bluuebunny/crossref_metadata_2025_split huggingface dataset:
1310-P: Effects of Insulin Resistance on Brain Responses to Caloric Sugars and Nonnutritive Sweetener
Authors: KULLMANN STEPHANIE , VEIT RALF , JANN KAY , YUNKER ALEXANDRA G. , LUO SHAN H. , ANGELO BRENDAN C. , ALVES JASMIN M. , MONTEROSSO JOHN R. , PAGE KATHLEEN A. 
Published: May 2022

Evidence suggests that insulin resistance (IR) affects feeding behavior by modulating neural responses to post-ingestive signals, including nutrients and taste. We examined associations between IR and activation of the hypothalamus and insula, brain regions involved in homeostasis and taste processing, to ingestion of sugars and the non-nutritive sweetener (NNS) , sucralose. Seventy-four participants (23.4±4 years; 42%male; BMI 27.2±5; HOMA-IR 5.3±5) completed 4 MRI visits with ingestion of drinks containing 75g sucrose, 75g glucose, sucralose, or water in a randomized cross-over design. Arterial spin labeling MRI was performed before, 15min and 30min after drink ingestion to measure cerebral blood flow (CBF) . Primary outcomes were associations between HOMA-IR and hypothalamic and insular CBF responses to glucose vs. sucrose, sucralose vs. water, and sucrose vs. sucralose. Mixed effects models included the following factors: drink contrasts, sex, time point, and BMI and HOMA-IR as continuous variables. Bonferroni-Holm was used to adjust for multiple comparisons. In the hypothalamus, HOMA-IR, independent of BMI, was associated with a greater hypothalamic CBF response to sucralose vs. water (p&lt;0.03) , but there was no association between HOMA-IR and hypothalamic response to sugar. In the insula, there was a drink by HOMA-IR interaction in the insular response to sucralose vs. water (p&lt;0.02) ; persons with IR showed greater increases in CBF after sucralose vs. water. We also found a main effect of HOMA-IR; persons with higher IR had greater insular CBF increases to sugar (p&lt;0.05) , and a drink by HOMA-IR interaction revealed a stronger association between IR and insular response to glucose vs. sucrose (p&lt;0.03) . There was no association between HOMA-IR and brain responses to sucralose vs. sucrose. These findings show that IR is associated with greater activation of brain regions involved in taste and energy homeostasis to ingestion of sugar and NNS, which may promote eating behavior.

Disclosure
S. Kullmann: Other Relationship; Novo Nordisk. R. Veit: None. K. Jann: None. S.H. Luo: None. B.C. Angelo: None. J.M. Alves: None. J.R. Monterosso: None. K.A. Page: None.

Funding
NIDDK R01DK102794
1316-P: Brainstem Neurons Regulating Energy Homeostasis
Authors: NECTOW ALEXANDER R. 
Published: May 2022

Energy balance is maintained by an extended circuitry in the central nervous system that carefully balances food intake with energy expenditure. We have recently shown that the brainstem’s dorsal raphe nucleus (DRN) is an important component of this extended circuit, capable of potently regulating both energy intake and expenditure, and ultimately body weight. Despite its important role in energy homeostasis, the DRN is markedly heterogenous, consequently hindering our ability to manipulate and record from its distinct cell subtypes. Towards this end, we have recently performed nuclear tagging of large classes of DRN neurons, enabling us to molecularly profile these cells at both ensemble and single-cell resolutions. Using this approach, we have found that even among a priori defined major cell types within the DRN - for example, those marked by the vesicular glutamate and GABA transporters - there is a marked degree of molecular heterogeneity. Despite this significant molecular heterogeneity, some subclasses of DRN neurons are hierarchically differentiable, leading to the identification of molecularly dissociable ‘clades.’ These clades have unique molecular handles; these handles are now enabling us to record from and perturb the activity of distinct DRN subpopulations, which were previously genetically inaccessible. Together, this work represents an important conceptual and technical advance, enabling us to classify DRN neurons with new resolution, as well as to genetically access them to establish their cell subtype-specific function.

Disclosure
A.R.Nectow: None.

Funding
American Diabetes Association (1-18-ACE-49)
1318-P: Repetitive Transcranial Magnetic Stimulation: A Potential Treatment for Obesity in Patients with Prader-Willi Syndrome
Authors: FERRULLI ANNA , CANNAVARO DANIELE , MACRÌ CONCETTA , MASSARINI STEFANO , LUZI LIVIO 
Published: May 2022

Prader-Willi Syndrome (PWS) is the most common syndromic type of human obesity. Multiple endocrine abnormalities due to hypothalamic dysfunction as well as cognitive and behavioral disorders occur in PWS. Hypothalamic dysfunction, dysregulated mesocorticolimbic reward system, and impaired prefrontal cortex (PFC) function are implicated in the pathophysiology of hyperphagia and obesity in PWS. All available therapeutic tools have not fully targeted at counteract the mechanisms underlying obesity in PWS. Previously, we demonstrated the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in inducing weight loss in obesity by modulating the brain dopaminergic system and enhancing the inhibitory activity of the PFC on eating behaviour (Ferrulli et al, DOM 2019) . In this case-report, for the first time, we tested the efficacy and safety of rTMS in a 23-year-old patient with PWS, in whom repeated interventions aimed at inducing weight loss have failed. A 5-week high frequency (18 Hz) rTMS treatment, associated with diet, resulted in a 3.5% weight loss (127.4 vs. 123 Kg, BMI: 50.4 vs. 48.6 Kg/m2, WHR: 1.14 vs. 1.12) . Concerning the metabolic parameters, an improvement in lipid profile has been shown (CHO/HDL/LDL/TG: 212/40/142/152 vs. 190/40/124/131 mg/dL) . While no significant changes emerged in the psychometric assessment of food craving, impulsiveness, quality of life, self-esteem, interestingly, a robust improvement in the Mini-Mental State Examination score (corrected for age and schooling) has been found [from 22 (severe impairment) to 27 (moderate impairment) ]. The improvement in the cognitive status assessed through the Montreal Cognitive Assessment was weaker (17/30 to 19/30) . In view of the urgent need of novel effective interventions for obesity in PWS, these findings support a potential role of rTMS in reducing food drive and behaviors impacting hyperphagia and obesity in PWS, with a possible impact also on cognitive functions.

Disclosure
A.Ferrulli: None. D.Cannavaro: None. C.Macrì: None. S.Massarini: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Speaker’s Bureau; Eli Lilly and Company, Novo Nordisk.

Funding
IRCCS Multimedica - Ricerca Corrente
1323-P: Insulin Secretion at Diabetes Remission in Obese Blacks Presenting with Diabetic Ketoacidosis
Authors: STEFANOVSKI DARKO , OLADEJO OMOLADE , UMPIERREZ GUILLERMO E. , VELLANKI PRIYATHAMA 
Published: May 2022

In obese Blacks presenting with diabetic ketoacidosis (DKA) at new-onset of diabetes, intensive insulin treatment improves β-cell function so that ˜70% achieve near-normoglycemia remission (HbA1c &lt; 7%, fasting blood glucose [BG]&lt;130 mg/dl while off insulin for ≥1 week) and maintain glycemic control without medications. The 2021 American Diabetes Association (ADA) consensus defined diabetes remission as HbA1c &lt;6.5% or BG 126 mg/dl while off medications for &gt;3 months. It is unknown whether glycemic measures and insulin secretion differ between patients who achieve the new ADA definition of remission (intensive remission [IR]) compared to near-normoglycemia remission (non-intensive remission [NIR]) .We performed 75-g, 240-minute (min) oral glucose tolerance tests (OGTT) in 13 obese (BMI&gt;30 kg/m2) Blacks who presented with DKA (BG&gt;250 mg/dl, HCO3&lt;18 mEq/L, pH&lt;7.3) and achieved remission from insulin. Glucose and C-peptide levels were measured at -15, 0, 10, 20, 30, 60, 90, 120, 180 and 240 min during OGTT. Insulin secretory rates (ISR) , first phase (Φdynamic) , second phase (Φstatic) and total (Φtotal) insulin secretion were calculated using a previously published model. Data was compared between IR, (HbA1c&lt;6.5%, n=7) vs. NIR, (HbA1c≥6.5%, n=6)) There were no differences in age, BMI and mean BG levels during OGTT between groups. Model estimates of Φdynamic were significant (P=0.046) and 5-fold higher in IR (Marginal Mean: 514.00, 95% CI: 134.53-893.47 [109]) vs. NIR (Marginal Mean: 100, 95% CI: 100.45, 95% CI: -41.97-242.87 [109]) . Estimates of Φstatic were significant (P=0.022) and 2-fold higher in the IR (Marginal Mean: 31.84, 95% CI: 19.88-43.80 [min-1]) vs. NIR (Marginal Mean: 14.59, 95% CI: 6.79-22.39 [min-1]) with no significant (P=0.058) group differences between Φtotal.In comparison to NIR, obese Blacks with IR exhibit marked preservation of β-cell function suggesting that HbA1c &lt;6.5% should be targeted for insulin remission after presentation with DKA.

Disclosure
D.Stefanovski: None. O.Oladejo: None. G.E.Umpierrez: Research Support; AstraZeneca, Dexcom, Inc., Novo Nordisk. P.Vellanki: n/a.

Funding
NIH/NIDDK K23 DK11324-01A1
133-LB: Relationship of HbA1c and Glucose by Ethnicity in UK Biobank
Authors: WILLIAMS JOHN A. , KARWATH ANDREAS , ROUND RACHEL A. , STRATTON IRENE M. , GHOSH SANDIP , MOSTAFA SAMIUL , ROBERTS GRAHAM , WEBBER JONATHAN , GKOUTOS GEORGIOS , MANLEY SUSAN E. 
Published: May 2022

The UK Biobank recruited 502,481 people aged 40 to 70 years who were invited to participate by post so not necessarily representative of the general population. The 405,363 participants with random glucose, HbA1c and the necessary demographic/clinical data were aged 56.5 (8.09) years, mean SD, with 54% female, and ethnicity 95.0% White W, 1.9 South Asian SA, 1.3% Black B, 0.9% Other O, 0.6% Mixed Background MB, and 0.3% Chinese C. Glucose was measured by hexokinase and HbA1c by BioRad VARIANT II TURBO analysers, reference range 20-42 mmol/mol in a dedicated central laboratory. Cohen's D statistic was used to compare glucose/HbA1c by ethnicity versus the largest group W. Mean glucose ranged from 5.04 to 5.41 mmol/L with HbA1c40.7 mmol/mol for SAversus36.0 for W (D=0.78 medium effect M) , B 39.3 (D=0.51 M) , O 38.4 (D=0.37 small S) , C 37.1 (D=0.17 very small V) & MB 36.6 (D=0.09 V) , all p values &lt;0.001. There were large differences by ethnicity in linear regression slopes for the glucose/HbA1c relationship when compared to W with correlation coefficient comparison Z-statistics for SA 16.74, B 8.69, O 10.94, C 8.96, all p&lt;0.001, except for MB 2.56, p=0.01. Such ethnic differences in HbA1c have been reported previously and questions raised as whether different cut-offs should be used for diagnosis of diabetes. However, more information on the prevalence of microvascular complications and differences in haematological profiles is required for such modifications.

Disclosure
J. A. Williams: None. S. E. Manley: n / a. A. Karwath: None. R. A. Round: None. I. M. Stratton: None. S. Ghosh: Other Relationship; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk. S. Mostafa: None. G. Roberts: None. J. Webber: None. G. Gkoutos: None.

Funding
Medical Research Council (MR/S003991/1) , MRC HDR UK (HDRUK/CFC/01) , NIHR Birmingham ECMC, NIHR Birmingham SRMRC, Nanocommons H2020-EU (731032) , MAESTRIA (965286)
1339-P: Plasma Heparin Cofactor II Activity Is Inversely Associated with the Development NAFLD in Patients with Diabetes
Authors: HARA TOMOYO , YAMAGAMI HIROKI , MASUDA SHIHO , MITSUI YUKARI , KURAHASHI KIYOE , YOSHIDA SUMIKO , OTODA TOSHIKI , YUASA TOMOYUKI , KURODA AKIO , ENDO ITSURO , MATSUHISA MUNEHIDE , ABE MASAHIRO , AIHARA KEN-ICHI 
Published: May 2022

Aims and Introduction: The prevalence and incidence of nonalcoholic fatty liver disease (NAFLD) have been increasing worldwide. Thrombin exerts various pathophysiological functions via activation of protease-activated receptors (PARs) , and activation of PARs promotes the development of NAFLD. Since heparin cofactor II (HCII) specifically inhibits thrombin action by binding to dermatan sulfate proteoglycans in various tissue matrices, we hypothesized that plasma HCII activity is associated with the development of NAFLD.
Materials and Methods: Plasma HCII activity and clinical markers for assessment of hepatic fibrosis including Fibrosis 4 (FIB-4) index, NAFLD fibrosis score (NFS) , and aspartate aminotransferase to platelet ratio index (APRI) were determined in 322 Japanese patients with diabetes mellitus (183 males and 139 females; mean age, 66.0±11.3 years) . The relationships between plasma HCII activities and the clinical markers were statistically evaluated.
Results: The mean plasma HCII activity in all participants was 94.0 ± 17.7%. Multivariate regression analysis with adjustments for confounding factors including age, sex, and serum albumin showed that plasma HCII activity independently contributed to reduction of the FIB-4 index (p &lt; 0.0001) , NFS (p &lt; 0.0001) , and APRI (p &lt; 0.05) .
Conclusions: Plasma HCII activity was independently and inversely associated with the clinical markers of hepatic fibrosis. The results suggest that HCII can serve as a novel therapeutic target for the development of NAFLD in patients with diabetes.

Disclosure
T.Hara: None. I.Endo: None. M.Matsuhisa: Research Support; Nissui , Sysmex Corp., Speaker’s Bureau; Astellas Pharma Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. M.Abe: None. K.Aihara: None. H.Yamagami: None. S.Masuda: None. Y.Mitsui: None. K.Kurahashi: None. S.Yoshida: None. T.Otoda: None. T.Yuasa: None. A.Kuroda: None.
134-LB: Prediabetes Geographic "Hotspots"—Opportunities for Targeted Diabetes Prevention
Authors: SCHMITTDIEL JULIE , YASSIN MAHER , RODRIGUEZ LUIS A. , THOMAS TAINAYAH , MOIN TANNAZ , LEGGETT ALLISON G. , SANCHEZ PERLA , KENRIK DURU O. 
Published: May 2022

Over 38% of U.S. adults have prediabetes, or elevated glucose levels linked to type 2 diabetes incidence. The U.S. Preventive Services Task Force recommends giving people who screen positive for prediabetes access to evidence-based prevention strategies such as the Diabetes Prevention Program (DPP) . However, there is little data on prediabetes case clusters (‘hotspots’) to guide in-person program placement and planning. We used ArcGIS software to geospatially map 760,044 adults ages 35-70 with an A1c or FPG screening test in 2019 to census tracts served by Kaiser Permanente Northern California, an integrated health care system with 4.5 million members. A total of 304,727 adults had prediabetes (40%) defined as A1c 5.7-6.4% or FPG 100-125 mg/dL. Seven prediabetes hotspots concentrated in Alameda, Fresno, Madera, Sacramento, San Joaquin, Santa Clara, and Solano counties emerged. Adults living in prediabetes hotspots were less likely to be non-Hispanic White (34% vs. 51%, p&lt;.001) . Hotspots had lower mean Census tract-level median household income ($93,670 vs. $98,216, p&lt;.05) and percent with a college degree or more (34% vs. 43%, p&lt;.001) , but higher percent receiving Medicaid (27% vs. 21%, p&lt;.001) . Prediabetes cases clustered in geographic hotspots with demographics that differed from other areas. Policy makers and health care providers can use this information to target diabetes prevention resources and outreach.

Disclosure
J. Schmittdiel: None. M. Yassin: None. L. A. Rodriguez: None. T. Thomas: None. T. Moin: None. A. G. Leggett: None. P. Sanchez: None. O. Duru: None.

Funding
National Institutes of Health (R18DK122372-01A1)
1342-P: Reduction of Glucokinase and Glucokinase Regulatory Protein Expression by siRNA Is Associated with the Reduction of Lactate and Pyruvate Export from Canine Hepatocytes
Authors: KABIR MORVARID , ADER MARILYN , BERGMAN RICHARD N. 
Published: May 2022

Glucokinase (GCK) mediates hepatic glucose uptake during hyperglycemia and is crucial for the regulation of glucose-responsive glycolysis genes. Mutations in GCK are responsible for maturity-onset diabetes of the young, and glucokinase regulatory protein (GKRP) , the regulator of hepatic GCK, is also a diabetes susceptibility locus. Recently in in vivo experiments, we used hepatic lactate export as a surrogate for GCK activity, which was a measure of “glucose effectiveness.” We hypothesized that in vitro GCK and GKRP suppression in hepatocytes promotes a reduction in lactate and pyruvate export from the liver. We used cryopreserved canine hepatocytes and knocked down GCK and GKRP via lipid delivery of siRNA. A control group did not receive siRNA. We measured lactate dehydrogenase D (LDHD) and pyruvate kinase (PK) gene expression and lactate and pyruvate release into the medium 24 and 48 h after siRNA delivery. Selective blocking of GCK and GKRP did not change cell proliferation but reduced the expression of these genes by 90% and 85%, respectively (P&lt;0.0vs. controls; n=4) . GCK and GKRP knockdown reduced LDHD by 71% and 74%, respectively (P&lt;0.001) ; similarly, PK was reduced by 84% and 82%, respectively (P&lt;0.001) . Lactate exported into the medium was reduced by 36% (P&lt;0.001) and 26% (P&lt;0.05) by GCK and GKRP siRNA, respectively, after 48 h of hepatocyte culture. However, pyruvate was reduced by 17% only after 48 h culture of GCK siRNA (P&lt;0.05) . Thus, we showed that direct suppression of GCK and GKRP genes by siRNA in vitro affects glucose-responsive glycolysis genes, consequently reducing lactate export which can be used as a surrogate for reduced glucokinase activity in hepatocytes. The use of antisense oligonucleotides or CRISPR gene-editing methods in animals will be useful methods to study the glucose-lactate relationship in vivo and will evaluate the role of glucose effectiveness in the pathogenesis of type 2 diabetes.

Disclosure
M.Kabir: None. M.Ader: None. R.N.Bergman: Consultant; Fractyl Health, Inc., Novo Nordisk, Research Support; AstraZeneca, Janssen Research & Development, LLC.

Funding
National Institutes of Health R01- DK027619-28
1345-P: Low-Dose Colchicine/Metformin Combination Ameliorates NASH via Regulating AMPK/NRF2/GDF15 Axis in Mice
Authors: HAM SUN AH , CHO HEE-YEON , JEONG CHOLONG , YOUN JU HO 
Published: May 2022

Nonalcoholic steatohepatitis (NASH) , a complex metabolic disease by multifactorial pathogenesis is demanded multiple pharmacological modes of action for robust treatment strategies. Colchicine has shown efficacy in various clinical settings which inflammation is a key component, however growing evidences suggest that the therapeutic effect of colchicine is multifaceted by intervening in several different pathways involved in inflammation. Here, we investigated the novel therapeutic effects of low-doses of colchicine (LDC) -metformin (LDC-Met) combination to targeting NASH. To induce NASH disorder, C57BL/6J male mice were fed a CDHFD (choline-deficient high fat diet) for 12 weeks, then were orally administrated by LDC-Met with CDHFD for an additional 12 weeks. In CDHFD induced NASH mice models, LDC-Met markedly decreased the NAS and fibrosis score along with reducing serum level of liver enzymes and total cholesterol increased by CDHFD feeding. Consistent with these data, hepatic gene expression of steatosis, fibrosis, inflammation and apoptosis markers increased by CDHFD was noticeably inhibited by LDC-Met. Interestingly, significant increased circulating GDF15 was found in LDC-Met group, which was accompanied by increased hepatic GDF15 expression. Additionally, LDC-Met significantly augmented hepatic phosphorylation of AMPK and NRF2 in CDHFD-fed mice and NLRP3 inflammasome activity were negatively controlled by LDC-Met. Finally, LDC-Met noticeably reduced CDHFD-induced total body weight gain by approximately 20%, along with epididymal white adipose tissue (eWAT) weight reduction. Taken together, we found that the combination of LDC-Met has the best synergistic effect on NASH resolution, suggesting significant implications for potential drug repurposing and new drug development. Moreover, this novel combination elevates circulating levels of GDF15, which is necessary to obtain beneficial effects on energy balance and body weight.

Disclosure
S.Ham: None. H.Cho: None. C.Jeong: None. J.Youn: None.
1347-P: High Prevalence of NAFLD and Lower Lean Mass in South Asian Youth
Authors: HITT TALIA A. , HUI STEVE C.N. , KAMEL IHAB R. , BARKER PETER B. , ZEMEL BABETTE S. , KELLY ANDREA , MAGGE SHEELA N. 
Published: May 2022

Background: South Asians (SA) have high rates of NAFLD. SA adults have NAFLD at lower BMI. We examined differences in ectopic fat between SA and White (W) youth, and its relationship to BMI z-score (BMIZ) , fat depots, and metabolic labs.
Methods: SA and W youth, 12-21y, BMI ≥ 80%ile (or ≥23kg/m2 if ≥18y) underwent MRS to measure liver fat and intramyocellular lipid (IMCL) (soleus) , and DXA to quantify total % body fat (%BF) and lean mass (LM) . Abdominal MRI was used to measure abdominal fat (AF) , visceral fat (VF) , SQ fat, deep SQ, and superficial SQ. HbA1c, fasting glucose (FBG) , and lipids were obtained. Univariate analyses used parametric or non-parametric methods as appropriate. Linear regression adjusted for potential confounding variables. NAFLD defined as &gt;5% liver fat.
Results: Participants (28 SA, 9 W) had similar age, sex, and BMIZ. Liver fat was higher in SA [2.0% (1.1, 7.4) ] compared to W [0.8% (0.7, 1.4) ], but not statistically different. NAFLD was present in 29% of SA youth, but in no W youth. There was no difference in IMCL (p=0.9) or VF between groups (p=0.5) . Adjusting for age, sex, puberty and BMIZ, SA had lower LM [β= -8.1, p=0.003] and higher %BF [β=5.8, p=0.01], AF [β=151.6, p=0.006], total SQ fat [β=65.9, p=0.001], deep SQ fat [β=1.9, p=0.005] and HbA1c [β=3.8, p=0.01] than W. FBG and lipids were similar between groups. In SA, liver fat correlated with HDL-C (p=0.02) , LDL-C (p=0.03) , non-HDL-C (p=0.03) and borderline with FBG (p=0.05) , HbA1c (p=0.06) , but not with BMIZ, LM, %BF, or triglycerides. In SA, VF was correlated with triglycerides (p=0.002) and non-HDL-C (p=0.04) and borderline with LM (p=0.05) and HDL-C (p=0.06) .
Conclusions: These preliminary results of an ongoing study demonstrate that 29% of SA youth had NAFLD compared to no W youth. Liver fat in SA youth was not related to typical metabolic risk factors. Notably SA youth had lower LM, and increased AF, deep SQ fat, and HbA1c compared to W youth, after adjustment. Further study is needed to clarify the mechanisms underlying excess liver fat in SA youth.

Disclosure
T.A.Hitt: None. S.C.N.Hui: None. I.R.Kamel: None. P.B.Barker: None. B.S.Zemel: None. A.Kelly: Research Support; vTv Therapeutics. S.N.Magge: None.

Funding
National Institutes of Health (R01DK115648)