bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of High-Glucose Concentration on the E3 Ubiquitin Ligase Activity of Mdm2
Authors: GERONIMO RAUL BARZALOBRE
Published: June 2018

The degradation of p53 occurs via ubiquitin-26S proteosome, after Mdm2 (murine double minute 2) marks p53 with ubiquitins. The concentration and phosphorylation of Mdm2 and p53, greatly affect the ubiquitination rate of p53, by avoiding the recognition and physical interaction between p53 and Mdm2. Phosphorylation of Mdm2 in Ser395 by ATM decreases its ability to direct the degradation of p53. Therefore, we aim to study the effects of high glucose concentrations on the RING domain of Mdm2 and its ubiquitin E3 ligase activity.

We cultured RINm5F cells in RPMI-1640 medium supplemented with 10% fetal bovine serum (v / v) at two concentrations of glucose 5 and 30 mM for up to 72 h, in a humid atmosphere at 37 ° C and 5% CO2. At the end of the treatment the cells were lysed to separate the nuclear and cytosolic fraction. After quantifying the proteins, they were visualized on SDS-PAGE and transferred to a PVDF membrane. Primary antibodies against Mdm2, Mdm2 p-Ser395, ATM, Arf, c-Abl, and ubiquitin were used and revealed using an amplified fluorescence kit from GE.

The results show that the stress caused by high concentrations of glucose stimulates the phosphorylation of Mdm2 in Ser 395 by ATM activation. The phosphorylation of Ser395 alters the RING domain of Mdm2 and decreases its ubiquitin E3 ligase activity, ubiquitination and degradation of p53. Therefore, stress due to increased glucose decreases the ubiquitin E3 ligase activity of Mdm2 by inducing the phosphorylation of this residue, which leads to the stabilization and increase of p53 and the subsequent activation of apoptotic events.

The Ser 395 residue of the RING domain is important for the efficient function of ubiquitin ligase of Mdm2 in β cells under conditions of hyperglycemia.

Disclosure

R. Barzalobre Geronimo: None.
Fetuin A—A Major Player in Lipid-Induced Islet Dysfunction and ß-Cell Apoptosis
Authors: KUNDU RAKESH , MUKHUTY ALPANA
Published: June 2018

Fetuin-A is a glycoprotein that is secreted from both liver and adipose tissue. Circulating Fetuin-A (FetA) is elevated in type 2 diabetes and causes impaired insulin sensitivity. Few recent findings suggested that FetA is responsible for palmitate induced inflammatory injury to the β-cell via TLR4 pathway. Yet it is unknown whether FetA is associated with β-cell death and reduction of functional islet mass that causes dearth of circulatory insulin in chronic hyperlipidemic condition. To validate this hypothesis MIN6 cells (mice insulinoma cells) were treated with various concentrations of palmitate and /or FetA for 48h and subjected to MTT assay and flowcytometry analysis. The results depicted higher mortality of cells (30-40%) with increasing dose of palmitate (0.25-0.75 mM) and/ or FetA (5-20 mM). Palmitate-FetA treated cells demonstrated substantial reduction in the cell proliferative markers (Akt, cyclin D1) while higher expression of apoptotic markers (Bax, caspase 3 and PARP). Silencing of NF-kB or TLR4 in MIN6 cells restore cell viability on palmitate-FetA treatment indicating significance of TLR4-NF-kB axis in β-cell mortality. Our recent findings demonstrated FetA secretion from MIN6 cells on stimulation of palmitate. Silencing of fetA in MIN6 cells, reduced cell mortality with improved GSIS (1.5 fold). Treatment of MIN6 cells or mice islets with cytokines, such as IL-1β and TNF-α, results β-cell apoptosis mimicking the inflamed conditions of the islets. Co-culture experiments of MIN6 cells with adipocytes or macrophages in presence of palmitate showed elevated levels of cytokines (IL-1β, IL6, TNF-α) in the media and significant number of apoptotic MIN6 cells (20-30%). In vivo analysis of islets structure and function in high fat diet (HFD) fed mice model for a period of 20 weeks demonstrated atrophied islets and accumulation of macrophages. Our present investigation therefore indicated FetA to be a major player in lipid induced pancreatic-β cell death and dysfunction in type 2 diabetes.

Disclosure

R. Kundu: None. A. Mukhuty: None.
The Effects of Antidiabetic Drugs on Cerebral Metabolism in Mice with Central Insulin Resistance
Authors: CAO YUE , WANG GUIXIA , LI ZHUO
Published: June 2018

Objectives: This study focused on the effects of antidiabetic drugs, alogliptin (Nesina), exenatide (Byetta) and pioglitazone (Actos), on astrocyte-neuron metabolic cooperation in mice with central insulin resistance. That may provide theoretical basis for clinical treatment of diabetes related cognitive dysfunction.

Methods: Male C57BL/6J mice were randomly divided into control group (Ctrl), high-fat group (HF), alogliptin (ALO) group, exenatide (EXE) group and pioglitazone (PIO) group. Ctrl group was served normal diet, and then the others were served high-fat diet for 12 weeks. Then ALO group, EXE group and PIO group were respectively treated with alogliptin (25mg/kg/day), exenatide (30ug/kg/day) and pioglitazone (10mg/kg/day) for 4 weeks. The memory was tested using the Morris Water Maze test after 16 weeks. Then mice were killed and the brains were removed to detect insulin signaling and metabolic parameters. All data were presented as mean±SD and P<0.05 was considered statistically different.

Results: 1. Antidiabetic drugs improved insulin signaling, IRS1/PI3K/Akt pathway in hippocampus and cortex. 2. Comparative analysis indicated that the latency in finding the platform significantly decreased, while frequency of crossing platform were increased in ALO group (3.75±1.14), EXE group (3.33±1.07) and PIO group (4.00±1.71) compared to HF group (1.66±1.23) (P<0.05). 3. The results showed that the expression of glucose transporter (GLUT) 1, GLUT3, monocarboxylate transporter (MCT)1, MCT2 and MCT4 in HF group were significantly lower than those in Ctrl group, no matter in hippocampus and cortex. ALO group, EXE group and PIO group obviously reversed metabolic parameters compared to HF group.

Conclusions: We demonstrated that reprogramming metabolic pathways is an elaborate way by which neural cells respond to central insulin resistance. And antidiabetic drugs can reverse metabolic pathways to protect memory.

Disclosure

Y. Cao: None. G. Wang: None. Z. Li: None.
Real-Time In Vivo Imaging of Whole Islet Ca2+ Dynamics Reveals Glucose-Induced Changes in Beta-Cell Connectivity in Mouse and Human Islets
Authors: SALEM VICTORIA , SUBA KINGA , ALONSO ALDARA MARTIN , CHABOSSEAU PAULINE L. , GEORGIADOU ELENI , STYLIANIDES THEODOROS , BRIANT LINFORD , HODSON DAVID , CARRAT GAELLE , LECLERC ISABELLE , GABORIAU DAVID C. , ROTHERY STEPHEN M. , RUTTER GUY A.
Published: June 2018

Imaging of Ca2+ dynamics in the intact islet in vitro has recently been subjected to connectivity analysis informed by similar approaches in neuronal systems. This has revealed the existence of intercellular networks between individual β cells which are increased by high glucose. Here, we sought to investigate if network connectivity also exists in islets in vivo under conditions of near-normal vascularisation and innervation. Donor mouse (C57BL/6J) islets were infected with adenovirus expressing the Ca2+ sensor GCaMP6m and transplanted into the anterior chamber of the eye in syngeneic recipients. Under isofluorane anaesthesia, fully implanted islets were imaged using a spinning disk confocal microscope (Nikon Ti-E, 25 x water dipping 1.0 NA objective, 300ms exposure time, 1 frame per second, 488nm excitation). Mean baseline blood glucose was 19mM and rose to >30mM following an IP bolus of 1.5g/L glucose. Human islets were infected with AV-GCaMP6m, transplanted into a nu/nu mouse recipient and imaged under conditions of normoglycaemia (blood glucose 3.9-4.9 mM followed by hyperglycaemia (blood glucose >30 mM). As circulating blood glucose increased, the proportion of connected cells in mouse islets rose from 65.5% to 88.3% (n=3 islets in 3 different animals, p=0.02) whilst the coefficient of correlation (a measure of the strength of the connectivity) showed a tendency to increase from 0.34 to 0.44 (p=NS). Data from human islets also revealed a tendency towards a rise in connectivity from 58.3% to 63.9% in response to rising circulating glucose. These data demonstrate that functional connectivity of Ca2+ dynamics between β cells is conserved in vivo in both mouse and human islets, with enhanced connectivity patterns observed in response to rising blood glucose levels. This technique, which allows β cell connectivity to be examined prospectively over time, will provide a powerful new approach for assessing its significance in health and disease.

Disclosure

V. Salem: None. K. Suba: None. A. Martin Alonso: None. P.L. Chabosseau: None. E. Georgiadou: None. T. Stylianides: None. L. Briant: None. D. Hodson: None. G. Carrat: None. I. Leclerc: None. D.C. Gaboriau: None. S.M. Rothery: None. G.A. Rutter: Research Support; Self; Servier.
Malate Dehydrogenase 2 (MDH2) as a New Diabetogene Causing Hyperglycemia in Families with Multigenerational Diabetes
Authors: JUNGTRAKOON PRAPAPORN , PEZZILLI SERENA , PEZZILLI ANTONELLA , PANNONE LUCA , FLEX ELISABETTA , BIAGINI TOMMASO , BURANASUPKAJORN PATINUT , LUDOVICO ORNELLA , MERCURI LUANA , HASTINGS TIMOTHY , PAOLA ROSA DI , ALBERICO FEDERICA , MENDONCA CHRISTINE , CERON JULIAN , PORTA DE LA RIVA MONTSERRAT , MARSELLI LORELLA , MAZZA TOMMASO , MARTINELLI SIMONE , TRISCHITTA VINCENZO , DORIA ALESSANDRO , PRUDENTE SABRINA
Published: June 2018

We are pursuing the identification of new diabetogenes by whole exome sequencing in families with multigenerational diabetes that do not carry MODY-gene mutations. Here we report two gain-of- function mutations (c.154 C>T p.Arg52Cys and c.478 G>A p.Val160Met) in the gene coding for Malate Dehydrogenase 2 (MDH2) that we have identified as segregating with hyperglycemia in two such unrelated families. The MDH2 enzyme is localized to the mitochondria where it catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the tricarboxylic acid cycle. MDH2 also plays a pivotal role in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. By molecular dynamic simulation, both the Arg52Cys and Val160Met substitutions were found to severely alter the atomic dynamics of the MDH2 structure. MDH2 enzymatic activity was significantly increased (p<0.01) in HepG2 cells transfected with either MDH2_T154 or MDH2_A478 as compared to WT_MDH2, despite no differences in MDH2 protein expression levels. Increased MDH2 activity is known to decrease NAD/NADH ratio—a biochemical alteration reported to affect both insulin signaling and secretion. In genetically modified C. elegans strains obtained by means of CRISPR/Cas9, the Arg52Cys mutant exhibited a significantly (p<0.05) prolonged lifespan and increased Paraquat resistance and lipid storage when compared to WT strains. These changes resemble those reported for C. elegans with defective insulin signaling—a condition which in humans predisposes to both insulin resistance and inadequate insulin secretion.

In conclusion, our data point to MDH2 as a new diabetogene, heterozygous mutations of which cause hyperglycemia in families presenting with multigenerational diabetes.

Disclosure

P. Jungtrakoon: None. S. Pezzilli: None. A. Marucci: None. L. Pannone: None. E. Flex: None. T. Biagini: None. P. Buranasupkajorn: None. O. Ludovico: None. L. Mercuri: None. T. Hastings: None. R. Di Paola: None. F. Alberico: None. C. Mendonca: None. J. Ceron: None. M. Porta de la Riva: None. L. Marselli: None. T. Mazza: None. S. Martinelli: None. V. Trischitta: None. A. Doria: Research Support; Self; Sanofi-Aventis. S. Prudente: None.
Effects of a High-Carb vs. High-Fat Meal on Glycemia, Insulin, Interleukin-6, TNF-Alpha, and Apo-B
Authors: STEINBERG HELMUT O. , STENTZ FRANKIE B. , SHANKAR NANDITA K.
Published: June 2018

Past studies have shown that food ingestion modulates vascular function within the first two hours of consumption and that food composition such as the amount of carbohydrates vs. fat may play a role. The goal of this study was to assess the effect of a high-carbohydrate (HC) meal vs. a high-fat (HF) meal on potential modulators of vascular function, insulin, interleukin-6 (IL-6), TNF-alfa and Apo-B. We studied a group of healthy volunteers; n=6, age 38 ± 13 years, BMI 24.5 ± 3.8 kg/m2 and systolic blood pressure 125.3 ± 9.1 mmHg. The meals were commercially available; HC meal consisted of 120 gm of carbohydrates (∼60% sugars) and 8 gm fat, and the HF meal consisted of 54 gm of carbohydrates (∼ 15% sugars) and 28 gm of fat and contained slightly (∼20%) less total calories. The meals were ingested within 5 minutes.

Results: Glucose and insulin levels increased in response to either meal but more robustly with HC. Glucose and insulin levels peaked at 30 minutes in response to HC and at 60 minutes in response to HF. IL-6 levels nearly doubled in response to either meal, but the time course appeared different; it peaked at 180 minutes and 60 minutes in response to HC and HF, respectively. TNF-alpha levels remained overall unchanged after either HC and HF meal. Apo-B levels also remained overall unchanged after either HC and HF meal.

Conclusions: Our study shows that food composition differentially affects the magnitude and time course of changes in metabolites, hormones and markers of inflammation. Ingestion of a HF meal resulted in a delayed and lower peak of glucose and insulin and a much earlier peak in IL-6. This early elevation of IL-6 in response to HF may potentially impair vascular function as described in the “big Mac” study. It is unclear if higher insulin levels during this period would be vaso-protective. Further research is needed to better understand the link between food composition and changes in metabolites, hormones and pro/anti-inflammatory mediators and its relation to vascular function.

Disclosure

H.O. Steinberg: None. F.B. Stentz: None. N.K. Shankar: None.
Function of Deubiquitinating Enzyme USP1 in Adipogenesis
Authors: LEE JINAH
Published: June 2018

Obesity and metabolic disorders are one of the most challenging issues to be solved in modern society. Adipogenesis, which is a cellular differentiation process of pre-adipocyte to become a fully differentiated adipocyte, is a key mechanism in increasing fat mass and lipid accumulation. This process is a very complex multistep and involves numerous cascades of transcriptional factor activation. Accordingly, adipogenesis is regarded as a crucial target in treating or preventing obesity. Post-translational modification is a significant process for a protein to acquire its functional diversity in cell signaling by the addition or cleavage of functional groups. Deubiquitination by deubiquitinating enzyme is one of the important post-translational modifications involved in various signaling pathways. In this study, we screened deubiquitinating enzymes with differentiating 3T3-L1 adipocytes and found out that the mRNA and protein expression of ubiquitin specific peptidase 1 (USP1) was gradually increasing during the adipogenesis process. Also, from the various mouse tissue mRNA sample, ubiquitin specific peptidase 1 displayed higher expression levels on adipose tissues compared to other tissues. From these data, we assumed that this enzyme might be an important factor involved in adipogenesis. In the knockdown study, when ubiquitin specific peptidase 1 is absent, all the adipogenic transcription factors (Peroxisome proliferator-activated receptor gamma, Ccaat-enhancer-binding proteins alpha, beta, fatty acid synthase, and fatty acid binding protein 4) were down regulated. Furthermore, according to the proliferation assay result, ubiquitin specific peptidase 1 3T3-L1 cells had lower proliferation rate which indicates significant effect of USP1 during the mitotic clonal expansion. In consequence, our results indicate that ubiquitin specific peptidase 1 plays an important role in adipogenesis process.

Disclosure

J. Lee: None.
Insulin Resistance and Type 2 Diabetes Mellitus Are Associated with Impaired Mitochondrial Function in Human Ventricular Myocardium
Authors: ZWECK ELRIC , SCHEIBER DANIEL , JELENIK TOMAS , HORN PATRICK , ALBERMANN SOPHIE , BOEKEN UDO , SAEED DIYAR , KELM MALTE , RODEN MICHAEL , WESTENFELD RALF , SZENDROEDI JULIA
Published: June 2018

Type 2 Diabetes Mellitus (T2DM) is related to increased cardiac morbidity and mortality. Underlying mechanisms are yet unclear. Recent studies detected mitochondrial abnormalities in atrial tissue acquired during open-heart surgery of T2DM patients suffering from ischemic or valvular heart disease. We hypothesized that mitochondrial capacity and coupling efficiency are reduced in ventricular tissue of humans with T2DM and normal heart function. High resolution respirometry was performed in transcatheter ventricle biopsies of 29 healthy heart transplant recipients with normal left ventricular ejection fraction (64±8%) and no allograft rejection. We assessed oral glucose insulin sensitivity (OGIS) and redox potential (ORP) reflecting systemic oxidative stress. Glucose tolerant humans (CON; n=16) and T2DM (n=13) had comparable age (54±14 vs. 58±12 years; p=0.45), sex (81% vs. 85% male) and time since transplantation (26±24 vs. 25±26 months; p=0.93), while body mass index was higher in T2DM (25.0±2.9 vs. 28.1±4.9 kg/m2; p<0.05). State 3 respiration on octanoyl-carnitine was 20% lower in T2DM (101±25 vs. 81±20 pmol/(s*mg); p<0.05). Lipid-linked respiration related negatively to HbA1C (r=-0.45; p<0.05) and fasting blood glucose levels (r=-0.41; p<0.05), but positively to OGIS (r=0.56; p<0.05). Respiratory control ratios (RCR) on lipids were 21% lower in T2DM compared to CON (1.6±0.4 vs. 1.2±0.3; p<0.05) and correlated negatively with HbA1C (r=-0.44; p<0.05). Substrates of mitochondrial complex I and II induced 22% lower RCR in T2DM (2.7±0.8 vs. 2.1±0.5; p<0.05). ORP was 24% higher in T2DM (127±23 vs. 157±25 mV; p<0.01). Ventricular myocardium of T2DM and insulin resistant humans shows diminished mitochondrial oxidative capacity and coupling efficiency for lipid and glycolytic substrates which is related to hyperglycemia and oxidative stress. This might indicate targets for treatment and prevention of T2DM-related heart failure.

Disclosure

E. Zweck: None. D. Scheiber: None. T. Jelenik: None. P. Horn: None. S. Albermann: None. U. Boeken: None. D. Saeed: None. M. Kelm: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. R. Westenfeld: None. J. Szendroedi: None.
The Novel Adipokine C1QTNF1 Significantly Predicts the Incidence of Future Major Cardiovascular Events in Patients with Type 2 Diabetes
Authors: MUENDLEIN AXEL , LEIHERER ANDREAS , SAELY CHRISTOPH H. , GEIGER KATHRIN , EBNER JANINE , BRANDTNER EVA-MARIA , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , DREXEL HEINZ
Published: June 2018

Increased serum levels of the novel adipokine C1q and tumor necrosis factor related protein 1 (C1QTNF1) have been linked with type 2 diabetes (T2DM) and ischemic heart disease. The impact of circulating C1QTNF1 on the incidence of future major cardiovascular events (MACE) is unclear and is addressed in the present study. We measured C1QTNF1 serum levels in 542 patients undergoing coronary angiography for the evaluation of established or suspected coronary artery disease (CAD) using an enzyme-linked immunosorbent assay. Prospectively, MACE were recorded over a mean follow-up period of 6.3 years. C1QTNF1 serum levels at baseline were significantly increased in patients with T2DM (n=160) compared to those without diabetes (521.4 ± 224.8 vs. 429.5 ± 130.3 ng/ml; p<0.001). Prospectively, the incidence of MACE increased significantly through tertiles of C1QTNF1 (17.8%, 24.7%, and 29.7% in the 1st, 2nd and 3rd tertiles, respectively; ptrend=0.010). Also after adjustment for age, sex, and T2DM as well as after additional adjustment for body mass index, hypertension, LDL cholesterol, HDL cholesterol, triglycerides, and angiographically determined baseline CAD, C1QTNF1 significantly predicted MACE, with adjusted HRs of 1.30 [1.04-1.61]; p=0.019 and 1.36 [1.09-1.70]; p=0.007, respectively. Patients with T2DM were at a significantly higher risk of MACE than those who did not have diabetes (48% vs. 26%; p=0.003). C1QTNF1 in subgroup analyses also in T2DM patients proved to be a strong predictor of MACE (adjusted HR 1.57 [1.10-2.24]; p=0.013). We conclude that high serum levels of C1QTNF1 significantly predict MACE, in particular in patients with T2DM.

Disclosure

A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. K. Geiger: None. J. Ebner: None. E. Brandtner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
Dynamic Changes in the Regulation of Energy Balance after Roux-en-Y Gastric Bypass Are Reflected in Time-Dependent Alterations in Liver Gene Expression
Authors: AGOSTINA SANTORO M. , BRANCALE JOSEPH , GARRISON JILL CARMODY , MACHINENI SRIRAM , LAJOIE SCOTT A. , KAPLAN LEE M.
Published: June 2018

Roux-en-Y gastric bypass (RYGB) leads to long-term weight loss and diabetes remission. Animal studies have shown that RYGB changes the physiology of energy regulation to favor a lower defended fat mass. To explore these effects, we developed a mouse model of enhanced response to dietary change, where RYGB abrogates the rapid obesogenic effects of re-exposure to a high-fat diet (HFD). HFD-induced obese mice that underwent RYGB- or Sham operation were fed chow for 9 weeks and switched back to HFD for 8 weeks. Glucose regulation was improved in RYGB animals independent of diet or body weight. During the first 2 days on HFD, Sham animals gained significant weight (1.8 g, p<0.05) due to a 10.6 kcal increase in energy intake (EI) compared to the chow period (p<0.05). In RYGB mice, weight and EI remained unchanged. By week 8 of HFD, Sham controls were 24% heavier than before surgery (p<0.05), while RYGB mice continued to maintain a lean weight. There was no difference in EI between groups, but RYGB mice exhibited 26% higher energy expenditure than Sham mice (p<0.05). Given the widespread changes in physiology in RYGB animals, we sought to identify differentially expressed (DE) genes in RYGB vs. Sham livers during the dynamic response to HFD. RNA-Seq showed that the number of DE genes after long-term HFD was 5.6 times larger than after 2 days (1,409 vs. 251, respectively), reflecting adaptation to a new metabolic state in Sham mice after chronic HFD. Differential expression of inflammatory, lipogenic, and cell cycle genes was substantially altered over time. These data suggest that the means by which RYGB modulates energy balance to resist the obesogenic effects of HFD is time-dependent. Further assessment of the molecular basis of this dynamic physiological response will provide important insight into the mechanisms most relevant to the therapeutic effects of RYGB and therefore guide development of less invasive therapies for metabolic disease.

Disclosure

M. Santoro: None. J. Brancale: None. J. Carmody Garrison: None. S. Machineni: Consultant; Self; Johnson & Johnson Services, Inc., Rhythm Pharmaceuticals Inc.. Other Relationship; Self; Novo Nordisk Inc.. S.A. Lajoie: None. L.M. Kaplan: None.
Effects of the Diabetes-Induced MicroRNA-155 on Wound Healing and Fibroblast Growth Factor 7 Expression
Authors: DALGAARD LOUISE T. , LEAL ERMELINDO C. , SVENDSEN RIKKE , MOURA JOÃO , SØRENSEN ANJA E. , JØRGENSEN PER T. , CARVALHO EUGENIA
Published: June 2018

Impaired wound healing is a serious late-diabetic complication resulting in significant morbidity. MicroRNAs (miRNAs), post-transcriptional gene-regulators, are differentially expressed in several conditions, such as diabetes. To assess the mechanistic action of miRNAs in diabetic wound healing streptozotocin (STZ)-induced diabetic and control mice (n=6/group, 6 weeks of diabetes) were subjected to 6-mm full-thickness excisional wounds. Biopsies were obtained at days 3 and 10 post-wounding. Wound healing was delayed in diabetic mice (p<0.05). The skin miRNA profile was determined for up to 561 unique miRNAs using Taqman MicroRNA array cards. We identified 288 different robustly expressed miRNA in skin. While half of them were decreased more than 1.5 fold, 41 were increased more than 1.5 fold, during wound healing. MiR-155-5p was increased in diabetic skin (15.8 fold (95% CI: 3.5-28.1), however, it was 9.7 fold (95% CI: 4.2-15.2) decreased at day 10 post wounding, as compared to nondiabetic mouse skin. Scratch assays in HaCaT cells showed increased scratch closure after 24 hours, when miR-155 was inhibited (Ctrl: 31%, miR-155 inhibitor: 8.1% of scratch remaining, P<0.001). In vivo, topical treatment of diabetic mouse wounds with miR-155 inhibitor dose-dependently accelerated wound closure with maximal effect at 2.5pmol (P<0.03). Interestingly, reporter-gene analysis identified fibroblast growth factor (FGF) 7 mRNA as a target of miR-155-5p. Moreover, miR-155 inhibitor treated mouse wounds showed significant increase in FGF7 protein expression by immunofluorescence. We present evidence that miR-155-5p expression is altered in diabetic mouse skin and its suppression significantly improves wound healing under diabetic conditions, indicating its potential as a novel chronic diabetic foot ulcer treatment.

Disclosure

L.T. Dalgaard: Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. E.C. Leal: None. R. Svendsen: None. J. Moura: None. A.E. Sørensen: Research Support; Self; Danish Diabetes Academy, Merck Serono. P.T. Jørgensen: None.
Tannic Acid–Encapsulated Islets Suppress Autoimmunity and Restore Euglycemia following Transplantation
Authors: BARRA JESSIE , TSE HUBERT M.
Published: June 2018

Type 1 diabetes (T1D) is an autoimmune disease of pancreatic β-cell death caused by islet-infiltrating leukocytes. Islet transplantation can restore β-cell function, however, limited islet availability, toxicity of immunosuppressants, and poor graft survival are major hurdles for clinical application. We hypothesize that islet encapsulation with a nanothin multilayer coating consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), will provide an immunoprotective barrier and maintain β-cell function after transplantation. In support of our hypothesis, we demonstrate that (PVPON/TA)-encapsulated syngeneic NOD.Rag islets restored euglycemia after transplantation under the kidney capsule of streptozotocin-treated diabetic NOD mice by more than 30 days in comparison to non-encapsulated islets. Encapsulated allogeneic B6 islets also restored euglycemia in diabetic NOD mice and delayed rejection by 7.5 days in contrast to non-encapsulated islets. Gene expression of allogeneic B6 islets at 5 days post-transplant displayed an increase in Ins2 (6-fold), Gcg (6-fold), Pdx1 (5-fold), Ccl22 (3-fold), and Arg1 (2.5-fold) mRNA accumulation with (PVPON/TA)-encapsulated islet grafts, suggesting a potential shift toward an alternatively-activated M2 macrophage phenotype. To address limited islet availability, the use of (PVPON/TA)-encapsulated differentiated neonatal porcine islets restored euglycemia and maintained β-cell function for more than 200 days after transplantation into diabetic NOD.scid mice. Our results support the hypothesis that islet encapsulation with (PVPON/TA) coatings maintain function and may elicit protection following islet allo- and xenotransplantation. Future studies will determine the immunological mechanism of protection following (PVPON/TA)-encapsulation of islets.

Disclosure

J. Barra: None. H.M. Tse: None.
Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to High Fructose Consumption in Mice
Authors: AHN IN SOOK , LANG JENNIFER , YING ZHE , BYUN HYAE RAN , ZHANG GUANGLIN , OLSON CHRISTINE , HSAIO ELAINE , LUSIS ALDONS , GOMEZ-PINILLA FERNANDO , YANG XIA
Published: June 2018

Both host genotypes and gut microbiota play a role in dietary responses and the control of host phenotypes. High fructose consumption has been strongly implicated in metabolic disorders including obesity, insulin resistance and diabetes, but individual variability in susceptibility has not been examined in diverse genetic backgrounds. We investigated the strain-specific response to fructose in terms of the shifts in gut microbiota as well as host phenotypes related to body mass, glycemic traits, and glucose intolerance using three mouse strains, C57BL/6 (B6), DBA, and FVB. After treatment with 8% fructose water for 12 weeks, the DBA mice demonstrated increased body weight, adiposity, plasma insulin, and glucose intolerance, whereas B6 and FVB mice were resistant to fructose-induced metabolic alterations. We also conducted 16S rRNA-sequencing analysis of gut microbiota and found that DBA had higher Firmicutes/Bacteriodetes ratio and lower basal levels of Turicibacter, Akkermansia, and S24-7_g compared to B6 and FVB. These microbes were correlated with body weight, adiposity, or glucose tolerance. To test the influence of gut microbiota on metabolic phenotypes, we performed fecal transplant by administering the B6 fecal content to DBA mice and vice versa. DBA mice with B6 fecal transplant stayed glucose tolerant and lean with fructose treatment, suggesting that B6 microbes attenuated fructose response in DBA mice. Our findings suggest that fructose induces strain-specific metabolic and microbiota responses, and gut microbiota are partially responsible for fructose sensitivity among mice with different genetic backgrounds.

Disclosure

I. Ahn: None. J. Lang: None. Z. Ying: None. H. Byun: None. G. Zhang: None. C. Olson: None. E. Hsaio: None. A. Lusis: None. F. Gomez-Pinilla: None. X. Yang: None.
Weight-Centric Management of Type 2 Diabetes Mellitus
Authors: MANDEL LINDSAY , SHUKLA ALPANA , KUMAR REKHA , WAITMAN JONATHAN , ARONNE LOUIS
Published: June 2018

Background: Obesity and type 2 diabetes mellitus (T2DM) are inextricably linked. Obesity is the pathophysiologic driver of T2DM, and as such, the treatment of obesity can improve glycemic control. Although there is some data from phase 3 trials of anti-obesity pharmacotherapy in patients with T2DM, there is currently a paucity of data related to the weight-centric management of T2DM in clinical practice. Data from clinical trials of these medications suggests that weight loss outcomes in patients with T2DM are inferior, likely due to the weight gain promoting effects of concomitant antidiabetic therapies.

Methods: In a retrospective study, electronic medical records of 359 consecutive new patients seen at the Weill Cornell Comprehensive Weight Control Center from 4/1/14-4/1/15 were reviewed and data related to demographics, medications, weight, and HbA1c was recorded.

Results: 48 of 359 patients had T2DM. Baseline age and BMI were 56.2±10.6 years and 39.5±7.6 kg/m2 in patients with T2DM and 48±14.7 years and 35.6±6.8 kg/m2 in patients without T2DM; 54.2% and 70.7% were female, respectively. Management strategies in patients with T2DM included the addition and dose escalation of metformin, GLP-1 agonists, and SGLT2 inhibitors, discontinuation of sulfonylureas and TZDs, and dose reduction of insulin when possible. 56.3% of patients with T2DM were started on anti-obesity pharmacotherapy including lorcaserin, phentermine, topiramate and bupropion. At 12 months, weight loss was 8.9±7.8% in patients with T2DM and 8.6±7.7% in those without T2DM. In patients with T2DM, HbA1c was 7.1±1.1% at initial visit and 6.7±1.3% at 12 months.

Conclusions: In this review, weight loss outcomes were similar in patients with and without T2DM. We show that by using a weight-centric approach to diabetes management, patients can achieve glycemic control with concomitant weight loss.

Disclosure

L. Mandel: None. A. Shukla: None. R. Kumar: Speaker's Bureau; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc.. J. Waitman: None. L. Aronne: Board Member; Self; Myos Corporation, Jamieson Wellness. Consultant; Self; Aspire Bariatrics, Eisai Inc., Novo Nordisk Inc.. Research Support; Self; Pfizer Inc.. Consultant; Self; Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Zafgen. Other Relationship; Self; BMIQ, Gelesis, ERX Pharmaceuticals, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; Sanofi, Janssen Pharmaceuticals, Inc., UnitedHealth Group.
The Common Food Additive Carrageenan Increases Intestinal Permeability without Affecting Whole-Body Insulin Sensitivity in Humans—Results from a Randomized, Double-Blind Crossover Study
Authors: WAGNER ROBERT , BÜTTNER JANINE , HENI MARTIN , FRITSCHE LOUISE , KULLMANN STEPHANIE , WAGMÜLLER MORITZ , PETER ANDREAS , PREISSL HUBERT , MACHANN JUERGEN , PAPE ULRICH-FRANK , VAN HALL GERRIT , PLOMGAARD PETER , KLEIN REINHILD , FRITSCHE ANDREAS , HAERING HANS-ULRICH , STEFAN NORBERT
Published: June 2018

It is not known whether food additives associated with western lifestyle, such as the widely used carrageenan, also play a role in the pathogenesis of diabetes. Animal data suggest that increased carrageenan consumption causes insulin resistance and diabetes, mainly by interfering with hepatic insulin signaling. This is the first trial in humans that tested whether carrageenan added to the diet affects key metabolic traits.

We conducted a randomized, double-blind, placebo-controlled, cross-over trial (registered as NCT02629705). Healthy males (N=20) were randomly allocated to 14 days of carrageenan (250 mg twice daily) or matching placebo. After a washout-period of 30±7 days, they received the other compound. At the end of each treatment phase, participants underwent an oral glucose tolerance test (OGTT), a hyperinsulinemic-euglycemic clamp with labeled glucose, whole-body MR-tomography and 1H-MR-spectroscopy, blood immune cell phenotyping and a lactulose-mannitol test for investigating intestinal permeability.

Participants had a mean (±SD) age of 27.6±4.8 years and a BMI of 24.4±2.6 kg/m2. Intestinal permeability significantly increased after carrageenan vs. placebo exposure (lactulose-mannitol-ratio 0.0196 vs. 0.015, p=0.03). Whole-body insulin sensitivity index (ISI) did not differ between placebo and carrageenan exposure (p=0.5 for both ISIclamp and ISIOGTT). No changes of hepatic fat content, body fat mass, distribution, liver transaminases and inflammatory cytokines were observed (all p>0.4).

In young healthy males, short-term carrageenan intake resulted in increased gut permeability. This was not accompanied by changes of whole-body insulin sensitivity, body fat mass, distribution and liver fat content. Further investigations of hepatic and brain insulin sensitivity, immune phenotyping will reveal whether carrageenan intake affected these variables.

Disclosure

R. Wagner: None. J. Büttner: None. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Inc.. L. Fritsche: None. S. Kullmann: None. M. Wagmüller: None. A. Peter: None. H. Preissl: None. J. Machann: None. U. Pape: None. G. van Hall: None. P. Plomgaard: None. R. Klein: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. H. Haering: None. N. Stefan: Consultant; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, OmniaMed Ltd..
Neighborhood Walkability and Diabetes-Related Complications
Authors: SHAH REEMA , LUO JIN , GERSTEIN HERTZEL C. , BOOTH GILLIAN
Published: June 2018

Neighborhoods that are more conducive to walking are associated with increased levels of physical activity and lower levels of obesity and diabetes, but the effect of neighborhood walkability on the clinical course of patients with diabetes is not known. We conducted a retrospective cohort study in 439,392 adults using population-based administrative health databases to evaluate the effect of neighborhood walkability on the incidence of diabetes related complications. Adults (≥30 years) with diabetes living in Southern Ontario cities were followed from April 1 2007 to March 31 2017. Neighborhood walkability was derived from a validated index and classified into quintiles from lowest (Q1) to highest (Q5). Cox proportional hazards models were used to estimate the hazard of neighborhood walkability on retinopathy (laser photocoagulation/vitrectomy/VEGF therapy), nephropathy (dialysis or kidney transplantation), foot complications (infection/amputation), and avoidable hospitalizations (hyper/hypoglycemia), adjusting for age, sex, ethnicity, income, and comorbid conditions, as well as significant interactions between these and walkability. Overall, baseline characteristics were similar across neighborhoods, however, low walkability areas tended to be wealthier than high walkability areas. The cohort sustained 30457 retinopathy events, 4883 nephropathy events, 40989 foot complications, and 24272 avoidable hospitalizations. There was an increased risk of retinopathy (Q1:Q5 adjusted HR 1.13, 95% CI 1.07-1.19, p<0.001), nephropathy (Q1:Q5 aHR 1.33, 95% CI 1.16-1.52, p<0.001), foot complications (Q1:Q5 aHR 1.27, 95% CI 1.18-1.37, p<0.001), and avoidable hospitalizations (Q1:Q5 aHR 1.49, 95% CI 1.36-1.64, p<0.001) in lower walkability compared to higher walkability neighborhoods. Neighborhood design may have beneficial effects on diabetes complications. This has important implications for policies to promote healthy environments to better manage the burden of chronic metabolic diseases.

Disclosure

R. Shah: None. J. Luo: None. H.C. Gerstein: Research Support; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Sanofi. Advisory Panel; Self; Sanofi. Other Relationship; Self; Sanofi. Advisory Panel; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Other Relationship; Self; Merck & Co., Inc.. Advisory Panel; Self; AstraZeneca. Research Support; Self; AstraZeneca. Other Relationship; Self; AstraZeneca. Advisory Panel; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Advisory Panel; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc.. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. G. Booth: None.
Prevalence of Diagnosed Diabetes and Total Diabetes among Asian Americans, 2011–2014
Authors: CHENG YILING J. , KANAYA ALKA M. , SAYDAH SHARON , ARANETA MARIA ROSARIO , KAHN HENRY S. , IMPERATORE GIUSEPPINA
Published: June 2018

Asian Americans (AAs) comprise ∼6% of the U.S. population. However, there is little national information on the prevalence of diabetes (DM) among AAs. In addition, there are no national estimates of DM prevalence according to AA ancestral subgroups. Among sampled AA adults (age ≥20 years) we estimated the population prevalence of DM for all AAs and major geographic AA ancestral subgroups using data from the U.S. National Health and Nutrition Examination Survey 2011-2014. DM status was categorized as diagnosed (DiagDM), undiagnosed (UndiagDM; no DiagDM but HbA1c ≥6.5% or fasting plasma glucose ≥126mg/dl or 2-hour plasma glucose ≥200 mg/dl), or nondiabetic. We defined 4 AA ancestral subgroups as East AA (Chinese, Japanese, and Korean), South AA (Indian, Pakistani, Sri Lankan, Bangladeshi, Nepali, and Bhutanese), Southeast AA (Filipino, Vietnamese, Cambodian, Laotian, Thai, Indonesian, Malaysian, Singaporean, and Hmong), and other AA. Age-sex adjusted prevalences and prevalence ratios were computed for the 4 AA subgroups, as well as for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans (Table). Compared to non-Hispanic whites, East AAs had a similar prevalence of DiagDM but higher UndiagDM. The elevated prevalence of UndiagDM among AAs suggests the relatively low awareness of their condition and reinforces the importance of diabetes screening in these populations.

Table.Age-sex adjusted prevalence of diabetes and prevalence ratio, NHANES 2011-2014Race/ethnicityn (weighted N, million)Prevalence (%, 95% CI)Prevalence Ratio (95% CI)DiagDMUndiagDMTotalDMDiagDMUndiagDMTotalDMNon-Hispanic AA1517 (12.5)11.2 (9.0, 13.5)9.3 (6.9, 11.8)20.6 (17.4, 23.7)1.4 (1.1, 3.9)2.6 (1.8, 9.0)1.8 (1.5, 2.2)East AA594 (4.8)7.2 (4.0, 10.4)8.8 (5.1, 12.6)16.0 (10.7, 21.3)0.9 (0.6, 1.4)2.5 (1.5, 4.1)1.4 (1.0, 2.0)South AA345 (2.9)15.4 (9.6, 21.2)9.4 (4.9, 13.9)24.8 (17.5, 32.2)2.0 (1.4, 2.8)2.7 (1.5, 4.5)2.2 (1.6, 6.7)Southeast AA414 (3.5)14.1 (11.0, 17.3)9.2 (5.5, 12.9)23.3 (18.4, 28.2)1.8 (1.4, 2.3)2.6 (1.7, 3.9)2.0 (1.6, 2.6)Other AA164 (1.3)9.8 (4.6, 15.0)8.7 (1.9, 15.5)18.5 (11.8, 25.2)1.2 (0.7, 2.1)2.4 (1.1, 5.5)1.6 (1.1, 2.4)Non-Hispanic W4472 (148.4)7.9 (6.9, 8.8)3.6 (2.6, 4.5)11.5 (10.1, 12.8)1.0 (Ref.)1.0 (Ref.)1.0 (Ref.)Non-Hispanic B2594 (25.5)14.6 (13.3, 16.0)6.2 (4.4, 7.9)20.8 (18.4, 23.2)1.9 (1.6, 2.2)1.7 (1.2, 2.6)1.8 (1.5, 2.2)Mexican Am1296 (18.9)14.8 (12.4, 17.2)8.3 (6.4, 10.2)23.1 (19.8, 26.5)1.9 (1.6, 2.3)2.3 (1.7, 3.2)2.0 (1.7, 2.4)AA: Asian American; Non-Hispanic W: Non-Hispanic white; Non-Hispanic B: Non-Hispanic black; Mexican Am: Mexican American

Disclosure

Y.J. Cheng: None. A.M. Kanaya: None. S. Saydah: None. M. Araneta: None. H.S. Kahn: None. G. Imperatore: None.
Subclinical Microvascular Lesions among Normoglycemic and Prediabetic Subjects—The PROP-ABC Study
Authors: UMEKWE NKIRU A. , OWEI IBIYE , DAGOGO-JACK SAMUEL
Published: June 2018

Background: We investigated the occurrence of microvascular lesions in nondiabetic offspring of parents with T2DM enrolled in the PROP-ABC (Pathobiology and Reversibility of Prediabetes in A Biracial Cohort)* study.

Design and Methods: We assessed albumin:creatinine ratio (MCR), vibration perception threshold (Vibratron II, Physitemp Instruments Inc, Clifton, NJ) and nonmydriatric retinal images (Zeiss digital camera, Carl Zeiss Meditec AG, Jena, Germany).

Results: There were 223 subjects (117 black, 106 white; 70% female), of whom 122 had prediabetes (impaired fasting glucose or impaired glucose tolerance) and 101 had normal glucose regulation (NGR; FPG <100 mg/dl and 2hrPG<140 mg/dl). The mean (± SD) age was 53.3 ± 9.1 years. Retinal lesions were found in 24 subjects (10.8% of the cohort), comprising macular changes (n=9), optic disc changes (n=8), epiretinal membrane (n=6), diabetic retinopathy (n=4), and vitreous opacities (n=2). The frequency of any retinal lesion was 12.3% vs. 8.9% among prediabetic vs. NGR subjects. The mean MCR was 9.95±2.1 ug/g among subjects with normal retina vs. 16.6 ±9.89ug/g among those with retinal lesions. There was a strong correlation between albuminuria and presence of retinal lesions (r=0.42, P<0.0001). The index finger vibration amplitude was 0.56 ±0.31 microns in prediabetic subjects vs. 0.43±0.25 microns in NGT subjects (P=0.013).

Conclusions: We here demonstrate a significant association between albuminuria and diverse retinal lesions in a biracial cohort of nondiabetic subjects, and further show relative impairment of vibration perception in prediabetic subjects (NCT02027571).

Disclosure

N.A. Umekwe: None. I. Owei: None. S. Dagogo-Jack: None.
CMHX008, a Novel Thiazolidinedione-Like PPARγ Partial Agonist, Enhances Insulin Sensitivity with Minor Influences on Bone Loss
Authors: XIAO XIAOQIU , HOU YI , CAO XUEMEI , LI JIAYU
Published: June 2018

Objective: Traditional thiazolidinediones (TZDs), rosiglitazone for instance, are peroxisome proliferator-activated receptor γ (PPARγ) potent agonists and can treat type 2 diabetes but carry unwanted effects including increased risk for fracture. Here we compared insulin-sensitizing efficacies and bone-loss side effects of CMHX008, a novel TZDs-like PPARγ partial agonist, with rosiglitazone.

Methods: TR-FRET PPARγ competitive binding assay was used to compare the binding affinity between CMHX0and rosiglitazone. High fat diet fed and ob/ob mice were administered with vehicle, CMHX0or rosiglitazone. Bone marrow mesenchymal stem cells (BMMSCs) were used to examine differences in differentiation into osteoblasts after treated with CMHX0and rosiglitazone.

Results: TR-FRET showed lower affinity to PPARγ by CMHX0compared with rosiglitazone. Mice treated with CMHX0for 16 weeks had the comparable effect of insulin sensitization as rosiglitazone, which was related to significant inhibition on PPARγ Ser 273 phosphorylation and improved insulin sensitivity by facilitating phosphorylation insulin receptor and AKT in adipose tissues. Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treated with CMHX0was weaker than rosiglitazone as evidence by consistent changes in BV/TV, Tb.N, Tb.Th, Tb.Sp, and mineral apposition rate. BMMSCs treated with CMHX0showed higher ALP activity and mRNA levels of bone formation markers than those treated by rosiglitazone in osteoblast differentiation test.

Conclusion: PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties. CMHX0shared the comparable insulin-sensitizing effects as rosiglitazone with lower risk of bone loss.

Disclosure

X. Xiao: None. Y. Hou: None. X. Cao: None. J. Li: None.
Intestinal Epigenetic Reprogramming Relates to Glycemic Improvement after Roux-en-Y Gastric Bypass Surgery
Authors: STEFATER MARGARET A. , PANCIOTTI COURTNEY , FELDMAN HENRY A. , GOURASH WILLIAM F. , SHIRLEY ELEANOR , COURCOULAS ANITA , STYLOPOULOS NICHOLAS
Published: June 2018

Despite the remarkable, early remission of T2D after RYGB, the surgery’s key mechanisms have yet to be defined in a way that can be translated to less invasive therapies. Recently, we demonstrated that improved glucose homeostasis after RYGB in rodents is associated with intestinal metabolic reprogramming: the Roux Limb (RL) exhibits dramatic morphologic and metabolic remodeling, leading to augmented utilization of metabolic fuels to support the increased bioenergetic demand. To address whether this phenomenon is important for T2D remission in human patients after RYGB, RL biopsies were obtained at the time of surgery and at 1 and 6 months postoperatively. Differentially expressed genes (DEG) were determined using Affymetrix HTA 2.0 microarrays; morphology was examined via electron microscopy, revealing a significant increase in microvillus length over time (P<0.01). Enrichment analysis showed robust changes cellular proliferation, cell cycle regulation, and cytoskeletal remodeling pathways at both timepoints. DEG suggest a metabolic shift away from fatty acid oxidation, toward utilization of glucose and amino acids. Common DEG (FDR<0.05) at 1 and 6 months were strongly correlated (R2=0.899, P<0.0001), suggesting that RL signatures are established early and persist. Interestingly, 91% of the top 100 DEG at 6 months were downregulated; GSEA revealed significant enrichment of genes regulating epigenetic reprogramming (P<0.01), e.g., DNMT1 and DNMT3B at 1 and 6 months. Remarkably, change in DNMT1 expression at 1 month, controlling for baseline body weight, predicted 6-month HbA1c change (R2=0.744, P=0.002). This suggests a mechanistic role for methylation to underlie glycemic improvement, and points to a potential predictive role for early RL DEG. We hypothesize that post-RYGB T2D improvement may relate to RL remodeling including increased energy utilization, and that the stimulus may be epigenetic reprogramming as a result of altered intestinal nutrient flow.

Disclosure

M.A. Stefater: None. C. Panciotti: None. H.A. Feldman: None. W.F. Gourash: Research Support; Self; Coviden, Ethicon US, LLC., National Institute of Diabetes and Digestive and Kidney Diseases. E. Shirley: None. A. Courcoulas: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Patient-Centered Outcomes Research Institute, National Institutes of Health, Coviden. N. Stylopoulos: None.