. L. A. Fowler: None. V. Parcha: None. P. Arora: None. W. Garvey: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Eli Lilly and Company, Merck &amp; Co., Inc., Alnylam Pharmaceuticals, Inc., Fractyl Health, Inc. Research Support; Novo Nordisk, Eli Lilly and Company, Epitomee, Pfizer Inc. Advisory Panel; Inogen. Research Support; Neurovalens. B. Gower: Consultant; Abbott.

980-P: Quantitatively Integrating Carbohydrate Counting, Insulin (I), and Continuous Glucose Monitoring (CGM)

Introduction: Diabetes Care Education Specialists teach patients with insulin requiring Type 1 and 2 diabetes to develop CHO/I ratios to manage mixed diet glucose (G) excursions and improve A1c. and qualitatively examine summary CGM data when available. Conversely, medical scientists have used complex mathematical models, with/without radiolabeled glucose to describe meal-related glucose excursions. Method: This study bypasses the above complexities as CGM regularly measures interstitial fluid glucose (ISFG) over time. CGM can define an individual’s meal specific G/I ratio as well as define Glucose Clearance (GCL) and Insulin Sensitivity Index (Si}. The approach uses referenced meal carbohydrate information (mg CHO). CGM frames the timing (T = t1 - t0) and amount (I) administered before the timed glucose excursion and return to baseline (t2 - t1). This and an Interstitial fluid (ISF) Volume of Distribution (Vd in dL) = 0.15*kg body weight*10 corrected for blood glucose values defines Timed Insulin Glucose Clearance ((T,I)GCL) = (T,I)Vd/(t2 - t1) and (T,I)Si = (T,I)GCL/I). (ISF) glucose for that meal.: Gisf = dietary glucose (Gd)/1.1. Rate Glucose disappearance from ISF space Gisf/(t2 - t1). Discussion: The above parameters are patient specific and refer to the insulin related glucose disposal for that meal. They assess the glucose excursion using the timing and amount of insulin as well the inferring effect of the other dietary components, e.g., protein and fat that contribute to T, and t2 - t1. It avoids complicated descriptions of the glucose curve as it begins with glucose input. It includes hepatic glucose uptake and glucose production, as well as insulin resistance as these are reflected in prolonging of t1-t0 and t2 - t1. Conclusion: CGM has provided the time values for the onset and duration of the meal-related glucose concentration curve. As with Vg, this will assist a patient to develop individualized (I) responses to complex meals using parameters unavailable before CGM. Disclosure J.S.Melish: None.

287-OR: An ABCC8 R1420H Loss-of-Function Variant Affects Insulin Secretory Function and Microvascular Disease in American Indians

The ABCC8 gene regulates insulin secretion and plays a critical role in glucose homeostasis. An R1420H loss-of-function variant in ABCC8 was previously detected in ~3% of people in an American Indian Community with a high prevalence of type 2 diabetes (T2D); heterozygous carriers had a doubling in T2D risk and developed this disease at younger ages and lower BMIs. To further examine the phenotype of this variant, we analyzed the relationship between insulin secretion (2-h post-load corrected insulin response) and insulin sensitivity index [104/(fasting insulin*glucose)] in 5701 members of this population without diabetes aged ≥5 years using standard major axis regression, which adjusts insulin secretion for sensitivity. We used hierarchical logistic regression models in up to 7672 individuals to study cross-sectional associations with diabetes complications including increased albuminuria [albumin to creatinine ratio (ACR) ≥30 mg/g], severe albuminuria (ACR ≥ 300 mg/g), reduced eGFR (eGFR&amp;lt;60 mL/min/1.73m2), and retinopathy assessed by fundoscopic examination. Variant carriers had worse beta-cell function than non-carriers both in children and adults (p=0.0003) with no difference in insulin sensitivity (p=0.50). This variant did not associate significantly with increased albuminuria, severe albuminuria or reduced eGFR after adjustment for age, sex, and presence and duration of diabetes. By contrast, carriers had significantly higher odds of retinopathy (OR=1.74, 95% CI: 1.19, 2.53). Increased odds of retinopathy were also observed among individuals with and without diabetes, and when adjusted for fasting plasma glucose (FPG) [carriers had higher FPG (b=6.1 mg/dl, 95% CI: 3.0, 9.2) adjusted for age, sex, and presence and duration of diabetes]. In sum, carriers of the R1420H ABCC8 variant have a higher risk of retinopathy but not of abnormal ACR or eGFR; this may be partially explained by higher glycemia levels and worse beta-cell function. Disclosure E.Vazquez arreola: None. W.C.Knowler: None. L.Baier: None. R.L.Hanson: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

263-LB: Food Intake Impacts on Insulin Secretion, Resistance, and Glucose Variability in Free-Living Individuals with Type 2 Diabetes Mellitus

Changes in eating habits and physical activity are the cornerstone of treatment of type 2 diabetes mellitus (T2D). Dietary composition has important effects on the postprandial glucose and insulin response, but little is known about its impact in a real-life context. We analyzed the self-reported daily food composition of 13 individuals with obesity and T2D not on insulin (7F/6M, age 48±9, BMI 33±2, A1C 7±1) with ASA24 (NIH), while wearing continuous glucose monitor (Dexcom G4) for 3±1 days. They also underwent an oral glucose tolerance test to explore correlations with standard indices of insulin secretion and sensitivity. The mean consumption per meal of total calorie was: 534±110Kcal, carbohydrate: 51±19g, total grains: 1.78±0.66g (refined 1.61±0.59g, whole 0.17±0.18g), total fat: 25±6g (10±3.17g monounsaturated fat), and protein: 24±7g. We observed a positive correlation between average intake of total and monounsaturated fat with the insulin secretion index (ρ= 0.630, p=0.02,) and Disposition Index (DI) (p=0.001, ρ=0.821). An inverse relationship between the consumption of total and refined grains was noted with the insulin sensitivity indexes (p=0.01, ρ= -0.663); as well as with whole grains and DI (p=0.03, ρ= -0.601). We documented glycemic variability (GV) related to meal nutrient intake through macro program: CGM peak and nadir analysis, Microsoft Excel. Total and monounsaturated fats correlated with lower GV (p=0.02), while total and refined grains were associated with greater GV (p&amp;lt;0.03). Glucose nadir after a meal and glucose at the time of the meal inversely correlated with insulin secretion indexes and with DI (p&amp;lt;0.05). These data suggest, in a real-life context, the impact of food composition on modulation of GV, with fats being associated with greater insulin secretion and refined grains with decreased insulin sensitivity, reinforcing the importance of the effect of diet on management of diabetes. Disclosure A. Comarella: None. R. Belfort-DeAguiar: Research Support; Fractyl Health, Inc., Silver Palate Kitchens. Funding National Institutes of Health (DK098286-02)