bluuebunny/crossref_metadata_2025 huggingface dataset:
TAp63 in Mature POMC Neurons Regulates Glucose and Energy Homeostasis
Authors: WANG CHUNMEI , HE YANLIN , XU PINGWEN , YANG YONGJIE , XU YONG
Published: June 2018

TAp63 is a transcription factor that has been reported to be important for energy and glucose homeostasis. However, where and how TAp63 functions is unclear. Chow-fed mutant mice with TAp63 deleted from pro-opiomelanocortin (POMC) neurons showed normal body weight and glucose metabolism in both sex. However, HFD fed male and female mice that lack TAp63 from POMC neurons both showed glucose intolerance (GTT) and insulin resistance independent of body weight. Strikingly, deletion of TAp63 in POMC neurons confers “male-like” diet-induced obesity (DIO) to female mice, but does not affect DIO phenotypes in male mice. In contrast, overexpression of TAp63 in POMC neurons partially prevents DIO in male mice but not in female mice. Here we show that POMC neurons in female mice display higher neural activities and express higher POMC mRNAs compared to male counterparts, and both these enhancements in female POMC neurons are correlated to higher expression levels of TAp63. Further, we found that the deletion of TAp63 reduced POMC neuronal activity and diminished the sexual dimorphism of POMC neural activity by decreasing the responsiveness of ERα-positive POMC neurons to the ERα agonist. Finally, we found that TAp63 binds to the promoter of POMC gene and regulate POMC gene expression in POMC neurons. In addition, the expression of energy homeostasis related genes like SRC-1, ERα and TAp63 target genes Sirt1, AMPKα2, LKB1 were also decreased in mice lacking TAp63 in POMC neurons. Collectively, TAp63 in mature POMC neurons regulates glucose homeostasis and TAp63 is one key molecular driver for the sexual dimorphism in energy homeostasis.

Disclosure

C. Wang: None. Y. He: None. P. Xu: None. Y. Yang: None. Y. Xu: None.
Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, Protects against Cardiovascular System in Cardiac I/R Injury and Hypertensive Rats
Authors: PARK JIN-SOOK , NAM DAE-HWAN , BAEK EUN-BOK
Published: June 2018

Cardiovascular disease (CVD) is implicated in the high morbidity and mortality in diabetic patients. Improvement in cardiovascular complications with maintaining glucose level and managing cardiovascular risk factors is important role. Currently, the impact of hypoglycemic medications on CVD is of increasing importance. Although dipeptidyl peptidase-4 inhibitors (DPP-4), a class of antidiabetic drugs, have pleiotropic protective effects on CVD in experimental studies, it remains undetermined whether gemigliptin has a beneficial effect on ischemia reperfusion (I/R)-induced myocardial injury and hypertension. Therefore, this study was performed to evaluate the effects of gemigliptin in the rat model of myocardial I/R injury and spontaneously hypertensive rats (SHR). Gemigliptin (20 and 100 mg/kg/day) was administered per oral to Sprague-Dawley rats for four weeks before I/R operation. Gemigliptin pretreatment improved hemodynamic function and limited infarction size against I/R injury. Additionally, gemigliptin (0.03% and 0.15%) was mixed into the powdered feed and fed to SHR. Gemigliptin treatment with SHR reversed hypertrophy and improved diastolic function. These results suggest that gemigliptin exerts beneficial effect not only on blood glucose but also on cardiovascular system in cardiac I/R injury and hypertensive rats.

Disclosure

J. Park: Employee; Self; LG Chem. D. Nam: Employee; Self; Korea Institute of Toxicology (KIT). E. Baek: Employee; Self; LG Chem.
Hypothalamic Spexin and Galanin Receptor 2 Are Novel Regulators of Energy Balance in Mice
Authors: HA NA-HEE , KIM NAM HOON , KIM CHANG-HOON , SONG MUN-GYU , LEE HYE-JIN , JIN BO-YEONG , PARK MI-RAE , SEONG JAE YOUNG , KIM SIN GON , KIM DONG-HOON
Published: June 2018

Spexin is a novel neuropeptide discovered by bioinformatics and has been proposed as a regulator of energy balance. However, its precise role and underlying mechanisms remain unclear. In this study, we investigated the role of spexin and its receptor, galanin receptor 2 (GALR2), in regulation of energy balance in the mediobasal hypothalamus of mice. Administration of spexin into the third ventricle near the hypothalamus (I3V) significantly decreased food intake and body weight with no change in energy expenditure in mice. The central spexin-induced anorexia and weight loss were reinstated by pre-I3V administration of GALR2 antagonist, M871, indicating hypothalamic GALR2-mediated action of spexin in the regulation of energy balance. In addition, we showed that I3V administration of spexin-based selective GALR2 agonist significantly reduced food intake and body weight in a dose-dependent manner with no signs of illness assessed by a conditioned taste aversion test, suggesting a novel role of hypothalamic GALR2 in the regulation of energy balance. Furthermore, we found that activation of GALR2 induced by spexin increased phosphorylation of CREB in the mediobasal hypothalamus of mice and cells overexpressing GALR2 different from galanin, suggesting a ligand-dependent switch of G protein coupled with GALR2. Taken together, these results suggested a critical role of hypothalamic spexin and GALR2 in the regulation of energy balance in mice.

Disclosure

N. Ha: None. N. Kim: None. C. Kim: None. M. Song: None. H. Lee: None. B. Jin: None. M. Park: None. J. Seong: None. S. Kim: None. D. Kim: None.
Novel Function of Increased Ventromedial Hypothalamus (VMH) Norepinephrine (NE) to Block Local VMH Hyperglycemia Sensing Coupled to Increased Insulin Action
Authors: STOELZEL CARL , CINCOTTA ANTHONY
Published: June 2018

It is well established that local glucoprivation at the VMH stimulates glucose inhibitory neurons and acute noradrenergic activity (NA) therein necessary for the sympathoadrenal counter regulatory response to such glucoprivation. However, paradoxically a wide variety of insulin resistant, glucose intolerant, hyperglycemic animal models exhibit chronic elevation of NA at the VMH. Further, chronic VMH infusion of NE to normal animals leads to insulin resistance and glucose intolerance similar to that observed following sustained exposure to a high fat diet. Since VMH glucose excitatory neurons are activated by physiological postprandial increase in local glucose level to increase peripheral insulin action, these VMH NA findings suggest a novel function of elevated VMH NA to block normal postprandial glucose sensing of VMH glucose excitatory (GE) neurons that potentiate postprandial insulin sensitivity. To test this postulate multi-barreled pipettes with carbon fiber recording electrodes were lowered into the VMH of anesthetized rats (N=10) (age 12 weeks, maintained on standard low fat rodent chow diet) and multi-unit responses (MURs) from the central recording electrode (∼.5 Mω) before and during glucose electro-osmotic injection into the VMH (to preferentially activate GE neurons) were obtained. Changes in MURs to such glucose administration (that were at least 15% above baseline, P<0.05) were compared when such glucose was co-administered with micro-iontophoretically injected NE and such NE treatment significantly and consistently reduced such glucose-induced MURs by 46% (P<0.05). Among those glucose-induced MURs greater than 100% above baseline, this NE inhibition was even greater (50%, P<0.05). These findings are the first to identify a novel role for increased VMH NA in the blockade of normal postprandial VMH glucose sensing that is involved in increasing subsequent post-meal peripheral insulin action.

Disclosure

C. Stoelzel: Employee; Self; VeroScience, LLC. A. Cincotta: Employee; Self; VeroScience, LLC.. Stock/Shareholder; Self; VeroScience, LLC..
Glucagon Regulates Energy Balance via FGF-21 Signaling in the Brain
Authors: NASON SHELLY , KIM TEAYOUN , ANTIPENKO JESSICA P. , PAUL JODI , FINAN BRIAN , DIMARCHI RICHARD , HABEGGER KIRK M.
Published: June 2018

Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. Thus, novel therapeutics that stimulate glucagon-receptor (GcgR) signaling are promising for treatment of obesity and diabetes; however, the mechanism(s) underlying these effects are yet to be fully elucidated. We previously identified that hepatic glucagon signaling increases the secretion of another fasting hormone, Fibroblast Growth Factor 21 (FGF-21), also known to be involved in regulating energy balance. We have recently observed that mice deficient for liver FGF-21 (FGF-21δLiver) are partially resistant to the anti-obesity effects of GcgR agonism, clearly implicating hepatic FGF-21 as an essential component of the glucagon’s weight-loss effects. FGF-21 signals through an obligate co-receptor (βKlotho, Klb), with expression limited to adipose tissue, liver, and brain, specifically within the suprachiasmatic nucleus (SCN) of the hypothalamus and the hindbrain. As the hypothalamus has known roles in regulating energy balance, we hypothesized that the anti-obesity action of the glucagon-FGF-21 system signals through a central mechanism. Mice deficient for neuronal Klb (KlbδCNS) are less susceptible to diet-induced obesity than wild type mice (P<0.01), with no observed differences in food intake or energy expenditure. Following chronic GcgR activation via the selective agonist IUB288, KlbδCNS mice exhibit a partial reduction in body weight (12%) in comparison to control mice (19%), suggesting that FGF-21 mediates glucagon’s anti-obesity properties through central action. Consistent with GcgR-stimulated, neuronal FGF-21 signaling, we found that neuronal activation, measured via immunohistochemical analysis of cFos expression, was increased in the SCN following IUB288 injection. Taken together, these data suggest that glucagon mediates part of its anti-obesity properties through FGF-21-KLB signaling in the SCN, and has implications for future treatments against obesity and the metabolic syndrome.

Disclosure

S. Nason: None. T. Kim: None. J.P. Antipenko: None. J. Paul: None. B. Finan: Employee; Self; Novo Nordisk Inc. R. DiMarchi: Employee; Self; Novo Nordisk Inc. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc..
Blood Pressure and Mortality in U.S. Adults with Diabetes
Authors: RAGHAVAN SRIDHARAN , HO YUK-LAM , RHEE MARY , VASSY JASON L. , GAGNON DAVID R. , CHO KELLY , WILSON PETER W. , PHILLIPS LAWRENCE S.
Published: June 2018

Recent clinical trials have led to revised hypertension guidelines, but the relationship between blood pressure (BP) control and mortality in diabetes patients receiving routine care has not been described in a contemporary national U.S. cohort. We studied 130,192 primary care patients in the Veterans Health Administration with diabetes (ICD-9 codes 250.xx + outpatient diabetes prescription), newly started on a BP medication in 2003-2005, and with a mean systolic BP (SBP) >130 mmHg in the year prior to BP drug initiation. Mean on-treatment outpatient SBP in the 2nd year after BP drug initiation was the primary exposure. All-cause and cardiovascular (CV) mortality through 2014 were the primary outcomes; mean follow-up was 9 years. We estimated associations between SBP and mortality using multivariable Cox proportional hazards regression, adjusting for age, sex, race, comorbidities, HbA1c, number of BP drugs, and CV risk factors. Relative to SBP 121-130 mmHg, all-cause and CV mortality were significantly higher in those with an SBP of 100-120 mmHg or >160 mmHg on treatment. All-cause mortality was lowest in those with an SBP of 131-140 mmHg; CV mortality did not differ significantly between those with an SBP between 121 and 160 mmHg.

Conclusions: There was only minor variation in mortality rates for BPs from 121 to 160 mmHg in patients with diabetes and hypertension in routine clinical care, but mortality was higher in those with treated BP <120 mmHg or >160 mmHg.

Disclosure

S. Raghavan: None. Y. Ho: None. M. Rhee: None. J.L. Vassy: None. D.R. Gagnon: None. K. Cho: None. P.W. Wilson: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc..
The Relationship of Fasting Free Fatty Acids, Adipose Tissue, Insulin Resistance, and Fasting Glucose Concentrations with Subsequent ß-Cell Function in Nondiabetic Subjects
Authors: HURTADO MARIA D. , ADAMS J.D. , LAURENTI MARCELLO C. , MAN CHIARA DALLA , COBELLI CLAUDIO , RIZZA ROBERT A. , JENSEN MICHAEL D. , VELLA ADRIAN
Published: June 2018

Elevations in both plasma free fatty acids (FFA) and glucose concentrations during fasting are associated with impaired β-cell function and predict progression from prediabetes to diabetes. Their interaction and subsequent effect on β-cell function as quantified by Disposition Index (DI) is unknown. We therefore measured total, saturated, mono-unsaturated and poly-unsaturated FFA concentrations using LC/MS in 120 nondiabetic subjects (across a range of fasting glucose < 6.9 mmol/l) who underwent a 2 hour oral glucose tolerance test (OGTT). Insulin secretion and action were quantified using the oral minimal model. The adipose tissue insulin resistance index (Adipo-IR) was calculated for each subject. Subjects were categorized by normal (NFG) or impaired (IFG) fasting glucose and by 2-hour glucose into normal (NGT) or impaired (IGT) glucose tolerance. Fasting total FFA were increased (p < 0.01) in IFG/IGT (835 ± 47 μmol/L) and in NFG/IGT (835 ± 30 μmol/L) but, intriguingly, not in IFG/NGT (593 ± 26 μmol/L) when compared to NFG/NGT (652 ± 29 μmol/L). These differences were no longer apparent within 60 minutes of OGTT and all groups suppressed FFA to the same nadir (166 ± 12 vs. 191 ± 18 vs. 184 ± 12 vs. 174 ± 17μmol/L, p = 0.59). On the other hand, an inverse relationship (p < 0.01) of fasting FFA (r = -0.33) and of Adipo-IR (r = -0.28) was observed with insulin action (Si). Fasting FFA did not correlate with β-cell responsivity (ϕ, r = 0.04). However, higher Adipo-IR was associated with higher values of ϕ (r = 0.36, p < 0.01). Fasting glucose concentrations did not alter these relationships; specifically no interaction of glucose with FFA during the fasting state to influence DI was evident. It remains to be ascertained whether the elevation in FFA reflects defects in production or in uptake, and whether the effect of changes in fasting glucose concentrations on DI is modulated by fasting FFA concentrations.

Disclosure

M.D. Hurtado: None. J. Adams: None. M.C. Laurenti: Other Relationship; Self; GlySens Incorporated. C. Dalla Man: None. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. R.A. Rizza: None. M.D. Jensen: Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG.
Effects of GLP-1 and GIP on Insulin Secretion in Glucose Intolerant, Pancreatic Insufficient Cystic Fibrosis
Authors: EIEL JACK N. , NYIRJESY SARAH , PELECKIS AMY J. , LEON DIVA DE , HADJILIADIS DENIS , KUBRAK CHRISTINA , TAMI ABIGAIL , SHEIKH SABA , RUBENSTEIN RONALD C. , KELLY ANDREA , RICKELS MICHAEL R.
Published: June 2018

Individuals with pancreatic insufficient cystic fibrosis (PI-CF) and glucose intolerance demonstrate impaired incretin and insulin secretion. The goal of this study was to assess β-cell responsiveness to the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) during glucose potentiated arginine (GPA) testing in adults with PI-CF and abnormal glucose tolerance. Participants were randomized to receive either GLP-1 (n=15) or GIP (n=15) and then underwent GPA testing during either incretin or placebo infusion in a randomized, cross-over fashion. OGTT was similar between groups (1hr: 214±8 vs. 208±7 mg/dL; 2hr: 141±18 vs. 150±18 mg/dL). During GPL-1 infusion, fasting glucose was lower after 30 min vs. placebo (p<0.001), and during the 230 mg/dL glucose clamp the glucose infusion rate (GIR) was higher (p<0.001). Second phase insulin levels were substantially increased prior to arginine administration under 230 mg/dL clamp conditions vs. placebo (p<0.001), but no difference in the acute insulin response (AIR) to GPA was present. At 230 mg/dL, proinsulin and C-peptide were increased under GLP-1 vs. placebo (both p<0.001), but the proinsulin secretory ratio (PISR) was unchanged. During GIP infusion, fasting glucose was slightly lower after 30 min vs. placebo (p<0.05), but no difference in the GIR required to achieve 230 mg/dL was found. Second phase insulin levels were not different during the 230 mg/dL glucose clamp. The AIR to GPA was lower during GIP vs. placebo (p<0.01). Second phase proinsulin and C-peptide levels were higher with GIP vs. placebo (both p<0.01) with an increased PISR (p<0.05). These results indicate that GLP-1 augments glucose-dependent insulin secretion while GIP may lead to disproportionate proinsulin secretion in glucose intolerant PI-CF. Further studies should determine whether GLP-1 may provide a therapeutic benefit in this population.

Disclosure

J.N. Eiel: None. S. Nyirjesy: None. A.J. Peleckis: None. D. De Leon: Employee; Spouse/Partner; Merck & Co., Inc.. Research Support; Self; Zealand Pharma A/S. Consultant; Self; XOMA Corporation, ProSciento. Research Support; Self; Biomarin Corporation. D. Hadjiliadis: None. C. Kubrak: None. A. Tami: None. S. Sheikh: None. R.C. Rubenstein: None. A. Kelly: None. M.R. Rickels: Consultant; Self; Hua Medicine, Xeris Pharmaceuticals, Inc..
Glucose Metabolism after Overnight and Prolonged Fasting in Healthy Subjects
Authors: TRIPOLT NORBERT J. , STEKOVIC SLAVEN , URL JASMIN , ABERER FELIX , PFERSCHY PETER N. , RIEDL REGINA , OBERMAYER-PIETSCH BARBARA M. , PIEBER THOMAS R. , MADEO FRANK , SOURIJ HARALD
Published: June 2018

Background: It is well known that the metabolic regulation of glucose can be influenced by dietary interventions, including alterations in meal timing. Aim of our analysis was to examine the glucose metabolism after an overnight fast (10 hours) and after prolonged fasting (36 hours of fasting).

Material and Methods: Glucose metabolism was assessed by a 75 g oral glucose tolerance test after an overnight fasting period of 10 hours and a fasting period of 36h. Beta-cell function was quantified by 1st and 2nd phase insulin secretion indices.

Results: We included 37 healthy subjects (mean age 48±10 years; 54% women) with a mean body mass index (BMI) of 25.2±3.4 kg/m2. After prolonged fasting mean 2h-glucose and AUC for glucose value were significantly higher than after 10h fasting (2h-glucose: 110±27 mg/dL vs. 89±24 mg/dL; p<0.001) (AUCglucose: 5336±3302 mg/dL/min vs. 3692±2266 mg/dL/min; p=0.002). First (745±500 vs. 982±573; p=0.012) and second phase insulin secretion (211 ± 115 vs. 266 ± 132; p=0.011) were significantly lower after 36h of fasting as compared to an overnight fast. Estimates for insulin sensitivity are similar after 10 and 36 hours of fasting.

Conclusion: Our data demonstrate higher glucose excursions and a reduced insulin response after a 36 hour fasting period as compared to an overnight fasting period in healthy subjects.After 10h fastingAfter 36h fastingp-valueFasting c-peptide (ng/mL)1.39 ± 0.651.09 ± 1.030.025Fasting insulin (mU/L)7.9 ± 5.15.7 ± 5.80.042Fasting glucose (mg/dL)88 ± 988 ± 180.830Insulin after 60min (mU/L)87.6 ± 85.853.4 ± 51.80.0361st phase insulin secretion982 ± 573745 ± 5000.012HOMA-IR1.75 ±  1.181.39 ± 2.070.303Stumvoll index (ISI)0.10 ± 0.030.09 ± 0.03 0.230

Disclosure

N.J. Tripolt: None. S. Stekovic: None. J. Url: None. F. Aberer: None. P.N. Pferschy: None. R. Riedl: None. B.M. Obermayer-Pietsch: None. T.R. Pieber: Consultant; Self; Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Employee; Self; CBmed. Research Support; Self; Novo Nordisk A/S, AstraZeneca. F. Madeo: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..
Beta-Cell Function after Gastric Bypass
Authors: SHAH ANKIT , LEVESQUE KIARRA , AHLERS MICHAEL , HOLTER MARLENA M. , ALAM FATIMA , PIERINI ESMERALDA , ROJAS BETSY L. , MARK VICTORIA , PATEL KAPILA , DUTIA ROXANNE , HARVEY EUGENIUS J. , PARK KOJI , KOSHY NINAN , BELSLEY SCOTT J. , MCGINTY JAMES J. , LAFERRERE BLANDINE
Published: June 2018

β-cell glucose sensitivity (BCGS) improves after gastric bypass (RYGB) in individuals in diabetes (DM2) remission. We sought to assess BCGS (pmol/kg/min/mM) after an oral glucose test (OGT) and an IV graded glucose infusion (GGI) in subjects with and without DM2 remission after RYGB.

Twenty five subjects with DM2 were studied with GGI and 75g-OGT before and 3 months after RYGB. Glucose, insulin, C-peptide, insulin secretion rate, GLP-1 and BCGS were assessed during the OGT and the GGI. Data are presented as mean±SD. Within and between group comparisons with paired and unpaired t-test; GLM with repeated measure to assess change during OGT or GGI were (SPSS 24).

Of the 25 subjects studied pre-surgery, 10 experienced DM2 remission (REM), 9 remained with DM2 (N-REM) at 3 months; 6 remained glucose intolerant and were not included in the analysis. Pre-surgery BMI (41.5±4.7 kg/m2), weight (108.3±15.9 kg), age (43.8±8.8 years), gender (95% female), HOMA-IR (12.1±6.7) and Matsuda index did not differ between groups; N-REM had longer DM2 duration (14 vs. 2.5 y p<0.001), higher HbA1c (8.2±1.0 vs. 7.0±0.8%, p=0.01) and more likely to be taking insulin (7/9 vs. 0/10 p<0.001). Prior to RYGB, OGT-BCGS was 4x greater (0.83±0.60 vs. 0.22±0.24, p=0.01) and GGI-BCGS was 2.5x greater (0.48±0.30 vs. 0.18±0.15, p=0.04) in REM vs. N-REM.

Weight loss did not differ for REM and N-REM (17±5%). HOMA-IR, GLP-1 and GGI-BCGS improved similarly in both groups. OGT-BCGS increased in both groups, but more in REM vs. N-REM (+1.31±1.0 vs. +0.30±0.28, p=0.01). The difference between OGT-BCGS and GGI-BCGS observed pre-RYGB (0.58±0.54 vs. 0.38±.035, p=ns) was exaggerated at 3 months by 4x in REM (2.13±1.vs. 0.58±0.15, p=0.001) and ∼2.5x in N-REM (0.60±.0.43 vs. 0.24±0.17, p=0.07).

In conclusion, β-cell function assessed during an IV GGI improves by the same magnitude regardless of DM2 remission status after RYGB. However, β-cell function improved more in REM than N-REM after oral glucose, suggesting a greater incretin effect, or other gut-related mechanisms, in REM after RYGB.

Disclosure

A. Shah: Employee; Spouse/Partner; Daiichi Sankyo Company, Limited. K. Levesque: None. M. Ahlers: None. M.M. Holter: None. F. Alam: None. E. Pierini: None. B.L. Rojas: None. V. Mark: None. K. Patel: None. R. Dutia: None. E.J. Harvey: None. K. Park: None. N. Koshy: None. S.J. Belsley: None. J.J. Mcginty: None. B. Laferrere: None.
Beta-Cell SCHAD Deficiency Causes Hypoglycemia in Mice
Authors: LUDEKE JOHANNA , VELASCO KELLY M. , DE JESUS DARIO F. , SLIPP BRITTANY A. , HU JIANG , STEINE SOLRUN J. , HELGELAND GEIR , NJØLSTAD PÅL RASMUS , KULKARNI ROHIT , MOLVEN ANDERS
Published: June 2018

Congenital Hyperinsulinism of Infancy (CHI) is a group of rare, inheritable disorders with persistent hypoglycemia due to hyperinsulinemia. CHI is caused by mutations in genes that affect regulation of insulin secretion in β-cells. One such gene is HADH, which encodes short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a metabolic enzyme of the fatty acid beta-oxidation pathway. Mutations resulting in SCHAD deficiency cause protein-sensitive CHI and increased systemic levels of some fatty acid oxidation metabolites.

To test the hypothesis that SCHAD-CHI is caused by a specific deficiency of this ubiquitously expressed protein in β-cells we created β-cell-specific SCHAD knock-out (β-SCHADKO) mice by crossing Hadh-floxed animals with mice expressing Cre under the regulation of the Ins1 promoter. Validity of the β-SCHADKO model was confirmed by PCR, Western Blot and immunofluorescence staining of pancreas tissue. Growth and development of β-SCHADKO mice was similar to littermate controls. Plasma glucose in the KOs was significantly reduced in the random fed state (♂ 158 ± 15 vs. 115 ± 28 mg/dL, p=0.0016; ♀ 143 ± 8 vs. 97 ± 19 mg/dL, p<0.0001) and after overnight fasting (♂ 82 ± 14 vs. 56 ± 13 mg/dL, p<0.0002; ♀ 62 ± 7 vs. 42 ± 4 mg/dL, p<0.0001). Insulin and C-peptide levels were elevated in female KOs after overnight fasting (insulin: 0.25 ± 0.15 vs. 0.38 ± 0.21 ng/mL, p=0.0507; C-peptide: 0.15 ± 0.07 vs. 0.26 ± 0.16 ng/mL, p=0.05), but unchanged in the fed state. GSIS and overall glucose homeostasis, as assessed by insulin and glucose tolerance tests, were not significantly altered. Overall, these data indicate that the β-SCHADKO mouse is a suitable model to investigate the hypoglycemic phenotype of underlying SCHAD deficiency.

Disclosure

J. Ludeke: None. K.M. Velasco: None. D.F. De Jesus: None. B.A. Slipp: None. J. Hu: None. S.J. Steine: None. G. Helgeland: None. P. Njølstad: None. R. Kulkarni: None. A. Molven: None.
Metabolic Clearance Rate of Insulin Is Not Saturable within the Physiological Range
Authors: BEDIAKO ISAAC ASARE , PASZKIEWICZ REBECCA L. , WOOLCOTT ORISON O. , BERGMAN RICHARD N.
Published: June 2018

The plasma concentration of insulin is determined by pancreatic beta cell secretion and the metabolic clearance of the hormone. It has been suggested that the concentration of insulin determines its metabolic clearance rate. Also, some reports suggest that clearance is saturable and insulin kinetics are non-linear even within physiologic ranges. We assessed the metabolic clearance rate of insulin at different physiologic concentrations to access if clearance changes with concentration. Using the dog model (n=12), insulin was infused peripherally at 3 incremental rates (dose-response) during the euglycemic clamp. Each infusion rate spanned 90mins, and the last 30mins was considered the steady state. The metabolic clearance rate of insulin was calculated as the ratio of the infusion rate to the steady state plasma concentration. The 3 infusion rates, 1.5, 3.0 and 4.5pmol/kg/min yielded steady state plasma insulin concentrations of 92 ± 8, 165 ± 12 and 256 ± 18pM respectively. The metabolic clearance rate of insulin was consistent and independent of dose (17.8 ±1.7, 19.1 ±1.2 and 18.6 ±1.4 ml/kg/min; p = ns) across the different plasma insulin infusion rates. Also, we found a strong linear correlation (r = 0.99) between the infusion rates and steady state insulin concentrations. Insulin kinetics are linear and the metabolic clearance of insulin is not saturable within physiologic ranges in the conscious dog. Though it’s possible that the site of degradation (i.e., liver vs. periphery) may change with dose.These data demonstrate that changing concentrations of plasma insulin within physiologic concentrations does not change the rate of insulin removal from the plasma.

Disclosure

I. Asare Bediako: None. R.L. Paszkiewicz: None. O.O. Woolcott: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.
Hemoglobin A1c (A1c) Genetics Contributes to A1c/Glucose Mismatches in the Multiethnic VA Million Veteran Program (MVP)
Authors: LEONG AARON , POSNER DANIEL , CHAREST BRIAN R. , RHEE MARY , MEIGS JAMES B. , WILSON PETER W. , COHEN ROBERT M. , MILLER DONALD R. , SUN YAN V. , CHO KELLY , PHILLIPS LAWRENCE S.
Published: June 2018

A1c accuracy is important for diabetes management but mismatches in A1c relative to underlying glucose can impede care. Since the basis for mismatches is poorly understood, we assessed the contributions of 22 A1c variants identified in GWAS that were associated with erythrocytic traits but not glycemia. 73,128 MVP patients had continuity of care and monitoring: >1 PCP visit, >1 outpatient random plasma glucose (RPG) and >1 A1c within each of 3 consecutive two-year periods. They had mean age 67 years and BMI 31 kgm-2; 71% were white and 21% were black; 51% had diabetes (ICD 9 codes and diabetes Rx). Mismatches were defined by the hemoglobin glycation index (HGI) calculated from regression residuals of mean A1c on mean RPG within each period, averaged over the 3 periods. We evaluated the associations with HGI of each A1c variant and a genetic risk score (GRS; sum of alleles weighted by their reported A1c effect sizes) by race. Mean HGI was -0.07% A1c units in whites and 0.2% in blacks. Of the 22 variants, 15 at 13 loci were associated with HGI (P<5 x 10-8, ANK1, CNTN5, ERAL1, G6PD, HBS1L/MYB, HK1, HIST1H4A/HFE, MYO9B, SENP1, SPTA1, SYN2, TMPRSS6 and PEIZO1). GRS was associated with HGI (whites P=2 x 10-189, blacks P=1 x 10-233) and explained HGI variance (whites 1.7%, blacks 5.1%), especially in those without diabetes (whites 3.5%, blacks 11.4%). People in the lowest 10% of GRS had a glucose-independent fall in A1c (mean HGI, whites -0.19%, blacks -0.31% A1c units) while those in the highest 10% of GRS had the opposite (mean HGI, whites 0.06%, blacks 0.29%). The variants with the largest effects on HGI were rs1800562/HIST1H4A/HFE [mean HGI, AA: -0.37%, GG: -0.06% A1c units] in whites and rs1050828/G6PD [mean HGI, T: -0.31%; C: 0.29% A1c units] in black men.

Conclusions: HGI is higher in blacks than whites - a glucose-independent higher A1c. Common genetic variation explains 2-11% of the variance in HGI. Accounting for genetic variation in A1c may improve its accuracy in guiding diabetes care.

Disclosure

A. Leong: None. D. Posner: None. B.R. Charest: None. J.B. Meigs: None. P.W. Wilson: None. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb Company. D.R. Miller: None. Y.V. Sun: None. K. Cho: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc..
The Postprandial C-peptide–to–Glucose Ratio Correlated with Beta-Cell Function in Japanese Patients with Type 2 Diabetes Mellitus
Authors: MATSUHASHI YUKI , CHIKAZAWA SHINJI , NAKAYAMA HIROFUMI , MURABAYASHI MASAYA , MIZUSHIRI SATORU , OSONOI SHO , TAKAHASHI KAZUHISA , OTAKA HIDEYUKI , YANAGIMACHI MIYUKI , MURAKAMI HIROSHI , DAIMON MAKOTO
Published: June 2018

The onset of type 2 diabetes mellitus(T2DM) is based on the insulin resistance and decreasing of insulin secretion. Residual β-cell function is a key factor in achieving optimal glycemic control in patients with type 2 diabetes. Glucagon induces insulin secretion by direcdtly stimulating β-cells, therefore glucagon stimulaton test(GST) is a reliable marker for β-cell function. Fasting C-peptide(CPR)-index(CPR[ng/ml] to glucose[mg/dl] ratio x100; F-CPRI) is used as a marker of insulin secretion. We evaluated the efficacy of postprandial CPR to glucose ratio(P-CPRI) as a tool for evaluating β-cell function. Japanese T2DM patients with inadequte glycemic control(HbA1c>7.0%) were enrolled in the study(n=333, insulin therapy =217). HbA1c, fasting CPR and glucose were measured, and F-CPRI was calculated. Postprandial(120 min after breakfast) CPR and glucose were measured, and P-CPRI was calculated. For the GST, CPR was determinated before and 6 min after 1mg of glucagon injection. GSTδCPR(CPR[6 min] - CPR[0 min]) was calculated. Factors correlated with GSTδCPR were analyzed using simple and multiple stepwise regression analysis. P value<0.was defined as statistically different. F-CPR-index, P-CPR-index and GSTδCPR were 1.42±0.85, 2.26±1.59 and 1.85±1.15, respectively. Simple regression analysis showed that GSTδCPR was significantly correlated with age, height, body weight(BW), BMI, gender, duration of diabetes, diebetic retinopathy, diabetic nephropathy, insulin therapy, F-CPRI and P-CPRI. Multiple stepwise regression analysis revealed that independent factors contributing to GSTδCPR were BW(β=0.331, p<0.001), P-CPRI(β=0.451, p<0.001), duration of diabetes(β= -0.104, p=0.025), diabetic retinopathy(β= -0.127, p=0.004), DPP-4 inhibitor(β= -0.089, p=0.036) and biguanide(β= -0.144, p=0.001). Our date demonstrated that P-CPRI was valuable in assessing β-cell function and can help clinicians in clinical practice.

Disclosure

Y. Matsuhashi: None. S. Chikazawa: None. H. Nakayama: None. M. Murabayashi: None. S. Mizushiri: None. S. Osonoi: None. K. Takahashi: None. H. Otaka: None. M. Yanagimachi: None. H. Murakami: None. M. Daimon: None.
Heparan Sulfate of ß Cells Regulates Insulin Secretion and Contributes to Normal Glucose Homeostasis
Authors: MATSUZAWA TAKURO , YOSHIKAWA TAKEO , SUGAWARA AKIRA , YANAI KAZUHIKO
Published: June 2018

Heparan sulfate (HS) is a linear polysaccharide and abundantly distributes around cell surface. HS can interact with various bioactive molecules and enhance their signal transduction. Thus, HS is involved in diverse biological functions including development, maturation and proliferation of various tissues. Previous reports demonstrated the expression of HS in β-cells and suggested the possible involvement of HS in functions of β-cells. However, the importance of HS for β-cells remains largely unknown. In the present study, we generated mice with β-cell specific deletion of Ext1 (cKO), which encodes an essential enzyme for HS synthesis, to investigate the detailed roles of HS in β-cell development and function. cKO mice had decreased body weight despite increased food intake compared to control mice. cKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge, without insulin resistance. Glucose-induced insulin secretion from isolated islets of cKO mice was also significantly reduced. These results indicate the contribution of HS in β-cells to insulin secretion and glucose homeostasis. The expression of several genes essential for glucose-induced insulin secretion was decreased in cKO islets. Pdx1 and MafA, which are important transcriptional factors for β-cell development and maturation, were reduced in cKO islets, indicating HS promotes development and maturation of β-cells. Immunohistochemical analysis of the cKO pancreas revealed reduced β-cell mass and islet number. The percentage of BrdU- or Ki67-positive β-cells was decreased in cKO islets, suggesting the involvement of HS in the proliferation of β-cells. Insufficient vascularization in cKO islets might contribute to the abnormal islet architecture. These data demonstrate that HS plays diverse roles in β-cell development and maturation, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis.

Disclosure

T. Matsuzawa: None. T. Yoshikawa: None. A. Sugawara: None. K. Yanai: None.
Diabetes Remission Clinical Trial (DiRECT)—Plasma Liver Function Tests Reflect Change in Liver Fat Content in Early Type 2 Diabetes
Authors: ZHYZHNEUSKAYA SVIATLANA V. , AL-MRABEH AHMAD , PETERS CARL , BARNES ALISON C. , HOLLINGSWORTH KIEREN G. , PILKINGTON HELEN , WELSH PAUL , SATTAR NAVEED , LEAN MICHAEL E. , TAYLOR ROY
Published: June 2018

We have evaluated changes in liver function tests and liver fat following 12-month weight change in the Tyneside participants of the prospective, randomised Diabetes Remission Clinical Trial (DiRECT). Complete data were available on 45 of the Intervention group participants. The group was typical of early type 2 diabetes: 53.7±1.2 years; 56% male; weight 99.6±2.6 kg; BMI 34.6±0.7 kg/m2, diabetes duration 3.3±0.2 years. Fasting liver fat content was measured by 3-point Dixon MRI.

Baseline fasting plasma glucose was 157±7 mg/dl, with liver fat grossly elevated at 16.2±1.5% (mean±SEM; upper level of normal 5.5%). Mean weight loss was 11.5±1.1 kg (0-37kg) and liver fat was normalised at 4.7±0.9% (p<0.0001). With weight losses of >10kg, 5-10kg, <5kg, liver fat decreased to 1.9±0.3%, 5.9±1.4% and 10.2±2.2% respectively. ALT decreased by 51% (32.5±3.0 to 16.0±1.1 U/l; p<0.0001), 37% (31.8±3.8 to 19.9±3.7U/l; p=0.002), and 35% (24.8±4.7 to16.1±1.6 U/l; p=0.058) respectively. Similar reductions were observed in GGT, by 53% (p<0.0001), 35% (p=0.003), 26% (p= 0.05) respectively. Lesser changes were observed in AST, by 29% (p<0.0001), 20% (p=0.29), and 28% (p=0.012) respectively. There were positive correlations between changes in liver fat and ALT (r=0.6, p<0.0001), GGT (r=0.4, p=0.009) and AST (r=0.4, p=0.016). Change in liver fat correlated with weight change (r=0.5, p<0.0001).

Following weight loss in type 2 diabetes, changes in ALT and GGT reflect change in liver fat even within the normal range. Early type 2 diabetes is associated with severe nonalcoholic fatty liver disease, and monitoring change by a simple inexpensive blood test is important in clinical practice.

Disclosure

S.V. Zhyzhneuskaya: None. A. Al-Mrabeh: None. C. Peters: None. A.C. Barnes: None. K.G. Hollingsworth: None. H. Pilkington: None. P. Welsh: Research Support; Self; Boehringer Ingelheim GmbH, Theracos, Inc. N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. M.E. Lean: Advisory Panel; Self; Novo Nordisk Inc., Orexigen Therapeutics, Inc.. Research Support; Self; Cambridge Weight Plan. Consultant; Self; Counterweight Ltd. Stock/Shareholder; Self; Eat Balanced. R. Taylor: None.
A Porcine Placental Extract Alleviates Lipotoxicity-Induced NASH by Polarizing M2 Macrophages and Attenuating Stellate Cell Activation in Mice
Authors: CHEN GUANLIANG , XU LIANG , NAGATA NAOTO , NAGASHIMADA MAYUMI , OTA TSUGUHITO
Published: June 2018

NAFLD is caused by excessive hepatic lipid accumulation and associated with activation of macrophage/Kupffer cells and oxidative stress, resulting in nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Placental extracts have been used to treat various chronic diseases due to their antioxidative effect. However, the effects of the extracts on the development of NASH have yet to be elucidated. Here, we investigated the effect of porcine placental extract (PPE) in a lipotoxicity-induced NASH model. C57BL/6 mice were fed a high-cholesterol, high-fat (CL) diet or a CL diet containing 0.1% PPE (CL+0.1%PPE) or 0.3% PPE (CL+0.3%PPE). Liver histology and fibrogenesis were examined. In addition, intrahepatic immune cell numbers were quantified by flow cytometry. After 15 weeks of administration, PPE alleviated lipid accumulation by reducing hepatic TG, TC and NEFA levels, as well as lipid peroxidation, which was assessed by TBARS. PPE improved glucose intolerance and enhanced the insulin signal, assessed by IRβ and Akt phosphorylation, in the liver, which was associated with the attenuation of MAPK (ERK/p38MAPK) and NF-kB activation. Flow cytometry analysis revealed that PPE reduced CD11c+CD206−(M1) by 44.2%, whereas it increased CD11c-CD206+(M2) by 1.4-fold, resulting in a predominance of M2 over M1 macrophage populations in the liver of NASH mice. In addition, PPE downregulated LPS-induced M1 marker mRNA expression in isolated murine peritoneal macrophages, but augmented IL-4-induced M2 marker mRNA expression in a dose-dependent manner. Furthermore, the PPE reduced the hepatic stellate cell (HSC) activation associated with the attenuated transforming growth factor-β/Smad3 signaling, both in the liver of NASH mice and in HSC line. Thus, PPE may be a potential approach to prevent NASH by limiting lipid peroxidation, promoting M2 macrophage polarization, and attenuating HSC activation.

Disclosure

G. Chen: None. L. Xu: None. N. Nagata: None. M. Nagashimada: None. T. Ota: None.
Hepatic Insulin Signaling Regulates Hepatokines to Coordinate Energy Expenditure and Weight Gain through Irs2 in Sim1 Neurons
Authors: TAO RONGYA , COPPS KYLE D. , STOEHR OLIVER , WHITE ORRIS F.
Published: June 2018

Insulin resistance is the underlying cause of type 2 diabetes; however, insulin resistance might also be a feed-back mechanism to protect cells and tissues from acute effects of over nutrition. Based upon our results with LDKO (hepatic specific Irs1L/LIrs2L/L CreAlbumin) mice, we found that hepatic insulin resistance elevated systemic oxygen consumption and energy expenditure, which was associated with a dramatic reduction of the RER (respiratory exchange ratio) and resistance to diet-induced obesity. Deletion of hepatic FoxO1 in LDKO-mice restored energy homeostasis and oxygen consumption, and increased the RER into the normal range. Contrary to the progressive peripheral insulin resistance of the LDKO-mice, Irs2 expression and insulin sensitivity increased in the PVH (paraventricular nucleus of hypothalamus). Interestingly, deletion of Irs2 in the PVH (Irs2L/L-mice intercrossed with CreSim1-mice) increased body weight and promoted obesity. To identify the molecular cross-talk between liver and brain, we used a neuronal cell line to screen for the effects of hepatokines that were dysregulated in LDKO-mice—but normalized in LTKO-mice. Among these dysregulated hepatokines, excess circulating NTF3 and GPX3 led to increased Irs2 expression and insulin sensitivity in neurons. Thus, our study suggests that hepatic FoxO1-dependent hepatokines—NTF3 or GPX3—modulate systemic energy expenditure and body weight through Irs2 expression in the PVH.

Disclosure

R. Tao: None. K.D. Copps: None. O. Stoehr: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories.
mGPDH Depress Hepatic Lipogenesis by Inhibition of ER Stress
Authors: ZHENG YI , ZHENG HONGTING
Published: June 2018

Background: NAFLD is the most common liver disorder worldwide. Mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a component of respiratory chain, and reported to involve in hepatic glucose homeostasis, however its function in hepatic lipid metabolism is unclear. We previously observed a low mGPDH expression in fatty liver. Thus, this study is to determine the role of mGPDH in liver lipid metabolism and steatosis.

Methods: mGPDH-/- mice were fed chow or HFD. ob/ob and HFD mice were treated adenovirus-associated virus (AAV) 8-mGPDH. Hepatic and plasma lipid profile were assessed. Livers were analyzed by histology, qRT-PCR and immunoblot. RNA-sequencing was performed using hepatocyte LO2 infected mGPDH under FFA.

Results: In fatty livers of NAFLD patients and mice (ob/ob, HFD and db/db), mGPDH expression is inhibited. Livers of mGPDH-/- mice become sensitivity to HFD and potentiate to steatosis. Mechanistically, RNA-sequencing reveals mGPDH regulates endoplasmic reticulum (ER)-related proteins, and we further confirm its effect on depressing hepatic lipogenesis is mainly through inhibiting ER stress by activation of the IRE1α branch of the UPR. Moreover, rescuing hepatic mGPDH deficient in ob/ob and HFD mice by liver target AAV8 may be a mechanism for ameliorating hepatic steatosis.

Conclusions: mGPDH serves as a novel suppressor for hepatic lipogenesis, and direct targeting of mGPDH may have therapeutic potential for NAFLD.

Disclosure

Y. Zheng: None. H. Zheng: None.
Ethnic Differences in Hepatic Insulin Clearance Seen since Childhood Suggest a Genetic Basis
Authors: PICCININI FRANCESCA , POLIDORI DAVID , GOWER BARBARA , FERNANDEZ JOSE R. , BERGMAN RICHARD N.
Published: June 2018

African American (AA) adult women (AAw) have 1/3 the hepatic insulin extraction as European American adult women (EAw). Lower hepatic (but not extrahepatic) insulin clearance in AAw contributes to hyperinsulinemia. Our aim was to examine whether hepatic insulin clearance impairment exists in AA since childhood. If so, genetic factors might explain ethnic differences in insulin clearance. The FSIGT was performed on 203 children [55 AAc, 88 EAc, 60 HAc (Hispanic American), ages 7-13 years, mean BMI = 19 kg/m2, basal plasma glucose = 99 mg/dL, insulin = 78 pM, C-peptide = 511 pM]. Data were analyzed with a recent mathematical model providing individual estimates of both hepatic fractional insulin extraction (FEL) and extrahepatic insulin clearance (CLP). Results are presented as mean (SD). Two-way ANOVA and ANCOVA were done: sex and ethnicity were used as groups for both the analysis, while age, Tanner stage and body fat from DXA were the covariates. FEL is lower in AAc (19% (20%)) than EAc (33% (20%)), p = 0.0007). Adjusting for the covariates, ethnicity was still associated with lower FEL in AAc vs. EAc (p = 0.0012); sex had a slight but significant effect (FEL=24% (10%) in boys vs. 29% (10%) in girls, p = 0.04). FEL in HAc (28% (21%)) was not significantly different than either AAc or EAc (p>0.05), with or without covariates correction. No correlation between FEL and age was found in these children. Unlike FEL, CLP was not impacted by ethnicity or sex; similar values were observed among the three groups [27 (12), 21 (12), and 24 (28) mL/kg/min for AAc, HAc, and EAc, respectively; p > 0.05]. As the between-group differences in FEL are seen early in childhood, this suggests genetic factors likely contribute to those, rather than lifestyle, that might have a less evident effect at that age, instead. Playing a more important role than previously realized, the reduced insulin degradation would lead to hyperinsulinemia, insulin resistance, and possibly greater risk for type 2 diabetes in AA, compared to other ethnic groups.

Disclosure

F. Piccinini: None. D. Polidori: Employee; Self; Janssen Research & Development. Stock/Shareholder; Self; Janssen Research & Development. B. Gower: None. J.R. Fernandez: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.