bluuebunny/crossref_metadata_2025_split huggingface dataset:
187-LB: Glucose Response Curve (GRC) Shapes in Mixed Meal Tolerance Tests (MMTTs) and Prediction of Response to Intervention in the TrialNet New-Onset Clinical Trials
Authors: NAJI ALMUTLAQ NOURAH , CLEVES MARIO A. , GITELMAN STEPHEN E. , DIMEGLIO LINDA , SOSENKO JAY M. , ISMAIL HEBA M. 
Published: June 2019

It is known that individuals with a biphasic (BiP; two peaks) GRC during 2-hr oral glucose tolerance tests are at lower type 1 diabetes (T1D) risk than those with monophasic (MoP; one peak) and monotonic (MoT; continuous rise) GRCs. We hypothesized that GRC shapes during MMTTs in persons with newly-diagnosed T1D can predict response to intervention and that the shape may change in response to therapy. We performed an analysis to 1) Determine if the baseline GRC shape can predict response to intervention, and 2) Evaluate GRC changes in responders (R) vs. non-responders (NR) to interventions; response=AUC C-peptide (C-P) at 12 months not &lt;5% of AUC C-P at baseline. Those with complete MMTT data at baseline (within 3 months of diagnosis) and at 12 months from all TrialNet intervention trials were included in the analyses (n=389, median (IQR) age 14.6 (8.1) years, BMI-z 0.6 (1.4), 56% male). At baseline, R had higher BiP GRCs [NR: 9.4% (25/227) vs. R: 20.6% (13/63); adjusted OR 2.92 (1.36-6.27); p=0.006)]. The overall shape distribution was significantly different between R and NR at 12 months (p=0.036) with a notable higher frequency of MoT GRCs in NR [NR: 30.1% (68/226) vs. R: 15.5% (9/58), p=0.031]. There were no differences between R and NR in the odds of changing from one GRC to another (p&gt;0.05 for all).
In conclusion, the finding that a BiP GRC at baseline was more common in R than NR suggests that MMTT GRCs can be used to predict responses to interventions in those newly diagnosed with T1D. Further, the higher proportion of MoT GRCs in NR at 12 months suggests that MMTTs with MoT GRCs are indicative of metabolic decline.

Disclosure
N.N. Almutlaq: None. M.A. Cleves: None. S.E. Gitelman: Advisory Panel; Self; Avortes, Intermountain Therapeutics, Lilly Diabetes, Tolerion, Inc. Research Support; Self; Caladrius Biosciences, Inc., Janssen Research & Development. Other Relationship; Self; Novo Nordisk Inc. L. DiMeglio: Research Support; Self; Amgen Inc., Caladrius Biosciences, Inc., Janssen Research & Development, Medtronic, Sanofi. Other Relationship; Self; Dexcom, Inc. J.M. Sosenko: None. H.M. Ismail: None.

Funding
National Institutes of Health
1873-P: NAFLD and Insulin Resistance Is Associated with a Specific Signature in Membrane Phospholipid Metabolites in Adolescents with Polycystic Ovary Syndrome (PCOS)
Authors: CARREAU ANNE-MARIE , REYES YESENIA GARCIA , NEWCOMER BRADLEY , BEFROY DOUGLAS E. , BROWN MARK S. , CREE-GREEN MELANIE 
Published: June 2019

Obese adolescents with PCOS are at high risk of nonalcoholic Fatty Liver Disease (NAFLD) which contributes to the risk of diabetes. Impaired hepatic energy metabolism is associated with diabetes and characterized by decreased inorganic phosphates (Pi) and ATP hepatic content. Membrane phospholipids measured by magnetic resonance spectroscopy (MRS) may reflect endoplasmic reticulum (ER) stress (phosphodiesters; PDE) or turnover/composition of membrane phospholipids: precursors (phosphomonoesters (PME): phosphoethanolamine (PE) and phosphocholine (PC)) and degradation products (PDE). It is not known if adolescents with PCOS and NAFLD have impaired hepatic energy metabolism or MRS signature associated with insulin sensitivity (Si). Obese adolescents with PCOS (n=25) underwent fasted hepatic 31phosphorus-MRS to measure ATP, Pi, PME and PDE relative to total phosphates (TP). Liver stiffness was measured with MR elastography and hepatic fat fraction (HFF) by MRI-proton density, with an HFF &gt;5.5% classified as NAFLD. A 6h oral sugar tolerance test (OSTT, 25g fructose+75g glucose) was performed. Insulin sensitivity (Si) was calculated with the oral minimal model. 12 girls (BMI 36.4 ±7.3 kg/m2, age 16 (15-17)) had NAFLD and 13 did not (BMI 34.0±4.9 kg/m2, age 16 (14-17)). PME/TP were lower in girls with NAFLD (p=0.007) as well as the ratio of PME/PDE (p=0.002). A lower PE/TP was associated with higher liver stiffness (r= -0.55; p=0.009) and lower Si (r=0.57; p= 0.03). Total ATP/TP, y-ATP/TP and Pi/TP were similar between groups (p&gt;0.15). Obese adolescents with PCOS and NAFLD have a distinct signature in hepatic 31P-MRS that is associated with Si suggesting alterations in membrane phospholipids. However, changes in energetics seen in adults with NAFLD are not present. Further work is needed to understand how these changes in hepatic phospholipids relates to insulin sensitivity and risk for diabetes.

Disclosure
A. Carreau: Advisory Panel; Self; Pfizer Inc. Y. Garcia Reyes: None. B. Newcomer: None. D.E. Befroy: None. M.S. Brown: None. M. Cree-Green: None.

Funding
National Institutes of Health (K23DK107871); Doris Duke Charitable Foundation; National Center for Advancing Translational Sciences (UL1TR002535); Diabetes Canada
1895-P: The Role of Endocannabinoid Receptor 1 (CB1R) in the Insulin Signaling Pathway
Authors: KIM YOO , EGAN JOSEPHINE M. 
Published: June 2019

Cannabinoid 1 receptors (CB1Rs) are G protein-coupled receptors that are present in peripheral organs such as liver, pancreas, adipose tissue and skeletal muscle where they are involved in fine-tuning many metabolic functions. It was previously reported that liver-specific genetic deletion of CB1R (hCNR1-/-) mice fed high fat diets (HFD) had similar body weight to HFD-fed hCNR1+/+ mice, but they retained insulin sensitivity comparable to normal chow-fed (NCD) hCNR1+/+ mice. Therefore, this study was undertaken to uncover how hCB1Rs impact the insulin signaling pathway. Male hCNR1-/- and hCNR1+/+ mice were fed with a high fat high sugar diet (HFSD: N = 8-12) for 15 weeks. In contrast with the previous study of HFD only, HFSD-fed hCNR1-/- mice had less body weight gain than HFSD-fed hCNR1+/+ mice (25.1±2.7 vs. 19.8±1.7g), less fat accumulation in the liver, 1.3-fold increase in glucose disposal and 1.7-fold increase in insulin sensitivity compared to HFSD-fed hCNR1+/+ mice. Further study demonstrated that the lack of hepatic CB1R resulted in upregulated phosphorylation in liver of protein kinase B (AKT), causing activation of downstream target molecules, such as proline-rich AKT substrate 40 (PRAS40) in the mammalian target of rapamycin complex 1 (mTORC1). Similarly, primary hepatocytes isolated from hCNR1-/- mice had increased amounts of phosphorylated AKT and PRAS40 in comparison to hepatocytes from hCNR1+/+ mice. The co-immunoprecipitation studies clearly revealed hepatic CB1R modulates insulin signaling by the association or dissociation of the components of mTORC1. In support of these data, the deficiency of hepatic CB1R leads to upregulation of phosphoinositide 3-kinase (PI3K) class IB, p110γ, resulting in increased association between p110γ and G-protein beta. These findings indicate that genetic deletion of hepatic CB1R contributes to improved glucose homeostasis. Therefore, modulation of CB1R activity in liver may be a useful therapeutic in obese and diabetic individuals.

Disclosure
Y. Kim: None. J.M. Egan: None.
190-LB: Dipeptidyl Peptidase-IV Promotes the Developmental Programming of Chronic Inflammatory Diseases due to Perinatal Exposure to Maternal Obesity
Authors: RAMIL MONTANIEL KIM , BUCHER MATTHEW S. , MALOYAN ALINA 
Published: June 2019

Perinatal exposure to maternal obesity promotes the development of chronic diseases such as cardiovascular (CVD) and metabolic diseases (T2DM) through a process known as developmental programming. The mechanisms of developmental programming are unclear. Dipeptidyl peptidase IV (DPP-4) is a pathogenic aminopeptidase that is upregulated in individuals with chronic diseases and its inhibitors are protective against T2DM and heart failure. DPP-4 can function as a membrane-anchored protein or as a soluble enzyme and can promote metainflammation and increased food intake. We found that DPP-4 enzymatic activity is upregulated over two-fold (P&lt;0.05) in the cord blood of male offspring of women with obesity. Hence, we hypothesized that perinatal exposure to maternal obesity promotes the pathogenesis of cardiometabolic diseases through the activation of DPP-4. To test this hypothesis, we used a mouse model of maternal western style diet (WSD) feeding and found that offspring of WSD (Off-WSD) vs. regular diet (Off-RD) -fed mice have upregulated DPP-4 activity in plasma (two-fold, P&lt;0.05) and PBMC (three-fold, P&lt;0.05). This is concurrent with significantly impaired glucose tolerance, decreased insulin sensitivity, increased adiposity and hepatosteatosis. Systemic inhibition of DPP-4 with Sitagliptin alleviated these pathologies. Immune cells are a major source of plasma DPP-4 and we found that an allogeneic bone marrow transplantation (BMT) of Off-WSD bone marrow to lethally irradiated mice led to a significant increase in DPP-4 activity in plasma and PBMC compared to BMT with Off-RD bone marrow. This is concurrent with significantly increased adiposity, impaired glucose tolerance and decreased insulin sensitivity.
In summary, our findings suggest a pathogenic role of DPP-4, and specifically, immune-derived DPP-4, in the developmental programming of chronic inflammatory diseases due to perinatal exposure to maternal obesity.

Disclosure
K. Montaniel: None. M.S. Bucher: None. A. Maloyan: None.

Funding
National Institutes of Health; Oregon Health & Science University
1912-P: Portal Vein Metabolomic Profiling Highlights One-Carbon Metabolism as a Key Pathway Affected by Roux-en-Y Gastric Bypass Surgery
Authors: STEFATER MARGARET A. , AVILA JULIAN , CLISH CLARY B. , STYLOPOULOS NICHOLAS 
Published: June 2019

After Roux-en-Y gastric bypass (RYGB) surgery, the intestine undergoes structural and metabolic reprogramming and appears to enhance utilization of energetic fuels including glucose and amino acids (AAs), changes that may be related to the surgery’s remarkable metabolic effects. Consistently, RYGB alters serum levels of AAs and other metabolites, changes hypothesized to underlie these benefits. To home in on the intestinal contribution, we performed metabolomic profiling in portal vein (PV) blood from lean, Long Evans rats after RYGB versus sham surgery. After RYGB, systemic blood (SB) metabolomic fingerprinting reflected changes in AA metabolism including serine/glycine/threonine metabolism, an important mechanism of one-carbon donation for folate metabolism. Principal component analysis (PCA) confirmed, among the metabolites most influential to the post-RYGB SB metabolome (PC1, P=0.0008), enrichment for these pathways as well as for sphingolipid and glycerophospholipid metabolism. PV profiling largely mirrored that of SB; using PCA to identify the PV metabolites most affected after RYGB (PC2, P=0.016), we found one-carbon metabolism (OCM) to be enriched. Among those metabolites significantly altered in PV versus SB, 15 were uniquely affected in sham-operated animals and 33 in RYGB-operated animals. Pathway analysis of the latter revealed overrepresentation of nitrogen, serine/glycine/threonine, and sphingolipid metabolism as well as ubiquinone biosynthesis. Together, our data provide novel insight into RYGB’s effects on the gut-liver axis and highlight a role for OCM as a key metabolic pathway affected by RYGB. OCM links cellular nutrient status to homeostatic mechanisms including purine biosynthesis, AA homeostasis, and epigenetic maintenance, and we hypothesize that in the intestine and liver, it might serve as a key fuel sensing pathway to mediate local changes in glucose metabolism, perhaps via epigenetic reprogramming.

Disclosure
M.A. Stefater: None. J. Avila: None. C.B. Clish: None. N. Stylopoulos: None.

Funding
National Institutes of Health
1913-P: Differences in Glucose Absorption in African American (AA) Patients Presenting with DKA and Severe Hyperglycemia (SH)
Authors: STEFANOVSKI DARKO , UMPIERREZ GUILLERMO E. , BOSTON RAYMOND C. , VELLANKI PRIYATHAMA 
Published: June 2019

Approximately 70% of obese AA patients with new-onset diabetes presenting with DKA and SH have near-normoglycemia remission with intensive insulin treatment. In addition to improvements in insulin secretion and/or sensitivity as potential mechanisms of remission, we hypothesize that gut glucose absorption may be associated with remission. To estimate gut glucose absorption, we developed a novel mathematical model that simultaneously estimates SI and gut glucose half-life (GIGt1/2, inversely related to glucose absorption). This study aimed to compare insulin sensitivity estimates of the novel model to estimates from Dalla Man’s OGTT model and also assess GIGt1/2.
We included 42 AA patients who presented with new-onset DKA (n= 17) and SH (n=25). All subjects had a 75-gm 2-hour OGTT 1 week after insulin remission (REM) or at 3 months after continuous insulin therapy (no-REM). We estimated insulin sensitivity using our novel first-order absorption OGTT model (SInew) and GIGt1/2 and Dalla Man’s OGTT model (SI).
SInew was highly concordant with SI (R=0.61, P&lt;0.001; Concordance=0.90). When separating subjects by DKA status, there were significant differences in the frequency of remission status (χ2=5.00, P=0.03). Subjects with DKA+REM (98±19 min) had a significantly longer GIGt1/2 compared to those with SH+no-REM (47±9 min, P=0.02). GIGt1/2 between DKA+no-REM (108±46 min) and SH+no-REM was also significantly different (P=0.045). SH+REM showed a statistical trend to be different from SH+no-REM (P=0.07). There were no significant differences identified between DKA+REM, DKA+no-REM and SH+REM.
The SInew from our novel OGTT model is highly concordant with SI from Dalla Man’s OGTT model. Our model additionally estimates GIGt1/2 and indicates slower gut glucose absorption is associated with remission. This new model shows that obese African American patients presenting with new-onset DKA or SH may benefit from interventions that target gut glucose absorption.

Disclosure
D. Stefanovski: None. G.E. Umpierrez: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc., Sanofi US. R.C. Boston: None. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. Research Support; Self; National Institutes of Health.

Funding
National Institutes of Health (K12HD085850 to P.V.)
1928-P: GDF15 Protects against Insulin Resistance in Individuals with Type 2 Diabetes
Authors: ZHANG HUI , DANTAS WAGNER , KING WILLIAM T. , AXELROD CHRISTOPHER L. , GIL SAULO , MURAI IGOR , ROSCHEL HAMILTON , GUALANO BRUNO , KIRWAN JOHN P. 
Published: June 2019

Reduced insulin sensitivity is the putative defect in the onset of type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) can restore euglycemia and improve insulin sensitivity in individuals with T2D. However, the mechanisms contributing to surgical remission of T2D are not fully understood. Growth Differentiating Factor 15 (GDF15) is a circulating stress-responsive cytokine with appetite suppressive properties and therapeutic potential for treating obesity and T2D. However, the effect of GDF15 on insulin sensitivity is not known. The purpose of this investigation was to assess the role of GDF15 in insulin sensitivity in type 2 diabetic populations and to evaluate the effect of exogenous GDF15 treatment in obese diabetic mice. Twelve human volunteers with T2D (age: 40±2, BMI: 46.2±1.7) underwent RYGB surgery. Glucose tolerance and fasting plasma GDF15 levels were assessed prior to and 3-month post-surgery. Additionally, 8-week-old db/db mice were injected every other day for 4 weeks with saline or rhGDF15. After 4 weeks of treatment, body composition, insulin tolerance, and blood metabolites were assessed. Plasma GDF15 significantly increased after RYGB (PRE: 581.6±93.0 POST: 910.1±137.4 pg/ml, P&lt;0.001). Change in GDF15 in humans with T2D correlated with improvements in insulin sensitivity based on the Matsuda index (R=0.6, P=0.05). Supporting our human data, 4 weeks of GDF15 treatment in db/db mice increased insulin sensitivity (P&lt;0.05) while body weight (P&lt;0.01), fasting blood glucose (P&lt;0.05) and plasma insulin (P&lt;0.05) were reduced.
In conclusion, GDF15 is associated with improved insulin sensitivity in humans with T2D, and increases insulin sensitivity in db/db mice. These data support a role for GDF15 as a therapeutic target for type 2 diabetes.

Disclosure
H. Zhang: None. W. Dantas: None. W.T. King: None. C.L. Axelrod: None. S. Gil: None. I. Murai: None. H. Roschel: None. B. Gualano: None. J.P. Kirwan: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; Louisiana Clinical & Translational Science Center
1940-P: Disruption of the Exocyst Trafficking Complex Results in Impaired Glucose Uptake in Skeletal Muscle
Authors: FUJIMOTO BRENT , CARTER LAMAR T. , WONG ADRIAN M. , PITTS MATTHEW W. , VILLIGER ROSS K. , YOUNG MADISON , FOGELGREN BEN , POLGAR NOEMI 
Published: June 2019

Objectives: Skeletal muscle cells are responsible for 80-90% of the insulin-induced glucose uptake in the body. Insulin signaling in skeletal muscle results in the targeted trafficking of glucose transporter type 4 (GLUT4) onto the cell membrane, enabling glucose uptake. Insulin resistant cells show defects in insulin-induced GLUT4 exocytosis. The eight-protein exocyst complex has an essential role in the insulin-induced exocytosis of GLUT4 vesicles in cultured adipocytes but it is not known if the exocyst-mediated molecular mechanism is conserved in other, insulin-responsive tissues, such as the skeletal muscle. We hypothesized that the exocyst complex is essential for the insulin-induced exocytosis of GLUT4-containing vesicles in skeletal muscle as well and that the exocyst is a master regulator of glucose homeostasis in insulin-responsive tissues.
Methods/Results: We have generated a tamoxifen-inducible skeletal muscle-specific knockout mouse strain of exocyst central subunit Exoc5 (Exoc5-SMKO) to assess the exocyst’s role in glucose homeostasis in vivo. Exoc5 knockout does not affect grip strength, motor coordination or locomotor activity levels in these animals. Both male and female Exoc5-SMKO mice present with elevated fasting glucose levels, as compared to control littermates. Glucose tolerance testing revealed an impaired glucose clearance in Exoc5-SMKO mice, while insulin tolerance, fasting insulin levels, and A1C levels were similar between knockouts and controls.
Conclusion: Our findings suggest that Exoc5 and the exocyst are necessary for insulin-stimulated glucose uptake in skeletal muscle. Ongoing work will further investigate the molecular mechanism of exocyst-mediated GLUT4 trafficking in skeletal muscle.

Disclosure
B. Fujimoto: None. L.T. Carter: None. A.M. Wong: None. M.W. Pitts: None. R.K. Villiger: None. M. Young: None. B. Fogelgren: None. N. Polgar: None.

Funding
National Institute of General Medical Sciences (5P20GM113134)
1946-P: Insulin-Like Growth Factor-1 Protects against the Detrimental Effects of Advanced Glycation End Products and High Glucose in Myoblastic C2C12 Cells
Authors: KANAZAWA IPPEI , ADACHI NAOKO , TANAKA KEN-ICHIRO , TAKENO AYUMU , NOTSU MASAKAZU , TANAKA SAYURI , SUGIMOTO TOSHITSUGU 
Published: June 2019

Previous studies have shown that diabetes mellitus increases the risk of sarcopenia. We previously reported that higher serum advanced glycation end product (AGE) and lower serum insulin-like growth factor-I (IGF-I) were independently associated with muscle mass reduction in patients with type 2 diabetes. The present study examined effects of AGEs and IGF-I on myogenic differentiation and apoptosis in C2C12 cells. Real-time PCR and western blot analyses showed that AGE3 significantly decreased the mRNA and protein expressions of MyoD and Myogenin, whereas IGF-I significantly increased them and reversed the effects of AGE3. AGE3 significantly decreased endogenous IGF-I expression and suppressed IGF-I-induced Akt activation. High glucose (22 mM), but not AGE3, significantly increased expression of receptor for AGEs (RAGE), while IGF-I significantly decreased it. Moreover, DNA fragment ELISA showed that AGE2 and AGE3 significantly increased apoptosis of C2C12 cells, whereas IGF-I significantly suppressed the AGE2- and AGE3-induced apoptosis. To investigate whether high glucose enhances the AGE3’ effects, the effects of co-treatment with high glucose and AGE3 were examined. Although high glucose alone did not affect the apoptosis of C2C12 cells, it enhanced AGE3-induced apoptosis. IGF-I significantly reversed the effects of co-incubation of high glucose and AGEs on the expression of MyoD and Myogenin as well as the apoptosis. These findings indicate that AGE3 inhibits myogenic differentiation and increases apoptosis in C2C12 cells, and that high glucose increases RAGE and enhances the AGE3-induced apoptosis, suggesting that AGEs and high glucose might contribute to the reduction of muscle mass and function. Moreover, IGF-I reversed the detrimental effects of AGEs and high glucose in myoblastic cells; thus, IGF-I-Akt signal could be a therapeutic target of DM-induced sarcopenia.

Disclosure
I. Kanazawa: None. N. Adachi: None. K. Tanaka: None. A. Takeno: None. M. Notsu: None. S. Tanaka: None. T. Sugimoto: None.
1947-P: Comparative Effects of PCSK9 Inhibitor and High-Dose Atorvastatin on Mitochondria of Red Muscle Fibers in Obese Female Rats
Authors: THONUSIN CHANISA , PALEE SIRIPONG , ARUNSAK BUSARIN , AMPUT PATCHAREEYA , PRATCHAYASAKUL WASANA , CHATTIPAKORN NIPON , CHATTIPAKORN SIRIPORN C. 
Published: June 2019

Obesity and dyslipidemia cause mitochondrial dysfunction of skeletal muscle. Low dose atorvastatin impairs mitochondrial function of white muscle fibers but does not damage that of red muscle fibers. However, the effects of PCSK9 inhibitors and high dose atorvastatin on mitochondrial function of red muscle fibers have not been identified. Twenty-four female rats (180-200 g) were divided into 2 groups. Six rats were fed with normal diet (ND) and 18 rats were fed with high-fat diet (HFD) for 15 weeks. At week 12, ND-fed rats were treated with vehicle (NDV), while HFD-fed rats were equally subdivided and treated with either vehicle (HFV), 4 mg/kg/day of PCSK9 inhibitor (HFP), or 40 mg/kg/day of atorvastatin (HFA) for another 3 weeks. HFV rats developed obesity and dyslipidemia, as indicated by increased weight, visceral fat, and total cholesterol. Treatment with atorvastatin and PCSK9 inhibitor improved obesity and dyslipidemia. Increased lipid peroxidation (MDA), mitochondrial fission (pDrp1/Drp1), mitochondrial ROS production, and mitochondrial membrane depolarization were found in soleus muscle of HFV rats. Treatment with atorvastatin and PCSK9 inhibitor similarly improved lipid peroxidation and mitochondrial fission. However, only PCSK9 inhibitor improved mitochondrial ROS production and mitochondrial membrane depolarization. Our findings suggest that obesity increases lipid peroxidation, mitochondrial fission, mitochondrial ROS production, and mitochondrial membrane depolarization in red muscle fibers. PCSK9 inhibitor attenuates those deleterious effects of obesity. High dose atorvastatin improves lipid peroxidation and mitochondrial fission, but does not attenuate obesity-induced mitochondrial ROS production and mitochondrial membrane depolarization in red muscle fibers. The results imply that high dose atorvastatin causes adverse effects on red muscle fibers despite its benefit on the improvement of obesity and dyslipidemia.

Disclosure
C. Thonusin: None. S. Palee: None. B. Arunsak: None. P. Amput: None. W. Pratchayasakul: None. N. Chattipakorn: None. S.C. Chattipakorn: None.

Funding
Thailand Research Fund