Greater Insulin Resistance Research Articles

Heterogeneity of gestational diabetes and risk for adverse pregnancy outcome: a cohort study.

Diabetes has increasingly been recognized as a heterogeneous disease, with clinical characteristics and outcomes risk varying across different phenotypes. Evidence on heterogeneity of gestational diabetes (GDM) is yet to be provided. To investigate the insulin physiology and pregnancy outcomes of GDM phenotypes characterized by fasting hyperglycemia or postload hyperglycemia. A total of 2050 women who underwent a 75-g oral glucose tolerance test were prospectively recruited and followed up until delivery. Women were categorized into normoglycemia (NGT, n = 936), isolated impaired fasting glucose (gestational-IFG, n = 378), and isolated impaired postload glucose tolerance (gestational-IGT, n = 736) groups. Fasting blood sample at mid-pregnancy were collected to measure C-peptide and insulin concentrations. Homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) were used to evaluate insulin physiology. Maternal and neonatal outcomes were recorded. Gestational-IFG had greater insulin resistance (HOMA-IR 3.11 vs. 2.25, QUICKI-CP 0.94 vs. 1.03, both P < 0.01), and gestational-IGT had worse β-cell function (C-peptide 2.00 vs. 2.26 ng/ml, P < 0.05) when compared to one another. Gestational-IFG was more strongly associated with excessive gestational weight gain (RR 1.62, 95% CI 1.18-2.23) and large-for-gestational-age infants (RR 1.45, 95% CI 1.03-2.03) than gestational-IGT. The risk for neonatal brain injury was increased in gestational-IGT (RR 2.03, 95% CI 1.04-4.09), but not in gestational-IFG (P = 0.439). Gestational-IGT showed a stronger association with the risk of preterm birth compared to gestational-IFG (RR 1.80, 95% CI 1.02-3.36). GDM exhibits distinct insulin physiology profiles. Pregnancy outcome varies between each phenotype. These findings provide evidence on risk stratification and diverse strategies for the treatment of GDM.

Gout and erectile dysfunction: Increased carotid intima-media thickness is independently associated with greater likelihood for erectile dysfunction.

The study aimed to compare gout patients and healthy subjects in terms of erectile dysfunction, carotid intima-media thickness (CIMT), and other variables and to investigate the relationship between CIMT and erectile dysfunction. This cross-sectional study was conducted with 134 male gout patients (median age: 56 years; range, 48 to 62 years) and 104 healthy males (median age: 47 years; range, 40.5 to 54.5 years) between September 2022 and June 2023. Age, comorbidities, height, weight, laboratory results, gout treatment data, insulin resistance evaluated by the homeostatic model assessment for insulin resistance, presence and severity of erectile dysfunction evaluated by the six-item International Index of Erectile Function erectile function domain (IIEF-EF), and CIMT measured by ultrasound were assessed. Hypertension, hyperlipidemia, greater insulin resistance, erectile dysfunction, and bilaterally increased CIMT were significantly more common in the gout group. The mean IIEF-EF score of gout patients was significantly lower than that of controls. Multivariable logistic regression revealed increased CIMT as the sole parameter independently associated with erectile dysfunction (p=0.010). When both groups were categorized into CIMT-based subsets, erectile dysfunction was present in 97.9% of patients with coexistence of gout and increased CIMT (≥0.9 mm), a significantly higher proportion compared to the other three subsets (p<0.001). Increased CIMT was the only factor independently associated with a greater likelihood of erectile dysfunction in patients with and without gout; however, coexistence of gout and increased CIMT appears to result in a significantly elevated risk for erectile dysfunction.

Challenges and pitfalls of youth-onset type 2 diabetes.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) are increasing. The rise in frequency and severity of childhood obesity, inclination to sedentary lifestyle, and epigenetic risks related to prenatal hyperglycemia exposure are important drivers of the youth-onset T2DM epidemic and might as well be responsible for the early onset of diabetes complications. Indeed, youth-onset T2DM has a more extreme metabolic phenotype than adult-onset T2DM, with greater insulin resistance and more rapid deterioration of beta cell function. Therefore, intermediate complications such as microalbuminuria develop in late childhood or early adulthood, while end-stage complications develop in mid-life. Due to the lack of efficacy and safety data, several drugs available for the treatment of adults with T2DM have not been approved in youth, reducing the pharmacological treatment options. In this mini review, we will try to address the present challenges and pitfalls related to youth-onset T2DM and summarize the available interventions to mitigate the risk of microvascular and macrovascular complications.

Abstract 2047: Pioglitazone Improves Apolipoprotein A1-associated Proteomic Composition More Than Weight Loss In Insulin Resistance

Insulin resistance (IR) is linked to an atherogenic dyslipidemia and an increased risk of ASCVD. Apolipoprotein A1 (ApoA1)-associated lipoproteins exert varying anti-atherogenic functions and have a large diverse proteome. It is, however, unknown whether IR contributes to atherogenic perturbations in these ApoA1-associated proteins. We thus tested the hypothesis that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions improve the proteome to a more anti-atherogenic composition. The study included 861 participants without diabetes (age 48 ± 12 years, female = 65.5 %). We measured IR directly using the steady-state plasma glucose (SSPG) concentration during the insulin suppression test, where a higher SSPG indicates greater IR. The ApoA1-associated proteome lipoproteins were measured by mass spectrometry. A subgroup of participants underwent pioglitazone treatment (PIO; n = 38) or weight loss (WL; n = 70) for 3 months. Paired t-testing was used to quantify within-subject changes in outcomes of interest pre- to post-treatment. At baseline, several components of ApoA1-associated proteome significantly correlated with SSPG concentration ( Figure ). Both PIO and WL significantly improved IR (p&lt;0.01). PIO led to significant increases in several ApoA1-associated proteins: ApoC1; ApoC2; ApoC3; ApoC4; ApoA2; ApoA4; ApoD; ApoE; ApoM; LCAT; LpPLA2; PLTP; PON1; and PON3. WL also led to significant increases in ApoA1-associated proteins: ANGT; ApoA4; ApoD; ApoM; LpPLA2; PLTP; PON1; and PON3. In conclusion, IR correlates with an atherogenic ApoA1-associated proteome. Both PIO and WL improve IR and the composition of the ApoA1-associated proteome, but PIO has a more pronounced effect on the proteome compared to WL. These findings support further exploration into the ApoA1-associated proteome for both understanding residual lipid-related ASCVD risk and targeted therapeutics for ASCVD reduction.

Prepregnancy physiology and subsequent preterm preeclampsia

BackgroundPreeclampsia is a common pregnancy complication with debated etiology. ObjectiveTo evaluate the contribution of prepregnancy physiology, biochemistry and anthropometrics to the subsequent development of preterm preeclampsia. Study DesignOne-hundred twenty-four participants were recruited through open recruitment and targeted mailings. Participants included 81 nulliparous women and 43 with a history of preterm preeclampsia. We characterized cardiovascular function, metabolic profile, and body composition in 100 non-pregnant women who went on to subsequent pregnancy. Measures included plasma volume, baseline cardiovascular function and cardiovascular response to volume challenge, body composition and circulating biochemical measures. Pregnancy outcome was obtained through chart review. Prepregnancy metrics for women who developed preterm preeclampsia were compared with measurements for those who did not, with adjustment for a history of prior preterm preeclampsia. Logistic regression modeling was used to identify the strongest prepregnancy factors associated with preterm preeclampsia. ResultsPregnancy outcomes included 11 women with preterm preeclampsia, 7 women with term preeclampsia, 20 women with other hypertension affecting their pregnancy, and 62 with uncomplicated pregnancies. We observed no difference in maternal age, study cycle day, lean body mass, uterine hemodynamics, or flow mediated dilation across groups. Women with preterm preeclampsia had greater android fat content 3215+1143 vs. 1918+1510 grams (p=0.002), faster supine pulse, 77+7 vs. 67+10 beats per minute (p=0.001), higher supine diastolic blood pressure 82+6 vs. 68+6 mmHg (p< 0.001), increased cardiac output 5.6+1.1 vs. 4.6+1 L/min (p=0.002), faster aortic-popliteal pulse wave velocity 4.5+0.7 vs. 3.8+0.5 m/sec (p<0.001), and exaggerated cardiac output response to volume challenge 20+9 vs. 9+12 L/min (p=0.002) compared to those with other pregnancy outcomes. Women who developed preterm preeclampsia also had reduced renal vascular resistance index 0.86+0.08 vs. 0.97+0.12 (p=0.005) compared with other pregnancy outcomes when assessed prior to pregnancy. Women with subsequent preterm preeclampsia had higher serum c-reactive protein 10.7+12.5 vs. 4.1+5.8mg/mL (p=0.003) and greater insulin resistance, as assessed by HOMA-IR calculation 2.2+1.1 vs. 1.2+0.9 (p<0.001). ConclusionPrepregnancy physiology is linked to subsequent preterm preeclampsia. The same factors associated with metabolic syndrome are more prominent in patients who develop preterm pre-eclampsia than those who do not, including increased vessel stiffness, low vascular compliance, high cardiac output, reduced renal vascular resistance index, insulin resistance and increased android fat, all consistent with subclinical features of the metabolic syndrome.

Differences in metabolic biomarkers in people with schizophrenia who are of Mexican descent compared to non-Hispanic whites

Metabolic dysfunction is highly prevalent and contributes to premature mortality among people with schizophrenia (PwS), especially in Hispanic/Latino/a/x/e PwS, compared to non-Hispanic White (NHW) PwS. This study evaluated the relative contributions of Mexican descent and schizophrenia diagnosis to metabolic biomarker levels. This cross-sectional study included 115 PwS and 102 non-psychiatric comparison (NC) participants – English-speakers aged 26–66 years, 27% Mexican descent, and 52% women across both groups. Assessments included evaluations of BMI, psychopathology, and fasting metabolic biomarkers. We used ANOVA analyses to compare metabolic outcomes between diagnostic and ethnic subgroups, linear regression models to examine associations between Mexican descent and metabolic outcomes, and Spearman's correlations to examine relationships between metabolic outcomes and illness-related variables in PwS. Mexican PwS had higher hemoglobin A1c levels, insulin resistance, and body mass index than NHW PwS. Mexican descent was associated with higher hemoglobin A1c levels, insulin resistance, body mass index, and leptin levels, controlling for age, sex, depression, education, and smoking. Among Mexican PwS, worse negative symptoms were associated with greater insulin resistance. These findings support the possibility of ethnicity-based differences in metabolic dysregulation, though further investigation is warranted to create targeted health interventions for Hispanic PwS.

Clinical Value and Mechanism Exploration of Serum miR-379 in Obesity-Polycystic Ovary Syndrome.

As a common endocrine and metabolic disorder, polycystic ovary syndrome (PCOS) is mostly associated with an obese phenotype. The present research focuses on the clinical significance of miR-379 in obesity-PCOS and attempts to elucidate its potential mechanisms. Healthy individuals (n = 46), obesity-PCOS (n = 92), and non-obesity PCOS (n = 31) subjects were enrolled. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to examine the level of serum miR-379. The receiver operating characteristic (ROC) curve and logistic regressions were applied to reveal the diagnostic significance. Dual luciferase reporters were performed to validate the targeting relationships. And cell count kit (CCK-8) assay was used to detect cell proliferation. Serum miR-379 was highly expressed in PCOS patients (P < 0.05), in especially obesity-PCOS patients. Higher miR-379 was associated with greater body mass index (BMI), higher bioavailable testosterone (bT), and greater insulin resistance (IR). Additionally, miR-379 was an independent risk factor for the development of obesity-PCOS. The sensitivity of miR-379 in identifying patients with obesity-PCOS from healthy or non-obesity-PCSO patients was 81.52% and 72.83%, and the specificity was 86.96% and 80.65%. Semaphorin 3 A (SEMA3A) was identified as a target of miR-379 and was reduced in the patients with obesity PCOS (P < 0.05). Inhibition of miR-375 reduced KGN proliferation, but this reduction was partially restored by silencing of SEMA3A (P < 0.05). Elevated miR-379 assists the diagnosis of obesity-PCOS and regulates the proliferation of KGN by targeting SEMA3A engaged in disease development.

OR07-03 UCP1 Expression In Human Brown Adipose Tissue Is Inversely Associated With Cardiometabolic Risk Factors

Abstract Disclosure: T. Kwok: None. L.E. Ramage: None. K.J. Suchacki: None. C. Gray: None. K. Alexandra: None. L.D. Boyle: None. R.K. Semple: None. S.I. Semple: None. T. MacGillivray: None. E.J. van Beek: None. S. Wakelin: None. R.H. Stimson: None. Brown adipose tissue (BAT) is a promising therapeutic target for obesity. 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) is the most commonly used imaging modality to quantify human BAT activity. 18F-FDG uptake may be reduced in obesity but insulin resistance has been suggested as a potential confounding factor. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT and thus serves as a surrogate measure of BAT thermogenic capacity. We quantified UCP1 expression in paired BAT and white adipose tissue (WAT) samples from 141 patients undergoing elective neck surgery. UCP1 mRNA was quantified in whole tissue (n=53) and differentiated pre-adipocytes (n=88). Data are presented as mean ± SEM. Individuals with high UCP1 expression in whole BAT (&amp;gt;2 arbitrary units) were younger (44.2 ± 3.5 vs 55.7 ± 2.0 years) with lower BMI (26.5 ± 1.2 vs 30.1 ± 1.0kg/m2), waist circumference (87.9 ± 2.9 vs 101.1 ± 2.6cm), waist-hip ratio (0.86 ± 0.01 vs 0.92 ± 0.01), fat percentage (29.1 ± 2.6 vs 35.3 ± 1.7%), insulin resistance (HOMA-IR 1.44 ± 0.18 vs 2.69 ± 0.35), systolic (131 ± 6 vs 143 ± 4mmHg) and diastolic blood pressure (79 ± 3 vs 86 ± 2mmHg) (all P&amp;lt;0.05). BAT UCP1 expression was lower in subjects on beta-blockers or with existing hypertension. BAT (but not WAT) UCP1 expression correlated negatively with age (r=−0.305), weight (r=−0.374), waist circumference (r=−0.296), fat mass (r=−0.388) and BMI (r=−0.282) (all P&amp;lt;0.05). However, UCP1 levels in differentiated brown adipocytes were not associated with any of the above measurements. In multiple regression, age was the only independent predictor of high BAT UCP1 expression. Interestingly, BAT UCP1 levels were not reduced in obese subjects aged &amp;lt;40 years. To determine whether BAT activity was preserved in young obese subjects in vivo, we performed 18F-FDG-PET/MR scanning during mild cold exposure (16-17°C) in 6 normal weight (BMI 22 ± 1kg/m2) and 6 obese (BMI 32 ± 1kg/m2) age-matched (22 ± 1 years) subjects. BAT 18F-FDG uptake (standard uptake value 5.1 ± 0.5 vs 4.2 ± 0.6 g/mL) and volume (69 ± 14 vs 72 ± 32 cm3) were similar between weight groups, despite greater insulin resistance in obese subjects (fasting glucose 5.5 ± 0.2 vs 4.3 ± 0.1mmol/L, insulin 11.9 ± 1.3 vs 5.8 ± 0.9mU/L, HOMA-IR 2.9 ± 0.3 vs 1.1 ± 0.2, free fatty acids 465 ± 78 vs 240 ± 34µM, all P&amp;lt;0.05), suggesting that 18F-FDG uptake by BAT is not significantly affected by insulin resistance. In conclusion, BAT UCP1 expression is reduced in individuals with adverse cardiometabolic risk factors, but these subjects retain brown pre-adipocytes with the capacity to form new thermogenic adipocytes after appropriate stimulation. UCP1 expression and cold-induced 18F-FDG uptake by BAT is preserved in young obese subjects. These data highlight the therapeutic potential of BAT mass expansion and activation as a therapeutic strategy to ameliorate the cardiometabolic consequences of obesity. Presentation: Thursday, June 15, 2023

Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy.

Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first 5 years postpartum in women reflecting the full spectrum of gestational glucose tolerance (spanning normoglycaemia to gestational diabetes) and hence a range of future diabetic risk. In this study, 302 women with normal glucose tolerance (NGT) on OGTT at 3 months postpartum underwent repeat OGTT at 1 year, 3 years and 5 years, enabling serial assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, HOMA-IR) and beta cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index [IGI]/HOMA-IR). Determinants of prediabetes/diabetes were ranked by change in concordance index (CCI) of Cox proportional hazard regression models. Over 5 years of follow-up, 89 women progressed from NGT to prediabetes/diabetes (progressors). At 3 months postpartum, though all women were normoglycaemic, future progressors had higher fasting glucose (p=0.03) and 2 h glucose (p<0.0001) than non-progressors, coupled with higher BMI (p=0.001), greater insulin resistance (both Matsuda index and HOMA-IR, p≤0.02) and poorer beta cell function (both ISSI-2 and IGI/HOMA-IR, p≤0.006). Unlike their peers, progressors exhibited deteriorating beta cell function from 1 year to 5 years (both p<0.0001). On regression analyses, the dominant determinants of progression to prediabetes/diabetes were time-varying ISSI-2 (change in CCI 25.2%) and IGI/HOMA-IR (13.0%), in contrast to time-varying Matsuda index (2.9%) and HOMA-IR (0.5%). Neither time-varying BMI nor waist were significant predictors after adjustment for beta cell function and insulin sensitivity/resistance. Declining beta cell function is the dominant determinant of incident prediabetes/diabetes in young women following pregnancy.

Effect of insulin resistance on gonadotropin and bone mineral density in nondiabetic postmenopausal women.

The effects of insulin resistance (IR) on bone mineral density (BMD) are unclear. This investigation aimed to assess the impact of IR and hyperinsulinemia on bone health. Determine whether IR mediates the link between follicle-stimulating hormone (FSH) and bone mass in nondiabetic postmenopausal women. Retrospective cross-sectional study. Health checkup center of Hangzhou Women's Hospital. This study comprised 437 nondiabetic postmenopausal women. BMD was evaluated using dual-energy X-rays. Fasting sera were analyzed for insulin and glucose levels, and indicators related to IR were determined. By pathway analysis, we examined the indirect effects of FSH on BMD via the mediators Homeostatic Model Assessment for insulin resistance (HOMA-IR) and fasting insulin (FINS) after correction for confounding factors. After adjusting for age and body mass index (BMI) in linear regression, HOMA-IR and FINS were linked with FSH (P<0.05). IR was stronger among women in the normal BMD group than those in the osteoporosis or osteopenia group. In unadjusted models, BMD was greater in those with higher HOMA-IR and FINS (β=0.027, P=0.006 and β=0.033, P=0.003, respectively). After correcting for BMI and other possible variables, these associations remained. In addition, path models for FSH demonstrated a negative association with BMD by HOMA-IR (95% confidence interval [CI]: -0.0174 to -0.0014) and FINS (95% CI: -0.0188 to -0.002). Greater IR was associated with increased BMD in nondiabetic postmenopausal women, regardless of BMI and other variables. HOMA-IR or FINS could play a novel mediating role in FSH-induced BMD suppression.

Approach to the Patient: Youth-Onset Type 2 Diabetes.

Youth-onset type 2 diabetes is a growing epidemic with a rising incidence worldwide. Although the pathogenesis and diagnosis of youth-onset type 2 diabetes are similar to adult-onset type 2 diabetes, youth-onset type 2 diabetes is unique, with greater insulin resistance, insulin hypersecretion, and faster progression of pancreatic beta cell function decline. Individuals with youth-onset type 2 diabetes also develop complications at higher rates within short periods of time compared to adults with type 2 diabetes or youth with type 1 diabetes. The highest prevalence and incidence of youth-onset type 2 diabetes in the United States is among youth from minoritized racial and ethnic groups. Risk factors include obesity, family history of type 2 diabetes, comorbid conditions and use of medications associated with insulin resistance and rapid weight gain, socioeconomic and environmental stressors, and birth history of small-for-gestational-age or pregnancy associated with gestational or pregestational diabetes. Patients with youth-onset type 2 diabetes should be treated using a multidisciplinary model with frequent clinic visits and emphasis on addressing of social and psychological barriers to care and glycemic control, as well as close monitoring for comorbidities and complications. Intensive health behavior therapy is an important component of treatment, in addition to medical management, both of which should be initiated at the diagnosis of type 2 diabetes. There are limited but growing pharmacologic treatment options, including metformin, insulin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Although long-term outcomes are not fully known, metabolic/bariatric surgery in youth with type 2 diabetes has led to improved cardiometabolic outcomes.

784-P: Characteristics of People with Young-Onset T2D in the SURPASS Program

Young-onset T2D, defined as diagnosed before age 40, is increasing around the world. Recent data suggest a faster deterioration in beta-cell function and earlier development of complications in this population, compared to later-onset T2D. This post-hoc analysis evaluated the baseline characteristics of people with young-onset vs later-onset T2D in the SURPASS clinical trial program. Baseline demographics and clinical characteristics were compared in participants with young-onset vs later-onset T2D from the SURPASS-1, -2, -3, and -5 clinical trials (N=4267). Analyses were performed by study. Across the SURPASS program, which included participants at various stages of T2D management, participants with young-onset T2D were younger, had longer duration of diabetes, worse glycemic control, higher mean body weight and BMI, and a worse lipid profile at baseline vs patients with later-onset T2D. Data from SURPASS-1 and SURPASS-2 also showed participants with young-onset T2D had greater insulin resistance (HOMA2-IR) at baseline. Despite their younger age at baseline, participants with young-onset T2D in the SURPASS program had an overall worse health status as compared to patients with later-onset T2D. Early intervention in young-onset T2D may be important to optimize long-term outcomes. Disclosure R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. P.Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson &amp; Johnson. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. V.Thieu: None. C.Nicolay: Employee; Eli Lilly and Company. S.Allen: None. B.Bergman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

1472-P: Polygenic Risk Score for Liver Fat Predicts Earlier Onset of Type 2 Diabetes in an East Asian Population

Liver, pancreas fat deposition and volume have been associated with type 2 diabetes (T2D) risk by Mendelian randomization study. However, it is unknown whether genetic variation in these traits impact on T2D onset, insulin resistance and drug use. We hypothesized that (1) genetic predisposition to smaller pancreas would be associated with earlier onset of T2D and earlier need for insulin; (2) genetic predisposition to higher pancreas and liver fat would be associated with greater insulin resistance, earlier onset of T2D and earlier need for insulin. This study utilized three Chinese cohorts of genotyped T2D patients in Hong Kong: Hong Kong Diabetes Register (HKDR, n=6011), Hong Kong Diabetes Biobank Phase 1 (HKDB-P1, n=6662) and Hong Kong Diabetes Biobank Phase 2 (HKDB-P2, n= 5899). We used lead SNPs (single nucleotide polymorphisms) associated with pancreas volume (13 SNPs), fat (7 SNPs) and liver fat (8 SNPs) from UK Biobank (n&amp;gt;32,000) to construct PRS (Polygenic risk score) in these cohorts. Linear regression models were employed to examine the associations between PRS and age of T2D onset and insulin resistance. Multivariable cox regression models were employed to examine association with time to insulin use. All models included age (except for age of T2D onset), sex and top 4 genetic principal components as covariates. To assess the confounding effects of BMI, we also performed BMI subgroup analysis by stratifying individuals into underweight, normal and overweight groups. Our analyses found that higher PRS for liver fat, but not pancreatic size or fat predicts earlier onset of T2D in HKDB-P1 (p&amp;lt;0.001, t=−3.43). The direction of association in HKDB-P2 was consistent though not significant. When stratified by BMI, higher PRS for liver fat predicts earlier onset of T2D in HKDB-P1 (p= 0.002, t=−3.14) and HKDB-P2 (p=0.029, t=−2.19) among the overweight group. Our results highlighted a PRS of liver fat as a potential biomarker for age of T2D onset, which needs further validation. Disclosure G.Yu: None. C.Huang: None. A.Luk: Research Support; Novo Nordisk, Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; Eli Lilly and Company. E.S.H.Lau: None. Hong kong diabetes biobank study group: n/a. R.C.Ma: Advisory Panel; AstraZeneca, Merck &amp; Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. C.H.Tam: None. M.Shi: None. B.Fan: None. C.K.Lim: Stock/Shareholder; GemVCare Ltd. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. M.N.Weedon: None. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. Funding Research Grants Council of the Hong Kong Special Administrative Region (CU-R4012-18); Croucher Foundation

Effects of PCSK9 inhibition on glucose metabolism and β-cell function in humans: a pilot study.

Anti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and β-cell function in humans. Fifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (β cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda). Glucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while β-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min-1m-2mM-1; p<0.05). Using linear regression, we found a significant correlation between βCGS changes and BMI (p=0.004). Thus, we compared subjects with values above and below the median (27.6 kg/m2) and found that those with higher BMI had a greater increase in βCGS after therapy (before: 85.37 ± 24.73; after: 118.62 ± 26.83 pmol min-1m-2mM-1; p=0.007). There was also a significant correlation between βCGS change and Matsuda index through linear regression (p=0.04), so we analyzed subjects who had values above and below the median (3.8). This subgroup analysis showed a slight though not significant improvement in βCGS in more insulin resistant patients, (before: 131.4 ± 69.8; after: 170.8 ± 92.7 pmol min-1m-2mM-1; p=0.066). Our pilot study demonstrates that six-month treatment with anti-PCSK9 mAb improves β-cell function, and does not alter glucose tolerance. This improvement is more evident in patients with greater insulin-resistance (low Matsuda) and higher BMI.

Cognitive-behavioral therapy and exercise training in adolescent females with elevated depression symptoms and at-risk for type 2 diabetes: Protocol for a randomized controlled trial

BackgroundAdolescent-onset type 2 diabetes (T2D) is a major public health concern of growing proportions. Prevention, therefore, is critical. Unfortunately, standard-of-care treatment for T2D prevention (e.g., exercise training) show insufficient effectiveness and do not address key modifiable barriers (e.g., depression symptoms) to exercise engagement. Depression symptoms are associated with both poorer physical fitness and greater insulin resistance, the key risk factor in adolescent-onset T2D. Thus, a targeted prevention approach that addresses depression symptoms in combination with exercise training may offer a novel approach to mitigating T2D risk. MethodsThis manuscript describes the design and study protocol for a multi-site, four-arm randomized controlled trial comparing the efficacy of group cognitive-behavioral therapy, group exercise training, and their combinations for the targeted prevention of worsening insulin resistance in N = 300 adolescent females at-risk for T2D with BMI ≥85th percentile and elevated depression symptoms. All four intervention arms will run in parallel and meet weekly for 1 h per week for 6-week to 6-week segments (12 weeks total). Outcomes are assessed at baseline, 6-week mid-treatment, 12-week follow-up, and 1-year follow-up. ResultsThe primary outcome is insulin resistance. Key secondary outcomes include insulin sensitivity, cardiorespiratory fitness, physical activity, depression symptoms, and body measurements. ConclusionStudy findings will guide the ideal sequencing of two brief T2D prevention interventions for ameliorating the course of insulin resistance and lessening T2D risk in vulnerable adolescents. These interventions will likely be cost-effective and scalable for dissemination, having the potential for significant public health impact on communities at risk for T2D.

Objective sleep and cardiometabolic biomarkers: results from the community of mine study.

Examining multiple dimensions of sleep health may better capture associations between sleep and health risks, including cardiometabolic disease (CMD). Hispanics have elevated risk for inadequate sleep and CMD biomarkers. Few studies have explored whether associations between sleep and CMD differ by Hispanic ethnicity. Leveraging data from the Community of Mine (CoM) study, a cross-sectional investigation of 602 ethnically diverse participants, we derived accelerometer-measured sleep duration and efficiency, and self-reported sleep quality. Accelerometer-measured sleep exposures were analyzed both as continuous and categorical variables. Multivariate and quantile regression models were used to assess associations between sleep and CMD biomarkers (insulin resistance, systolic blood pressure, and low-density-lipoprotein cholesterol), controlling for age, sex, ethnicity, education, smoking status, and body mass index. We examined the potential effect modification of Hispanic ethnicity. We observed mixed results based on CMD biomarkers and sleep exposure. Increased sleep duration was significantly related to low-density lipoprotein cholesterol in adjusted models (estimate = 0.06; 95% CI: 0.02, 0.11). Poor sleep efficiency was associated with greater insulin resistance in the adjusted quantile (estimate = 0.20; 95% CI: 0.04, 0.36) model at the 90th percentile. Self-reported sleep quality was not associated with CMD outcomes. There was no evidence of effect modification by Hispanic ethnicity. In this cohort, sleep health measures were found to have mixed and at times opposing effects on CMD outcomes. These effects did not demonstrate an interaction with Hispanic ethnicity.

Associations of somatic depressive symptoms with body mass index, systemic inflammation, and insulin resistance in primary care patients with depression.

The somatic depressive symptom cluster (including appetite and sleep disturbances) is more strongly associated with insulin resistance (a diabetes risk marker) than other depressive symptom clusters. Utilizing baseline data from 129 primary care patients with depression but no diabetes in the eIMPACT trial (Mage=59 years, 78% female, 50% Black), we examined associations of somatic depressive symptoms with insulin resistance (HOMA-IR), body mass index (BMI), and high-sensitivity C-reactive protein (hsCRP). We tested BMI and hsCRP as mediators and race as a moderator of these relationships. Hyperphagia was positively associated HOMA-IR (β = 0.19, p = .048) and BMI (β = 0.30, p < .001); poor appetite was negatively associated with HOMA-IR (β=-0.24, p = .02); hypersomnia was positively associated with HOMA-IR (β = 0.28, p = .003), BMI (β = 0.26, p = .003), and hsCRP (β = 0.23, p = .01); and disturbed sleep was positively associated with hsCRP (β = 0.21, p = .04). BMI partially mediated hyperphagia and hypersomnia's associations with HOMA-IR; hsCRP partially mediated the hypersomnia-HOMA-IR association; and race moderated the hyperphagia-HOMA-IR association (positive for White participants but null for Black participants). People with depression experiencing hyperphagia and/or hypersomnia may be a subgroup with greater insulin resistance; BMI and hsCRP are likely pathways in these relationships. This study highlights the importance of considering the direction of somatic depressive symptoms in the context of cardiometabolic disease risk.

Hyperinsulinemia induces early and dyssynchronous puberty in lean female mice.

Girls with obesity are at increased risk of early puberty. Obesity is associated with insulin resistance and hyperinsulinemia. We hypothesized that insulin plays a physiological role in pubertal transition, and super-imposed hyperinsulinemia due to childhood obesity promotes early initiation of puberty in girls. To isolate the effect of hyperinsulinemia from adiposity, we compared pre-pubertal and pubertal states in hyperinsulinemic, lean muscle (M)-insulin-like growth factor 1 receptor (IGF-1R)-lysine (K)-arginine (R) (MKR) mice to normoinsulinemic WT, with puberty onset defined by vaginal opening (VO). Our results show MKR had greater insulin resistance and higher insulin levels (P < 0.05) than WT despite lower body weight (P < 0.0001) and similar IGF-1 levels (P = NS). Serum luteinizing hormone (LH) levels were higher in hyperinsulinemic MKR (P = 0.005), and insulin stimulation induced an increase in LH levels in WT. VO was earlier in hyperinsulinemic MKR vs WT (P < 0.0001). When compared on the day of VO, kisspeptin expression was higher in hyperinsulinemic MKR vs WT (P < 0.05), and gonadotropin-releasing hormone and insulin receptor isoform expression was similar (P = NS). Despite accelerated VO, MKR had delayed, disordered ovarian follicle and mammary gland development. In conclusion, we found that hyperinsulinemia alone without adiposity triggers earlier puberty. In our study, hyperinsulinemia also promoted dyssynchrony between pubertal initiation and progression, urging future studies in girls with obesity to assess alterations in transition to adulthood.

Epidemiology of Thyroid Cancer.

Epidemiology of Thyroid Cancer.

Development of pups born to rats established as a model of underweight Japanese women and the onset of impaired glucose tolerance

An increasing number of Japanese women of childbearing age are underweight (BMI <18.5), but the association between this and the increased number of low-birth-weight babies born remains unclear. Here, a rat model was established to mimic the undernutrition (85% of the energy required for those with normal activity levels) experienced by such women and to evaluate the associated impaired glucose tolerance. The undernourished Wistar rat group showed increased serum corticosterone level reflecting stress, and greater adrenal weight and size. It also showed greater insulin resistance, higher expression of FOXO-1, a transcription factor related to muscle atrophy, and lower expression of p-Akt, an insulin-dependent signaling factor. Overall, this work shows the key role of undernutrition during pregnancy as a cause of impaired glucose tolerance and increased diabetes risk in offspring. The findings of this study may inform preemptive measures to prevent the development of metabolic syndrome in offspring of undernourished mothers.