Lower Insulin Sensitivity Index Research Articles

Effect of glucose infusion on glucose and insulin metabolism in early- and mid-lactation ewes and goats fed diets differing in starch and highly digestible fiber concentration

This study aimed to test possible metabolic differences between ewes and goats in response to an intravenous glucose infusion. Thirty-six animals, 18 mature Sarda dairy ewes and 18 mature Saanen goats (from 15 to 150 ± 11 d in milk [DIM], mean ± SD; body weight: 49.8 ± 6.8 kg for ewes, 60.6 ± 7.3 kg for goats) were compared simultaneously. In early lactation, both species received the same high-starch diet (HS: 20.4% starch, 35.4% neutral detergent fiber [NDF], on dry matter [DM] basis), whereas from 92 ± 11 DIM both species were randomly allocated to 2 dietary treatments: HS (20.0% starch, 36.7% NDF, on DM basis) and low-starch (LS: 7.8% starch, 48.8% NDF, on DM basis) diets. At 50 and 150 ± 11 DIM, ewes and goats were challenged with an intravenous glucose tolerance test and peripheral concentrations of glucose and insulin were determined 15 min before and 5, 10, 15, 30, 45, 90, and 180 min after glucose infusion. In early lactation, baseline plasma glucose and insulin concentrations tended to be higher in ewes than in goats (glucose: 55.8 vs. 42.9 ± 7.3 mg/dL; insulin: 0.13 vs. 0.05 ± 0.04 µg/L). After glucose infusion, glucose and insulin concentrations were higher in ewes than in goats (278.6 vs. 247.6 ± 13.1 mg/dL; 0.82 vs. 0.46 ± 0.12 µg/L). In mid-lactation, the dietary treatment (HS vs. LS) did not affect glucose and insulin metabolism. Baseline plasma glucose was numerically highest in ewes, while baseline insulin was higher in ewes than in goats (0.39 vs. 0.12 ± 0.099 µg/L). After glucose infusion, glucose concentration did not differ between ewes and goats, while insulin concentration was highest in ewes. Compared with goats, ewes showed in both periods a higher peak insulin, insulin increment, linear insulin area under the curve, insulin resistance index, and lower insulin sensitivity indices. In conclusion, despite the limitations associated with the use of intravenous glucose tolerance test to assess glucose regulation mechanisms, this study indicated large species differences in both early and mid-lactation and a more evident anabolic status in the ewes compared with the goats.

Association of thyroid function with insulin resistance: data from two population-based studies.

ObjectiveThyroid dysfunction is associated with relevant disturbances in glucose metabolism. Moreover, thyroid function undergoes important changes with ageing. The objective of this study was to investigate the association of thyroid function with insulin resistance with particular consideration of possible age-related effect modifications.DesignA sample of 4193 participants from two independent epidemiological studies, the Study of Health in Pomerania-TREND-0 and the Berlin Aging Study II, was included in this cross-sectional analysis.MethodsInsulin resistance was estimated by homeostasis model of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI). Associations of thyroid biomarkers (thyroid-stimulating hormone, free thyroxine, and free triiodothyronine (fT3)) with parameters of glucose metabolism were analysed by regression models adjusted for age, sex, smoking status, and study site.ResultsA higher fT3 was significantly associated with higher fasting glucose and higher fasting and 2-h postload insulin levels, a higher HOMA-IR, and lower ISI. A higher fT3 was also associated with a higher risk for impaired fasting glucose (RR 1.09, 95 CI 1.02; 1.18; P = 0.017). Many of these associations between thyroid markers and parameters of glucose metabolism were significant in young and middle-aged participants but not in older individuals.ConclusionsThe main finding of this study was a consistent association of fT3 with almost all markers of insulin resistance. However, this effect seems to be wearing off in higher age highlighting a potential age-related modification of the interaction between thyroid function and glucose metabolism. Further studies are needed to clarify causal relationships.

Effect Modification of Body Mass Index and Kidney Function on Insulin Sensitivity Among Patients With Moderate CKD and Healthy Controls

IntroductionInsulin resistance and obesity are prevalent in chronic kidney disease (CKD) patients. The interaction of body mass index (BMI) and kidney function across the continuum of estimated glomerular filtration rate (eGFR) is unknown.MethodsIn a cross-sectional study of 139 patients, 52 with CKD stages 3 and 4 and 87 patients with normal eGFR, we measured the insulin sensitivity index (ISI) using the hyperinsulinemic euglycemic clamp and homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the interaction between eGFR and BMI in their association with ISI and HOMA-IR using linear models with robust standard errors.ResultsMedian age was 56 (42, 66) years, 50.4% were female, and 36% were African American. Patients with low eGFR (∼30 ml/min per 1.73 m2) had low ISI (2.3 mg/min per μU/ml) regardless of BMI. Among patients with preserved eGFR (>90 ml/min per 1.73m2), BMI had a greater effect on ISI (6.3 mg/min per μU/ml at a BMI of 20 kg/m2 vs. 4.6 mg/min per μU/ml at a BMI of 30 kg/m2) (P for interaction = 0.046). In models adjusted for demographics, and log transformed interleukin-6, high-sensitivity C-reactive protein, leptin, and adiponectin, a 1-SD (28 ml/min per 1.73 m2) lower eGFR was associated with a statistically significant 1.14-unit decrease in ISI (95% confidence interval = −1.80, −0.48) among nonobese patients. Among obese patients, the effect estimate was −0.25 (95% confidence interval = −0.88, 0.39). The association between BMI and HOMA-IR was stronger in patients with lower eGFR (P for interaction = 0.005).ConclusionBoth eGFR and BMI are independently associated with insulin sensitivity, but the strength of the association between BMI and insulin sensitivity varies significantly across eGFR.

Early postpartum abnormal glucose metabolism subtype differs according to mid-trimester lipid profile in women with gestational diabetes mellitus

BackgroundIt is unknown whether early postpartum abnormal glucose metabolism (AGM) in women with previous gestational diabetes mellitus (GDM) is related to their mid-trimester lipid profile. The aim of this study was to characterize the mid-trimester lipid profile of women who experienced GDM and developed into different pathophysiologic subtypes of early postpartum AGM.MethodsA retrospective cohort study of 498 women with history of GDM was conducted. A 75-g oral glucose tolerance test (OGTT) and plasma lipid measurements were performed at 24–28 weeks of gestation and 6–12 weeks of postpartum. Insulin secretion and sensitivity were estimated using early postpartum OGTT-based indices.ResultsWomen in the mid-trimester dyslipidemia group had higher postpartum 30-min and 2-h plasma glucose, higher postpartum 2-h plasma insulin, higher postpartum triglyceride (TG), higher postpartum low density lipoprotein cholesterol (LDL-c) concentrations, lower postpartum 30-min insulinogenic index (IGI30), lower postpartum insulin sensitivity index (ISI), and lower postpartum disposition index than those in the normal lipid group (all P < 0.05). Abnormal mid-trimester TG and LDL-c concentrations were associated with postpartum AGM (adjusted odds ratio [OR] = 1.786, 95 % confidence interval [CI] = 1.142–2.425; and adjusted OR = 1.621, 95 % CI = 1.323–2.051, respectively; both P < 0.05). AGM women with low IGI30 and low ISI had higher mid-trimester total cholesterol and LDL-c concentrations, and AGM women with low ISI had higher mid-trimester TG concentrations than women with NGT or other subtypes of AGM (all P < 0.05).ConclusionsGDM women with abnormal mid-trimester TG and LDL-c were predisposed to early postpartum AGM. Postpartum AGM women who experienced GDM had heterogeneous mid-trimester lipid profile when classified according to their pathophysiologic subtype.

Dissociation Between Insulin Resistance and Abnormalities in Lipoprotein Particle Concentrations and Sizes in Normal-Weight Chinese Adults.

Insulin resistance in obesity coincides with abnormalities in lipid profile and lipoprotein subclass distribution and size even before abnormalities in glucose homeostasis manifest. We aimed to assess this relationship in the absence of obesity. Insulin sensitivity (3-h intravenous glucose tolerance test and minimal modeling) and lipoprotein particle concentrations and sizes (proton nuclear magnetic resonance spectroscopy) were evaluated in 15 insulin-resistant and 15 insulin-sensitive lean Asians of Chinese descent with normal glucose tolerance, matched on age, sex, and body mass index. Despite a ~50% lower insulin sensitivity index (Si) in insulin-resistant than in insulin-sensitive subjects, which was accompanied by significantly greater acute insulin response to glucose (AIRg) and fasting insulin concentration but not different fasting glucose concentration, there were no significant differences between groups in the blood lipid profile (p ≥ 0.44) or the lipoprotein subclass concentrations (p ≥ 0.30) and particle sizes (p ≥ 0.43). We conclude that, contrary to observations in subjects with obesity, insulin resistance is not accompanied by unfavorable changes in the plasma lipid profile and lipoprotein particle concentrations and sizes in lean Asians with normal glucose tolerance. Therefore, insulin resistance at the level of glucose metabolism is mechanistically or temporally dissociated from lipid and lipoprotein metabolism.Trial Registration: clinicaltrials.gov, NCT03264001.

Body Composition is Associated With Islet Function After Pancreatectomy and Islet Autotransplantation for Pancreatitis.

Body composition in total pancreatectomy with islet autotransplantation (TPIAT) has never been studied. Determine whether presurgical body composition is associated with islet function and insulin sensitivity after TPIAT. In 88 adults undergoing TPIAT (median age 41.0 years, IQR 32.8-48.0), beta-cell function and insulin sensitivity were assessed using mixed meal tolerance test and frequent sample intravenous glucose tolerance test before surgery and 12 and 18 months afterward. Body composition was measured by dual x-ray absorptiometry. Analyses used linear and logistic regression. Before surgery, 8 individuals (9.1%) were underweight, 40 (45.5%) normal weight, 20 (22.7%) overweight, and 20 (22.7%) obese. Overweight/obese patients had higher area under the curve C-peptide and lower insulin sensitivity index. Baseline body weight was positively associated with first-phase insulin secretion (AIRg) at 12 months (average 38.5 [SE 17.1] mU/L/min higher per extra kg; P = 0.03) and 18 months (38.3 [18.5]; P = 0.04), while baseline lean mass was inversely associated with AIRg at 12 months (-0.05 [0.02] per extra kg; P = 0.01) and 18 months (-0.05 [0.02]; P = 0.03). Percent gynoid fat was inversely associated with disposition index at 18 months (-206.0 [97.2] per extra percent; P = 0.04). Percent body fat and percent gynoid fat were associated with glucose effectiveness index at 18 months (1.9 × 10-3 [0.9 × 10-3] per extra percent; P = 0.04 and -1.96 × 10-3 [0.8 × 10-3]; P = 0.02, respectively). Insulin independence was not significantly associated with body weight or composition. Half of these chronic pancreatitis patients were overweight/obese; underweight was uncommon. Preoperative body weight and composition were associated with islet function but not insulin independence after TPIAT.

SUN-621 Body Weight and Body Composition in Patients with Chronic Pancreatitis Are Associated with Islet Function After Total Pancreatectomy and Islet Cell Transplantation

Background: Total pancreatectomy with islet autotransplant (TPIAT) is done in patients with chronic pancreatitis to treat intractable pain. In TPIAT, islets are isolated after pancreatectomy and infused into the liver via the portal vein to mitigate post-operative diabetes. Outcomes vary, with ≥60% needing exogenous insulin supplementation to maintain normoglycemia. The current study’s aim was to determine if pre-surgical body composition is associated with islet function and insulin sensitivity after TPIAT. Methods: We characterized body weight and composition as related to insulin sensitivity and dependence and diabetes outcome in 88 adults who underwent TPIAT for chronic pancreatitis at the University of Minnesota. At baseline, 12 and 18 months after TPIAT, insulin independence was assessed; metabolic testing used mixed meal tolerance testing and frequent sample intravenous glucose tolerance testing. Body composition was measured by Dual X-ray absorptiometry (DXA). Statistical analyses used linear and logistic regression. Results: At baseline, mean age was 39.9 (SD 11.1) years. 9.1% were underweight (BMI<18.5 kg/m2), 45.5% normal weight (BMI=18.5–24.9), 22.7% overweight (BMI=25–29.9) and 22.7% obese (BMI≥30). Islet equivalent per kg did not differ between body weight categories (p=0.17). Overweight/obese patients had higher peak and AUC c-peptide and lower insulin sensitivity index, as expected. Compared to baseline, android to gynoid fat ratio was lower at 12 (0.80 vs 0.88; p=0.012) and 18 months (0.81 vs 0.88; p=0.041), and lean mass was lower at 18 months (38848 vs 42338 kg; p=0.029). Baseline body weight was positively associated with acute insulin response to glucose (AIRg) at 12 months (effect size 38.5, SE 17.1 mU/L/min; p=0.029) and 18 months (38.3, SE 18.5 mU/L/min; p=0.045), while baseline lean mass was inversely associated with AIRg at 12 (p=0.01) and 18 months (p=0.033). Baseline body weight was positively associated, and fat mass inversely associated with disposition index (Di; islets’ ability to secrete insulin normalized to insulin resistance) at 18 months (p=0.019 for both).Percent body fat and percent gynoid fat predicted Sg (glucose effectiveness index, i.e., ability of glucose to promote its own disposal and inhibit hepatic glucose production absent an incremental insulin effect) at 18 months (p=0.042 and p=0.019, respectively). Insulin independence at 12 and 18 months was not significantly associated with baseline body weight or body composition. Conclusions: Overweight/obesity is common in patients with chronic pancreatitis. After TPIAT, patients had lower muscle mass and A/G ratio. Preoperative body weight and composition were associated with islet function but not insulin independence after TPIAT surgery.

Upregulation of MC4R and PPAR-α expression mediates the anti-obesity activity of Moringa oleifera Lam. in high-fat diet-induced obesity in rats.

various extracts of Moringa oleifera Lam. leaves, were reported to possess antiobesity effect in experimental animals models, yet its active doses and mechanism of action are still unclear. The metabolic profiling of 70% ethanol extract of M. oleifera (MO) leaves was performed using HPLC-MS/MS analysis. The antiobesity activity of MO was tested in high fat diet induced obesity in rats at 200 and 400mg/kg body weight orally for 1 month. Total cholesterol (TC), high density lipoproteins (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides (TGs), insulin resistance, insulin sensitivity, and adipose tissue index were monitored. In addition, fatty acid synthase (FAS) and HMG-CoA reductase mRNA from liver tissue, Peroxisome Proliferator-Activated Receptor alpha (PPARα) and Melanocortin-4 receptor (MC4R) RNA from adipose tissue were quantified using qRT-PCR. MO hard gelatin capsules (400 mg/capsule) were formulated and standardized using HPLC-RP analysis and tested on fifteen female participants, aged 45-55 with a BMI of 29-34kg/m2. Thirteen metabolites were tentatively identified using HPLC-MS/MS analysis including flavonols, flavones and a phenolic acid. MO 400 showed a prominent effect on reducing the rats' final weights, % weight increase and adiposity index (P<0.05). Glucose, insulin and HOMA-IR were significantly reduced and R-QUICKI was significantly increased by MO 400 (P<0.001). Mean tissue level of leptin and vaspin were significantly reduced, adiponectin, omentin and GLUT-4 expression were increased significantly by MO 400 (P<0.01). MO 400 significantly suppressed FAS and HMG-CoA reductase and increased mRNA expression of MC4R and PPAR-α (P<0.01). Eight weeks administration of MO hard gelatin capsules to obese patients showed significant reduction of the average BMI, TC and LDL compared to the baseline values (p<0.05). Our results presented a scientific evidence for the traditional use of M. oleifera leaves as antiobesity herbal medicine.

Pathophysiological characteristics in patients with latent autoimmune diabetes in adults using clamp tests: evidence of a continuous disease spectrum of diabetes.

This study aimed to assess islet insulin secretion and insulin resistance in Chinese patients with latent autoimmune diabetes in adults (LADA). Twelve patients with LADA, 10 with type 1 diabetes mellitus (T1DM), 10 with type 2 diabetes mellitus (T2DM), and 10 nondiabetic healthy controls (HCs) were included. Patients with LADA were subtyped according to the glutamic acid decarboxylase antibody (GADA) titer (LADA1, GADA titer ≥ 180 U/mL; LADA2, GADA titer 18-180 U/mL). Insulin secretion and sensitivity were assessed using hyperglycemic and hyperinsulinemic-euglycemic clamp tests, respectively. The first-phase insulin secretion gradually increased in patients with T1DM, LADA1, LADA2, and T2DM to HCs (29.32 ± 6.00mU/L vs. 68.71 ± 4.50mU/L vs. 87.60 ± 11.60mU/L vs. 138.27 ± 13.18mU/L vs. 248.49 ± 21.97mU/L; P < 0.05). The second-phase insulin secretion (2ph) and maximum insulin secretion (MIS) were significantly lower in patients with LADA2 and T2DM than in HCs, but higher in those with LADA1 and T1DM. No significant differences in 2ph and MIS were observed between patients with LADA1 and T1DM, and between those with LADA2 and T2DM. The levels of insulin sensitivity index (ISI) during hyperinsulinemic-euglycemic clamps were lower in patients with LADA and T2DM than in those with T1DM. Patients with T1DM displayed lower ISI compared with HCs. Chinese patients with LADA and T1DM had impaired insulin sensitivity and β-cell function. Furthermore, the hypothesis that diabetes is a continuous spectrum from T1DM, LADA1, LADA2 to T2DM was confirmed in this study.

3574 Effect modification between kidney function and adiposity in the association with central and peripheral insulin sensitivity among Nondiabetic patients with moderate Chronic Kidney Disease and Healthy Controls

OBJECTIVES/SPECIFIC AIMS: The main aim of this study was to investigate the interaction between glomerular filtration rate (GFR) and body mass index (as well as serum leptin) as determinants of peripheral and central insulin sensitivity (IS). METHODS/STUDY POPULATION: This was a cross-sectional investigation of 140 nondiabetic participants – 56 with CKD (GFR = 15-59 ml/min/1.73m2) and 94 with normal GFR (≥ 60 ml/min/1.73m2) – recruited as part of the relationship of insulin sensitivity in kidney disease and vascular health (RISKD) study. Peripheral (skeletal muscle) and central (hepatic) IS were assessed with the hyperinsulinemic euglycemic glucose clamp (HEGC) and homeostasis assessment of insulin resistance (HOMA-IR) respectively. Creatinine-based estimated GFR (eGFR) was obtained using the CKD-EPI equation and body mass index (BMI) was computed from baseline weight and height measurements. Linear regression models with robust standard errors (to relax homoscedasticity assumptions) and interaction terms were used to investigate GFR and BMI as predictors of HEGC-derived insulin sensitivity index (ISI) and HOMA-IR. RESULTS/ANTICIPATED RESULTS: The mean (SD) age was 53.9 (14.5) years; 50.7% were female and 36.7% were African-American. Compared to controls, CKD patients had significantly lower mean (SD) ISI [5.4 (3.2) vs. 3.1 (1.6), p &lt; 0.0001]. Log ISI was positively correlated (r = 0.39, p &lt; 0.0001) with eGFR and inversely correlated (−0.30, p &lt; 0.0001) with BMI and log leptin (−0.42, p &lt; 0.0001). In multivariable models adjusted for age, sex and race, a 10 ml/min/1.73m2 lower eGFR was associated with a greater decrease in ISI among non-obese (0.48; 95% CI: −0.25, −0.70) compared to obese participants (−0.18; 95% CI: −0.02, −0.35) (p-interaction = 0.04). Patients with low eGFR (in particular, the lower margin of the CKD stage 3 range, 30ml/min) had lower ISI even with BMI within normal range (Figure 1a). At higher eGFR, BMI had a greater impact on ISI. P-interaction = 0.046, for differential BMI effects at lower vs. higher eGFR. Log HOMA-IR was inversely correlated with eGFR (r = - 0.49, p &lt; 0.0001) and positively correlated with BMI (r = 0.52, p &lt; 0.0001) and log leptin (0.46, p &lt; 0.0001). HOMA-IR was lower for persons with higher GFR compared to lower GFR, at any BMI value. For example, at a BMI of 30 and a GFR of 120, HOMA-IR was 1.2 compared to 4.8 at a GFR of 30 (Figure 1b). Also, persons with high GFR had low HOMA-IR even with BMI in the obese range. BMI had a greater effect on HOMA-IR at lower eGFR. P-interaction = 0.005, for differential BMI effects at lower vs. higher eGFR. Similar findings were obtained when using log leptin in lieu of BMI in models for ISI and HOMA-IR. DISCUSSION/SIGNIFICANCE OF IMPACT: Measures of adiposity (BMI and leptin) and GFR were independently predictive of insulin sensitivity (IS) but the magnitude of the effect of BMI (or leptin) on IS varied significantly across GFR levels and type of IS (peripheral versus central). The effect of BMI on central IS (HOMA-IR) was more pronounced at lower GFR with small changes in BMI translating into greater variations in IS. Conversely, at low GFR, peripheral IS (ISI) is less affected by BMI. Persons with GFR at the lower margin of the CKD stage 3 range were significantly insulin resistant (low ISI) regardless of their BMI. More studies are required to further elucidate these interaction patterns for central and peripheral IS.

Correlation of Clinical and Histopathologic Parameters with Ultrasonographic Grades in Pediatric Non-Alcoholic Fatty Liver Disease.

BackgroundLiver biopsy is the gold standard for diagnosing non-alcoholic steatohepatitis (NASH), but liver biopsy in children is not available in many institutes and many parents are reluctant to agree with the procedure. We investigated the correlation of clinical and pathologic parameters with the severity of non-alcoholic fatty liver disease (NAFLD) in pediatric patients using ultrasonographic examination methods and measured the prevalence of fatty pancreas in pediatric NAFLD.MethodsLiver biopsy and abdominal ultrasound (US) examinations were performed in 58 children (42 boys, 16 girls; mean age, 12 years; age range, 4–19 years) between March 2006 and August 2017. Fatty liver and fatty pancreas were evaluated by two independent radiologists using US according to 4- and 3-point scales, respectively. We then analyzed the correlations of clinical, laboratory, and histopathologic parameters with the ultrasonographic grade of steatosis.ResultsForty-two children showed simple steatosis (NAFLD activity score [NAS] ≤ 5) while 16 showed NASH (NAS > 5). Higher body mass index (BMI) percentile, waist circumference, hematocrit, insulin resistance, and lower insulin sensitivity index were significantly positively correlated with the grade of fatty liver. NAFLD activity score, amount of steatosis, and fibrosis significantly worsened as the fatty liver grade increased. Higher BMI, lower insulin sensitivity index, and boy were significantly positively correlated with the fatty pancreas grade.ConclusionAltogether, ultrasonographic severity of fatty liver shows good correlation with that of clinical parameters and hepatic pathology.

Differences in Glucose Metabolism Among Women With Spinal Cord Injury May Not Be Fully Explained by Variations in Body Composition

ObjectiveTo investigate the differences in glucose metabolism among women with paraplegic, and tetraplegic spinal cord injury (SCI) in comparison to their able-bodied (AB) counterparts after adjusting for differences in body composition. DesignCross-sectional study. After an overnight fast, each participant consumed a 75-g glucose solution for oral glucose tolerance test (OGTT). Blood glucose, insulin, and C-peptide concentrations were analyzed before and 30, 60, 90, and 120 minutes after ingesting glucose solution. Insulin sensitivity index (ISI) was estimated using the Matsuda index. Percentage fat mass (%FM) and total body lean mass (TBLM) were estimated using data from dual-energy x-ray absorptiometry. Visceral fat (VF) was quantified using computed tomography. Outcome measures were compared among groups using analysis of covariance with %FM (or VF) and TBLM as covariates. SettingResearch university. ParticipantsWomen (N=42) with SCI (tetraplegia: n=8; paraplegia: n=14) and their race-, body mass index-, and age-matched AB counterparts (n=20). InterventionsNot applicable. ResultsAt fasting, there was no difference in glucose homeostasis (glucose, insulin, C-peptide concentrations) among 3 groups of women. In contrast, glucose, insulin, and C-peptide concentrations at minute 120 during OGTT were higher in women with tetraplegia versus women with paraplegia and AB women (P<.05, adjusted for TBLM and %FM). In addition, women with tetraplegia had lower ISI (P<.05, adjusted for TBLM and %FM) versus AB women. These differences remained after adjusting for VF and TBLM. ConclusionOur study confirms that impaired glucose metabolism among women with tetraplegia may not be fully explained by changes in their body composition. Future studies exploring additional factors involved in glucose metabolism are warranted.

The metabolic outcomes of growth hormone treatment in children are gender specific.

ObjectiveTo evaluate the impact of gender on the clinical and metabolic parameters in prepubertal growth hormone deficiency (GHD) children at diagnosis and during GH treatment (GHT).DesignThe data of 105 prepubertal children (61 males, 44 females, mean age 6.8 ± 0.7 years) affected by idiopathic GHD were retrospectively evaluated.MethodsBody height, BMI, waist circumference (WC), IGF-I, HbA1c, lipid profile, fasting and after-OGTT glucose and insulin levels, insulin sensitivity and secretion indices were evaluated at baseline and after 24 months of GHT.ResultsAt baseline, no significant difference was found in all clinical, hormonal and metabolic parameters between males and females. After 24 months of GHT, both males and females showed a significant increase in height (both P < 0.001), BMI (both P < 0.001), WC (P < 0.001 and P = 0.004, respectively), IGF-I (both P < 0.001), fasting glucose (P < 0.001 and P = 0.001, respectively), fasting insulin (both P < 0.001) and Homa-IR (both P < 0.001), with a concomitant significant decrease in insulin sensitivity index (ISI) (both P < 0.001) and oral disposition index (DIo) (P = 0.001 and P < 0.001, respectively). At 24 months of GHT, females showed significantly higher BMI (P = 0.027), lower ISI (P < 0.001) and DIo (P < 0.001), in concomitance with a significant greater change from baseline to 24 months of BMI (P = 0.013), WC (P < 0.001), ISI (P = 0.002) and DIo (P = 0.072), although the latter does not reach statistical significance.ConclusionsTwenty-four months of GHT in prepubertal children leads to different metabolic outcomes according to gender, with a greater reduction in insulin sensitivity in females, regardless of auxological and hormonal parameters. Therefore, prepubertal GHD females should probably need a more proper monitoring in clinical practice.

Insulin sensitivity and vascular responses to flow mediated dilation in Metabolic Syndrome women.

PurposeSedentary populations with obesity and metabolic syndrome (MetSyn) have presented with impaired vascular dysfunction, including vasodilation reduced 40–50%. The mechanisms of vascular endothelial dysfunction have also been associated to the bioavailability of nitric oxide levels and in metabolic compromised individuals the diminished content of endothelial NO are a prime mechanistic target for study. The present study was designed to examine the association between insulin sensitivity and endothelial dysfunction with respect to the nitric oxide eNOS pathway in MetSyn women using flow mediated dilation (FMD). We hypothesize that lower production of nitric oxide and lower Insulin Sensitivity Index (ISI) will be observed in MetSyn compared to age matched‐control patients, primarily due to mechanistic dysfunction of the eNOS pathway.MethodsIn this study, 30 participants (10 MetSyn and 20 Controls) were recruited for FMD testing and vascular changes were recorded using Doppler ultrasound with a linear vascular probe. A blood pressure cuff was placed on the upper forearm and upper calf for analysis of brachial and popliteal arteries sheer rate and reactive hyperemia. Images were continuously analyzed with Brachial Analyzer software and sheer rate calculated by digital recordings of blood velocity through with a digital auditory transducer recordings with a BIOPAC 150 system and AcqKnowlege software. Insulin sensitivity index was assessed by an oral glucose tolerance test with fasting and post‐prandal glucose measured with a glucometer and insulin measured by a Human Insulin ELISA kit (Cayman Chemical). The resting bioavailability of Nitric Oxide assessed by Nitrate/Nitrite ELISA assay and NO EPR spectroscopy measurementsResultsIn the brachial arteries there is significant differences (P&lt;0.05) in the time and rate to peak diameter from reperfusion but not within the % Dilation or sheer rate between the MetSyn and Control sedentary groups. In the popliteal arteries there is a significant difference between the % dilation, time and rate to peak from reperfusion. We observed correlations among changes in arterial measurements, Insulin Sensitivity Index (ISI) and resting Nitric oxide concentration (NO). ISI is observed to be correlated to Peak Diameter (p=0.0943, r= 0.59) and Rate to Peak (p=0.07, r=.0628) measurements in the MetSyn group in the brachial arteries with no calculated relationship identified in the popliteal artery.ConclusionWe predict that significant deficiencies will be observed between the control and MetSyn group. These comparisons may explain the vascular mechanisms of developing deficits associated with the metabolic deficiencies and provide a target for the decline in vascular function within this sedentary population. A postulated mechanism of this endothelial dysfunction during insulin resistance begins with the decreased sensitivity of the insulin receptor preventing the effect of insulin and the AKT/PKB eNOS pathway.Support or Funding InformationResearch reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103451.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Associations between measures of health-related physical fitness and cardiometabolic risk factors in college students

abstractObjective: To determine the influence of health-related fitness on cardiometabolic risk factors in college students. Participants: 75 traditional students (33 men and 42 women, 21.8±1.8 years old) at a university in southeastern U.S. Methods: Height, weight, waist circumference, body composition, blood pressure, lipids, glucose, insulin, c-reactive protein, and glucose tolerance were measured. Indices of insulin sensitivity were calculated. Aerobic and muscular fitness were measured. Regression and correlation analyses, and comparisons of cardiometabolic markers in low- vs high-fit participants were performed. Results: Men and women with low muscular fitness exhibited higher fasting insulin, and poorer insulin sensitivity index scores than those with high muscular fitness. In addition, women with high body fat percentage exhibited higher fasting and 2-hour insulin levels and lower insulin sensitivity index scores than those with low body fat percentages. Conclusions: College students possessing low levels of health-related physical fitness exhibited less favorable cardiometabolic risk profiles.

One-hour post-load plasma glucose level is associated with a worse metabolic profile in children with GH deficiency.

In children, the plasma glucose value at 1 h (1hPG) during OGTT higher than 132.5mg/dl is a predictor of alterations in glucose metabolism. We aimed to metabolically characterize GHD children according to 1hPG levels. Fifty-one GHD children (35M, 16 F; mean age 8.6years), grouped according to 1hPG, were evaluated at diagnosis and after 12months of GH treatment (GHT) and compared with 50 matched controls at baseline. Auxological parameters, insulin-like growth factor-1 (IGF-1), glucose and insulin during OGTT, lipid profile, the oral disposition index (DIo), the homeostasis model assessment estimate of insulin resistance (Homa-IR), and the insulin sensitivity index (ISI) were evaluated. At baseline, 31.4% of GHD children and 12% of controls (p=0.016) showed 1hPG≥132.5mg/dl. The first ones showed higher mean 1hPG (p=0.025) and LDL cholesterol (p=0.029) and lower HDL cholesterol (p=0.014) than controls. GHD with higher 1hPG showed a significant decrease in DIo (p<0.001) without improvement in lipid profile after GHT, compared with children with lower 1hPG. After 12months, the higher 1hPG group showed lower ISI Matsuda (p=0.047) and DIo (p<0.001) than the lower 1hPG group. 1hPG levels proved to be positively correlated with Homa-IR (p=0.010) and LDL cholesterol (p=0.032) and negatively with ISI Matsuda (p=0.001) and DIo (p=0.019). The 1hPG value at baseline was the only independent variable significantly associated with DIo at 12months (p=0.041). 1hPG level at baseline may be a useful tool to identify and properly follow up children with enhanced metabolic risk who probably need more surveillance during GHT.

Bisphenol A, phthalate metabolites and glucose homeostasis in healthy normal-weight children.

IntroductionBisphenol A and several of the most commonly used phthalates have been associated with adverse metabolic health effects such as obesity and diabetes. Therefore, we analyzed these man-made chemicals in first morning urine samples from 107 healthy normal-weight Danish children and adolescents.MethodThis was a cross-sectional study. Participants were recruited as part of the Copenhagen Puberty Study. The subjects were evaluated by an oral glucose tolerance test (OGTT), a dual-energy X-ray absorptiometry (DXA) scan, direct oxygen uptake measurement during cycle ergometry and fasting blood samples. First morning urine was collected and phthalate metabolites and BPA were measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS) with prior enzymatic deconjugation. Individual chemical concentrations were divided into tertiles and analyzed in relation to biological outcome.ResultsChildren in the lowest tertile of urinary BPA had significantly higher peak insulin levels during OGTT (P = 0.01), lower insulin sensitivity index (P < 0.01), higher leptin (P = 0.03), triglyceride (P < 0.01) and total cholesterol levels (P = 0.04), lower aerobic fitness (P = 0.02) and a tendency toward higher fat mass index (P = 0.1) compared with children in the highest tertile for uBPA. No significant differences in anthropometrics, body composition or glucose metabolism were associated with any of the phthalate metabolites measured.ConclusionThis pilot study on healthy normal-weight children suggests an inverse association between BPA and insulin resistance. Our findings contrast other cross-sectional studies showing a positive association for BPA, which may be due to confounding or reverse causation because diet is an important source of both BPA exposure and obesity.

Insulin resistance and hyperandrogenism drive steatosis and fibrosis risk in young females with PCOS.

Background and aimsNonalcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) recognize obesity and insulin resistance (IR) as common pathogenic background. We assessed 1) whether PCOS is a risk factor for steatosis, and 2) the impact, in PCOS patients, of IR and hyperandrogenism on steatosis and fibrosis.MethodsWe considered 202 consecutive Italian PCOS nondiabetic patients and 101 age-matched controls. PCOS was diagnosed applying the Rotterdam diagnostic criteria. Steatosis was diagnosed if hepatic steatosis index (HSI) >36, while fibrosis by using the FIB-4 score. As surrogate estimate of insulin sensitivity we considered the insulin sensitivity index (ISI). Free androgen index (FAI) was calculated as estimate of biochemical hyperandrogenism.ResultsIn the entire population, steatosis was observed in 68.8% of patients with PCOS, compared to 33.3 of controls (p<0.001), this association being maintained after adjusting for metabolic confounders (OR 3.73, 95% CI 1.74–8.02; P = 0.001). In PCOS patients, steatosis was independently linked to WC (OR 1.04, 95% CI 1.01–1.08; P = 0.006) and ISI Matsuda (OR 0.69, 95% CI 0.53–0.88; P = 0.004), not to free androgen index (OR 1.10, 95% CI 0.96–1.26; P = 0.14). Notably, ISI Matsuda was confirmed as independently associated with steatosis in both obese (OR 0.42, 95% CI 0.23–0.77, P = 0.005) and nonobese (OR 0.69, 95% CI 0.53–0.91, P = 0.009), patients, while FAI (OR 1.45, 95% CI 1.12–1.87; P = 0.004) emerged as an independent risk factor only in nonobese PCOS. Similarly, higher FIB-4 was independently associated with higher FAI (p = 0.02) in nonobese and with lower ISI Matsuda (p = 0.04) in obese patients.ConclusionsWe found that PCOS is an independent risk factor for steatosis, and that, IR and hyperandrogenism, this last especially in nonobese patients, are the key players of liver damage in PCOS.

Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children

BackgroundChildhood obesity prevalence has increased worldwide and is an important risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). The production of inflammatory adipokines by obese adipose tissue contributes to the development of T2D and CVD. While levels of circulating adipokines such as adiponectin and leptin have been established in obese children and adults, the expression of adiponectin and leptin receptors on circulating immune cells can modulate adipokine signalling, but has not been studied so far. Here, we aim to establish the expression of adiponectin and leptin receptors on circulating immune cells in obese children pre and post-lifestyle intervention compared to normal weight control children.Methods13 obese children before and after a 1-year lifestyle intervention were compared with an age and sex-matched normal weight control group of 15 children. Next to routine clinical and biochemical parameters, circulating adipokines were measured, and flow cytometric analysis of adiponectin receptor 1 and 2 (AdipoR1, AdipoR2) and leptin receptor expression on peripheral blood mononuclear cell subsets was performed.ResultsObese children exhibited typical clinical and biochemical characteristics compared to controls, including a higher BMI-SD, blood pressure and circulating leptin levels, combined with a lower insulin sensitivity index (QUICKI). The 1-year lifestyle intervention resulted in stabilization of their BMI-SD. Overall, circulating leukocyte subsets showed distinct adipokine receptor expression profiles. While monocytes expressed high levels of all adipokine receptors, NK and iNKT cells predominantly expressed AdipoR2, and B-lymphocytes and CD4+ and CD8+ T-lymphocyte subsets expressed AdipoR2 as well as leptin receptor. Strikingly though, leukocyte subset numbers and adipokine receptor expression profiles were largely similar in obese children and controls. Obese children showed higher naïve B-cell numbers, and pre-intervention also higher numbers of immature transition B-cells and intermediate CD14++CD16+ monocytes combined with lower total monocyte numbers, compared to controls. Furthermore, adiponectin receptor 1 expression on nonclassical CD14+CD16++ monocytes was consistently upregulated in obese children pre-intervention, compared to controls. However, none of the differences in leukocyte subset numbers and adipokine receptor expression profiles between obese children and controls remained significant after multiple testing correction.ConclusionsFirst, the distinct adipokine receptor profiles of circulating leukocyte subsets may partly explain the differential impact of adipokines on leukocyte subsets. Second, the similarities in adipokine receptor expression profiles between obese children and normal weight controls suggest that adipokine signaling in childhood obesity is primarily modulated by circulating adipokine levels, instead of adipokine receptor expression.

In pregnancy increased maternal STAI trait stress score shows decreased insulin sensitivity and increased stress hormones

IntroductionChronic or acute stressors influence maternal and fetal Hypothalamus-Pituitary-Adrenal Axes (HPA) during pregnancy. In this study, the effect of maternal stress into maternal insulin sensitivity was investigated during pregnancy. Materials and methodsEighty-two pregnant women [aged 27.1±2.5 (mean±SD) yrs; BMI=25±2.2kg/m2] had at the 2nd and 3rd trimesters anthropometry, fasting blood samples (cortisol, Corticotropin Releasing Hormone (CRH), active amylin, Interleukin (IL6)), Oral Glucose Tolerance Test (OGTT) for glucose and insulin, state-trait anxiety inventory (STAI) trait and state questionnaires (for stress assessment). ResultsMaternal cortisol, CRH and STAI state score increased significantly from 2nd to 3rd trimester. At these trimesters women with STAI trait scores ≥40 had greater serum cortisol and CRH concentrations and lower insulin sensitivity index (ISI) values than those with scores <40 while STAI trait score predicted negatively ISI. At the 2nd trimester maternal CRH concentrations correlated positively with maternal STAI state, Homeostatic Model Assessment Insulin Resistance (HOMAR), 1st and 2nd phase insulin secretion and negatively with ISI. STAI trait correlated negatively with ISI. STAI state correlated positively with maternal systolic blood pressure and HOMAR. At the 3rd trimester STAI trait correlated negatively and positively with ISI and STAI state, respectively, while STAI state correlated positively with HOMAR. In women with STAI state scores ≥40, these scores correlated positively with maternal CRH. ConclusionsIn normal pregnant women, enhanced long-term stress is associated with decreased insulin sensitivity. Both long- and short- term stress are associated with enhanced maternal HPA axis and increased placental CRH secretion.