Suppression Of Free Fatty Acids Research Articles

Severity of sleep apnea impairs adipose tissue insulin sensitivity in individuals with obesity and newly diagnosed obstructive sleep apnea

IntroductionObstructive sleep apnea (OSA) is a common sleep disorder associated with increased risk for the development of type 2 diabetes. While studies have examined the effects of sleep on whole-body insulin sensitivity, little is known about the effects of sleep on adipose tissue insulin sensitivity in patients with OSA. We analyzed if the severity of OSA, measured by apnea-hypopnea index (AHI), is associated with adipose tissue insulin sensitivity.MethodsWe examined the relationship between sleep parameters and adipose tissue insulin sensitivity in non-diabetic participants with obesity and newly diagnosed OSA who underwent overnight polysomnography and a 2 h oral glucose tolerance test during which circulating free fatty acids were measured. In total, 16 non-diabetic participants with obesity and newly diagnosed OSA (sex, 81.3% males; mean age, 50.9 ± 6.7 y; BMI, 36.5 ± 2.9 kg/m2; AHI, 43 ± 20 events/h) were included in the analysis.ResultsIn our study participants, AHI is inversely associated with free-fatty acid suppression during oral glucose challenge (R = −0.764, p = 0.001). This relationship persisted even after statistical adjustment for age (R = −0.769, p = 0.001), body mass index (R = −0.733, p = 0.002), waist-to-hip ratio (R = −0.741, p = 0.004), or percent body fat mass (R = −0.0529, p = 0.041). Furthermore, whole-body insulin sensitivity as determined by the Matsuda index was associated with percent REM sleep (R = 0.552, p = 0.027) but not AHI (R = −0.119, p = 0.660).ConclusionIn non-diabetic patients with OSA, the severity of sleep apnea is associated with adipose tissue insulin sensitivity but not whole-body insulin sensitivity. The impairments in adipose tissue insulin sensitivity may contribute to the development of type 2 diabetes.

The PKA-SREBP1c Pathway Plays a Key Role in the Protective Effects of Lactobacillus johnsonii JNU3402 Against Diet-Induced Fatty Liver in Mice.

The present study aims to assess the protective effect of Lactobacillus johnsonii JNU3402 (LJ3402) against diet-induced non-alcoholic fatty liver disease (NAFLD) and determine the mechanism underlying its beneficial effect on the liver in mice. Seven-week-old male mice are fed a high-fat diet (HFD) with or without oral supplementation of LJ3402 for 14 weeks. In mice fed an HFD, LJ3402 administration alleviates liver steatosis, diet-induced obesity, and insulin resistance with a decreased hepatic expression of sterol-regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), and an increased phosphorylation of SREBP-1c. The mechanistic study shows that LJ3402 inhibits SREBP-1c transcriptional activity by enhancing protein kinase A (PKA)-mediated phosphorylation and reduces the expression of its lipogenic target genes in AML12 and HepG2 cells, thereby attenuating hepatic lipid accumulation. Moreover, silencing the PKA α catalytic subunit or the inhibition of PKA activity by H89 abolishes LJ3402 suppression of free fatty acid (FFA)-induced SREBP-1c activity in hepatocytes. In addition, LJ3402 administration elevates the plasma lactate levels in mice fed an HFD; this lactate increases PKA-mediated SREBP-1c phosphorylation in AML12 cells with a decreased expression of its target genes, reducing hepatic lipid accumulation. LJ3402 attenuates HFD-induced fatty liver in mice through the lactate-PKA-SREBP-1c pathway.

1579-P: Impact of Adipose Tissue Insulin Sensitivity on Hepatic Insulin Sensitivity Preservation in Longitudinal Observation of Patients with NAFLD

Hepatic insulin resistance associated with NAFLD is a major pathogenesis of type 2 diabetes and its complications. In addition to reducing lipids in the liver, identifying the factors that may preserve hepatic insulin sensitivity (H-IS) is crucial. In this study, we investigated the factors that may preserve H-IS in patients with NAFLD in longitudinal observations. Comprehensively, putative biomarkers in blood and urine, body composition, tissue-specific lipid accumulation and insulin sensitivity by 1H-MRS and hyperinsulinemic euglycemic clamp, respectively, and pathological diagnosis using liver biopsy were assessed in patients with NAFLD (n=62) at baseline. After more than one year of general treatment, consented 36 patients (average age 51.3±11.2, men n=21, diabetes n=23) were subjected to the same assessment as baseline. To investigate the indices associated with H-IS, all indices were compared between upper and lower one third patients of Δ% suppression of endogenous glucose production (EGP) (+11.5±4.0 vs. -10.9±5.1%, respectively). As results, body weight, fasting plasma glucose, HbA1c, muscle and adipose tissue insulin sensitivity, visceral fat, and adiponectin levels were significantly improved in improved H-IS group. Interestingly, Δhepatic lipid content or fibrosis index was not different between the improved and worsened H-IS groups. Furthermore, simple regression analysis with Δ% suppression of EGP and all indices revealed that Δ% suppression of free fatty acid, visceral fat area, and adiponectin levels were significantly associated with Δ% suppression of EGP. Multiple regression analysis with Δ% suppression of EGP and these three indices showed that only Δ% suppression of free fatty acid significantly associated with Δ% suppression of EGP. Taken together, not only lipid volume but also the quality of accumulated lipid is important to preserve hepatic insulin sensitivity in patients with NAFLD. Disclosure F.Shigiyama: None. S.Hiruma: None. N.Kumashiro: Research Support; Terumo Corporation, LifeScan Diabetes Institute, Sumitomo Dainippon Pharma Co., Ltd., Speaker's Bureau; Daiichi Sankyo, Novo Nordisk.

730-P: Effects of Obstructive Sleep Apnea Treatment on Whole-Body and Adipose Tissue Insulin Sensitivity—Role of Senescence and Mitigation by Adjuvant Metformin Therapy

Introduction: Obstructive sleep apnea (OSA) is a prevalent sleep disorder linked to high type 2 diabetes risk. Positive airway pressure (PAP) therapy is the standard of care for OSA, but it inconsistently improves glucose homeostasis. Senescent cells are common in adipose tissue (AT) of patients with OSA and may impair insulin signaling. However, the effects of PAP therapy on AT senescence are not known. Addition of metformin, an insulin-sensitizer with anti-senescent effects, may be a good adjuvant therapeutic strategy to improve glycemic control in patients with OSA. Methods: We randomly assigned 16 nondiabetic participants with OSA (Mean± SD; age: 50.9 ± 6.7 y, BMI: 36.5 ± 2.9 kg/m2) in a 1:1 ratio to receive either 2g metformin or placebo daily along with PAP therapy for 3 months in a double-blind pilot study. Whole body and AT insulin sensitivity was determined by 2h oral glucose tolerance test (OGTT). AT biopsy was obtained to estimate tissue insulin signaling and senescence. Results: The metformin and placebo groups had comparable age, BMI and OSA severity at baseline. PAP compliance was 38% and 75% in the metformin and placebo groups, respectively. Matsuda Index, glucose area under the curve (2h AUC), and free-fatty acid suppression at baseline and follow-up were not different in metformin or placebo treated groups. Compared to baseline, insulin AUC and insulin to glucose AUC ratio during OGTT was unchanged in the metformin but increased in the placebo group. Metformin, but not placebo, was associated with increased insulin mediated AKT phosphorylation and decreased senescence biomarkers (p21 and MCP1) in AT during the follow-up visit. Conclusion: Metformin, as adjunct to PAP therapy, attenuated insulin rises during OGTT, improved AT insulin signaling, and lowered senescence biomarkers in OSA patients. Larger trials of longer treatment duration are needed to determine if metformin can prevent diabetes in OSA patients. Disclosure S. Rodrigues: None. W.S. Dantas: None. R.A. Beyl: None. R.C. Hebert: None. I. Griffith: None. M. Tanksley: None. E.C. Mader: None. J.P. Kirwan: None. C.L. Axelrod: None. E. Ravussin: Research Support; Eli Lilly and Company, Novartis AG. Advisory Panel; Novartis. P. Singh: None. Funding National Institutes of Health (P30DK072476, U54GM104940); CAPES (88887.470405/2019-00 to S.R.)

Insulin Sensitivity and β-Cell Function During Early and Late Pregnancy in Women With and Without Gestational Diabetes Mellitus.

To evaluate the metabolic alterations associated with gestational diabetes mellitus (GDM) in women with overweight or obesity. We compared fasting and postprandial plasma glucose and free fatty acid (FFA) concentrations, insulin sensitivity (IS; Matsuda index), and β-cell function (i.e., β-cell responsiveness to glucose) by using a frequently sampled oral glucose tolerance test (OGTT) at 15 and 35 weeks' gestation in women with overweight or obesity who had GDM (n = 29) or did not have GDM (No-GDM; n = 164) at 35 weeks. At 15 weeks, IS and β-cell function were lower, and fasting, 1-h, and total area-under-the-curve plasma glucose concentrations during the OGTT were higher (all P < 0.05) in the GDM than in the No-GDM group. At 35 weeks compared with 15 weeks, IS decreased, β-cell function increased, and postprandial suppression of plasma FFA was blunted in both the GDM and No-GDM groups, but the decrease in IS and the increase in postprandial FFA concentration were greater and the increase in β-cell function was less (all P ≤ 0.05) in the GDM than in the No-GDM group. A receiver operating characteristic curve analysis showed that both fasting plasma glucose and 1-h OGTT glucose concentration at 15 weeks are predictors of GDM, but the predictive power was <30%. Women with overweight or obesity and GDM, compared with those without GDM, have worse IS and β-cell function early during pregnancy and a greater subsequent decline in IS and blunted increase in β-cell function. Increased fasting and 1-h OGTT plasma glucose concentration early during pregnancy are markers of increased GDM risk, albeit with weak predictive power.

390-P: Adipose Insulin Resistance Relates to Perturbed Renal Hemodynamics in Obese Youth with and without Type 2 Diabetes

Our objective was to compare renal hemodynamic function between obese youth with and without type 2 diabetes (T2D) and relate these measures to adipose insulin resistance (IR) . We assessed insulin sensitivity and kidney function in obese youth with (n=31, 15.8 ± 1.8 years, BMI 35.6 ± 6.6 kg/m2) , and without (n=20, 15.3 ± 2.1 years, BMI 38.2 ± 7.4 kg/m2) T2D. A hyperglycemic clamp was performed with 20% dextrose to maintain mild hyperglycemia for 240 minutes. Free fatty acids (FFA) were measured at baseline and every minutes during the steady state. FFA suppression (baseline FFA subtracted from steady state FFA) was used to estimate adipose IR. Iohexol and p-aminohippurate clearances were used to measure GFR and renal plasma flow, respectively. Renal hemodynamic parameters were calculated using Gomez equations. FFA suppression was attenuated in youth with T2D compared to obese controls (55.6% vs. 92.1%, p&amp;lt;0.0001) . Impaired FFA suppression was associated with higher intraglomerular pressure (r= -0.49, p=0.005) , higher efferent arteriolar resistance, (r= -0.53, p=0.002) and higher renal vascular resistance (r= -0.59, p=0.0005) . Youth with T2D had impaired FFA suppression compared to obese controls, indicating adipose IR. Impaired FFA suppression was associated with perturbed renal hemodynamics, indicating a potential role for adipose IR in the development of early diabetic kidney disease. Disclosure C.Platnick: None. P.V.Prasad: None. L.Li: None. L.Pyle: None. R.G.Nelson: None. D.Van raalte: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Sanofi, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Sanofi. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company.

Reduction-responsive RNAi nanoplatform to reprogram tumor lipid metabolism and repolarize macrophage for combination pancreatic cancer therapy

Pancreatic cancer (PAC) is one of the most lethal malignant neoplasms with poor prognosis and high mortality. Emerging evidence has revealed that abnormal tumor lipid metabolism and tumor-associated macrophages (TAMs) significantly contribute to PAC development and progression. Therefore, concurrently reprogramming tumor lipid metabolism and regulating TAMs function could be a promising strategy for effective PAC therapy. Herein, we identified an important enzyme catabolizing lipids (monoacylglycerol lipase, MGLL) and a key receptor regulating macrophage phenotype (endocannabinoid receptor-2, CB-2) that are over-expressed in PAC cells and on TAMs, respectively. Based on this finding, we developed a reduction-responsive poly (disulfide amide) (PDSA)-based nanoplatform for systemic co-delivery of MGLL siRNA (siMGLL) and CB-2 siRNA (siCB-2). This nanoplatform could utilize its reduction-responsive characteristic to rapidly release siRNA for efficient silencing of MGLL and CB-2, inducing concurrent suppression of free fatty acids (FFAs) generation in PAC cells and repolarization of TAMs into tumor-inhibiting M1-like phenotype. With this suppressed FFAs generation to inhibit nutrient supply for tumor cells and repolarized TAMs to secrete tumoricidal cytokines such as TNF-α and IL-12, a combinational anticancer effect could be achieved in both xenograft and orthotopic PAC tumor models.

Fetuin-B, a potential link of liver-adipose tissue cross talk during diet-induced weight loss\u2013weight maintenance

Background/objectivesNumerous hepatokines are involved in inter-organ cross talk regulating tissue-specific insulin sensitivity. Adipose tissue lipolysis represents a crucial element of adipose insulin sensitivity and is substantially involved in long-term body weight regulation after dietary weight loss. Thus, we aimed to analyze the impact of the hepatokine Fetuin-B in the context of weight loss induced short- and long-term modulation of adipose insulin sensitivity.Subjects/methods143 subjects (age > 18; BMI ≥ 27 kg/m2) were analyzed before (T-3) and after (T0) a standardized 12-week dietary weight reduction program. Afterward, subjects were randomized to a 12-month lifestyle intervention or a control group. After 12 months (T12) no further intervention was performed until 6 months later (T18) (Maintain-Adults trial). Tissue-specific insulin sensitivity was estimated by HOMA-IR (predominantly liver), ISIClamp (predominantly skeletal muscle), and free fatty acid suppression during hyperinsulinemic-euglycemic clamp (FFASupp) (predominantly adipose tissue). Fetuin-B was measured at all concomitant time points.ResultsCirculating Fetuin-B levels correlated significantly with estimates of obesity, hepatic steatosis as well as HOMA-IR, ISIClamp, FFASupp at baseline. Fetuin-B decreased during dietary weight loss (4.2 (3.5–4.9) vs. 3.8 (3.2–4.6) µg/ml; p = 2.1 × 10−5). This change was associated with concomitant improvement of HOMA-IR (r = 0.222; p = 0.008) and FFASupp (r = −0.210; p = 0.013), suggesting a particular relationship to hepatic and adipose tissue insulin sensitivity. Weight loss induced improvements of insulin resistance were almost completely preserved until months 12 and 18 and most interestingly, the short and long-term improvement of FFASupp was partially predicted by baseline level of Fetuin-B.ConclusionsOur data suggest that Fetuin-B might be a potential mediator of liver-adipose cross talk involved in short- and long-term regulation of adipose insulin sensitivity, especially in the context of diet-induced weight changes.Trial registrationClinicalTrials.gov number: NCT00850629, https://clinicaltrials.gov/ct2/show/NCT00850629, date of registration: February 25, 2009.

Insulin-Mediated Substrate Use in Women With Different Phenotypes of PCOS: the Role of Androgens.

Few studies have explored in vivo insulin action on substrate use in women with PCOS. In particular, no data are available in women with different PCOS phenotypes. The aim of the study was to evaluate insulin action on glucose (Gox) and lipid (Lox) oxidation, nonoxidative glucose metabolism (Gnonox), and serum free fatty acids (FFAs) in different PCOS phenotypes. Participants included 187 nondiabetic women with PCOS diagnosed according to the Rotterdam criteria. Data from a historical sample of 20 healthy women were used as reference values. Whole-body substrate use data were obtained by the hyperinsulinemic euglycemic clamp associated with indirect calorimetry. Serum androgens were assessed by liquid chromatography-mass spectrometry and equilibrium dialysis. During hyperinsulinemia, the increase of Gox (ΔGox), Gnonox, as well as the suppression of Lox (ΔLox) and serum FFA (Δ% FFA) were altered in each PCOS phenotype. Moreover, Gnonox and Δ% FFA were lower in women with the classic phenotype than in those with the ovulatory or the normoandrogenic phenotypes, and ΔGox was lower in women with the classic than in those with the ovulatory phenotype. In multivariable analysis fat mass and free testosterone were independent predictors of ΔGox, Gnonox, and Δ% FFA, whereas only fat mass predicted ΔLox. In women with PCOS, regardless of phenotype, insulin-mediated substrate use is impaired. This phenomenon is greater in individuals with the classic phenotype. Free testosterone plays an independent role in insulin action abnormalities in glucose and lipid metabolism.

Diet and lung disease-Are fruits and vegetables the ideal whole-food intervention?

Diet and lung disease-Are fruits and vegetables the ideal whole-food intervention?

Metabolic flexibility across the spectrum of glycemic regulation in youth.

BACKGROUNDMetabolic flexibility (MF) refers to the relative ability to utilize lipid and carbohydrate substrates and to transition between them. It is not clear whether MF is impaired in obese youth and what the determining factors are.METHODSWe investigated the determinants of MF (increased respiratory exchange ratio [ΔRER] under insulin-stimulated conditions) in pubertal youth (n = 104; 15.6 ± 1.8 years) with obesity across the spectrum of glucose tolerance compared with normal weight (NW) controls, including body composition (fat-free mass [FFM], %body fat), visceral adipose fat (VAT) (MRI), glycemia, and insulin sensitivity (IS) [3-hour hyperinsulinemic-euglycemic clamp with measurement of lipolysis ([2H5] glycerol), free fatty acids (FFAs), and RER (indirect calorimetry)].RESULTSYouth with prediabetes and type 2 diabetes had lower ΔRER and oxidative and nonoxidative glucose disposal compared with NW, with no significant difference in ΔRER between NW and obese with normal glucose tolerance. In multiple regression analysis, ISFFM (β = 0.4, P = 0.004), percentage suppression of FFAs (r = 0.26, P = 0.007), and race/ethnicity (β = –0.23, P = 0.02) contributed to the variance in ΔRER (R2 = 0.30, P < 0.001) independent of percentage body fat (or VAT), sex, Tanner stage, and hemoglobin A1c.ConclusionMF is defective at the extreme of the metabolic phenotype in obese youth with dysglycemia related to a defect in IS limiting substrate utilization.FUNDINGUSDA/ARS Project Number 3092-51000-057.

Adipose Insulin Resistance and Decreased Adiponectin Are Correlated With Metabolic Abnormalities in Nonobese Men

Adipose tissue dysfunction is characterized by decreased adiponectin (AN) levels and impaired adipose tissue insulin sensitivity (ATIS), and is associated with metabolic disorders. While Asians readily develop metabolic disease without obesity, it remains unclear how decreased AN level and impaired ATIS affect metabolic abnormalities in non-obese Asians. To investigate the relationships between decreased AN level, impaired ATIS, and metabolic abnormalities, we studied 94 Japanese men whose body mass index was less than 25kg/m 2. We divided the subjects into four groups based on their median AN level and ATIS, the latter calculated as the degree of insulin-mediated suppression of free fatty acids during hyperinsulinemic euglycemic clamp, and compared the metabolic parameters in the four groups. The High-ATIS/High-AN group (n=29) showed similar anthropometric data to the High-ATIS/Low-AN group (n=18). In contrast, both the Low-ATIS/High-AN (n=18) and Low-ATIS/Low-AN (n=29) groups showed significantly lower muscle insulin sensitivity than the High-ATIS groups. The intrahepatic lipid level in the Low-ATIS/Low-AN group was significantly higher than that in the High-ATIS groups. In addition, the Low-ATIS/Low-AN group had a significantly higher fasting serum triglyceride level and significantly lower high-density lipoprotein cholesterol level than the other three groups. In non-obese Japanese men with high ATIS, the AN level was not associated with metabolic characteristics. On the other hand, subjects with low ATIS showed reduced muscle insulin sensitivity and those with a decreased AN level demonstrated multiple metabolic abnormalities, represented by fatty liver and dyslipidemia.

Effects of Dietary Carbohydrate Content on Circulating Metabolic Fuel Availability in the Postprandial State.

ContextAccording to the carbohydrate-insulin model of obesity, an elevated insulin-to-glucagon ratio in response to a high-carbohydrate diet directs metabolic fuels toward storage, resulting in lower circulating energy.ObjectiveTo determine differences in total circulating energy post-meal related to dietary carbohydrate.DesignAncillary study within the Framingham State Food Study.SettingUniversity community.Participants29 adults (aged 20 to 65 years) with overweight or obesity (body mass index ≥25 kg/m2)InterventionAfter achieving 10% to 14% weight loss on a run-in diet, participants were randomized to weight-loss-maintenance test diets varying in carbohydrate content (high-carbohydrate, 60% of total energy, n = 11; moderate-carbohydrate, 40%, n = 8; low-carbohydrate, 20%, n = 10) and controlled for protein (20%). During 24-hour metabolic ward admissions between 10 and 15 weeks on the test diets, metabolic fuels and hormones were measured.Main Outcome MeasureEnergy availability (EA) based on energy content of blood glucose, beta-hydroxybutyrate, and free fatty acids, in the late postprandial period (180 to 300 minutes). Insulin at 30 minutes into the test meal (Meal Insulin-30) was measured as an effect modifier.ResultsInsulin-to-glucagon ratio was 7-fold higher in participants on the high- vs low-carbohydrate diet (2.5 and 0.36, respectively). Late postprandial EA was 0.58 kcal/L lower on the high- vs low-carbohydrate diet (P < 0.0001), primarily related to suppression of free fatty acids. Early postprandial EA (30 to 180 minutes) declined fastest in the high-carbohydrate group, and Meal Insulin-30 modified this diet effect.ConclusionsDuring weight-loss maintenance on a high-carbohydrate diet, late postprandial EA is reduced, consistent with the carbohydrate-insulin model.

SAT-617 Potential Utility of the Mixed Meal Test for Differential Diagnosis of Partial Lipodystrophy from Common Type 2 Diabetes and Truncal Obesity

Background: Better clinical tools are needed to improve the differential diagnosis of partial lipodystrophy (PL) from type 2 diabetes (DM) with truncal obesity. Here, we investigated differences in metabolic parameters during a mixed meal test in PL and DM patients to determine if this test may have a role in this regard. Methods: We retrospectively evaluated data collected from 17 PL patients (4M/13F, ages 12-64) and 20 DM patients (13F/7M, ages 24-72) with truncal obesity, who also had nonalcoholic fatty liver disease. All patients underwent a Mixed Meal Test (MMT) with 474 ml of Optifast (320 kcal, 50% carbs, 15% fat, and 35% protein). Blood was collected before and at 30, 60, 90, 120, and 180 minutes post-meal to measure glucose, insulin, free fatty acids (FFA), triglycerides, inflammatory markers, GIP, GLP-1, PYY, and Ghrelin. All samples of the same cohort were run at the same time in duplicates and results were averaged. Mixed linear models were constructed to compare PL and DM cohorts taking into account within-subject effects. Data were controlled for BMI, sex and age, and glucose when necessary. Results: Patients with PL had higher glucose and triglyceride levels throughout the MMT at all-time points (p < 0.05). While the glucose levels showed an increase and subsequent decrease, the triglyceride levels remained flat throughout the test in both groups. Free fatty acid levels were suppressed compared to baseline during the test, but PL patients had significantly higher FFA from time 30 to time 180 (p < 0.05) and tended to suppress less. While controlling for the differences in glucose levels, GIP levels displayed a large peak at time 30 min in both groups but were significantly higher over the course of the test in the PL group (AUC: 32542, pg/mL x min (20528-57728) vs. 3343 pg/mL x min (1728-4498), p < 0.05). In contrast, GLP-1 levels (also peaking at time 30 min in both groups), were significantly lower in PL throughout the test (AUC: 3017 pg/mL x min (2309-6051) vs. 28387 pg/mL x min (20422-36045), p < 0.05). Ghrelin and PPY levels did not differ significantly between the two groups. Interpretation/Conclusion: PL patients displayed more profound hyperglycemia and impaired suppression of FFAs. Interestingly, PL patients did not show substantial increases in triglyceride levels during MMT. There was a striking difference in the incretin responses between the two populations despite controlling for glucose, suggesting that MMT may have a role in differential diagnosis PL. Also, altered incretin response should be investigated as a contributor to metabolic perturbations and pathophysiology of PL.

Decreased arterial distensibility and postmeal hyperinsulinemia in young Japanese women with family history of diabetes

IntroductionTo assess vascular function and characterize insulin secretion using a physiological approach in Japanese women with family history of type 2 diabetes (FHD).Research design and methodsStandardized mixed-meal tests were performed...

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women.

Retinol‐binding protein‐4 (RBP4) is elevated in serum and adipose tissue (AT) in obesity‐induced insulin resistance and correlates inversely with insulin‐stimulated glucose disposal. But its role in insulin‐mediated suppression of lipolysis, free fatty acids (FFA), and endogenous glucose production (EGP) in humans is unknown. RBP4 mRNA or protein levels were higher in liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in morbidly obese subjects undergoing Roux‐en‐Y gastric bypass surgery compared to lean controls undergoing elective laparoscopic cholecystectomy. RBP4 mRNA expression in SAT correlated with the expression of several macrophage and other inflammation markers. Serum RBP4 levels correlated inversely with glucose disposal and insulin‐mediated suppression of lipolysis, FFA, and EGP. Mechanistically, RBP4 treatment of human adipocytes in vitro directly stimulated basal lipolysis. Treatment of adipocytes with conditioned media from RBP4‐activated macrophages markedly increased basal lipolysis and impaired insulin‐mediated lipolysis suppression. RBP4 treatment of macrophages increased TNFα production. These data suggest that elevated serum or adipose tissue RBP4 levels in morbidly obese subjects may cause hepatic and systemic insulin resistance by stimulating basal lipolysis and by activating macrophages in adipose tissue, resulting in release of pro‐inflammatory cytokines that impair lipolysis suppression. While we have demonstrated this mechanism in human adipocytes in vitro, and correlations from our flux studies in humans strongly support this, further studies are needed to determine whether this mechanism explains RBP4‐induced insulin resistance in humans.

A placebo-controlled randomized study with testosterone in Klinefelter syndrome: beneficial effects on body composition.

Context and objectiveMales with Klinefelter syndrome (KS) are typically hypogonadal with a high incidence of metabolic disease, increased body fat and mortality. Testosterone treatment of hypogonadal patients decrease fat mass, increase lean body mass and improve insulin sensitivity, but whether this extends to patients with KS is presently unknown.Research design and methodsIn a randomized, double-blind, placebo-controlled, BMI-matched cross-over study, 13 males with KS (age: 34.8 years; BMI: 26.7 kg/m2) received testosterone (Andriol®) 160 mg per day (testosterone) or placebo treatment for 6 months. Thirteen age- and BMI-matched healthy controls were recruited. DEXA scan, abdominal computed tomography (CT) scan and a hyperinsulinemic–euglycemic clamp, muscle strength and maximal oxygen uptake measurement were performed.ResultsTotal lean body mass and body fat mass were comparable between testosterone-naïve KS and controls using DEXA, whereas visceral fat mass, total abdominal and intra-abdominal fat by CT was increased (P < 0.05). Testosterone decreased total body fat (P = 0.01) and abdominal fat by CT (P = 0.04). Glucose disposal was similar between testosterone-naïve KS and controls (P = 0.3) and unchanged during testosterone (P = 0.8). Free fatty acid suppression during the clamp was impaired in KS and maximal oxygen uptake was markedly lower in KS, but both were unaffected by treatment. Testosterone increased hemoglobin and IGF-I.ConclusionTestosterone treatment in adult males with KS for 6 months leads to favorable changes in body composition with reductions in fat mass, including abdominal fat mass, but does not change measures of glucose homeostasis.

Suppression of Free Fatty Acids by Oral Glucose in Patients with Cystic Fibrosis

The oral glucose tolerance test (OGTT) is part of the routine management and readily detects impaired insulin secretion in the majority of adult patients with cystic fibrosis (CF). To assess an activity of endogeneous insulin on adipose tissue in these patients, we analyzed serum levels of insulin and free fatty acids (FFA) in response to oral glucose since glucose-induced insulin decreases FFA and thus, suppression of FFA reflects an insulin effect on adipose tissue.

1559-P: Differential Effects of Type 1 (T1D) and Type 2 Diabetes (T2D) on the Growth Hormone (GH)-Insulin-Like Growth Factor (IGF) Axis in Youth

T1D and T2D are characterized by hyperglycemia and insulin resistance (IR), but in T1D the IR occurs even in the absence of metabolic syndrome features. The loss of β-cell insulin secretion in T1D results in lower portal and thus hepatic insulin concentrations in T1D than in T2D or nondiabetic (non-DM) individuals, affecting the GH-IGF axis, as exogenous insulin is subcutaneously delivered in T1D. In this study, we examined how the GH-IGF axis differs by diabetes type, and how it relates to IR. This study included youth (mean age 15±2 years, 37% female) with T1D (n=16), T2D (n=27) and non-DM controls (n=38). A morning fasting blood sample was obtained to measure GH, IGF-1, and IGF binding proteins (IGF BP-1, 2 and 3). Hyperinsulinemic euglycemic clamps were performed to measure glucose infusion rate (GIR), an estimate of skeletal muscle IR, and serum free fatty acid (FFA) suppression. GH, IGF BP-1 and IGF BP-2 were higher in T1D compared to non-DM youth (Figure). Higher IGF BP-3 was associated with lower GIR (more muscle IR) in all youth, but lower IGF BP-1 and 2 were associated with lower GIR in non-DM youth only. Higher GH, IGF BP-1 and IGF BP-3 were associated with less FFA suppression (more adipose IR) in T1D youth only. The GH-IGF-1 axis is altered and is differentially correlated to IR in T1D versus T2D. These data provide clues regarding the unique phenotype of IR in T1D. Disclosure J.K. Snell-Bergeon: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck &amp; Co., Inc. A.D. Baumgartner: None. M. Cree-Green: None. K.J. Nadeau: None. Funding American Diabetes Association (7-13-CD-10 to J.K.S-B.)

Effects of Modest Weight Gain On Circulating Free Fatty Acids

BackgroundIncreases in circulating free‐fatty acids (FFAs) contribute to obesity‐associated cardiometabolic pathology and may be considered a surrogate marker for adipose tissue dysfunction. However, alterations in FFA metabolism resulting from modest weight gain have not been previously evaluated.ObjectiveExamine the changes in FFAs during modest weight gain in healthy individuals and to investigate the relationship between regional fat depots.Study DesignWe evaluated the effects of overfeeding in 8 healthy, non‐obese participants (4 men; age 29 ± 5.7 years; BMI: 25.1 ± 2.1 kg/m2). FFA concentrations were measured using liquid chromatography/mass spectrometry under fasting conditions and during oral‐glucose tolerance test (OGTT) at baseline and after 8 weeks of weight gain. Prior to the baseline and weight gain visits, subjects consumed isocaloric macro‐nutrient stable diet for three days (50% carbohydrate, 35% fat and 15% protein). Body composition and regional fat depots were assessed using dual‐energy X‐ray absorptiometry and abdominal computed tomography scans.ResultsOverfeeding was accompanied by 3.9 ± 1.6 kg weight gain (p=0.01) resulting from 2.9 ± 0.9 kg (p=0.01) increase in fat mass and 1.0 ± 0.9 kg (p=0.04) increase in fat‐free mass. Compared to baseline, fasting FFA (439 ± 162 μM vs. 368 ± 123 μM, p=0.55) and area under the curve (AUC) for FFA during OGTT (23319 ± 11686 μM. min−1 vs. 20495 ± 4847 μM.min−1, p=0.55) did not change with weight gain. However, at 120 min. of the OGTT FFA were significantly greater after weight gain (60 ± 18 μM vs. 77 ± 34 μM, p=0.04). We found a negative relationship between relative changes in visceral fat area and FFA at 120 min of glucose challenge (rho=−0.76, p=0.03). Furthermore, relative changes in fasting FFA and AUC for FFA during OGTT with weight gain were associated with baseline total fat mass (fasting FFA: rho=0.76, p=0.03; AUC FFA: rho=0.81; p=0.02) and baseline abdominal fat area (fasting FFA: rho=0.76, p=0.03; AUC FFA: rho=0.79; p=0.02).ConclusionsModest weight gain does not alter fasting FFA or overall FFA response to oral glucose challenge. However, our data suggest development of early stages of adipose tissue insulin resistance which is apparent via lesser suppression of FFA at 120 min. of OGTT. Furthermore, the relationships between fasting FFA, AUC‐FFA, and baseline fat mass suggest that individuals with high baseline adiposity may be more susceptible to develop adipose tissue insulin resistance with weight gain.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.