bluuebunny/crossref_metadata_2025 huggingface dataset:
180-LB: Impact of a Multidisciplinary Diabetes Care Team in Primary Care Settings on Glycemic Control
Authors: HANDLOW NICOLE E. , NOLTON BRITTANY , WINTER SARAH E. , WESSEL CYNTHIA M. , PENNOCK JENNIFER
Published: June 2019

Purpose: A multidisciplinary team approach to diabetes management involves various healthcare members to optimize patient outcomes. However, there are limited studies that look at the effect of a multidisciplinary team on diabetes outcomes outside of endocrinology services. This study aimed to evaluate the impact of a primary care multidisciplinary team on glycemic control and additional risk reduction during a 12-week diabetes program.

Methods: Retrospective review of medical records for patients who completed the 12-week diabetes program at three primary care clinics from January to August of 2018 occurred. The primary outcome was mean change in hemoglobin A1c (HbA1c). Secondary outcomes included 24-week HbA1c, mean change in blood pressure, weight, Diabetes Distress Scale (DDS) score, and Patient Health Questionnaire (PHQ9) score. Other secondary objectives included the number of patients on statin therapy and ACE inhibitor or angiotensin receptor blocker therapy as indicated. Patients enrolled in the diabetes program were seen by a provider, pharmacist, dietician, and behavioral health specialist at an initial visit and a 12-week follow-up visit. Follow-up occurred either telephonically or face-to-face in the interim for lifestyle counseling and medication adjustments.

Results: In total, 85 patients were included in the final analysis. At 3 month follow-up, the mean A1c was significantly decreased (2.1+/-2.3, p < 0.001), 54.1% of patients met their A1c goal (p < 0.001), 80.5% were on statin therapy (p < 0.001), and the mean change in weight (kg) was -1.96+/- 3.9 (p = 0.001) from baseline.

Conclusion: This study demonstrates that a multidisciplinary approach to diabetes management can reduce HbA1c and other risk factors. A multidisciplinary model can be replicated in primary care offices to allow for comprehensive care and improvement in health outcomes for a broader patient population who may not have access to specialty services.

Disclosure

N.E. Handlow: None. B. Nolton: None. S.E. Winter: None. C.M. Wessel: None. J. Pennock: None.

Funding

R.K. Mellon Foundation
181-OR: ADA Presidents' Select Abstract: Fox01 Deficiency Impedes Beta-Cell Compensation for Maternal Insulin Resistance and Causes Gestational Diabetes in Female Mice
Authors: YAMAUCHI JUN , ZHANG TING , LEE SOJIN , DONG H. HENRY
Published: June 2019

Beta-cell compensation is an adaptive mechanism by which beta-cells increase insulin secretion to overcome insulin resistance for maintaining euglycemia in obesity. Likewise, beta-cell compensation occurs during pregnancy, a physiological state that is characterized by increased insulin demand from the fetus. This effect, along with acquired insulin resistance in the mother, promotes beta-cell compensation for maintaining glucose homeostasis during gestation. Insufficient beta-cell compensation for maternal insulin resistance contributes to gestational diabetes. To understand the underlying mechanism of gestational diabetes, we determined the role of FoxO1 in regulating beta-cell mass and function in response to maternal insulin resistance. FoxO1 is a key transcription factor that mediates insulin action on cell metabolism, survival, proliferation, differentiation and oxidative stress. We found that beta-cell FoxO1 expression becomes markedly upregulated, coinciding with the induction of beta-cell compensation in pregnant mice. To gain mechanistic insight into FoxO1-mediated induction of gestational beta-cell compensation, we generated FoxO1-KO mice, in which FoxO1 is conditionally deleted in mature islets of adult mice using an inducible Pdx1-Cre-ERT system. We showed that prior to gestation, female FoxO1-KO mice exhibited normal blood glucose metabolism. However, at gestational day 14.5, pregnant FoxO1-KO mice exhibited fasting hyperglycemia and glucose intolerance. These effects were attributable to abnormal glucose-stimulated insulin secretion profiles in pregnant FoxO1-KO vs. control female mice. Using in vivo Brdu-labeling assay, we showed that FoxO1-deficient islets were associated with impaired abilities to mount a compensatory induction in beta-cell mass during pregnancy. Our data characterize FoxO1 as a pivotal factor for regulating the adaptive changes of beta-cell mass and function during pregnancy.

Disclosure

J. Yamauchi: None. T. Zhang: None. S. Lee: None. H. Dong: None.

Funding

National Institutes of Health
1816-P: Sex-Specific Metabolic Imbalance and Hypothalamic Inflammation Triggered by Low-Grade Benzene Exposure
Authors: DEBARBA LUCAS K. , MULKA ADAM , AWADA ABEAR A. , DIDYUK OLESYA , KLUEH ULRIKE , SADAGURSKI MARIANNA
Published: June 2019

Current studies have shown that insulin resistance, T2D have been associated with long- term exposure to air and traffic pollution. Benzene is a highly volatile liquid, which is a constituent of crude petroleum. Given its ubiquitous utilization in industry as well as consumer products, it is classified as a common airborne pollutant. We hypothesized that benzene, at levels below carcinogenic contributes to insulin resistance and inflammatory responses linking persistent organic pollutants exposure to T2D mellitus. For this purpose, C57BL/6 mice in inhalation chambers were exposed to benzene concentration of 50 ppm for 6h/day for 4 weeks. We found that under these conditions, exposure to benzene did not significantly influence mice body weight, neither had it trigger any toxic responses in these animals. Despite normal fasting glucose and insulin levels, benzene-exposed male mice displayed significantly impaired glucose tolerance. Consequently, we detected an increase in hepatic genes associated with gluconeogenesis, G6Pase and Pck1, and the expression of SREBP-1c and SREBP-2, genes associated with lipid synthesis was significantly elevated in livers from benzene exposed male mice as compared to control mice. Female mice were completely resistant to the negative metabolic consequences of chronic benzene exposure. Further sex differences were apparent in neuroinflammatory responses, with greater male vulnerability observed in the hypothalamus of benzene- exposed animals. Benzene exposure promoted hypothalamic gliosis and robust neuronal activation in the arcuate, paraventricular, ventromedial and dorsomedial hypothalamic nucleus. These findings demonstrate male vulnerability to air pollution, and provide evidence that exposure to benzene induces metabolic imbalance and severe neuroinflammatory responses in a sex-specific manner. Persistent ambient benzene exposure may be a heretofore unrecognized contributor to metabolic diseases with male bias.

Disclosure

L.K. Debarba: None. A. Mulka: None. A.A. Awada: None. O. Didyuk: None. U. Klueh: Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC. M. Sadagurski: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
1817-P: Metabolic Surgery Affects Brain Glucose Metabolism, Cognitive Function, and Neuroplasticity in Humans
Authors: DANIELE GIUSEPPE , DARDANO ANGELA , VOLTERRANI DUCCIO , CICCARONE ANNAMARIA , GIUSTI LAURA , AGHAKHANYAN GAYANE , CECCARINI GIOVANNI , SANTINI FERRUCCIO , MORETTO CARLO , BINDA PAOLA , LUNGHI CLAUDIA , MORRONE MARIA CONCETTA , PRATO STEFANO DEL
Published: June 2019

Risk of neurodegenerative disorders, cognitive dysfunction and impaired neuroplasticity (NP) is increased in obesity. We evaluated the effect of metabolic surgery (RYGB) on insulin sensitivity, brain glucose utilization, cognitive function and NP. Thirteen obese subjects (BMI 46±4.9 kg/m2; HbA1c 40.1±5.9 mmol/mol; age 42.4±9.8 years) with no history of psychiatric illness and psychoactive drug use and major brain disorders were recruited. Subjects underwent a 75 gr OGTT during a 60 min FDG dynamic brain PET study, standardized neurocognitive tests and NP by psychophysical technique at baseline and 6-months after RYGB. Plasma glucose, insulin, GLP-1, GIP, VIP, BDNF and leptin were measured during OGTT. After RYGB, BMI declined (45.7±1.6 to 34.3±1.6 kg/m2; p<0.001) and insulin sensitivity improved (HOMA-IR 4.7±0.9 to 1.6±0.4; P=0.006). Cerebral glucose metabolic rate (CMRg; by voxel-wise paired analysis) declined in several brain regions (p=0.005, kE>50). Token and Trail Making Test score change correlated with CMRg change in orbitofrontal (r=0.6, r=-0.81), parietal (r=0.64, r=-0.77), temporal (r=0.6, r=-0.78) and visual cortex (r=0.64, r=-0.75), hippocampus (r=0.6, r=-0.71) and caudate/putamen (r=0.64, r=-0.80; all p=0.03 or less), respectively. After RYGB, NP increased (0.01± 0.03 to 0.11±0.04; p=0.008) and correlated with CMRg change in orbitofrontal cortex (r=0.59; p=0.03) and hippocampus (r=0.58; p=0.03). CMRg of several cortical and subcortical areas correlated with HOMA-IR (p<0.001) but not with BMI. GLP-1/GIP levels increased (P<0.002) with no correlation with CMRg, VIP or BDNF levels. Fasting leptin decreased (73.8±45.5 to 14.3±5.9 pmol/l; p<0.008) and correlated with CMRg change in hippocampus (r=0.6; r=0.03). These results show that metabolic surgery modulates CMRg in brain areas involved in cognitive function and neuroplasticity, suggesting reduction of brain glucose utilization decrease may contribute to brain neuroprotection.

Disclosure

G. Daniele: None. A. Dardano: None. D. Volterrani: None. A. Ciccarone: None. L. Giusti: None. G. Aghakhanyan: None. G. Ceccarini: None. F. Santini: None. C. Moretto: None. P. Binda: None. C. Lunghi: None. M. Morrone: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited.
1822-P: Transient Insulin Deprivation Alters Cognition and Brain Energy Metabolism in People with Type 1 Diabetes
Authors: CREO ANA , CORTES TIFFANY M. , HUEBNER ANDREA R. , LTEIF AIDA , PORT JOHN , NAIR K. SREEKUMARAN
Published: June 2019

Introduction: Diabetes is associated with impaired cognition but the effect of the transient insulin deprivation on cognition and its underlying mechanisms remain unclear.

Objective: We determined whether transient insulin deprivation in type 1 diabetic adults (T1D) and adolescents alters brain structure, functions and blood flow compared to nondiabetics (ND).

Methods: We performed structural MRI, phosphorous31 NMR spectroscopy, and neuropsychiatric testing at baseline and following 6 hours of insulin deprivation in 14 adolescent (14-17 years) and adult (18-44 years) T1D and age- sex- and BMI-matched ND controls.

Results: There were no significant changes on baseline structural MRI between the groups. After insulin deprivation, T1D had a significantly greater blood glucose (272 vs. 85 mg/dL), greater beta hydroxybutyrate (1.45 vs. 0.3 mmol/L), and decreased bicarbonate level (25.5 vs. 21.5 mmol/L) at six hours compared to ND. Following insulin deprivation, there was a significant difference in T1D left cortical volume compared to ND. On diffusion tensor imaging at baseline and after insulin deprivation, T1D had a higher fractional anisotropy compared to ND. T1D also had a significant decline in phosphocreatine/ATP after insulin deprivation compared to ND. Lastly after insulin deprivation, T1D failed to have learned improvement on repeat neuropsychiatric testing, with ND having significantly greater improvements in executive function, attention and working memory compared to T1D.

Conclusion: Transient hyperglycemia and insulin deprivation caused a significant decline in some important aspects of cognition and brain energy metabolism, indicating that even transient insulin deprivation affects brain function and morphology. This may have important clinical implications as many diabetic patients inadvertently have occasional periods of transient insulin deprivation.

Disclosure

A. Creo: Consultant; Self; Ultragenyx. T.M. Cortes: None. A.R. Huebner: None. A. Lteif: None. J. Port: None. K. Nair: None.
1825-P: Reduced Insulin Clearance Compensates for Impaired ß-Cell Function to Maintain Normal Insulinemia in Normotolerant Women with History of Gestational Diabetes
Authors: PACINI GIOVANNI , TURA ANDREA , VEJRAŽKOVÁ DANIELA , LUKÁŠOVÁ PETRA , VcELÁK JOSEF , VAnKOVÁ MARKÉTA , BENDLOVA BELA
Published: June 2019

Gestational diabetes (GDM) is one of the most common complications of pregnancy and it is frequently predictive of later maternal type 2 diabetes. A defect in insulin secretion is assumed to contribute to the development of GDM, which may be regarded as a prediabetic state. However, lean former GDM maintain normal insulinemia despite elevated glucose during oral test (OGTT).

Aim of this study was to evaluate some of the main processes involved in glucose tolerance in a large cohort of non-obese normotolerant former GDM. A total of 721 women participated in the study: 344 with recent GDM history (FGDM, 0.5-1 year after delivery; age=34±5 years, BMI=23±4 kg/m2, HbA1c=36±5 nmol/mol) and 377 non-pregnant matching control women (32±12 years, 24±4 kg/m2, p=0.3). All underwent 75g-3h OGTT with frequent sampling for glucose, insulin and C-peptide. Insulin sensitivity (OGIS, ml/minute m2) and insulin secretion from C-peptide (CPS, nmol) were assessed through mathematical modelling and deconvolution; beta cell function (BCF) as the ratio of the areas under the curves of C-peptide and glucose; insulin clearance (INCL) as the ratio CPS/AUCINS. Data are given as mean±SD. FGDM had higher basal glucose (85±6 mg/dl vs. 82±7, p<0.0001), but similar insulin levels (7±6 µU/ml vs. 7±5, p=0.2). OGTT stimulated glucose was higher in FGDM (AUCGLUC=19±3 minute g/dl vs. 17±3, p<0.0001); OGIS was analogous (521±63 vs. 530±67, p=0.1); BCF was lower in FGDM (342±88 nmol/mmol vs. 396±110, p<0.002), but AUCINS was similar (37.8±24.6 minute nmol/l vs. 34.8±21.6, p=0.1). INCL was reduced (16.1±4.5 ml/minute vs. 18.7±5.8, p<0.0001).

Conclusion: non-obese, normotolerant FGDM are characterized by normal insulin sensitivity and reduced B-cell function. However, a concomitant reduction of insulin clearance acts to maintain relatively normal insulin levels, which however are not sufficient to keep a lower glycemia.

Disclosure

G. Pacini: None. A. Tura: None. D. VejraŽková: None. P. Lukášová: None. J. Vcelák: None. M. Vanková: None. B. Bendlova: None.

Funding

Ministry of Health of the Czech Republic (RVO00023761)
1830-P: Empagliflozin as Well as Anakinra Reduces Symptomatic Postprandial Hypoglycemia after Gastric Bypass
Authors: HEPPRICH MATTHIAS , SCHELKER BENJAMIN , WIEDEMANN SOPHIA J. , TRINH BECKEY , BÖNI-SCHNETZLER MARIANNE , DONATH MARC Y.
Published: June 2019

Background: Postprandial hypoglycemia (PPH) is a debilitating complication after bariatric surgery, due to an exaggerated hyperinsulinemic response after carbohydrate ingestion. Recent studies have shown that IL-1β contributes to the postprandial stimulation of insulin. Similarly, lowering hyperglycemic peak by SGLT2-inhibition may reduce insulin secretion. We investigated whether the IL-1 receptor antagonist anakinra or empagliflozin influence PPH in patients after gastric bypass.

Methods: We included 12 subjects with PPH after gastric bypass in a placebo controlled, double-blind, randomized, cross-over proof-of-concept study. Subjects received on each of the 3 study days either empagliflozin, anakinra or the respective placebos followed by a mixed-meal-test (MMT) with assessment of hypoglycaemia.

Results: Treatment with empagliflozin reduced glycaemia at 30 (11.2 vs. 10.1 mmol/l), 60 (9.1 vs. 6.9 mmol/l) and 90 (4.5 vs. 3.5 mmol/l) minutes of the MMT compared to placebo and was followed by a significant reduction of hypoglycemic events (n = 2, 16.6%) compared to placebo (n = 8, 61.5%). Treatment with anakinra showed a similar glucose curve as placebo, but was also followed by a significantly reduced rate of hypoglycemic events (n = 2, 16.6%). Both treatment interventions showed lowered insulin and c-peptide levels compared to placebo (p<0.001).

Conclusion: Empagliflozin as well as Anakinra significantly reduced hypoglycemic episodes in patients after gastric bypass by decreased insulin secretion. Therefore, empagliflozin and IL-1 antagonism, could be promising novel therapeutic options for patients with refractory PPH after gastric bypass.

Disclosure

M. Hepprich: None. B. Schelker: None. S.J. Wiedemann: None. B. Trinh: None. M. Böni-Schnetzler: None. M.Y. Donath: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi.

Funding

University of Basel
1838-P: Vertical Sleeve Gastrectomy Improves Glycemia Independent of Caloric Restriction through a Coordinated Regulation of Incretin Secretion, Insulin Sensitivity, and Islet Function
Authors: DOUROS JONATHAN D.
Published: June 2019

Vertical sleeve gastrectomy (VSG) alleviates diabetes in 40-50% of patients, however the degree to which weight loss drives this phenomenon is unclear. To address this question, we compared key factors for glucose regulation for 90d between mice with a VSG and sham-operated controls (PF-Sham)that were pair-fed to match caloric restriction between groups. Animals received separate mixed meal, intraperitoneal glucose, and insulin tolerance tests (MMTT, IPGTT, ITT) within 14d of surgery, and again 70-80d postoperatively. After the 90d observation period, pancreatic islets were isolated and measurements of glucose-stimulated insulin secretion (GSIS) and Ca2+ oscillations were performed using ex vivo perifusion. Over 90 days the mean body weight of the VSG and PF-Sham mice did not differ presumably due to the pair-feeding regimen. Glucose clearance and insulin secretion during MMTTs were greater in VSG mice compared to controls at both 12 and 80d, as were prandial GLP-1, GIP, and glucagon levels. Notably, the MMTT blood glucose rose in the PF-Sham group from day 12 to 80, but improved further in the VSG group during the same time period despite similar body weight gain. Glucose disposal and insulin secretion were enhanced during IPGTTs at both 10 and 70d in the VSG group, while islets isolated from VSG mice displayed elevated GSIS and glucose-stimulated Ca2+ oscillations ex vivo. Insulin sensitivity was enhanced in the VSG group at 75d following surgery, but not 14d. Our data suggest a multifactorial model for the improvement in glucose metabolism after VSG in which insulin secretion is rapidly enhanced after surgery due in part to enhanced incretin secretion and islet glucose sensitivity. Prandial incretin levels dampen over time, while enhanced to islet function persist chronically after surgery. Insulin sensitivity improves after VSG independent of BW, but only at later time points as incretin levels wane.

Disclosure

J.D. Douros: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (F32DK115031-01)
1848-P: Effect of Brain Glucagon Action on Hepatic Glucose Production
Authors: EDGERTON DALE S. , KRAFT GUILLAUME , FARMER BEN , SMITH MARTA S. , CHERRINGTON ALAN D.
Published: June 2019

Recent studies suggested that glucagon, or blockers of glucagon action, injected into the hypothalamus of rodents can regulate hepatic glucose production (HGP). Direct hepatic glucagon action stimulates HGP but this effect rapidly wanes for reasons that are unclear. To test the hypothesis that this is due to an inhibitory CNS effect of glucagon, as previously proposed, the hormone was administered via a peripheral vein or the head arteries to conscious dogs. After tracer equilibration and basal sampling periods somatostatin was used to disable the endocrine pancreas (0-240 minute) and insulin and glucagon were replaced intraportally at basal rates. Glucagon was also infused either into a leg vein to raise its level at the liver (2.3 ng/kg/minute; CON; n=6) or into the carotid and vertebral arteries (2.8 ng/kg/minute; HEAD; n=6) to create the same increase in glucagon at the liver as in CON, while further increasing brain glucagon exposure. Plasma insulin levels remained basal in both groups. Hepatic glucagon increased from 40±4 to 87±7 and 34±3 to 91±8 pg/ml in CON and HEAD, respectively. The levels of glucagon entering the brain were 85±9 vs. 196±19 pg/ml, respectively, based on jugular vein glucagon levels (brain glucagon extraction was 20%). Hypothalamic cAMP was 2-fold greater in HEAD (140±26 vs. 296±46 pmol/g, respectively). HGP increased from basal (3.0±0.2 and 2.4±0.2 mg/kg/minute in CON and HEAD, respectively) in response to glucagon, peaking rapidly within 30 minutes (6.5±0.5 vs. 6.2±0.4 mg/kg/minute, respectively; P=0.6), quickly declining over the next 30 minute, and then falling slowly to near-basal rates at 240 minute (2.7±0.2 vs. 2.8±0.2 mg/kg/minute, respectively). Arterial plasma glucose levels increased from basal (∼110 mg/dl) and plateaued over the last 3 hours (178±10 vs. 192±5 mg/dl, in CON and HEAD, respectively). Despite the differences in the glucagon level and engagement at the brain, no difference in hepatic glucose metabolism was detected. This suggests that brain glucagon action is not responsible for the waning of its effect on HGP.

Disclosure

D.S. Edgerton: Speaker's Bureau; Self; Novo Nordisk A/S. G. Kraft: Consultant; Self; Metavention. B. Farmer: None. M.S. Smith: None. A.D. Cherrington: Board Member; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Abvance, Boston Scientific Corporation, California Institute for Biomedical Research, Galvani Bioelectronics Limited, MedImmune, Novo Nordisk Inc., Thetis Pharmaceuticals LLC. Research Support; Self; Abvance, Diasome Pharmaceuticals, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; Abvance, Biocon, Fractyl Laboratories, Inc., Metavention, Novo Nordisk Inc., Sensulin, LLC., Thetis Pharmaceuticals LLC, Zafgen, Inc.

Funding

National Institutes of Health
185-OR: Effects of Exposure to Maternal Obesity In Utero on White Matter Connections between the Hypothalamus and Hippocampus in Children
Authors: PAGE KATHLEEN A. , LUO SHAN , CHOW TING , CABEEN RYAN PAYNE , CLARK KRISTI , ALVES JASMIN , MARTINEZ MAYRA P. , BUCHANAN THOMAS A. , XIANG ANNY
Published: June 2019

Exposure to maternal obesity in utero is associated with a greater risk for obesity and cognitive deficits in children. The mechanisms are not yet established, but rodent studies suggest that disruption of connectivity between the hypothalamus and hippocampus might be involved. We tested the hypothesis that exposure to maternal overweight/obesity (OW/OB) is associated with reduced integrity of the fornix, a tract connecting the hippocampus and hypothalamus, in children. Seventy-four children (42 girls, 32 boys) ages 7 to 11 years who were born at Kaiser Permanente Southern California participated. Maternal pre-pregnancy BMI was obtained from electronic medical records. Child’s height and weight were measured directly. Diffusion tensor imaging (DTI) was used to measure left and right fornix fractional anisotropy (FA), a measure from zero to one that reflects white matter integrity in coherent fiber bundles. Intracranial volume (ICV) was measured with an anatomical scan. Linear regression was used to compare FA in the fornix of children born to normal-weight (NW) mothers vs. children born to OW/OB mothers without and with adjustment for potential confounding variables. Seventeen mothers were NW (BMI <25 kg/m2) and 57 were OW/OB (BMI ≥25 kg/m2) prior to pregnancy. Children’s mean (±SD) BMI was 18.6±4 kg/m2. FA in the fornix ranged from 0.25 to 0.34. Children born to OW/OB mothers had lower FA in both left and right fornix than children born to NW mothers, with the difference for the right fornix statistically significant (p=0.01). Results remained after adjusting for child ICV, age, sex, BMI (p=0.04) and further adjusting for maternal GDM and socioeconomic status (p=0.02). Results show that in utero exposure to maternal OW/OB is associated with reduced integrity of the hypothalamic-hippocampal pathway in children and suggest a possible mechanism linking maternal obesity to metabolic and cognitive deficits in offspring.

Disclosure

K.A. Page: None. S. Luo: None. T. Chow: None. R.P. Cabeen: None. K. Clark: None. J. Alves: None. M.P. Martinez: None. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. A. Xiang: None.

Funding

American Diabetes Association (1-14-ACE-36 to K.A.P.)
1854-P: Reduced Liver Fat Is Associated with Improved Insulin Sensitivity and Reduced ß-Cell Secretory Demand following Gastric Banding
Authors: XIANG ANNY , WU JUN , CHOW TING , MARTINEZ MAYRA P. , HWANG DARRYL H. , TRIGO ENRIQUE , KATKHOUDA NAMIR , BEALE ELIZABETH , NAYAK KRISHNA S. , BUCHANAN THOMAS A. ,   THE RISE CONSORTIUM
Published: June 2019

Weight loss induced by gastric banding improves insulin sensitivity and reduces secretory demand on β-cells in the Restoring Insulin Secretion (RISE) Consortium BetaFat Study. Here we examined the role of liver fat in this process. Total % body fat (%BF) was measured by DXA; visceral fat volume (VFV) and hepatic fat fraction (HFF) by MRI; and insulin sensitivity (steady-state glucose infusion rate/insulin [M/I]) and β-cell function (acute, steady state [SSCP] and arginine-stimulated maximum ([ACPRmax]) C-peptide concentrations by hyperglycemic clamp. Associations were assessed using linear regression models adjusted for age and sex. Baseline included 73 adults with moderate obesity and impaired glucose tolerance or early type 2 diabetes (81% female; mean±SD age of 49±10 years., BMI 35±3 kg/m2, %BF 44±6%, VFV 3.3±1.4 L and HFF 12±8%). At baseline, BMI and HFF were significantly associated with M/I (r=-0.27 and -0.33 respectively; p≤0.02) and SSCP (r=0.26 for each; p=0.02). Adjustment for M/I eliminated the significance of the associations with SSCP (r≤0.11 for each; p>0.3). %BF and VFV were not significantly associated with M/I or β-cell measures. During follow-up, 23 subjects from the gastric banding group repeated baseline tests at 2-years after surgery. BMI, %BF, VFV and HFF decreased by 3.7±2.9 kg/m2, 3.2±3.6%, 0.6±0.7 L, and 5.0±7.2% respectively during the 2-years follow-up (all p≤0.0003). Change in BMI was significantly associated with change in M/I (r=-0.42, p=0.049) but not with changes in β-cell measures. Change in HFF was significantly associated with changes in M/I (r=-0.59, p=0.003) and ACPRmax (r=0.55, p=0.007); adjustment for change in M/I reduced the association of HFF with ACPRmax to r=0.39 (p=0.06). Changes in %BF and VFV were not significantly associated with changes in M/I or β-cell measures. Thus, changes in hepatic fat may contribute to improved insulin sensitivity and reduced secretory demand on β-cells following gastric banding.

Disclosure

A. Xiang: None. J. Wu: None. T. Chow: None. M.P. Martinez: None. D.H. Hwang: None. E. Trigo: None. N. Katkhouda: Consultant; Self; Bard davol, Baxter, Medtronic, Storz. E. Beale: None. K.S. Nayak: None. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery.

Funding

National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases
186-OR: Plasma Glycated CD59 (pGCD59) Predicts Early Gestational Diabetes (GDM) and Abnormal Neonatal Outcomes: DALI Study Secondary Analysis
Authors: HALPERIN JOSE , MA DONGDONG , LUQUE-FERNANDEZ MIGUEL A. , BOGDANET DELIA , DESOYE GERNOT , DUNNE FIDELMA P. ,   ON BEHALF OF DALI STUDY
Published: June 2019

pGCD59 is an emerging biomarker for diabetes and GDM. In 1,000 women undergoing 2-step GDM screening, pGCD59 at weeks 24-28 classified GDM subjects with high sensitivity and specificity and was associated with the risk of large for gestational age (LGA) babies. GDM early in pregnancy is a public health challenge because it increases the risk of adverse outcomes. To assess pGCD59 as a predictor of early GDM and abnormal outcomes, levels of pGCD59 were measured in 807 samples from women undergoing a 1-step OGTT (75gr-2hr; WHO 2013 criteria) at <20 weeks gestation in the DALI study, a European trial of women at high risk of GDM.

Results: Among 807 samples, 481 subjects had normal glucose tolerance throughout the pregnancy (Controls) and 205 met WHO 2013 criteria for GDM at <20 weeks (Cases). Age, race/ethnicity, and BMI were similar among Cases and Controls. pGCD59 accurately predicted the diagnosis of GDM in early pregnancy (AUCROC = 0.9). The risk of LGA (>90thpercentile) was positively associated with pGCD59 (p = 0.04) in Cases but not in Controls. Cases who delivered LGA newborns had higher median levels of pGCD59 than those who delivered non-LGA newborns (pGCD59 (SPU): Case-LGA: 4.4[1.5], Case-non-LGA 3.8[1.2]; p = 0.03). In contrast, median levels of pGCD59 were similar in Controls who delivered LGA or non-LGA newborns. The risk of congenital malformations or neonatal hypoglycemia was also associated with higher maternal levels of pGCD59: i) mothers who delivered babies with malformations had 60% higher mean pGCD59, ii) the odds ratio of a malformation was 3.4 (95% CI: 1.1, 10.1) in the 4th as compared with the 1st quartile of pGCD59, and iii) one unit increase in pGCD59 was associated with a 70% higher odds ratio of neonatal hypoglycemia. HbA1c failed to predict GDM or abnormal neonatal outcomes.

Conclusion: Our results indicate that pGCD59 is a simple and accurate biomarker for early detection of GDM and for risk assessment of its potentially serious complications.

Disclosure

J. Halperin: Stock/Shareholder; Self; Mellitus, LLC. D. Ma: None. M.A. Luque-Fernandez: None. D. Bogdanet: None. G. Desoye: None. F.P. Dunne: None.

Funding

National Institutes of Health (R01DK101442 to J.H.); European Union (242187)
1860-P: Liver Fat and Visceral Fat Are Associated with Different Metabolic and Pathophysiologic Profiles but with Similar Relationships with Whole Body Insulin Resistance
Authors: PARK IE BYUNG , LEE KIYOUNG , LEE DAEHO
Published: June 2019

MRI-based examinations of hepatic steatosis and body fat are becoming more familiar and useful for metabolic studies including NAFLD. MRI-estimated proton density fat fraction (MRI-PDFF) can haptic fat exactly without biopsy, enabling us to evaluate the effect of liver fat more sophisticatedly than ever. Although hepatic fat and visceral fats are both important for metabolic and cardiovascular diseases, detailed evaluation of the effect of each fat depot on various metabolic profiles have not been performed, In the present study, we evaluated the differential effect between hepatic and visceral fats on various metabolic profiles including glucose and lipid metabolism, islet cell function, insulin resistance, and inflammation. A total of 82 subjects (25 healthy volunteers and 57 patients with suspected, or proven NAFLD) who underwent MRI examinations for MRI-PDFF and visceral fat measurement. Additionally, anthropometric and laboratory studies and total body fat measurement by DXA were also performed. Other causes of chronic liver diseases, such as alcoholic, autoimmune or viral hepatitis, and other diseases, were excluded from the study. The amounts of hepatic fat and visceral fats measured by MRI showed similar significant correlations with HOMA-IR (r=0.540 vs. r=0.538, p <0.01, respectively) as with A1C (r=0.448 vs. r=0.495, p <0.01 each). However, hepatic fat showed more close association with FBS, triacylglycerol, complement factor C3, and cytokeratin 18. Visceral fat correlated more with fasting plasma insulin, glucagon and angiotensinogen levels. Total body fat measured by DXA did not show such characteristic patterns of correlations and showed only a weak or no correlation with those parameters. Thus, our results showed that both hepatic fat and visceral fat depots are important determinants of whole-body insulin resistance and glucose metabolism.

Disclosure

I. Park: None. K. Lee: None. D. Lee: None.
1863-P: The Hepatic Role of Heat Shock Protein 72 in the Pathogenesis of Type 2 Diabetes
Authors: KONDO TATSUYA , KITANO SAYAKA , MIYAKAWA NOBUKAZU , WATANABE TAKURO , GOTO RIEKO , ONO KAORU , IGATA MOTOYUKI , KAWASHIMA JUNJI , MOTOSHIMA HIROYUKI , MATSUMURA TAKESHI , ARAKI EIICHI
Published: June 2019

Cell stresses, such as ER stress or oxidative stress are considered to be key mediators in pathophysiology of type 2 diabetes. Heat shock protein (HSP) 72, a major inducible HSP against heat, serves to protect cells from those cellular stresses and works in protein quality control. Induction of HSP72 improves glucose intolerance in type 2 diabetic model mice. In this study, we investigated glucose metabolism in whole body HSP72 deficient (KO) mice. The effects of hepatic HSP72 induction in KO mice were also investigated. KO mice and control mice were subjected to a high-fat diet regimen. Metabolic parameters and pathophysiological examination were performed. HSP72 was overexpressed in mice by lenti-virus to investigate the role of HSP72 in liver. There were no significant differences in body weight and food intake between two groups. Fasting and random-fed blood glucose levels were significantly higher in KO mice than those in control mice. The fasting insulin level was significantly lower in KO mice. Upon glucose challenge, blood glucose levels were higher in KO mice. On insulin tolerance test, KO mice exhibited insulin resistant phenotype. Visceral fat mass was increased and hepatic steatosis was obvious in KO mice with increased SREBP-1c mRNA expression. Upon insulin stimulation, phosphorylation of Akt was decreased in KO liver, with increased activation of JNK. Hepatic gluconeogenesis was not suppressed in KO accompanied by increased gluconeogenic enzymes. When restoring HSP72 expression in liver by lenti-virus on KO mice, blood glucose, hepatic steatosis and gluconeogenesis were ameliorated. Interestingly, visceral fat size and macrophage infiltration were both reversed by hepatic HSP72 induction. Deficiency of HSP72 leads to type 2 diabetic phenotype. As induction of HSP72 in liver is beneficial to improve glucose homeostasis in KO, the abundance of HSP72 in liver is critical in diabetic pathophysiology, and appropriate HSP72 induction may serve as a target in the treatment of type 2 diabetes.

Disclosure

T. Kondo: None. S. Kitano: None. N. Miyakawa: None. T. Watanabe: None. R. Goto: None. K. Ono: None. M. Igata: None. J. Kawashima: None. H. Motoshima: None. T. Matsumura: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi.

Funding

Japan Society for the Promotion of Science
1868-P: Bromocriptine (BC) Improves Hepatic Steatosis, Inflammation, and ER Stress in a Mouse Obesogenic Dietary Model of Nonalcoholic Steatohepatitis (NASH)
Authors: TSAI TSUNG-HUANG , CINCOTTA ANTHONY
Published: June 2019

The pathogenesis of NASH is a complex interaction among hepatic lipotoxicity, oxidative stress, mitochondrial dysfunction and ER stress leading to hepatic inflammation, cell death, and fibrosis. Bromocriptine, a dopamine D2 receptor agonist is known to reduce adipose lipolysis, plasma hyperFFAemia, and hepatic lipogenesis and inflammation. Also, the antidiabetes drug, bromocriptine-QR has been demonstrated to reduce cardiovascular events. Therefore, we investigated the impact of BC on hepatic pathophysiology in a mouse obesogenic dietary model of NASH. Six-week-old C57B6 male mice (N=8/gr) were maintained on a 40 kcal% fat diet with 5% fructose in the drinking water for 12 weeks to induce NASH then randomized to BC (10mg/kg) or vehicle daily treatment for an additional 3 weeks while maintained on the diet. A group of mice on normal diet was used as a normal reference control. Such BC therapy reduced plasma glucose (28.6%), insulin (31.4%), leptin (42.7%), cholesterol (21.9%) and body weight (14.2%) relative to vehicle (P<0.01). Also, plasma biomarkers of hepatic inflammation: elevated ALT, AST, and LPS, were reduced by BC (32.6, 38.8, and 38.1%, respectively, P<0.05) vs. vehicle. Treatment with BC significantly reduced four gene expression markers each for steatosis (SREBP1c, FASN, ACC1, PLIN2), fatty acid oxidation (PPARα, PGC1α, CPT1, UCP1), inflammation (TNFa, IL1β, MCP1, iNOS), ER stress (DDIT3, ATF, sXBP1, HSPA5), and fibrosis (αSMA, TGFβ, COL1A, TXNIP) by 16-76, 17-47, 31-75, 20-55, and 21-70%, respectively (P<0.05 for each gene). Finally, histological analysis of the liver revealed BC therapy reduced steatosis, inflammation, and ballooning degeneration resulting in a 63% reduced NAFLD activity score (2.6 vs. 7.1, P<0.01). The BC effects on NASH resulted in hepatic physiology closely resembling the normal diet control group. These results suggest that BC could be an effective therapy for NAFLD and NASH.

Disclosure

T. Tsai: Employee; Self; VeroScience LLC. A. Cincotta: Employee; Self; VeroScience LLC.
1870-P: Glucagon-Receptor Signaling Reverses Hepatic Steatosis Independent of Leptin Receptor Expression
Authors: NASON SHELLY , KIM TEAYOUN , ANTIPENKO JESSICA P. , FINAN BRIAN , DIMARCHI RICHARD , HABEGGER KIRK M.
Published: June 2019

Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that GCGR signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in DIO mice; however, the mechanisms underlying this aspect of glucagon biology remains unclear. Investigation of downstream GCGR targets elucidated potent and previously unknown regulation of liver leptin receptor (Lepr) expression. Intriguingly, we found GCGR agonism induces hepatic Lepr expression in vivo and in vitro. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Administration of the selective GCGR agonist IUB288 in both lean and diet-induced obese (DIO) mice increases both total hepatic Lepr (p<0.001) expression and the signaling isoform Lepr-b (p<0.05) in acute and chronic settings. In addition, Lepr-b increased in IUB288 treated primary hepatocytes (p<0.05), suggesting cell-autonomous regulation. Further, GCGR activation potentiates leptin-stimulated phosphorylation of AMPK (Thr172) in a dose-dependent manner, suggesting an increase in hepatic leptin sensitivity. Mice deficient for the hepatic leptin receptor (LeprΔliver) displayed increased hepatic triglycerides on a chow diet alone (p<0.001), which persisted in a DIO state, with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO WT and LeprΔliver mice resulted in similar reductions of liver triglycerides. Glucagon also reduces plasma lipids during oral lipid challenge. Similar to liver triglycerides, there were no differences in response to IUB288 between WT and LeprΔliver mice. Together these data suggest that although hepatic glucagon and leptin signaling have similar lipid targets, these appear to be two distinct pathways.

Disclosure

S. Nason: None. T. Kim: None. J.P. Antipenko: None. B. Finan: Employee; Self; Novo Nordisk A/S. R. DiMarchi: Employee; Self; Novo Nordisk Inc. K.M. Habegger: Consultant; Self; Glyscend, Inc., Novo Nordisk Inc. Research Support; Self; Glyscend, Inc. Stock/Shareholder; Self; Glyscend, Inc.

Funding

National Institutes of Health (T32HL1053491, R011DK112934-01)
1874-P: A Novel Role for SerpinB1 in the Regulation of Insulin Signaling in Hepatocytes
Authors: ORIME KAZUKI , DE JESUS DARIO F. , JHALA ULUPI , KULKARNI ROHIT
Published: June 2019

Compensatory expansion of β cell mass has been pursued as a potential therapeutic strategy to cure diabetes. We previously identified SerpinB1 as a hepatocyte-derived circulating factor that contributes to adaptive beta cell expansion in the liver-specific insulin receptor knockout (LIRKO) mouse. To understand how SerpinB1 is regulated and secreted, we began by first investigating the mechanism(s) and signaling pathways that modulate the gene and protein expression of SerpinB1 in hepatocytes. Hepatic SerpinB1 expression was elevated in insulin resistant mouse models such as db/db and ob/ob, and circulating interleukin-6 (IL-6) levels were higher in these mice. Indeed, IL-6 induced SerpinB1 expression in HepG2 cells and human primary hepatocytes via the JAK/STAT3 pathway, indicating an important role for this cytokine in inducing the expression of the protease inhibitor in insulin resistant states. Conversely, silencing of SERPINB1 gene in hepatocytes decreased INSR gene and protein expression with a consequent alteration of expression of several downstream signaling genes related to gluconeogenesis and cell proliferation in hepatocytes. Ribosomal protein S3 (RPS3), identified as a binding partner of SerpinB1 in HepG2 cells, exhibited reduced expression in db/db and ob/ob mice liver along with reduced insulin receptor (IR) expression. Silencing of RPS3 gene in HepG2 cells, phenocopied the effects of SerpinB1 gene silencing, and decreased IR protein expression with consequent alterations in downstream signaling proteins. Additional studies are required to examine the precise regulation of IR expression by SerpinB1 and how the latter is secreted from insulin resistant hepatocytes. These results indicate that SerpinB1 expression is upregulated in insulin resistance by IL-6 and the SerpinB1/RPS3 complex plays a role in regulating insulin signaling in hepatocytes.

Disclosure

K. Orime: None. D.F. De Jesus: None. U. Jhala: None. R. Kulkarni: None.
1880-P: The Protein-Tyrosine Phosphatase Shp1 Interacts with PPAR Gamma and Regulates Its Transcriptional Activity through Dephosphorylation of Selected Tyrosine Sites
Authors: KUMAR AMIT , LAVALLEE-BOURGET MARIE-HELENE , FOREST MARIE-PIER , SCHWAB MICHAEL , BELLMANN KERSTIN , HOUDE VANESSA , MAAROUFI HALIM , BEAUCHEMIN NICOLE , MARETTE ANDRE
Published: June 2019

Src homology region 2 domain-containing phosphatase-1 (Shp1) plays an important role in modulating insulin signaling and thereby glucose homeostasis. Our laboratory has demonstrated that despite being more prone to hepatic steatosis, mice with a liver specific Shp1 knock out (Shp1H-KO) on high-fat diet (HFD) exhibit improved fasting glycaemia, reduced insulin resistance and lower inflammation than their flox/flox littermates. Microarray analysis of HFD-fed Shp1H-KO versus Shp1fl/fl livers revealed elevated levels of peroxisome proliferator-activated receptor gamma (PPARγ), an important transcription factor controlling adipogenesis. In addition, overexpression of Shp1 decreased PPARγ activity in vitro. The aim of this study was to investigate the mechanism of regulation of PPARγ by Shp1. Molecular modeling analyses suggested that Shp1 interaction with PPARγ depends on the tyrosine phosphorylation status of PPARγ. We found, by co-immunoprecipitation, that Shp1 N-terminal SH2-domains binds to PPARγ. We confirmed PPARγ tyrosine-phosphorylation and demonstrated that this phosphorylation could be reduced by Shp1 in vitro. Using mass spectrometry, we identified 5 phosphorylated tyrosine residues in PPARγ. Mutagenesis experiments showed that PPARγ significantly lost its activity when two of these sites were selectively and independently mutated to the non-phosphorylatable phenylalanine but did not interfere with the nuclear localization of PPARγ. Additionally, we generated Shp1 knockout HepG2 cells using CRISPR-Cas9 technology. We found that expression of several PPARγ regulated transcripts was upregulated in Shp1-KO cells as compared to control cells. Altogether, we show that PPARγ is a novel substrate of Shp1. Our results reveal a fine regulation of PPARγ tyrosine phosphorylation by Shp1, which might lead to novel therapeutic approaches for treating metabolic disorders related to obesity.

Disclosure

A. Kumar: None. M. Lavallee-Bourget: None. M. Forest: None. M. Schwab: None. K. Bellmann: None. V. Houde: None. H. Maaroufi: None. N. Beauchemin: None. A. Marette: Advisory Panel; Self; Plexus, Valbiotis. Consultant; Self; Danone Nutricia Research.
1884-P: Serum ANGPTL2, ANGPTL3, and ANGPTL4 as Potential Biomarkers for Diagnosis of Nonalcoholic Fatty Liver Disease
Authors: MA YAN , WANG YAN , WANG XIN , YANG LONGYAN , LANG JIANAN , ZHAO DONG
Published: June 2019

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that seriously affects public health around the world. We investigate the circulating levels of ANGPTL2, ANGPTL3 and ANGPTL4, and detects the correlation with metabolic and biochemical parameters, then examines the efficacy of ANGPTLs for the assessment of NAFLD. Serum levels of ANGPTL2, ANGPTL3, ANGPTL4 and ANGPTL6 in NAFLD patients (n=52) and non NAFLD subjects (n=52) were quantified by ELISA. Then we further evaluated the utility of ANGPTLs as biomarkers for predicting NAFLD by employing receiver operating characteristic (ROC) analysis. Our data demonstrate that (1) serum levels of ANGPTL2 and ANGPTL4 increased, ANGPTL3 level decreased along with the transition from no NAFLD to NAFLD and from mild NAFLD to moderate-to-severe NAFLD patients. However, ANGPTL6 level unchanged altered among these stages; (2) Pearson association analysis demonstrated that ANGPTL2 levels were positively correlated with ALT, AST and GGT; but ANGPTL3 levels were negatively associated with ALT and GGT; ANGPTL4 levels were positively correlated with ALT, AST and GGT; (3) The area under the ROC curve (AUC) for ANGPTL2, ANGPTL3 and ANGPTL4 were 0.647, 0.746 and 0.666; When the three factors were jointly analyzed, the area under the ROC curve was 0.778, exhibiting the strongest capability in predicting diagnosis in NAFLD patients; (4) The changes of serum ANGPTL2 and ANGPTL3 in NAFLD patients may be due to the changed expression in liver tissues of NAFLD patients; (5) Gene enrichment analysis results show a positive correlation between ANGPTL2 level and the activation of NF-κB signaling in NAFLD samples, and a negative correlation between ANGPTL3 level and the activation of JNK signaling in NAFLD samples. Taken together, ANGPTL2, ANGPTL3 and ANGPTL4 levels might be new and important predictors of the severity of NAFLD.

Disclosure

Y. Ma: None. Y. Wang: None. X. Wang: None. L. Yang: None. J. Lang: None. D. Zhao: None.

Funding

National Natural Science Foundation of China; National Science Funding in China