bluuebunny/crossref_metadata_2025_split huggingface dataset:
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&lt;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&gt;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&lt;0.001) but not with BMI. GLP-1/GIP levels increased (P&lt;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&lt;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&lt;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&lt;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&lt;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&lt;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&lt;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 &lt;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&gt;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 &lt;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 &lt;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 (&gt;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)