bluuebunny/crossref_metadata_2025 huggingface dataset:
1878-P: Glucagon Is neither Necessary nor Sufficient for Ketosis in Mice
Authors: CAPOZZI MEGAN , COCH REILLY , WAIT JACOB B. , KOECH JEPCHUMBA J. , CAMPBELL JONATHAN , D'ALESSIO DAVID A.
Published: June 2019

The current consensus mechanism for hepatic ketogenesis posits a key role for islet hormones, with insulin inhibiting and glucagon stimulating formation of ketone bodies. In this model the action of glucagon in the presence of low portal insulin concentrations causes ketosis. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are effective for lowering glucose in diabetic patients, and cause a relative insulinopenia. These agents have been described to increase ketone production, and have been associated with cases of diabetic ketoacidosis. SGLT2i have been recently reported to stimulate islet α-cells, suggesting the hypothesis that SGLT2i-induced glucagon secretion drives ketogenesis. To test this hypothesis, mice were given the SGLT2i dapagliflozin (dapa) in the presence or absence of glucagon signaling. Fasting-induced ketosis was used as a positive control. In both dapa-treated mice and 16 hour fasted mice, blood glucose decreased to the 4-5 mM range, β-OHB increased 2-3 fold, and NEFA rose 30-50%. Fasting had minimal effects on plasma glucagon, but dapa increased glucagon concentrations, albeit at a delayed rate compared to changes in glycemia, β-OHB, or NEFAs. Interruption of glucagon signaling with either: 1) a glucagon receptor antagonist (GRA); or 2) mice with a deletion of the proGlucagon gene had no effect on the development of ketosis in response to dapa or fasting, indicating that glucagon is not necessary for ketosis in these conditions. To test its sufficiency, glucagon (20µg/kg) was given to fed mice, 16 hour fasted mice, dapa-treated mice, and mice with insulin receptor blockade (IRB). Fasting, dapa and IRB all increased β-OHB significantly but glucagon did not add to this. In contrast, epinephrine significantly elevated ketone levels under these conditions. These findings indicate that the current model of the regulation of ketogenesis needs to be reconsidered, and that in mice glucagon does not have a significant role in this process.

Disclosure

M. Capozzi: None. R. Coch: None. J.B. Wait: None. J.J. Koech: None. J. Campbell: Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. D.A. D'Alessio: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Eli Lilly and Company, Merck & Co., Inc.

Funding

National Institutes of Health (F32-DK116542)
1883-P: Phosphoproteomics Reveals Mechanistic Insight into Glucagon-Mediated Inhibition of Hepatic Lipogenesis and How MEDI0382, an Oxyntomodulin-Like Peptide with Targeted GLP-1/Glucagon Receptor Activity, Reverses Steatosis
Authors: LAKER RHIANNA C. , BOLAND MICHELLE , NAWROCKI ARKADIUSZ , MATHER KARLY M. , JERMUTUS LUTZ , LARSEN MARTIN R. , TREVASKIS JAMES , RHODES CHRISTOPHER J.
Published: June 2019

MEDI0382 is an oxyntomodulin-like peptide with targeted GLP-1/glucagon receptor activity that is in clinical development for type 2 diabetes (T2DM), NASH, and obesity and provides glycemic control and weight loss as well as marked improvements of liver outcomes in humans and mice. In mice, reductions in hepatic lipid were independent of weight loss and resulted from improved mitochondrial respiration and turnover and reduced de novo lipogenesis. As hepatocytes lack the GLP-1 receptor, this effect of MEDI0382 is predominantly modulated via glucagon receptors. After treatment with MEDI0382 or g1437, a glucagon analog, isolated hepatocytes showed increased basal and maximal oxygen consumption, increased mitophagosome number, and a ∼6-fold induction in expression of mitochondrial biogenesis regulator PGC-1α (P ≤ 0.0001). We used phosphoproteomics to identify potential mechanisms of action of MEDI0382 and g1437 on lipogenesis inhibition. After g1437 treatment, primary murine hepatocytes exhibited increased phosphorylation on AMPK, GSK3-α, PHK-β, ChREBP, and HSL—all known PKA substrates. We also identified new glucagon-induced phosphorylations on PHK-α2, PYGL, and ChREBP that were not necessarily PKA consensus motifs, implicating involvement of kinases downstream of PKA. In obese mice, MEDI0382 given for 7 days showed time-dependent phosphorylation of the same sites on AMPK, ChREBP, ACC2, ACLY, and DGAT1. These phosphorylation events are predicted to be inhibitory for lipogenesis. To understand translational potential, we treated primary human hepatocytes with g1437 and found 12 homologous phospho sites, including those on AMPK, ACLY, and DGAT1. Thus, MEDI0382 provides unique antisteatotic benefits for obesity/T2DM comorbidities of NASH/NAFLD via enhanced mitochondrial function and novel glucagon-mediated inhibition of lipogenesis.

Disclosure

R.C. Laker: Employee; Self; MedImmune. M. Boland: Employee; Self; Gubra, MedImmune. A. Nawrocki: None. K.M. Mather: None. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.R. Larsen: None. J. Trevaskis: Employee; Self; Gilead Sciences, Inc., MedImmune. Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Employee; Self; AstraZeneca, MedImmune.

Funding

AstraZeneca
1885-P: Caveolin1 Attenuates Palmitic Acid-Induced Hepatic Steatosis through Upregulating PGC1α-sirt3 Axis
Authors: LIN CHUWEN , ZENG WEN , LIN SHUO , LIU KUNYING , ZENG LONGYI
Published: June 2019

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Caveolae are flask-shaped invaginations of the plasma membrane enriched with cholesterol and phospholipid. Caveolin1 is the resident structural protein of caveolae and has previously been reported to involve in hepatic steatosis and NAFLD, while the mechanism remains elusive. Here we examined the effects of caveolin1 on palmitic acid (PA)-induced hepatic steatosis. Stable caveolin1 overexpressing HepG2 cells were developed by transfection with lentiviral particles containing human CAV1 protein (Lenti-CAV1). Lenti-Control served as a negative control. Compared with BSA treatment, PA treatment of HepG2 cells for 24 hours increased the lipid droplets and TG level (P<0.01). Compared with negative control, overexpression of caveolin1 attenuated the accumulation of lipid droplets and triglyceride content in HepG2 cells (P<0.05). At the same time, quantitative real-time PCR revealed that the mRNA expression of PGC1α and sirt3 were increased in caveolin1 overexpressing cells (P<0.05).

In conclusion, caveolin1 may improve PA-induced hepatic steatosis through up-regulating PGC1α-sirt3 axis.

Disclosure

C. Lin: None. W. Zeng: None. S. Lin: None. K. Liu: None. L. Zeng: None.
1886-P: Hepatic Type 2 Innate Lymphoid Cells Suppress Gluconeogenesis via the IL-33/GATA3/IL-13 Axis
Authors: FUJIMOTO MASANORI , YOKOTE KOUTARO , TANAKA TOMOAKI
Published: June 2019

Type 2 innate lymphoid cells (ILC2s) were recently identified as essential components of innate immunity. Besides, beneficial roles of ILC2s in metabolic diseases are attracting attentions. Although the liver contains various immune cells including T cells and ILC2s, little is known about ILC2s in hepatic gluconeogenesis. We therefore investigated the role of ILC2s and the effect of IL-33, a potent ILC2 activator, on hepatic gluconeogenesis in mice. We found that recombinant IL-33 injection decreased fasting blood glucose levels in wild type mice. This effect was not observed in NOD/SCID Il2rg null (NSG) mice lacking certain immune cells including ILC2s, whereas the similar response was seen in another immune deficient mice Foxnnu/nu (nude mice), which have normal development in ILC2s. IL-33 treatment also suppressed hepatic gluconeogenesis assessed by pyruvate tolerance test in wt mice, while there was no response in NSG. Moreover, ILC2 transplantation was able to rescue the absence of glucose response by IL-33 in NSG. We observed a marked increase of IL-13+ ILC2 population in liver after IL-33 treatment, and Il13-/- mice did not show the decrease of blood glucose or the suppression of gluconeogenesis by IL-33 treatment. Additionally, the transfer of Il13-/- ILC2 failed to gain IL-33 induced glucose response in NSG, suggesting that the hypoglycemic effect of IL-33/ILC2s depends on IL-13. In consistent with these results, the differentially expressed gene analysis revealed that IL-13 treatment mostly altered the gene expressions of glucose metabolic process in primary hepatocytes. Notably, we identified GATA3 as a direct regulator of the effecter molecules such as Il5, Il13 and I1rl1 in hepatic ILC2s. These phenomena were also reproducible in human ILC2s and primary hepatocyte.

In conclusion, these findings indicate that hepatic ILC2s suppress hepatic gluconeogenesis via the IL-33/GATA3/IL-13 axis, thus reducing blood glucose levels.

Disclosure

M. Fujimoto: None. K. Yokote: None. T. Tanaka: None.
1888-P: Impaired Insulin Clearance Relates to Increased Liver Fat Content in Recent-Onset Type 2 Diabetes and to Impaired Glucose Control in Recent-Onset Type 1 Diabetes
Authors: ANTONIOU SOFIA , ZAHARIA OANA P. , STRASSBURGER KLAUS , KARUSHEVA YANISLAVA , BODIS KALMAN , KUPRIYANOVA YULIYA , BURKART VOLKER , MUESSIG KARSTEN , GASTALDELLI AMALIA , RODEN MICHAEL , SZENDROEDI JULIA
Published: June 2019

Hepatic insulin metabolism in patients with newly diagnosed diabetes is not yet understood. Insulin clearance seems to be decreased in patients with obesity, visceral adiposity and type 2 diabetes (T2D), but data compared to glucose tolerant humans have been inconclusive. To this end, persons with type 1 diabetes (T1D; n=124) or type 2 diabetes (T2D; n=401) and glucose-tolerant humans (CON; n=245) underwent hyperinsulinemic-euglycemic clamps to assess insulin sensitivity (IS) and whole-body insulin clearance (ICWBIC, ml x kg-1 x min-1). Hepatic insulin clearance was also calculated from the ratio of the areas under the curve of plasma C-peptide and insulin (0-60 min) during intravenous glucose-tolerance test (IVGTT, 0-60 min) and mixed meal tolerance test (MMTT, 0-180 min). Hepatocellular lipid content (HCL) was measured by 1H-magnetic resonance spectroscopy. Analyses were adjusted for age, sex and BMI. In T1D, ICIVGTT (1.71±1.1 vs. 2.3±0.3 and 3.2±0.3, all p<0.05) as well as ICMMT (1.6±0.7 vs. 2.0±0.4 and 2.1±0.3, all p<0.05) were lowest compared to T2D and CON respectively and correlated negatively with HbA1c (r=-0.242 and r=-0.279, both p<0.05). In T2D, ICIVGTT was positively correlated with HbA1c (r=0.178, p<0.05) as well as with IS (r=0.242, p<0.05). T2D patients with hepatic steatosis (n=73) had lower ICIVGTT, ICWBIC as well as ICMMT (2.2±0.31 vs. 2.4±0.31, 1.4±0.4 vs. 1.5±0.4 and 1.9 ±0.3 vs. 2.1±0.2 respectively, (i.e., differences of 8%, 9% and 7%, all p<0.05) compared to T2D without steatosis (n=53). CON with steatosis also had lower ICIVGTT (n=103, 2.1±0.2 vs. 2.3±0.35, p<0.05). ICMMT positively correlated with IS (r=0.338 and r=0.187, both p<0.05) in T1D and T2D, but not in CON.

In conclusion, glycemic control likely impairs insulin clearance particularly in T1D patients, whereas steatosis affects insulin clearance in T2D and in glucose tolerant humans.

Disclosure

S. Antoniou: None. O.P. Zaharia: None. K. Strassburger: None. Y. Karusheva: None. K. Bodis: None. Y. Kupriyanova: None. V. Burkart: None. K. Muessig: None. A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. J. Szendroedi: None.
1889-P: Inhibition of Acid Sphingomyelinase Attenuates Nonalcoholic Steatohepatitis and Atherosclerosis Induced by High-Fat Diet and LPS in LDL Receptor-Deficient Mice
Authors: LU ZHONGYANG , LI YANCHUN , LOPES-VIRELLA MARIA F. , HUANG YAN
Published: June 2019

Macrophage-mediated inflammation plays an essential role in diabetes-associated nonalcoholic steatohepatitis (NASH) and atherosclerosis. Our previous study has shown that acid sphingomyelinase (ASMase) plays a key role in the synergistic stimulation of inflammatory signaling by saturated fatty acid palmitate and lipopolysaccharide (LPS) in macrophages. In the current study, we assessed the effect of ASMase inhibition on NASH and atherosclerosis induced by lard-based, high palmitate-containing high-fat diet (HP-HFD) in combination with LPS in LDL receptor-knockout (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD for 20 weeks and treated with or without a low dose of LPS and amitriptyline, an inhibitor of ASMase. Metabolic assays showed that amitriptyline reduced bodyweight, lipids and insulin resistance induced by HP-HFD or HP-HFD plus LPS. Histological study and Oil Red O staining of livers showed that while mice fed HP-HFD without LPS treatment had hepatic steatosis and hepatocellular ballooning, LPS further increased steatosis and ballooning by 70%. However, amitriptyline attenuated the effect of HP-HFD or HP-HFD plus LPS by 66%. Immunohistochemistry study showed that while mice fed HP-HFD without LPS treatment had a marked immunostaining of F4/80, a biomarker for macrophages, LPS further enhanced F4/80 immunostaining. However, amitriptyline significantly reduced F4/80 immunostaining. Furthermore, results showed that amitriptyline also attenuated atherosclerosis induced by HP-HFD plus LPS. To elucidate the underlying mechanisms, we found that amitriptyline downregulated proinflammatory cytokines by potently reducing sphingosine 1 phosphate, a bioactive sphingolipid. Taken together, this study showed that ASMase inhibition attenuated both NASH and atherogenesis induced by HP-HFD plus LPS and one of the mechanisms potentially involved in the attenuation is inhibition of S1P production.

Disclosure

Z. Lu: None. Y. Li: None. M.F. Lopes-Virella: None. Y. Huang: None.

Funding

U.S. Department of Veterans Affairs (1I01CX001825-01); National Institutes of Health
1891-P: Histone Acetylation Was Involved in the Mechanism of Regulation of PNPLA3 Gene Expression
Authors: XU XIAO , LIANG HUA , CHEN YUNZHI
Published: June 2019

Background: PNPLA3 is a gene regulated by nutritional status, which is closely related to non-alcoholic fatty liver disease. However, the mechanism of regulation for PNPLA3 remains to be fully clarified. The aim of this study was to investigate the acetylation level of H3K9 in the promoter region of PNPLA3 gene under different physiological and nutritional conditions, which might lay a foundation for understanding the epigenetic mechanism of PNPLA3 expression regulation. C57BL/6 mice were fed ad libitum (NC, N=10), fasted (N=10) for 24 hours, and re-fed (N=10) for 12 hours. Chromatin immunoprecipitation(CHIP)-qPCR were used in assaying the enrichment for histone active marks H3K9ac in liver PNPLA3. Real-time PCR was used to measure the mRNA expression of PNPLA3, and SIRT1 which is a known deacetylase affected by nutritional status.

Results: The results showed that the H3K9ac level in the PNPLA3 promoter was significantly decreased by fasting as compared with NC mice, while the inhibited H3K9ac level of fasting increased significantly after refeeding. The PNPLA3 mRNA level was markedly downregulated during fasting (0.90±0.16 vs. 2.03±0.55, P<0.05) and upregulated about 6-fold when fasted mice were refed (6.25±0.96 vs. 0.90±0.16, P<0.05). While contrary to PNPLA3, the mRNA expression of SIRT1 increased significantly during fasting (2.06±0.10 vs. 1.01±0.13, P<0.05) and decreased significantly after refeeding (0.99±0.04 vs. 2.06±0.10, P<0.05).

Conclusions: PNPLA3 gene expression is regulated by histone acetylation and SIRT1 may be involved in this regulatory mechanism.

Disclosure

X. Xu: None. H. Liang: None. Y. Chen: None.
1897-P: Vertical Sleeve Gastrectomy Corrects the Metabolic Dysregulation Induced by Hepatocyte-Specific Ablation of p53 in Mice
Authors: HOLTER MARLENA M. , GARIBAY DARLINE , MCGAVIGAN ANNE K. , NGUYEN LILY , MOORE ELIZABETH , DAUGHERITY ERIN , COHEN PAUL , KELLY KATHLEEN M. , WEISS ROBERT , CUMMINGS BETHANY
Published: June 2019

p53 has been implicated in the pathogenesis of obesity and diabetes, in part, by regulating whole body energy homeostasis. Conflicting evidence from mice with global alterations in p53 expression suggests the effects of p53 on metabolism are tissue-specific. Despite the critical metabolic role of the hepatocyte, the role of hepatocyte p53 is undefined. Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and improves energy homeostasis at the cellular level. To define the role of hepatocyte p53 in metabolic regulation and the impact of VSG in this context, we performed VSG or sham (S) surgery in high fat diet-fed male hepatocyte-specific p53 knockout (KO) and wild type (WT) mice (n=9-12). Sham-operated mice were fed ad libitum (S-AL) or food restricted to match their body weight to VSG-operated mice (S-WM). Body weight, food intake, adiposity, energy expenditure, and oral glucose tolerance were measured. Hepatocyte p53 ablation increased body weight which was corrected by food restriction and VSG (final weight (g): S-AL-WT=33±1, S-WM-WT=27±1, VSG-WT=29±1, S-AL-KO=38±1, S-WM-KO=28±1, VSG-KO=28±1, P<0.05). Hepatocyte p53 ablation decreased energy expenditure which was corrected by VSG but not by food restriction (EE (kcal/kg/min x 24hr): S-AL-WT=452±19, S-WM-WT=428±13, VSG-WT=527±37, S-AL-KO=396±10, S-WM-KO=422±10, VSG-KO=533±31, P<0.05). Hepatocyte p53 ablation impaired glucose homeostasis which was improved by food restriction and to a greater extent by VSG (glucose iAUC (mg/dl x 120min): S-AL-WT=17390±2736, S-WM-WT=16191±742, VSG-WT=8769±1214, S-AL-KO=21975±1841, S-WM-KO=14764±1190, VSG-KO=8832±867, P<0.05). These data reveal hepatocyte p53 is a key regulator of body weight and glucose homeostasis, largely through regulation of energy expenditure. VSG overcomes energetic impairments induced by hepatocyte p53 ablation by improving energy expenditure and glucose metabolism.

Disclosure

M.M. Holter: None. D. Garibay: None. A.K. McGavigan: None. L. Nguyen: None. E. Moore: None. E. Daugherity: None. P. Cohen: None. K.M. Kelly: None. R. Weiss: None. B. Cummings: None.

Funding

Cornell University; National Cancer Institute (R21CA195002)
1900-P: Very Low-Density Lipoprotein Ceramides and Hepatic Lipid Accumulation
Authors: MUCINSKI JUSTINE M.
Published: June 2019

Ceramides (CER) have been implicated, along with other lipotoxic lipids (diacylglycerols, triacylglycerols, TG) that play important roles in the development and progression of nonalcoholic fatty liver disease (NAFLD). No study to date has measured CER in very low-density lipoproteins (VLDL), along with other lipids from obese men with characteristics of the metabolic syndrome. Twelve subjects with metabolic abnormalities that put them at risk for NAFLD (mean±SD, age 42.1±5.4y, BMI 37.8±3.5 kg/m2, ALT 45±21 U/L) were studied. VLDL particles were isolated in the fasted state and CER measured via UPLC-MS/MS analysis. VLDL-apoB100 was measured by ELISA and intrahepatic triglycerides (IHTG) analyzed by MRS. Total VLDL-CER were positively correlated with both VLDL-TG (r = 0.572, P=0.004) and VLDL-apoB100 (r = 0.557, P=0.005). CER were negatively correlated with IHTG (r = -0.447, P= 0.02), as was VLDL-TG concentration (r = -0.551, P=0.006). These data suggest that CER and TG are packaged together in the liver and secreted on VLDL particles, and do not support the addition of CER to particles after they have been secreted. In these relatively healthy men, the data support the concept that liver lipid secretion is associated with a decreased risk for fat accumulation in the liver. An excretion of lipotoxic lipids like TG and CER in VLDL can protect the liver from excess lipid accumulation.

Disclosure

J.M. Mucinski: None.
1916-P: Effects of Dietary Iron and Hypoxia on Glucose Homeostasis in a Fast Food-Diet Mouse Model
Authors: HARRISON ALEXANDRIA V. , JAIN SHALINI , LORENZO FELIPE , MCCLAIN DON
Published: June 2019

Excess intake of the micronutrient iron has been associated with increased risk of type 2 diabetes (T2D). Sentinel abnormalities observed in T2D are reduced insulin sensitivity, impaired insulin secretion, and increased hepatic glucose production. All three hallmarks are significantly affected by tissue iron levels, with these effects in part being exerted through the iron-dependent hypoxia sensing pathway. The interplay between iron and hypoxia in the progression of T2D has not been thoroughly investigated. We therefore fed mice a fast food (FF) diet with varying iron concentrations, from a low 4 mg/kg to a high 2000 mg/kg, under normoxic and hypoxic conditions. There was a reduction in weight for hypoxic mice (by 23% for 4mg-Fe diet, 14% for 35mg-Fe diet, and 10% for 2000mg-Fe diet; p<0.05) as compared to normoxic mice, independent of food consumption. Although higher iron was generally associated with worsening of fasting glucose (FG) and glucose tolerance for both normoxic and hypoxic mice, these parameters were significantly improved under hypoxia (10-40% improvement for FG, p<0.05 and 24-36% improvement for glucose tolerance, p<0.01). High iron decreased the homeostasis model assessment of insulin resistance (HOMA-IR) in normoxic mice, and hypoxic mice were less insulin resistant than those in normoxia (p<0.05). Higher iron also decreased the homeostasis model assessment of beta-cell function (HOMA-B) for both normoxic and hypoxic mice, and hypoxic mice trended to have higher HOMA-B. Hypoxia-inducible factor 1-alpha (HIF1α) protein is stabilized under hypoxia, and expression increases with iron. We conclude that the effects of dietary iron to alter glucose homeostasis are, in part, dependent on oxygen levels. Both iron and hypoxia affect glucose tolerance in mice on a FF diet, and their synergistic effects may be mediated by the two regulatory arms of the hypoxia inducible factor (HIF) pathway, iron-dependent dioxygenases prolyl-hydroxylase (PHD) and factor inhibiting HIF (FIH).

Disclosure

A.V. Harrison: None. S. Jain: None. F. Lorenzo: None. D. McClain: None.

Funding

U.S. Department of Veterans Affairs; National Institute of Diabetes and Digestive and Kidney Diseases
1917-P: Primary Weight Loss Failure after Gastric Bypass Is Characterized by Impaired Gut-Hormone-Mediated Suppression of Food Intake
Authors: BOJSEN-MOLLER KIRSTINE N. , SVANE MARIA S. , MARTINUSSEN CHRISTOFFER , DIRKSEN CARSTEN , JØRGENSEN NILS B. , KRISTIANSEN VIGGO BJERREGAARD , HARTMANN BOLETTE , HOLST JENS J. , MADSBAD STEN
Published: June 2019

Roux-en-Y gastric bypass (RYGB) induces large and sustained weight loss in most patients. However, a minority of patients (5-10%) never obtain a successful weight loss after RYGB. The aim of this study was to characterize the role of gut hormones for appetite regulation in patients with primary weight loss (WL) failure defined as maximal excess BMI loss (EBLmax= ΔBMIpreoperative-postoperative/ΔBMIpreoperative-25) <50% compared with patients with successful WL (EBLmax >60%) after RYGB. Twenty women with primary WL failure (EBL 24% [9;27], median [IQR]) were matched to 20 women with successful WL (EBL 74% [70;83]) on age (51±9 vs. 51±9 years, mean ± sd), preoperative BMI (43.1±4.0 vs. 43.0±3.6 kg/m2) and time from RYGB (4.8±2.0 vs. 4.8±1.4 years). On separate days, a patient blinded subcutaneous injection of the somatostatin analogue Octreotide (Oct) 1 µg/kg bodyweight (max 100 µg) or saline (placebo) was given in randomized order followed by a mixed meal test at T=30 min and an ad libitum meal with measurement of food intake at T=270 min. The WL failure group had similar GLP-1 (tAUC, median [IQR], 4039 [3336;6018] vs. 4669 [3006;5891] pM·min, p=0.30) and PYY secretion (tAUC, 1935 [1493;2783], 1778 [1163;2756] pM·min, p=0.65) on the placebo day compared with the successful WL group. Injection of Oct diminished GLP-1 and PYY secretion in both groups. Oct had no effect on ad libitum food intake in the WL failure group (-0.5% [-13, 12], mean [95% CI]), while food intake was increased after Oct in the successful WL group (+23% [1.6, 44]) (ANOVA Group x Oct p=0.04).

In conclusion, primary WL failure after RYGB was not explained by lower secretion of GLP-1 or PYY. However, inhibition of hormone secretion with octreotide increased food intake only in patients with successful WL, whereas the effect was absent in patients with primary WL failure. These results support that an impaired gut-hormone mediated suppression of appetite could contribute to primary weight loss failure after RYGB.

Disclosure

K.N. Bojsen-Moller: None. M.S. Svane: None. C. Martinussen: None. C. Dirksen: None. N.B. Jørgensen: Stock/Shareholder; Self; Novo Nordisk A/S. V. Kristiansen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None.

Funding

Danish Council for Independent Research
192-OR: A CRISPR Screen Identifies Rfwd2 as a Regulator of Brown Fat Glucose Transport
Authors: LYNES MATTHEW , HUANG QIAN , YI PENG , TSENG YU-HUA
Published: June 2019

Brown adipose tissue (BAT) generates heat to regulate body temperature, and to support this energy expending activity it takes up glucose from circulation. Cold exposure regimens that activate BAT improve insulin sensitivity, presumably by decreasing circulating glucose levels. Interestingly, glucose uptake during cold is specific to BAT and occurs at low circulating insulin levels, suggesting alternative pathways that do not exist in other insulin sensitive tissues may regulate brown adipocyte glucose uptake. To identify putative regulators of brown adipocyte glucose uptake, we performed a whole genome CRISPR screen using the uptake of the fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) as the readout on mouse brown adipocytes differentiated in vitro. By sorting single brown adipocytes according to their fluorescence, we separated the top 5%, bottom 5% and the remainder of cells using fluorescence activated cell sorting (FACS) and then sequenced to identify genes acting as both putative positive and negative regulators of glucose uptake. Genes identified as potential hits could be classified by gene ontology and belonged mostly to groups related to metabolism and energy homeostasis. A list of 25 potential regulatory genes were validated using the same 2-NBDG strategy used to identify them as well as radiolabeled glucose uptake in vitro. From these genes, 5 were further validated using a second CRISPR based strategy to block gene function. One gene that we identified is the E3 ubiquitin ligase Rfwd2, which is highly expressed in BAT and is known to regulate lipid metabolism. When Rfwd2 was deleted from brown adipocytes the global ubiquitination pattern was changed and glucose uptake was increased in both the basal and insulin stimulated states. These data suggest that targets of this ligase may play a role in the cell-signaling cascade that activates glucose uptake and these targets could further regulate BAT glucose uptake in vivo.

Disclosure

M. Lynes: None. Q. Huang: None. P. Yi: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.

Funding

National Institutes of Health (P30DK036836, R01DK077097, R01DK102898, F32DK102320, K01DK111714)
1923-P: Quantitative Measurement of Whole-Body Glycogen Metabolism and Gluconeogenic Flux
Authors: TESLAA TARA
Published: June 2019

Circulating glucose levels are maintained during fasting by endogenous production of glucose through: 1) the breakdown of glycogen and 2) from gluconeogenesis. Recently published work from our lab has utilized stable isotope tracing with cutting edge LC-MS methods to determine metabolic fluxes in vivo. During these studies we observed a surprising lack of labeling in glycolytic intermediates in the majority of tissues when infusing 13C-glucose. Based on these results we hypothesized that glycogen metabolism and gluconeogenesis were active in more tissues than was previously thought. To gain a holistic understanding of glycolysis, glycogenolysis, and gluconeogenesis in vivo, we performed a series of intravenous infusions to determine the flux through these pathways. To measure the contribution of glycogen breakdown to glycolytic intermediate we performed pulse chase infusions of glucose (16h pulse of glucose infusion followed by an 8-hour chase with no infusion) and measured labeling in key glycolytic intermediates. To determine contribution from gluconeogenic, we infused stable isotope labeled lactate, glycerol, alanine, and glutamine. Finally, by utilizing a linear algebra approach to account for substrate interconversion, we were able to determine the direct contribution of glucose, glycogen breakdown, and different gluconeogenic substrates to glycolytic intermediate in 11 tissues.

Disclosure

T. TeSlaa: None.

Funding

National Institutes of Health
1925-P: Apparent Plateau in Diabetes Diagnosis Explained by Misuse of Updated Diagnosis Criteria in Simulation Modeling Study of Macronutrient Consumption Trends in U.S.
Authors: MOHANTY SMITA , CHELINI COLLEEN M. , D'ALESSANDRO PAUL , DWIVEDI GAURAV
Published: June 2019

Introduction: Increase in diabetes prevalence in the U.S. is likely due to demographic and dietary changes, but epidemiological studies do not show large enough changes in either to explain the magnitude of diabetes increase. We used a validated diabetes model to decompose the impact of diet on diabetes prevalence from 2001-2014, while considering demographics data and new diabetes diagnosis criteria.

Methods: We used a published model of diabetes that considers macronutrient intake, demographics and individual physiology to simulate a virtual population matched to U.S. demographics in 2001 and advanced it annually by updating demographic distribution (matched to U.S. Census) and diet (estimated by training the model to CDC-estimated diabetes prevalence from ‘01-’06). Prevalence was forecast for ‘07-’14 assuming the estimated diet trend continued linearly.

Results: Predicted prevalence was within 0.24% (absolute error) of CDC estimates between ‘07-‘14. Diabetes rates were largely explained by increase in carbohydrate (5%) and decrease in fat intake (11%) between ‘01-’14. The apparent plateau in diagnosed diabetes after 2010 (Figure) is inconsistent with model prediction unless both high HbA1c and glucose are used to diagnose diabetes, suggesting possible misuse of the ‘10 criteria in clinical practice.

Disclosure

S. Mohanty: None. C.M. Chelini: Employee; Self; Pwc. P. D'Alessandro: None. G. Dwivedi: None.
1931-P: Skeletal Muscle (SM) Insulin Resistance (IR) in Coronary Artery Disease (CAD) in Type 1 Diabetes (T1D)
Authors: WILLIAMS KATHERINE V. , SHAY CHRISTINA M. , PRICE JULIE , ORCHARD TREVOR J. , KELLEY DAVID
Published: June 2019

IR in T1D may contribute to CAD risk. We recently reported that SM IR in T1D primarily involves oxidative SM while glycolytic SM is comparable to healthy controls. This study compared systemic glucose disposal (GD) and SM IR in T1D with and without CAD. Insulin-infusion glucose clamps measured systemic GD concurrent with positron emission tomography (PET) imaging of SM glucose uptake with [18F]fluorodeoxyglucose (FDG) to profile glucose transport and phosphorylation, rate-limiting steps for GD. PET images were co-registered with MRI of the calf to determine FDG uptake (Patlak K) in soleus (SO) SM (largely oxidative muscle, type 1 fibers) vs. tibialis anterior (TA) SM (largely glycolytic muscle, type 2 fibers). Subjects with (n=9) and without (n=10) CAD were from the Epidemiology of Diabetes Complications (EDC) study, a 30-year prospective study of childhood onset T1D. Those CAD+ were older (52.4 vs. 43.1 years, p <0.01), heavier (BMI 28.0 vs. 24.3 kg/m2, p<0.05), and had higher systolic blood pressure (137 vs. 116 mmHg, p <0.05), each a factor disposing to IR. Groups did not differ in HbA1c (7.6 vs. 7.6%), insulin dose (0.59 vs. 0.59 U/kg), waist circumference (91.7 vs. 85.2 cm, p=0.07 controlled for sex), creatinine (1.0 vs. 0.9 mg/dL), CKD-EPI (78.9 vs. 93.1 mL/minute/1.73m2), or lipids. Those CAD+ did not differ from CAD- in systemic GD (5.40 vs. 4.95 mg/kg-FFM, p=0.59). In SM, FDG uptake in SO did not differ in T1D CAD+ vs. CAD- (0.0080 vs. 0.0075 mL/cm3-minute), though these values were reduced by 40% compared to controls (n=13). FDG uptake in TA SM was greater in T1D CAD+ vs. CAD- (0.0133 vs. 0.0077 mL/cm3-minute, p<0.01), and was also higher than in controls. Neither systemic nor SM IR were more severe in T1D with CAD compared to T1D without CAD. SM IR in T1D is present in oxidative type SM regardless of CAD, yet IR in T1D is not evident in glycolytic SM. Moreover, insulin-stimulated glucose transport/phosphorylation is increased in TA SM of T1D with CAD, perhaps as a compensatory heightening of insulin action in glycolytic SM.

Disclosure

K.V. Williams: None. C.M. Shay: None. J. Price: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. D. Kelley: Consultant; Self; Kallyope, Regeneron Pharmaceuticals, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Merck & Co., Inc.

Funding

National Institutes of Health (DK071487)
1937-P: miR-23b-3p Upregulates Glucose Uptake in C2C12 Myotube Cells by Regulating the Expression of PTEN
Authors: OKAMURA TAKURO , HASHIMOTO YOSHITAKA , OSAKA TAKAFUMI , SENMARU TAKAFUMI , HAMAGUCHI MASAHIDE , FUKUI MICHIAKI
Published: June 2019

Sarcopenia, i.e., the loss of muscle mass and degradation of muscle that can occur with aging, increases an individual's risk of death. MicroRNAs are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. Here we investigated the role of microRNA in sarcopenia. Orchiectomized (ORX) mice have decreased body weight and muscle mass, a smaller cross-sectional area of muscle, and impaired glucose tolerance. In our microarray analysis of the microRNA expression in skeletal muscle, the expression of miR-23b-3p in ORX mice was significantly higher than that in Sham mice; the expression in ORX mice treated with androgen was conversely lower. The overexpression of miR-23b-3p in C2C12 myotube cells significantly upregulated the expression of myosin heavy chain, protein synthesis, ATP activity, and glucose uptake. Reporter assays revealed direct post-transcriptional regulation involving miR-23b-3p and the 3'-untranslated region of PTEN mRNA. Among male subjects with type 2 diabetes, the serum miR-23b-3p levels in the subjects with sarcopenia was significantly higher compared to the levels of the subjects without sarcopenia. Our results indicate that miR-23b-3p negatively regulates the expression of PTEN in myotube cells and induces the upregulation of glucose uptake. In addition, the serum level of miR-23b-3p can be a surrogate marker of sarcopenia.

Disclosure

T. Okamura: None. Y. Hashimoto: Research Support; Self; Asahi Kasei Pharma. T. Osaka: None. T. Senmaru: None. M. Hamaguchi: None. M. Fukui: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Johnson & Johnson, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
1941-P: The Relationship among Intramyocellular Lipid, Peak Oxygen Consumption, and Insulin Resistance in Nonobese Japanese Men
Authors: YAMASAKI NOZOMU , TAMURA YOSHIFUMI , TAKENO KAGEUMI , KAKEHI SAORI , SOMEYA YUKI , FUNAYAMA TAKASHI , FURUKAWA YASUHIKO , KAGA HIDEYOSHI , SUZUKI RURIKO , SUGIMOTO DAISUKE , KADOWAKI SATOSHI , SATO MOTONORI , KAWAMORI RYUZO , WATADA HIROTAKA
Published: June 2019

Accumulation of intramyocellular lipid (IMCL) is observed not only in insulin resistant obese subjects with low peak oxygen consumption (VO2peak), but also in insulin sensitive endurance athletes with high VO2peak (athlete’s paradox). While the relationship among intramyocellular lipid, peak oxygen consumption and insulin resistance is variable among the different subjects, its relation within non-obese non-athlete subject has not been elucidated yet. To investigate this relation, we studied 61 non-obese (BMI<25kg/m2) non-athlete Japanese men. We evaluated muscle insulin sensitivity (M-IS) by a 2-step hyperinsulinemic euglycemic clamp. We divided the subjects into 4 groups based on the median value of VO2 peak (31.4 ml/kg per min) and the IMCL in soleus muscles (14.3 s-fat/Cre), then we compared M-IS. Compared with Low-VO2peak/High-IMCL group, M-IS was significantly higher in High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group (Fig). On the other hand, M-IS was comparable between High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group. These results suggest that in non-obese non-athlete Japanese men, VO2peaklevel is an important determinant of muscle insulin sensitivity in IMCL accumulated subjects. In addition, IMCL accumulation is not an important determinant of muscle insulin sensitivity in subjects with high VO2peak.

Disclosure

N. Yamasaki: None. Y. Tamura: None. K. Takeno: None. S. Kakehi: None. Y. Someya: None. T. Funayama: None. Y. Furukawa: None. H. Kaga: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. M. Sato: None. R. Kawamori: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.
1945-P: The Mitochondrial Protein DRP1 Is Required for Endogenous Fatty Acid Oxidation
Authors: KING WILLIAM T. , AXELROD CHRISTOPHER L. , DAVULURI GANGARAO , NOLAND ROBERT C. , KIRWAN JOHN P.
Published: June 2019

Introduction: Mitochondria are organelles that routinely undergo fission and fusion in a process known as mitochondrial dynamics. Increased mitochondrial fission is implicated in the pathogenesis of obesity, type 2 diabetes, and metabolic disease. DRP1 has been identified as a key regulator of mitochondrial fission. We and others have demonstrated that loss of DRP1 is associated with improvements in glucose homeostasis, however, the role of DRP1 in mitochondrial fatty acid oxidation is unknown. The purpose of this study was to measure endogenous fatty acid oxidation in DRP1-deficient skeletal muscle cells.

Methods: C2C12 myoblasts were stably transfected with DRP1 shRNA (KO) or a scrambled control (CT). Myoblasts were then cultured in a substrate-limited DMEM (0.5mM glucose, 0.5mM carnitine, 1mM glutamine, and 1% FBS) overnight. 15 minutes prior to assay, etomoxir was added to inhibit endogenous fatty acid oxidation (FAO). Cells were then challenged with either bovine serum albumin (BSA) or palmitate (PA) and assessed for mitochondrial function using whole cell respirometry (Agilent XFe24). Additionally, cells were treated with 14C-labeled PA in the absence and presence of increasing glucose concentrations to assess metabolic flexibility and fatty acid oxidation.

Results: Basal whole cell (P<0.05) and endogenous fatty acid (P<0.05) oxygen consumption were reduced in KO cells relative to CT (P<0.05). Furthermore, ATP linked fatty acid oxidation was blunted in the KO cells (P<0.05).

Conclusion: Here, we show that DRP1 is required for FAO. After inhibition of FAO with etomoxir, basal and ATP-linked respiration were ablated in DRP1-deficient cells. These findings suggest that loss of DRP1 ablates the ability of cells to use endogenous fatty acids as substrate when carbohydrate is not available. These data suggest that impaired lipid metabolism, rather than inhibition of mitochondrial fission, may explain improvements in glucose homeostasis with the loss of DRP1.

Disclosure

W.T. King: None. C.L. Axelrod: None. G. Davuluri: None. R.C. Noland: None. J.P. Kirwan: None.

Funding

National Institutes of Health (R01DK108089, U54GM104940, R01DK103860)
1952-P: Glucagon Receptor Antagonism Increases Plasma Amino Acids and Glucagon
Authors: HAEDERSDAL SOFIE , WEWER ALBRECHTSEN NICOLAI JACOB , LUND ASGER B. , GALSGAARD KATRINE D. , WINTHER-SOERENSEN MARIE , HOLST JENS J. , KNOP FILIP K. , VILSBØLL TINA
Published: June 2019

Hyperglucagonemia in type 2 diabetes (T2D) may result from impaired hepatic glucagon signaling and consequent reduced glucagon-induced amino acid (AA) turnover leading to higher AA concentrations and stimulation of glucagon secretion. In a double-blinded, cross-over study, blood was sampled from 10 overnight fasted patients with T2D (BMI [mean±SD]: 33.0±5.4 kg/m2; HbA1c: 46.2±6.1 mmol/mol, 6.4±0.6%) and 10 matched healthy controls (BMI: 31.7±4.2 kg/m2; HbA1c: 33.9±3.0 mmol/mol, 5.3±0.3%) after a single-dose of the glucagon receptor antagonist (GRA) LY2409021 or placebo. Total AA and glucagon concentrations are means of 3 samples (15 minutes apart) on 3 GRA and 3 placebo days. Fractioned AA were analyzed from one sample per day. Total AA concentrations were increased by GRA compared to placebo by 1.4 fold in T2D and 1.3 fold in controls (P≤0.001) with threonine, proline and the glucagonotropic AAs alanine and tyrosine exhibiting the greatest increases in T2D (1.6-2 fold) and controls (1.4-1.5 fold). GRA also increased plasma glucagon concentrations by more than 3-fold (P≤0.0001), and the glucagonotropic AAs alanine (R2 0.24, P=0.0012) and tyrosine (R2 0.30, P=0.0002) were correlated to glucagon.

In conclusion, acute inhibition of glucagon receptor signaling by GRA causes hyperaminoacidemia linked to hyperglucagonemia, supporting the importance of the liver-alpha cell axis in regulating circulating glucagon and AA in humans.

Disclosure

S. Haedersdal: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. A.B. Lund: None. K.D. Galsgaard: None. M. Winther-Soerensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. T. Vilsbøll: None.

Funding

Novo Nordisk Foundation
1957-P: The Role of Glucose-Dependent Insulinotropic Polypeptide in Regulation of Splanchnic Blood Flow and Lipid Metabolism in Humans
Authors: ASMAR ALI , HOLST JENS J. , ASMAR MEENA
Published: June 2019

The aim of this study was to investigate the effect of glucose-dependent insulinotropic polypeptide (GIP) per se and in combination with hyperglycemia and hyperinsulinemia on splanchnic blood flow and further to investigate the role of GIP in splanchnic lipid metabolism in humans. Eight healthy lean males were examined in a randomized order on four different occasions. Splanchnic blood flow and lipid metabolism were measured by Fick’s Principle using indocyanine green as indicator during GIP (1.5 pmol/kg/min) or saline infused intravenously alone or in combination with a hyperglycemia and hyperinsulinemia (Hygluc-Hyinsu) clamp. During all four experiments, splanchnic blood flow increased similarly. Splanchnic triglyceride output decreased similarly during the Hygluc-Hyinsu clamp with and without GIP (8.6 ± 1.8 and 10.3 ± 2.6 µmol/min, respectively, P=NS). Likewise, during the clamp alone and with GIP, free fatty acids uptake decreased similarly (3.5 ± 3.8 and 6.7 ± 4.6 µmol/min, respectively, P=NS). GIP does not seem to play a key role in the acute regulation of splanchnic blood flow or lipid metabolism under these particular conditions in vivo.

Disclosure

A. Asmar: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M. Asmar: None.
196-LB: Prenatal and Lifestyle Contributions to Child Insulin Sensitivity
Authors: ALVES JASMIN , CHOW TING , ZINK JENNIFER , LUO SHAN , MARTINEZ MAYRA P. , ROMERO ANA , XIANG ANNY , PAGE KATHLEEN A.
Published: June 2019

Background: Early life exposures play an important role in metabolic health throughout life. We examined how prenatal exposures to maternal obesity or gestational diabetes mellitus (GDM) and low levels of physical activity and increased food intake may contribute to reductions in insulin sensitivity in childhood.

Methods: Participants were 7-10 year old children who were born at Kaiser Permanente Southern California. Maternal pre-pregnancy BMI and GDM status were extracted from electronic medical records. Child weight and height were measured, and oral glucose tolerance tests were performed. Insulin sensitivity was estimated using the Matsuda insulin sensitivity index (ISI). Diet was assessed using 24-hour dietary recalls and daily energy intake (EI) was calculated. Physical activity was assessed using a 3-day physical activity recall and average min/day of moderate to vigorous physical activity (MVPA) was calculated. Linear regression was used to assess ISI associations with the exposures.

Results: 92 children (52 girls; 40 boys; 55 GDM-exposed; 37 unexposed) participated. Maternal pre-pregnancy BMI ranged from 19.0-50.4 kg/m2. Mean±SD child age was 8.3±0.9 years, BMI z-score: 0.60±1.1, ISI: 10.6±5.9, EI: 1790.7±444.2 kcal, and MVPA: 118.7±93.8 min/day. Children who spent more time in MVPA had better insulin sensitivity (β=0.82; P=.02). Adjusting for maternal pre-pregnancy BMI, GDM exposure, child age, sex, and EI, did not affect this relationship (β=0.87; P<.01), nor did further adjusting for BMI z-score (β=0.78; P=.01). Prenatal exposure to GDM and child ISI (β=0.19, P=.28) and maternal pre-pregnancy BMI were not significantly associated with child ISI (β=-0.01, P=0.40), nor was child’s EI associated with ISI (β=0.001; P=.59).

Conclusions: Time spent in MVPA was the strongest predictor of child insulin sensitivity. Our findings suggest that engaging in MVPA during childhood is beneficial for insulin sensitivity and may help ameliorate future risk for metabolic disease.

Disclosure

J. Alves: None. T. Chow: None. J. Zink: None. S. Luo: None. M.P. Martinez: None. A. Romero: None. A. Xiang: None. K.A. Page: None.

Funding

American Diabetes Association (1-14-ACE-36 to K.A.P.); National Institutes of Health (1F31MH115640-01A1)