bluuebunny/crossref_metadata_2025 huggingface dataset:
188-LB: MicroRNA-126-3p Impacts Insulin Signaling in Smooth Muscle Cells
Authors: TRYGGESTAD JEANIE B.
Published: June 2019

Human umbilical vein endothelial cells (HUVEC) are a rich source of miRNA-126-3p. HUVEC package miR-126-3p into exosomes and secrete them into the extracellular space, potentially influencing other cells. Smooth muscle cells (SMC) take up miR-126-3p in a co-culture model with endothelial cells. miR-126-3p targets mRNAs in the insulin signaling pathway impacting their protein abundance. To test the hypothesis that miRNA-126-3p would decrease abundance of IRS1 and Akt, targets of miR-126-3p, SMC were isolated from the umbilical veins of infants born to women with (DM group; n=2) and without (control group; n=3) diabetes during pregnancy. miR-126-3p or a non-coding control mimic (NTC; 50 nM per miRNA) was transfected into SMC. After 48 h, SMC were stimulated for 10 min with 0 or 10 nM insulin. For analysis, abundance of all proteins was set relative to the NTC-transfected, unstimulated control group SMC (set at 100%). The fold change in IRS1 abundance was 85% +/- 72% and 85% +/- 30% for the control and DM groups, respectively. Abundance of Akt was 107% +/- 32% and 112% +/- 19% for the control and DM groups, respectively. pAkt abundance was 67% +/- 21% and 40% +/- 9% for the control and DM groups, respectively. Upon insulin stimulation, pAkt abundance in the control group increased to 114% +/- 29% of NTC, while in the DM group, abundance only reached 68% +/- 27% of control NTC. Furthermore, pAS160, necessary for GLUT4 translocation, was largely unchanged in the control group with or without insulin stimulation (96% +/- 23% and 99% +/- 45%, respectively). However, pAS160 abundance in the DM group was 45% +/- 4% of NTC and this reduction was not rescued by insulin stimulation (42% +/- 28%). These data suggest that miRNA-126-3p can decrease abundance of insulin signaling pathway proteins, and these decreases are more substantial in DM-exposed SMC. miRNA-126-3p appears to exert its affects through a decrease in IRS1, rather than through Akt. Future studies are planned to examine the impact of miRNA-126-3p on SMC function.

Disclosure

A.M. Teague: None. J.B. Tryggestad: None.

Funding

National Institutes of Health (1K23DK106533-01A1 to J.B.T.); Children's Medical Research Institute Metabolic Research Program; Harold Hamm Diabetes Center; University of Oklahoma Health Sciences Center
1890-P: Lipocalin-Type Prostaglandin D2 Synthase Deficient Mice Develop Dyslipidemia Resulting in Nonalcoholic Fatty Liver Disease Independent of Obesity
Authors: SRIVASTAVA ANKITA , PALAIA THOMAS , HALL CHRIS , LEE JENNY , STEVENSON MATTHEW , RAGOLIA LOUIS
Published: June 2019

Nonalcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus (T2DM), cardiovascular disease, and all-cause mortality. Obesity is a major determinant of the high prevalence of NAFLD and T2DM worldwide. Previously, we demonstrated that lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in causing NAFLD in L-PGDS knockout (KO) and control C57BL/6 mice (n=6/group) on both low fat and high fat diets for 14 weeks. We observed that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster, even on the low fat diet. In addition, we found elevated fasting glucose and insulin levels in L-PGDS KO mice with increased lipid accumulation in the liver with time on both diets as compared to controls. We also found total cholesterol and LDL levels were significantly elevated in L-PGDS KO mice. Finally, lipogenesis marker proteins such as SREBP-1c and LXRα, and CD36, a fatty acid transporter protein, were also found to be increased in L-PGDS KO mice on both diets as compared to control mice. These data confirm that absence of L-PGDS results in hyperinsulinemia and dyslipidemia. Therefore, we conclude that L-PGDS plays a significant role in developing NAFLD independent of obesity and may serve as a novel therapeutic target for the treatment of NAFLD.

Disclosure

A. Srivastava: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None.

Funding

George Link, Jr. Foundation, Inc.; American Heart Association
1894-P: HIF-2α Induced by Hypoxia Exacerbates Nonalcoholic Fatty Liver Disease Progression via Suppressing PPARα
Authors: CHEN JIANDI , CHEN JIANXU , FU HUIRONG , LI YUN , LUO SHUNKUI , WANG LINGLING , LU HONGYUN
Published: June 2019

Background: Hypoxic condition induced by obstructive sleep apnea syndrome (OSAS) involves in the development of NAFLD. Previous studies indicated HIF-2α was correlated with lipid metabolism. However, the potential mechanisms of HIF-2α in the progress of NAFLD was unclear. Our study aimed to detect the molecular mechanisms.

Methods: We established steatosis LO2 cells model and mouse NAFLD model, then exposed to intermittent hypoxia (IH) treatment, We detected the lipid accumulation in liver and the expression of HIF-1α and HIF-2α. Furthermore, we treated steatosis hepatocytes with hypoxia, HIF-2α siRNA, PPARα agonists and inhibitors respectively. Meanwhile, we exposed mouse NAFLD mode to IH or IH with PPARα agonists.

Results: Steatosis hepatocytes exhibited more sensitive to hypoxia and more likely to occur lipid accumulation. Moreover, we found lipid accumulation in hepatocytes was ameliorated by HIF-2α silence or PPARα agonist. HIF-2α overexpression suppressed PPARα leading to PGC-1α, NRF-1, ESRRα downregulation and impaired mitochondrial function. We also found lipolysis genes such as CPT1α, CPT2α, ACOX1, ACOX2 were downregulated, and lipogenesis genes including LXRα, FAS, SCD1 were upregulated.

So we concluded HIF-2α induced by hypoxia exacerbates NAFLD progression by suppressing β-oxidation via PPARα.

Disclosure

J. Chen: None. J. Chen: None. H. Fu: None. Y. Li: None. S. Luo: None. L. Wang: None. H. Lu: None.

Funding

National Natural Science Foundation of China (81670815); Natural Science Foundation of Guangdong Province (2016A030313279); Sun Yat-sen University (17YKZD23)
1901-P: CK1 δ/ε Inhibitor PF-05006739 Ameliorates Hepatic Steatosis and Hyperinsulinemia in Dio Mice
Authors: PELOQUIN MATTHEW , LITCHFIELD JOHN , ZHANG BEI B. , CHANG CHENG , MILLER RUSSELL A. , BERNARDO BARBARA , LUTHRA SUMAN , CORTES CHRISTIAN , LI XIANGPING , ZOU CHANG J.
Published: June 2019

The circadian rhythm allows for metabolic processes to be primed to anticipate the expected daily cycling of behaviors like food consumption and lipid storage. Previous genetic and epidemiological studies have implicated circadian disruption as a potential causal determinant for metabolic diseases such as obesity, diabetes and fatty liver. Here we leverage diet induced obese (DIO) mice to test the potential for circadian modulation by inhibition of casein kinase 1δ/ε (CK1 δ/ε) to improve endpoints in metabolic disease models. Our data reveal that the CK1 δ/ε inhibition with small molecule PF-05006739 was able to significantly lower fasted and fed insulin levels, fasted glucose and hepatic lipid content with a concomitant ∼9% decrease in body weight. PF-05006739 was also capable of shifting the gene expression of circadian oscillating transcripts in the liver, consistent with reported actions of this compound in previous preclinical evaluations. Furthermore, this shift in gene expression also correlated with a shift in respiratory exchange ratio (RER) and energy expenditure (EE) in vivo. Taken together these data suggest CK1 δ/ε inhibition as a potential therapeutic approach for metabolic diseases, specifically hyperinsulinemia and NAFLD/NASH.

Disclosure

M. Peloquin: Employee; Self; Pfizer Inc. J. Litchfield: Employee; Self; Pfizer Inc. B.B. Zhang: Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc. Employee; Self; Pfizer Inc. Other Relationship; Self; Eli Lilly and Company. C. Chang: Employee; Self; Pfizer Inc. R.A. Miller: Employee; Self; Pfizer Inc. B. Bernardo: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. S. Luthra: None. C. Cortes: None. X. Li: Employee; Self; Pfizer Inc. C.J. Zou: None.
1904-P: The Hepatocyte Integrin ß1 Subunit Links ECM-Integrin Signaling to Insulin Resistance in Obese Mice
Authors: TREFTS ELIJAH , ROBY DEBORAH A. , POZZI AMBRA , ZENT ROY , WASSERMAN DAVID
Published: June 2019

Insulin resistance (IR) is a primary contributor to obesity related pathologies including type 2 diabetes. Hepatic IR manifests as a loss of insulin’s suppressive action on hepatic glucose output, and correlates with extracellular matrix (ECM) expansion. Integrin receptors are the primary input for ECM derived signals to the intracellular environment. Given the correlation of ECM deposition with hepatic IR our goal is to define contributions of integrin signaling to this pathologic process.

Integrin receptors are heterodimeric membrane receptors with an α and β subunit. Hepatocytes are involved in hepatic insulin responsiveness and express four integrin subunits. Utilizing mice with hepatocyte specific knockout of integrin α5 (hepα5-KO) or β1 (hepβ1-KO) we aimed to determine contributions of these integrin subunits to IR.

A high-fat (HF) fed model of diet induced obesity (DIO) caused weight gain in hepα5-KO, hepβ1-KO, and respective control littermates. Using hyperinsulinemic-euglycemic clamps in the conscious catheterized mouse we demonstrate that hepα5-KO mice on a standard diet (chow) have normal insulin sensitivity and develop IR during DIO similar to controls. While insulin sensitivity of chow fed hepβ1-KO is no different from controls, DIO hepβ1-KO mice are protected from IR. Significant increases in glucose disappearance (Rd) and suppression of endogenous glucose appearance (EndoRa) during the clamp drive preservation of insulin sensitivity in these mice. Interestingly the primary hepatocyte knockout of the β1 subunit has effects on extrahepatic tissue as DIO hepβ1-KO mice also demonstrate increased glucose metabolic indexes (Rg) in several tissues, likely contributing to enhanced Rd.

Overall, these findings demonstrate the direct link between IR and ECM-integrin signaling through integrin β1. This further establishes the involvement of ECM-integrin signaling during metabolic disease and the potential for this pathway as a novel therapeutic avenue.

Disclosure

E. Trefts: None. D.A. Roby: None. A. Pozzi: None. R. Zent: None. D. Wasserman: None.

Funding

National Institutes of Health (DK007563), (DK112553 to E.T.), (DK069221, DK083187 to R.Z.), (CA162433, DK095761 to A.P.), (DK050277, DK054902 to D.W.)
1905-P: Artificial Decline in HbA1c Level during Treatment of Hepatitis C with Interferon-Free, Direct-Acting Antiviral Regimen Combined with Ribavirin
Authors: MORIYA AKIO , IWASAKI YOSHIAKI , ANDO MASAHARU
Published: June 2019

HbA1c is an important marker for glycemic control; however, not only plasma glucose levels but also RBCs' lifespan determines the value. Some of interferon-free, direct-acting antiviral regimens for hepatitis C are combined with ribavirin, which causes hemolytic anemia. Hemolytic anemia shortens the RBCs' lifespan and lowers HbA1c levels. We monitored HbA1c levels in 28 patients during and after antiviral therapy with daily sofosbuvir (400 mg) plus weight-based ribavirin for hepatitis C. Five cases (18%) had antidiabetic medication. The hemoglobin concentration, 13.9 ± 1.4 g/dl at the baseline, significantly fell to 12.0 ± 1.3 g/dl at the 4th week of treatment (P < 0.001). It hardly declined further during the treatment and immediately recovered after the end of treatment. Although there was no significant change in the random plasma glucose levels, the HbA1c level, 5.8% ± 0.7% at the baseline, gradually declined to 4.3% ± 0.7% (- 1.5% ± 0.7%, P < 0.001) at the end of treatment. It partly recovered to 4.8% ± 0.6% at the 4th week after treatment, then further increased to 6.2% ± 0.9% at the 12th week, and eventually returned to 5.7% ± 0.7%, which was similar to the value at baseline.

Conclusions: interferon-free, direct-acting antiviral regimen combined with ribavirin temporally causes artificial declines in HbA1c levels.

Disclosure

A. Moriya: None. Y. Iwasaki: None. M. Ando: None.
1906-P: Effects of a Carbohydrate-Restricted Diet on Hepatic Lipid Content in Adolescents with Nonalcoholic Fatty Liver Disease
Authors: GOSS AMY M. , DOWLA SHIMA , ASHRAF AMBIKA P. , BOLDING MARK , MORRISON SHANNON A. , GOWER BARBARA
Published: June 2019

Background: NAFLD has emerged as the most common liver disease among adolescents in industrialized countries. Results from trials in adults with NAFLD suggest that reducing CHO intake may deplete liver fat to a greater extent than other dietary approaches, even when there was no difference in weight loss between diet groups. The objective of this study was to determine the effects of a CHO-restricted vs. fat-restricted diet in adolescents with NAFLD on reduction in hepatic lipid and insulin resistance.

Methods: Twenty-three adolescents (age 9-17) with obesity (BMI ≥85th percentile) and confirmed NAFLD were randomized to a CHO-restricted (<10:25:>65% energy from CHO:protein:fat) or fat-restricted diet (55:25:20) for 8 weeks. Caloric intakes were calculated to be weight maintaining. Participants and one parent attended bi-weekly counselling with a registered dietitian. To encourage compliance, groceries were delivered to participants’ families during the first 2 weeks of the study. Both diets included minimally processed foods with limited added sugar. Change in hepatic lipid content was measured via MRI, body composition via DXA, and insulin resistance via a fasting blood sample.

Results: After 8 weeks, the CHO-restricted diet group experienced a significant decrease in hepatic lipid content (-6.0±4.7%, p<0.001), whereas the fat-restricted diet group showed no change. We found significantly greater decreases in insulin resistance (HOMA-IR, -1.2±5.1, <0.05), abdominal fat mass (-1.7 ±1.1 kg, p<0.01), and body fat mass (-3.1±4.0 kg, p<0.01) in response to the CHO-restricted vs. fat-restricted diet.

Conclusion: The CHO-restricted diet approach may be markedly beneficial in improving fatty liver, body composition, and insulin resistance in adolescents with NAFLD even in the absence of intentional caloric restriction. Practitioners should consider recommending this diet approach to effectively improve disease course in this patient population.

Disclosure

A.M. Goss: None. S. Dowla: None. A.P. Ashraf: Research Support; Self; Opko. Speaker's Bureau; Spouse/Partner; Bristol-Myers Squibb Company, Celgene Corporation, Insys, Pfizer Inc. M. Bolding: None. S.A. Morrison: None. B. Gower: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases; Thrasher Research Fund
1907-P: GLP-1RA and iSGLT2 Combination Treatment Effects over Fatty Liver Index
Authors: CARRETERO GÓMEZ JUANA , AREVALO LORIDO JOSE CARLOS , GÓMEZ-HUELGAS RICARDO , SEGUÍ-RIPOLL JOSÉ MIGUEL , TEMBRA MANUEL SUAREZ , CASAS JOSÉ MANUEL , CARRASCO JAVIER , DIABETES OUP ,   OBESITY AND NUTRITION SPANISH WORKING GR
Published: June 2019

Aim: To analyze changes in Fatty Liver Index (FLI) in obese and T2DM patients under treatment with GLP-1RA - SGLT2i combination.

Methods: Observational, prospective, multicenter study. Patients were stratified according to predetermined treatment schedule groups (successively vs. simultaneously).

Results: We included 142 patients (59.1% men, mean age 60.8±8.9 years). 76.7% had hypertension and 81.7% dyslipidemia. The BMI was 36.9 ±.7.1 kg/m2, FLI was 97±11, A1C was 8.0% ±1.5%, Triglyceride (Tg) was 158±102 mg/dl, Waist circumference (WC) 120.3 cm and gamma-glutamyl-transferase (GGT) was 43±45 UI/L. At 26 weeks follow-up we found a significant reduction in FLI (-5 points; p<0.0000), A1C (-1.1%; p<0.0001), BMI (-2.1 kg/m2; p<0.00003), GGT (-11 UI/L; p<0.0003), WC (-6.7 cm; p<0.000) and Tg (-28.5; p<0.01). Table 1 expands results in predetermined groups.

Discussion: Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the absence of other causes of steatosis. FLI is an accurate algorithm which can be used as a surrogate marker of steatosis; it combines measures of Tg, GGT, WC and BMI. GLP-1RA have direct effects on hepatocytes improving liver histology and reducing GGT levels. However, data on SGLT2i over the liver fat are scarce. Our study demonstrated that the combination of GLP-1RAs-SGLT2i reduces liver fat in patients with T2DM being positively correlated with improvement in A1C, BMI, WC and GGT.

Disclosure

J. Carretero Gómez: None. J. Arevalo Lorido: None. R. Gómez-Huelgas: None. J. Seguí-Ripoll: None. M. Suarez Tembra: None. J. Casas: None. J. Carrasco: None.
1910-P: SOCS3 Deficiency on a High-Fat Diet Accelerates Systemic Inflammation and Results in Lethal Myeloid Hematopoiesis without Obesity and Adiposity
Authors: CHO KAORI , USHIKI TAKASHI , ISHIGURO HAJIME , KATAGIRI TAKAYUKI , SUWABE TATSUYA , HIRAI HIDEYO , NAKAGAWA YOSHIMI , MASUKO MASAYOSHI , ALEXANDER WARREN , SHIMANO HITOSHI , SONE HIROHITO
Published: June 2019

Introduction: Suppressors of cytokine signaling (SOCS) are negative regulators of cytokine signaling; SOCS3 controls myeloid hematopoiesis by suppressing G-CSF. SOCS3 haploinsufficiency attenuates diet-induced obesity by enhanced leptin sensitivity while improving insulin resistance. We established SOCS3 conditional knock-out (KO) mice to elucidate how high fat diets (HFD) affect inflammation and obesity in complete SOCS3 deficiency.

Methods: Embryonic lethality of complete SOCS3 deficiency was overcome using a conditional Socs3 allele inactivated by tamoxifen (TAM)-inducible cre-recombinase with SOCS3fl/flRosa26-CreERT2T/+ mice. They were fed HFD (60 kcal% fat) or control chaw (10 kcal% fat) starting at 4 weeks of age and TAM or vehicle administration was done at 8 weeks.

Results: Although insulin resistance improved and obesity and fatty liver were not confirmed in SOCS3-KO with HFD (S3HFD), the S3HFD group looked moribund around day 30 post-TAM by systemic inflammation; their mean survival was 62.5 days after TAM. Other groups did not look moribund. Significant granulopoiesis was also observed in S3HFD (peripheral blood neutrophil counts 29301 ± 20581/mm3). This myeloid hematopoiesis occurred in the spleen and not the bone marrow. S3HFD exhibited the progression of various granulocytes from progenitor cells (c-kitint∼highLy6G-) to mature granulocytes (c-kit-Ly6G+).Hematopoietic infiltration was confirmed in the liver in S3HFD with granulocytes, monocytes, and macrophages. Inflammasome-associated genes (IL-1β and Caspase1) were elevated in the liver at day 65 post-TAM in S3HFD.

Conclusion: SOCS3 deficiency showed myeloid proliferation under HFD without obesity and adiposity. SOCS3-KO may help in the clarification of the specific mechanism of myeloid proliferation and invasion in HFD-induced inflammation.

Disclosure

K. Cho: None. T. Ushiki: None. H. Ishiguro: None. T. Katagiri: None. T. Suwabe: None. H. Hirai: None. Y. Nakagawa: None. M. Masuko: None. W. Alexander: None. H. Shimano: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.
1918-P: Carbohydrate and Fat Oxidation Fasting and in Response to a Hyperinsulinemic Clamp is Similar in Obese Youth Regardless of PCOS Status
Authors: WIROMRAT PATTARA , RYNDERS COREY A. , NADEAU KRISTEN J. , CREE-GREEN MELANIE
Published: June 2019

Whole-body metabolic flexibility (MF), i.e., switching substrate oxidation between fasting and fed states often becomes abnormal with insulin resistance (IR). Data regarding MF in women with PCOS, whom often have IR, are mixed and confounded by varied diets and habitual physical activity. No study has assessed MF in response to a multi-phase hyperinsulinemic-euglycemic clamp in PCOS females relative to non-PCOS with similar habitual physical activity and controlled diet. Adolescent girls with obesity and PCOS (age 14.9 ± 1.5 years; BMI 35 ± 4 kg/m2), 10 obese controls (age 13.5 ± 1.3; BMI 32 ± 2) and 13 normal BMI PCOS (age 16.2 ± 1.5; BMI 22.8 ± 2) were included. All girls were sedentary per questionnaire and 7 day accelerometry. A 4-phase hyperinulinemic-euglycemic clamp (basal, 10, 16 and 80 mU/m2/min of insulin) including glucose and glycerol tracers was performed. Glucose rate of disappearance (Rd), glycerol rate of appearance (Ra) and respiratory quotient (RQ) were assessed during each clamp phase. MF was defined as a change in RQ from baseline to each phase (ΔRQ). Basal RQs were not different between groups. Lean PCOS had higher ΔRQ at phase 10 compared to obese PCOS (p=0.005) and obese controls (p=0.003). All groups had similar ΔRQs at 16 and 80 phases. In multivariable regression models, Δ 10 glycerol Ra (Δ from baseline to 10 phase) was associated with phase 10 ΔRQ, independent of age and BMI (p=0.04); Δ 80 glycerol Ra and Δ 80 glucose Rd were associated with phase 80 ΔRQ, independent of age and BMI (p=0.048). Sedentary obese adolescents regardless of PCOS status have lower MF compared to lean PCOS during the low insulin dose which was associated with whole body lipolysis. However, this difference is not found during the high insulin dose, suggesting obese girls have only subtle defects in MF. Further, PCOS is not associated with lower MF once diet and habitual activity are matched.

Disclosure

P. Wiromrat: None. C.A. Rynders: None. K.J. Nadeau: None. M. Cree-Green: None.

Funding

American Diabetes Association (7-11-CD-08 to K.J.N.); American Heart Association (13CRP14120015); Thrasher Research Fund; National Center for Research Resources Colorado (TL1TR002533); Pediatric Endocrinology Society; National Institute of Diabetes and Digestive and Kidney Diseases (T32DK063687, K23DK107871)
192-LB: Serum Magnesium Levels and Its Relationship with Alterations of Glucose Metabolism during Pregnancy
Authors: LÓPEZ CASTRO ALICIA , ZAVALZA GOMEZ ANA BERTHA , HERNANDEZ GONZALEZ SANDRA OFELIA , ESPINEL-BERMUDEZ MARIA CLAUDIA , ORTIZ HERNANDEZ JOSE RICARDO
Published: June 2019

Intracellular magnesium contributes in the regulation of the effects of insulin and glucose uptake; its deficits strongly associated with hyperglycemia, hypertriglyceridemia and insulin resistance (IR). Studies in healthy, hypertensive, and diabetes mellitus type 2 (DM2) subjects have shown a lower concentration of intracellular magnesium, higher glucose increase. It is unknown if there is hypomagnesemia related to hyperglycemia and insulin resistance during pregnancy. Analytical cross-sectional study in pregnant women who signed consent, ≥18 years old, any trimester of pregnancy. Patients with chronic diarrhea, alcohol intake (≥30 g/day), use of diuretics and/or calcium channel blockers, reduced renal function, or supplemented with magnesium for at least six months prior to the study were not included. Clinical variables were determined, anthropometry, vital signs, serum magnesium levels, fasting glucose and 2-h plasma glucose (2-h PG) value during a 75-g oral glucose tolerance test (OGTT), lipid profile and glycosylated hemoglobin (A1C) were measured. We analyzed 84 patients with whom the 3 study groups were formed: healthy pregnant women, with IR (TyG index) and gestational diabetes (GD) (Table). Hypomagnesemia was found in all 3 groups without a clear relationship between low magnesium levels and alterations in glucose status.

Disclosure

A. López Castro: None. A. Zavalza Gomez: None. S. Hernandez Gonzalez: None. M.C. Espinel-Bermudez: None. J.R. Ortiz Hernandez: None.
1920-P: Coingestion of Glucose and Fructose Has Synergistic Effects on Lipoprotein Risk Factors for Cardiovascular Disease in Healthy Young Adults
Authors: HIERONIMUS BETTINA , MEDICI VALENTINA , LEE VIVIEN , NUNEZ MARINELLE , HAVEL PETER J. , STANHOPE KIMBER L.
Published: June 2019

Global sugar consumption is at an all-time high. In previous studies, we and others have demonstrated that, compared with glucose (Gluc), consumption of fructose (Fruc) increases risk factors for cardiovascular disease (CVD), diabetes and metabolic syndrome. However, humans almost exclusively consume Fruc in combination with Gluc. Our aim was to study effects of Gluc, Fruc and their combination - high fructose corn syrup (HFCS) - and identify effects on metabolic risk factors.

We performed a parallel-armed, double blinded intervention study wherein the subjects consumed beverages sweetened with 25% of their energy requirement (Ereq) as Gluc, Fruc or HFCS, or 17.5% Ereq as Fruc or HFCS, or Aspartame (ASP) for two weeks with their usual diet. Procedures, which included fasting and postprandial blood draws, were conducted over a 48-h period at baseline and at the end of intervention while subjects consumed standardized meals containing 30% Ereq as fat, 15% protein, 55% carbohydrate (mainly complex during baseline; complex + sweetened beverage during intervention). As expected, the increases for 24h triglyceride area under the curve (AUC), 24h uric acid AUC, and postprandial apoCIII were highest in both Fruc groups (all P<0.01 versus ASP), next highest in both HFCS groups (all P<0.05 25% Ereq HFCS versus ASP), and lowest in the Gluc group (all P>0.05 versus ASP). Unexpectedly, the increases of LDL- and non-HDL-cholesterol (C) and ApoB were highest in the HFCS groups (all P<0.001 25% HFCS versus ASP, P<0.01 versus Gluc). Re-analyzing the outcomes based on the amounts of Fruc and Gluc contained in the beverages revealed significant interactions between Fruc and Gluc on fasting and postprandial concentrations of LDL-C, non-HDL-C and ApoB (all P<0.01).

While sole consumption of Fruc leads to increases of metabolic risk factors, those increases are exacerbated for several risk factors when Fruc is co-ingested with Gluc as HFCS.

Disclosure

B. Hieronimus: None. V. Medici: None. V. Lee: None. M. Nunez: None. P.J. Havel: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc. K.L. Stanhope: None.

Funding

National Heart, Lung, and Blood Institute (1R01HL09133, 1R01HL107256); National Center for Research Resources (UL1RR024146); Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD051958); Office of Research on Women’s Health; Office of Dietary Supplements; National Institute on Aging (to K.L.S.)
1921-P: The Role of BCAA Catabolism in Glucose Homeostasis
Authors: NISHI KIYOTO , ABELL LAUREN , MCMILLEN TIMOTHY , TIAN RONG
Published: June 2019

The rate limiting step of BCAA (Branched-chain amino acid; Valine, Leucine and Isoleucine) catabolism is regulated by the branched-chain keto acid dehydrogenase complex (BCKDC). PPM1K is a phosphatase which regulates BCAA catabolism by activating BCKDC through dephosphorylation. We and other groups have reported impaired BCAA catabolism and elevated blood BCAA levels in PPM1K-defiient mice (KO). Several studies have shown that elevated blood BCAA levels are associated with obesity and glucose intolerance. In addition, PPM1K expression is reduced in obesity model animals (leptin-deficient mice, etc.) and GWAS data shows loss-of-function SNP of PPM1K gene is associated with diabetes. Based on these findings, loss/reduction of PPM1K is thought to induce glucose intolerance. However, no previous study has directly analyzed the role of PPM1K in obesity and glucose metabolism. Therefore, in this study, we analyzed KO and wild type mice (WT) with diet-induced obesity. Firstly, KO and WT were fed with either normal chow diet (NCD) or high-fat diet (HFD; 60% of kcal from fat). KO showed normal body weight gain in both NCD and HFD condition. Next, KO and WT underwent intra-peritoneal glucose tolerance test (ipGTT). NCD-fed KO showed normal glucose tolerance. Surprisingly, HFD-fed KO showed significantly better glucose tolerance (AUC WT 58192±7828 vs. KO 47526±6646 min*mg/dL, p<0.05). As impaired BCAA catabolism leads to both decreased BCAA catabolite and increased BCAAs, to distinguish the effect of these two factors, we did ipGTT in WT fed with BCAA-restricted diet (LB; the amount of BCAA were reduced to one-third of control), which has decreased BCAA catabolite without increased BCAAs. LB showed improved glucose tolerance (AUC Cont 38639±5748 vs. LB 32087±5072 min*mg/dL, p<0.05), indicating that decreased BCAA catabolite rather than increased BCAAs may cause better glucose tolerance in KO.

In summary, these results suggest the critical role of PPM1K and BCAA catabolism in the regulation of glucose homeostasis.

Disclosure

K. Nishi: None. L. Abell: None. T. McMillen: None. R. Tian: None.

Funding

Japan Heart Foundation; National Institutes of Health
1926-P: Regulation of Soluble Epoxide Hydrolase by Gut Bacteria and Acetate
Authors: YOUN JANG , OH YOUNG-TAEK
Published: June 2019

Epoxyeicosatrienoic acids (EETs) are lipid mediators with beneficial effects on metabolic and cardiovascular (CV) health. EETs are metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EETs, has been shown to improve glucose homeostasis, blood pressure, and CV health in insulin-resistant or diabetic animals and proposed as an effective strategy to treat diabetes and CV diseases. Despite its importance to metabolic and CV health, little is known about mechanisms by which sEH is regulated in vivo. Our recent study demonstrated that in vivo sEH activity, assessed from plasma oxylipin levels, profoundly (3-fold) decreased after a meal in rats. Interestingly, this effect was completely abolished in rats with gut bacteria depleted by antibiotic treatment, suggesting that a gut-bacteria-derived factor(s) may be responsible for the postprandial effect. Gut bacteria produce short chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, from nutrients, and plasma SCFA levels rise during feeding. In the present study, we tested the possibility that SCFAs may be involved in the postprandial inhibition of sEH activity. For this, we examined the effects of SCFAs on sEH activity in vitro by measuring EET conversion to diol in liver homogenates. Acetate showed a profound effect to inhibit sEH activity (up to 91%) with EC50 of 39 ± 3 µM (n = 4). In contrast, propionate and butyrate had no significant effects (n = 4 and 5, respectively). The acetate effect occurred at physiological concentrations, suggesting acetate may be an endogenous inhibitor of sEH, and the postprandial inhibition of sEH activity may be mediated by acetate produced by gut bacteria after a meal. Because acetate is produced in vivo predominantly by gut bacteria, these data may explain why the postprandial effect to inhibit sEH was absent in gut-bacteria-depleted rats. Taken together, our data suggest sEH activity may be regulated in vivo by gut bacteria through the production of acetate.

Disclosure

J. Youn: None. Y. Oh: None.

Funding

American Diabetes Association (1-16-IBS-332 to J.Y.)
193-LB: Levels of Adherence to a Mediterranean Diet and Risk of Gestational Diabetes Mellitus: Modulation Effects of MTNRB1_rs10830963, TCFTL2_rs7903146, and MC4R_rs17782313 Gene Polymorphisms
Authors: BARABASH ANA , VALERIO DEOGRACIA JOHANNA , ASSAF-BALUT CARLA , DEL VALLE LAURA , DE LA TORRE NURIA GARCIA , BORDIU ELENA , DURAN ALEJANDRA , FUENTES MANUEL , INES JIMENEZ , CUESTA MARTIN , RUBIO MIGUEL A. , CALLE ALFONSO L.
Published: June 2019

Background: A high adherence (adh.) to a MedDiet pattern was associated with a reduced GDM risk. Studies have shown associations between MTNR1B rs10830963, TCF7L2 rs7903146, MC4R rs17782313 SNPs and GDM risk. The conferring risk could be modified by a MedDiet. This study’s aim was to investigate if the association between the degree of adh. to a MedDiet and GDM incidence is modulated by MTNR1B rs10830963 C>G, TCF7L2 rs7903146 C>T and MC4R rs17782313 T>C polymorphisms.

Methods and Findings: 874 women were stratified into 3 groups defined as high, moderate or low adh. according to late first-trimester (>12 gestational weeks) compliance with 6 food targets: vegetables >12 s/w, fruits >12 s/w, juice <2 s/w, nuts> 3 s/w, consumption of extra virgin olive oil (EVOO) >6 d/w and 40 mL/d EVOO. High adh. was defined as complying with 5-6 targets; moderate 2-4 targets and low 0-1 targets. Patients were genotyped for rs10830963, rs7903146 and rs17782313. Logistic regression analysis was adjusted for ethnicity, age, parity and BMI.

Results: There was a significant association between rs10830963 risk allele G and GDM risk (OR) 1.87(1.29-2.73); and fasting 1.77(0.88-2.66) and 1 h glycaemia 6.27 (1.72-10.83) during 75g OGTT (all p<0.0001). Subjects with rs10830963 G allele who had low adh. had higher fasting glucose (mg/dL) compared to carriers with high adh. (88.24±0.93 vs. 84.59±0.85, p inter< 0.05). For T carriers of rs7903146 and C carriers of rs17782313 the genetic risk for GDM was significantly lower in women with high adh. 0.43 (0.23-0.80) compared to low adh. 0.2 (0.14-0.99), p-inter <0.01. The genetic risk score confirmed a significant gene-MedDiet interaction (p=0,05) for GDM. There was no effect in non-risk genotype carriers for the 3 SNPs.

Conclusions: MTNR1B, TCF7L2, MC4R genes modulate the effect of a DietMed on the development of impaired glucose metabolism and GDM.

Disclosure

A. Barabash: None. J. Valerio Deogracia: None. C. Assaf-Balut: None. L. Del Valle: None. N. Garcia de la Torre: None. E. Bordiu: None. A. Duran: None. M. Fuentes: None. J. Ines: None. M. Cuesta: None. M.A. Rubio: None. A.L. Calle: None.

Funding

Instituto de Salud Carlos III of Spain; Fondo Europeo de Desarrollo Regional; Sociedad de Endocrinolog?a Nutrici?n y Diabetes de la Comunidad de Madrid (IPI/2017/NR2)
1933-P: Acute Hyperglycemia + Hyperinsulinemia Increases Carotid-Femoral Arterial Stiffness and Perfusion of Skeletal Muscle in Healthy Subjects
Authors: HORTON WILLIAM B. , JAHN LINDA , HARTLINE LEE , PATRIE JAMES T. , BARRETT EUGENE
Published: June 2019

Introduction: Chronic hyperglycemia injures both micro-and microvasculature. Conversely, insulin stimulates vascular nitric oxide production and acts as a vasodilator. Whether acute hyperglycemia (AH) inhibits insulin’s vasodilator action in healthy vasculature is unknown. Here we tested whether AH interfered with insulin’s action to recruit microvasculature, enhance endothelial function, or diminish vascular stiffness.

Methods: Nine healthy, fasting subjects (ages 18-35 years; BMI 18-25 kg/m2) twice received a 1 mU/kg/minute 2-hour insulin clamp. On one occasion, subjects were euglycemic (EH); and on the second, were hyperglycemic (∼200 mg/dL) (HH) for 2 hours before and throughout the clamp. Octreotide infusion blocked endogenous insulin in both studies. We assessed endothelial function by flow-mediated dilation (FMD) and arterial stiffness with pulse wave velocity (PWV) and augmentation index (AI). We used contrast-enhanced ultrasound to measure insulin-mediated capillary recruitment in skeletal and cardiac muscle. Linear mixed model was used for statistical analysis, with Bonferroni correction for comparison between studies.

Results: Insulin increased carotid-femoral PWV (p=0.02 for Δ PWV) but decreased AI (p= 0.02) during HH, with AI significantly reduced in HH compared to EH (p=0.04). Insulin recruited microvasculature (p<0.05) with either EH or HH, and microvascular blood volume (p=0.03) and blood flow (p=0.04) significantly increased in skeletal muscle after HH. No changes were observed in FMD or cardiac microvascular perfusion with either condition.

Discussion: This study provides evidence that 4 hours of AH evokes insulin-induced increases of carotid-femoral arterial stiffness in healthy subjects. Insulin’s ability to recruit microvasculature is preserved during AH.

Disclosure

W.B. Horton: None. L. Jahn: None. L. Hartline: None. J.T. Patrie: None. E. Barrett: Research Support; Self; AstraZeneca.

Funding

National Institutes of Health (F32HL142304-01)
194-OR: A Versatile Platform for Intravital Imaging of Biosensor-Labelled Beta Cells In Situ
Authors: REISSAUS CHRISTOPHER A. , TERSEY SARAH A. , DUNN KEN W. , LINNEMANN AMELIA K. , MIRMIRA RAGHAVENDRA
Published: June 2019

The pancreatic islet is a complex system containing numerous cell types, including endocrine, immune, and endothelial. The pathologies of T1D and T2D originate in this organized, multicellular environment in vivo, and thus can only be fully understood in this context. We have developed several adaptable tools to generate a versatile platform combining intravital microscopy (IVM), virally-packaged biosensors, and abdominal imaging windows (AIW) allowing us to gather β cell specific measurements in vivo longitudinally. Here, we present characterization of in vivo physiology of mouse β-cells using two virally-packaged biosensors roGFP2 and GcAMP6s. To achieve in vivo expression of the biosensors, we used IP injected AAV8 to transduce in situ β cells. Using redox-sensitive roGPF2, we measured the response in biosensor signal after IV administration of the cytotoxic glucose analog alloxan from islets in situ (∼5-fold change vs. saline). To test the portability of the platform, we utilized Alox15 knockout mice (Alox15-/-), which show protection against oxidative stress. We observed a rapid 4.6-fold increase in biosensor signal ratio in WT mice, compared to a 3.3-fold increase in Alox15-/- mice after IV alloxan treatment. Using AAV8-GcAMP6s, we measured calcium activity of β-cells in situ after a glucose bolus and detected a small sub-population of β cells that oscillate at a 2x frequency compared to the entire islet. To overcome the endpoint nature of standard IVM, we next implanted AIWs over the pancreas of biosensor-labeled mice, which allows for stable, longitudinal imaging of islets in situ over for several weeks. Using IVM through AIW’s in AAV8-roGFP2 transduced mice, we monitored individual islets, before, during, and after streptozotocin-induced β cell ablation. We measured a ∼75% reduction in islet area by 10 days post ablation. Altogether, this versatile platform can lead to novel experiments examining β-cell physiology and signaling in vivo longitudinally in a variety of unique scenarios.

Disclosure

C.A. Reissaus: None. S.A. Tersey: None. K.W. Dunn: None. A.K. Linnemann: None. R. Mirmira: None.
195-LB: How Does a Prepregnancy Weight Loss Program Affect Gestational Diabetes Risk?
Authors: LEBLANC ERIN S. , SMITH NING , VESCO KIMBERLY , ROSALES ANA G. , STEVENS VICTOR J.
Published: June 2019

Although numerous organizations recommend that women with obesity or overweight lose weight prior to pregnancy, to our knowledge no data have addressed whether interventions that help women lose weight before pregnancy affect gestational diabetes risk in mothers. We successfully randomized 164 pregnant women to receive either a behavioral weight-loss intervention (n = 87) or usual care (n = 77) from prepregnancy through delivery. Intervention participants achieved significantly more weight loss before pregnancy than the usual care group (3.7 kg vs. 0.5 kg; p=<0.001). A diabetologist who was blinded to intervention status used EMR data to determine whether women had a clinical diagnosis of GDM. We compared rates of GDM in the intervention and usual care groups using logistic regression. Higher weight at randomization, previous GDM diagnosis, Hispanic ethnicity, and lower income were associated with higher risk of GDM. After adjusting for these variables, women in the intervention group were less likely to develop GDM (Table), although the difference was not statistically significant. However, based on our sample size of 164, we only had a power of 37% to detect the observed difference of 11% in GDM rates. Future, fully powered studies should test the role of prepregnancy weight loss interventions in preventing gestational diabetes.

Disclosure

E.S. LeBlanc: None. N. Smith: None. K. Vesco: None. A.G. Rosales: None. V.J. Stevens: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK0099882)
1951-P: Prolonged (12-Hour) Glucagon Infusion Leads to Transient Elevation of Plasma Glucose but Sustained Elevation of Hepatic Glucose Production
Authors: CHEN XI , MEROVCI AURORA , CASE EMINA , DEFRONZO RALPH A. , TRIPATHY DEVJIT
Published: June 2019

Recently, novel non-glycemic effects of glucagon have been described. Although short-term glucagon infusion is well known to elevate plasma glucose levels, long-term effect of increased plasma glucagon on glucose and lipid metabolism is unclear. The aim of the present study was to evaluate the effect of 12-hour glucagon infusion on hepatic glucose production and lipid metabolism in healthy NGT individuals. 8 NGT subjects (5M/3F, age=35± 5 years, BMI = 24 ± 1 kg/m2, HbA1c 5.2± 0.1%) received an 2-hour (75gram) OGTT. On a different day subjects received a 12-hour (6PM to 6 AM) glucagon infusion (3ng/kg/minutes) with the measurement of hepatic glucose production (HGP) with 3-3H-glucose on the following morning from 6-10 AM. HGP in glucagon infused subjects was compared to values in 20 age/gender/weight matched NGT subjects studied after an overnight fast from 6-10 AM. Plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations were obtained every 15 minutes during OGTT. Plasma glucagon concentrations increased from 40 ± 4 to 120 ± 34 pg/ml at 6 AM. Plasma glucose increased 2 hours after the start of infusion from 95 ± 6 to 111 ± 6 mg/dl (p<0.005); after 12 hours of glucagon infusion the plasma glucose concentration declined to the mean baseline levels. After 12-hour glucagon infusion (6 AM), plasma insulin and C-peptide were not significantly changed. Basal hepatic glucose production was significantly higher following prolonged (12-hour) glucagon infusion compared to NGT control subjects following 12-hour overnight fast (3.1 ± 0.1 vs. 2.2 ± 0.2 mg/kg/minutes, p<0.05). Plasma FFA concentrations did not change following 12-hour glucagon infusion (0.629±0.1 vs. 0.670±0.2mml/l, p=ns). Thus 12-hour glucagon infusion led to higher basal rate of HGP, but unchanged plasma FFA levels. These results demonstrate that prolonged physiologic hyperglucagonemia results in a transient elevation of plasma glucose concentration but sustained increase in hepatic glucose production.

Disclosure

X. Chen: None. A. Merovci: None. E. Case: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D. Tripathy: None.
1956-P: Increased Salt Intake Amplifies the Postprandial Glucagon-Like Peptide-1 Secretion
Authors: ASMAR ALI , CRAMON PER K. , SORENSEN CHARLOTTE MEHLIN , MADSBAD STEN , MORO CEDRIC , HARTMANN BOLETTE , HOLST JENS J. , JENSEN BOYE L. , ASMAR MEENA
Published: June 2019

We have previously demonstrated that physiologically relevant changes in circulating glucagon-like peptide-1 (GLP-1) elicit a rapid increase in renal sodium excretion during intravenous sodium loading. The present study was designed to investigate the hypothesis that postprandial GLP-1 secretion is sensitive to dietary salt intake and is part of a feedforward natriuretic system. Under fixed sodium intake, 11 lean healthy males were examined twice in random order. Arterial blood samples were collected in 10-20 min intervals for 140 minutes after 75-g oral glucose load vs. 75-g oral glucose + 6-g oral salt load. Subjects remained supine during the experiments. Prior to each experiment, all subjects conducted a 4-day standardized diet with fixed salt intake and 24-h urine collections were completed successfully with urinary sodium excretions being similar between subjects (116±10 mmol). Arterial GLP-1 levels increased transiently in both studies and were higher around 80 min after the glucose+salt load compared to glucose alone (46 ± 4 pmol/L vs. 33 ± 3 pmol/L, p=0.011). The postprandial increase in arterial CCK levels was reduced by the glucose+salt load throughout the study (1.9 ± 0.1 pmol/L vs. 2.8 ± 0.2 pmol/L, p<0.001), whereas arterial GIP and gastrin levels increased transiently and similarly in both studies. The transient increase in arterial glucose, insulin and c-peptide levels were similar on both study days. Arterial renin and aldosterone levels did not change within subjects and between study days, whereas angiotensin II was significantly reduced around 80 min after the glucose+salt load (10.9 ± 1.5 pg/mL vs. 14.4 ± 1.5 pg/mL, p=0.004). Arterial proANP, ANP, and BNP levels remained unchanged on both days. This study demonstrates that an increased salt intake amplifies the postprandial GLP-1 secretion in healthy individuals, supporting a possible GLP-1-mediated feedforward natriuretic system, likely via a suppression of angiotensin II.

Disclosure

A. Asmar: None. P.K. Cramon: None. C.M. Sorensen: None. S. Madsbad: None. C. Moro: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. B.L. Jensen: None. M. Asmar: None.
1965-P: Glucagon Receptor Agonism Stimulates Body Weight Loss in Antibiotic Treatment in Obese Mice
Authors: KIM TEAYOUN , ANTIPENKO JESSICA P. , NASON SHELLY , PRESEDO NATALIE , VAN DER POL WILLIAM J. , FINAN BRIAN , DIMARCHI RICHARD , MORROW CASEY D. , HABEGGER KIRK M.
Published: June 2019

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss in diet-induced obese (DIO) mice. Glucagon’s role as a primary counterregulatory hormone to insulin action has long received scientific attention, yet its broader therapeutic potential is an evolving research interest. We reported that chronic glucagon receptor (GCGR) activation increased energy expenditure and plasma bile acids (BA) in an farnesoid X receptor (FXR) dependent manner. Glucagon stimulates the conversion of cholesterol to BAs, with an increase in cholic and chenodeoxycholate species, critical regulators of FXR activity. Gut microbiota are known to alter the chemical structure of bile acids to produce secondary and tertiary BA. Thus, in these studies we tested the hypothesis that GCGR agonism regulates the gut microbiome to alter circulating BAs and stimulate FXR. GCGR agonism stimulated a profound change in the gut microbiome of DIO mice. These changes were largely associated with an increase in Actinobacteria and a decrease in Deferribacteria phylums. Assessment of functional microbiome composition via PICRUSt uncovered significant impacts on 130 out of 160 total KEGG pathways, including those involved in BA synthesis. To investigate the role of the gut microbiome on GCGR-stimulated weight loss we treated DIO mice with an antibiotic (AB) cocktail (ampicillin, vancomycin, metronidazole, neomycin, and amphotericin B) or vehicle. Mice were then treated with the GCGR agonist, IUB288, or vehicle for 14d to stimulate weight-loss. Surprisingly, AB-treated mice lost a similar amount of body-weight when treated with IUB288, suggesting that the gut microbiome may be dispensable for the weight loss effect. However, post hoc analysis of the cecal microbiome identified only a partial ablation of microbiota in AB-treated mice, with unexpected increases in Proteobacteria and Tenericutes. Thus, it is possible that GCGR-agonism acts via one of the resistant microbes to regulate weight loss.

Disclosure

T. Kim: None. J.P. Antipenko: None. S. Nason: None. N. Presedo: None. W.J. Van Der Pol: None. B. Finan: Employee; Self; Novo Nordisk A/S. R. DiMarchi: Employee; Self; Novo Nordisk Inc. C.D. Morrow: None. K.M. Habegger: Consultant; Self; Glyscend, Inc., Novo Nordisk Inc. Research Support; Self; Glyscend, Inc. Stock/Shareholder; Self; Glyscend, Inc.

Funding

National Institutes of Health