bluuebunny/crossref_metadata_2025_split huggingface dataset:
189-LB: Plasma Sphingolipids in Healthy Black and White Adults With or Without Parental Type 2 Diabetes
Authors: MANDAL NAWAJES , WAN JIM Y. , STENTZ FRANKIE B. , NYENWE EBENEZER , PATEL AVNISHA A. , DAGOGO-JACK SAMUEL 
Published: May 2022

Objective: Ceramides (CER) and sphingolipids (SPL) have been linked to type 2 Diabetes (T2D) . Here we compared plasma SPL profiles in Black and White adults without a family history of T2D (FH−) vs. those with parental T2D (FH+) .
Methods: We studied 240 healthy subjects: 140 FH+ (70 B, 70 W) and 100 FH− (50 B, 50 W) . Assessments included OGTT, insulin sensitivity (Si-clamp) and insulin secretion (AIRg) . Liquid chromatography/mass spectrometry was used to assay fasting plasma levels of 54 SPL species (18 each from 3 major classes: CER, monohexosyl ceramide {MHC}, and sphingomyelins {SM}) . We compared mole percent composition of SPL species within each class in FH+ and FH− groups.
Results: The subjects’ mean (SD) age was 43.1 + 12.0 y, BMI 29.4 + 6.21, fasting glucose 91.4 + 6.90 mg/dl and 2-hr plasma glucose (2hPG) 123 + 26.3 mg/dl. Total levels of SPL, CER, MHC and SM did not differ by race or sex, and correlated with 2hPG and AIRg but not age, BMI, FPG or Si-clamp. FH+ and FH− adults were concordant for 37 of 54 SPL and discordant for 17 species. Compared with FH−, the FH+ subjects had higher molar abundance of 8 CER, 4 MHC and 2 SM, but lower values for C24:0 Cer, C24:0 MHC, and C26:0 MHC (Table 1) .
Conclusion: Plasma SPL species correlate with glucose tolerance, are altered by parental T2D history, and may reflect heritable elements linking SPL and glucose metabolism.

Disclosure
N. Mandal: None. J. Y. Wan: None. F. B. Stentz: None. E. Nyenwe: None. A. A. Patel: None. S. Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi.

Funding
National Institutes of Health (5R01DK128129)
197-OR: Glucagon Receptor Agonism Stimulates Time-Dependent Glycemic Regulation
Authors: NASON SHELLY , KIM TEAYOUN , ANTIPENKO JESSICA P. , FINAN BRIAN , DIMARCHI RICHARD , HABEGGER KIRK M. 
Published: May 2022

Historically, glucagon is proposed to be a key factor in the development of diabetes. However, we demonstrated that while chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and insulin action. These paradoxical actions suggest the mechanisms regulating GCGR-mediated glucose metabolism have yet to be fully elucidated. Glucose metabolism and glucagon-stimulated glucose production are both regulated in a circadian manner. Thus, we hypothesized that chronic GCGR signaling regulates glycemia in a time-of-day dependent manner. We treated lean mice for 4d with vehicle or the GCGR agonist IUB288 administered either during the early (ZT 3) or late (ZT9) light period. Ad libitum glycemia was assessed every 4h over a 24h period after the last injection. Independent of the time injected, IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls. This suggests that chronic GCGR agonism is not exclusively hyperglycemic and variations in GCGR-stimulated glycemia are dependent on the time after treatment, rather than the time of day. Interestingly, ad libitum insulin levels were no different between IUB288 and vehicle-treated mice, suggesting differences in insulin sensitivity. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a greater duration than chow IUB288-treated mice. We used hyperinsulinemic-euglycemic clamps to further dissect the mechanisms of these benefits. In DIO mice, IUB288 treatment increased glucose infusion rate, suppression of endogenous glucose production, and phosphorylation of AKT (S473 and T308) . Together, these data increase our understanding of GCGR pharmacology and its therapeutic role in diabetes and obesity treatment.

Disclosure
S.Nason: None. T.Kim: None. J.P.Antipenko: None. B.Finan: Employee; Novo Nordisk. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Glyscend Inc.

Funding
T32 AI007051
2-OR: Exosomes from Adipose Tissue Macrophages Can Mediate Insulin-Sensitizing Effects of Rosiglitazone
Authors: ROHM THERESA V. , REIS FELIPE C.G. , ISAAC ROI , PASZEK MILES , BANDYOPADHYAY GAUTAM , OLEFSKY JERROLD M. 
Published: May 2022

Background: The beneficial metabolic effects of the PPARγ agonist rosiglitazone (Rosi) are associated with anti-inflammatory changes in adipose tissue macrophages (ATMs) . One study aim was to characterize the in vivo Rosi-induced phenotypic switch of ATMs using a variety of macrophage markers, including the lipid-associated macrophage markers CD9 and Trem2. As a second aim, since ATM-derived exosomes can exert insulin-sensitizing or desensitizing effects dependent on ATM cell context, we assessed the effects of ATM exosomes from Rosi-treated obese mice on in vitro insulin actions.
Research Design and Method: ATMs were isolated from 4 months HFD/obese mice treated for the last month with Rosi (60 mg/kg HFD) compared to HFD or chow-fed controls. Among CD11b+F4/80+ or CD64+ macrophages, we identified pro-inflammatory (“M1-like” CD11c+ and/or CD9+) , anti-inflammatory (“M2-like” CD11c-CD206+) and lipid-associated (CD9+ and/or Trem2+) ATMs by flow cytometry. Bone marrow-derived macrophages (BMDMs) were treated in vitro with µM Rosi for 24h. 3T3-L1 adipocytes, L6 myotubes, and primary hepatocytes were cultured 24h with exosomes isolated from ATMs of Rosi treated obese mice or in vitro Rosi treated BMDMs and then assessed for insulin sensitivity.
Results: Rosi treatment reduced adipose tissue inflammation, as seen by reduced numbers of pro-inflammatory (“M1-like”) ATMs and increased the Trem2 signature in “M2-like” ATMs. Importantly, Rosi directly induced Trem2 expression in vitro in BMDMs. Additionally, exosomes isolated from Rosi-treated obese mice or M1 BMDMs increased glucose uptake and insulin signalling (pAKT) in adipocytes and myotubes and reduced glucose production in hepatocytes compared to control exosomes.
Conclusion: Our data indicate that Trem2 is a PPARγ target gene. Since exosomes from Rosi treated ATMs or BMDMs enhance cellular insulin action, this could provide a new explanation for the well-known insulin-sensitizing effects of PPARγ agonists.

Disclosure
T.V.Rohm: None. F.C.G.Reis: None. R.Isaac: None. M.Paszek: None. G.Bandyopadhyay: None. J.M.Olefsky: None.

Funding
Swiss National Science Foundation (SNF) Early Postdoc.Mobility grant (to T.R.) .
204-LB: An Unusual Case of Autoantibody-Negative Ketosis-Prone Diabetes (KPD) Secondary to Marked Insulin Resistance
Authors: INFANTE MARCO , DIPERNA PASQUALE , PASSERI MARINA , MONETTA ROSANNA , PAPOLA FRANCO , BRANCATI FRANCESCO , CAPRIO MASSIMILIANO , FABBRI ANDREA 
Published: May 2022

KPD is classically regarded as an atypical form of diabetes caused by near-complete beta-cell failure. A 37-year-old Egyptian man (BMI: 27.7 Kg/m2) presented with hyperglycemia (362 mg/dL) and DKA (arterial pH 7.20, ketonemia 5.0 mmol/L, ketonuria 80 mg/dL) . He was afebrile, with recent polyuria, polydipsia and weight loss. HbA1c was 107 mmol/mol (11.9%) and blood tests excluded diabetes secondary to endocrinopathies. SARS-CoV-2 RT-PCR test was negative. IV insulin infusion (0.1 IU/kg/h) and IV fluid therapy were started. He was shortly transitioned to a sc basal-bolus insulin regimen (0.7 IU/kg/day) . Mixed-meal tolerance test (MMTT) revealed a peak 120-min stimulated C-peptide of 12.3 ng/mL, suggesting marked insulin resistance. Islet autoantibodies (ICA, IAA, GADA, IA-2A, ZnT8A) and insulin receptor autoantibodies (IgG/IgM) were negative. HLA genotyping detected the following haplotypes: DRB1*01,*04; DQA1*01:01P,*03:01P; DQB1*03:02P,*05:01P. Insulin dose was gradually reduced and insulin therapy was discontinued after 4 months in favor of metformin (2550 mg/day) plus sc semaglutide (up to 1 mg/week) . After one year, MMTT revealed a peak 60-min stimulated C-peptide of 8.25 ng/mL. During the 18-month follow-up period, fasting capillary beta-hydroxybutyrate values were &lt;0.2 mmol/L and HbA1c remained &lt;48 mmol/mol (&lt;6.5%) , indicating disease remission. This case suggests the existence of an autoantibody-negative KPD subtype driven by marked insulin resistance rather than by insulinopenia.

Disclosure
M. Infante: None. P. Diperna: None. M. Passeri: None. R. Monetta: None. F. Papola: None. F. Brancati: None. M. Caprio: None. A. Fabbri: None.
205-OR: Nutrient Sensor OGT Regulates Glucose Homeostasis through ß-Cell Autophagy via mTORC1 Pathway
Authors: JO SEOKWON , ALEJANDRO EMILYN 
Published: May 2022

A key aspect of type 2 diabetes (T2D) is the failure of β-cells to secrete sufficient insulin to tightly control blood glucose. Nutrient sensor mTORC1 balances cell growth and degradative process (autophagy) to maintain β-cell health and function. Changes to mTORC1 activity and autophagy are linked with T2D and β-cell failure; however, the underlying mechanisms driving these relationships remain unclear. Our work highlights nutrient sensor O-GlcNAc Transferase (OGT) as a critical regulator of β-cell health; β-cell OGT deletion (βOGTKO) causes diabetes due to severe β-cell mass loss and insulin secretion deficits. In response to changes in nutrient levels, OGT glycosylates key target proteins to impact multiple cellular processes. We hypothesize that under nutrient stress, OGT directly modulates the mTORC1 pathway, and thereby, autophagy-dependent β-cell function. βOGTKO islets exhibited decreased mTORC1 activity and increased autophagy. To delineate the untested signaling crosstalk between OGT and mTORC1 pathways, we generated a mouse model of increased mTORC1 activity, by deleting TSC2 (mTORC1 inhibitor) in βOGTKO mice. The βTSC2/OGTKO mice exhibited complete rescue in the diabetic phenotype of the βOGTKO mice. Normalization of blood glucose was associated with full rescue in β-cell mass deficit, but not improvement in secretory function, which suggests non-overlapping biological processes between OGT and mTORC1. Of these downstream processes, we tested whether mTORC1-driven autophagy affects OGT dependent β-cell function. To do this, we deleted ULK1 (autophagy initiator downstream of mTORC1) in the βOGTKO mice. Supporting our hypothesis directly, βULK/OGTKO mice showed improved glucose tolerance with attenuated hyperglycemia compared to the βOGTKO mice by increasing β-cell function but not mass. Altogether our data show a novel and important role of OGT as a master nutrient-sensor affecting downstream mTORC1 and autophagy to drive β-cell function and mass.

Disclosure
S.Jo: None. E.Alejandro: None.

Funding
National Institute of Health (DK115720)
207-OR: ADA Presidents' Select Abstract: Apolipoprotein C-III Proteoforms and Their Relationships with Plasma Lipids and Cardiovascular Events in Multiethnic Study of Atherosclerosis (MESA)
Authors: KOSKA JURAJ , SINARI SHRIPAD , HU YUEMING , FURTADO JEREMY , BILLHEIMER DEAN , NEDELKOV DOBRIN , MCCLELLAND ROBYN , REAVEN PETER 
Published: May 2022

Apolipoprotein C-III (apoC-III) exists in four major proteoforms - unglycosylated form (C-III0a) , and glycosylated forms with zero (C-III0b) , one (C-III1, most abundant) or two (C-III2) sialic acids - which modify lipoprotein metabolism. The relation of these proteoforms with plasma lipids and cardiovascular disease (CVD) risk in a general population is unknown. Total apoC-III concentrations and apoC-III proteoforms were measured in baseline plasma of 5,787 MESA participants. Plasma lipids and CVD risk were assessed over 15 years. Proteoform percentages correlated modestly with total apoC-III (r2&lt;0.10) . ApoC-III0b decreased and C-III2 increased with age (by 11% per 5 yrs) . Compared to non-Hispanic whites, African Americans had lower (35%) total apoC-III and C-III0b and higher C-III2 (88%) , and Chinese Americans and Hispanics had higher C-III0a (88%; 40%) . Females had higher total apoC-III, C-III1 and C-III0b (23%; 31%; 30%) , and lower C-III0a and C-III2 (17%; 28%) . Total apoC-III, C-III0b, C-III1 and C-III2 were higher in diabetes. Prospectively, in models that included baseline characteristics, lipid-lowering medications and total apoC-III, higher C-III2 to C-III1 ratio (C-III2/III1) was associated with lower triglycerides (22%) and higher HDL (19%) . After adjustment for baseline characteristics (including lipids) and total apoC-III, higher C-III0b to C-III1 ratio was associated with reduced risk of CVD (n=629 events, HR= 0.89) and coronary heart disease (n=426, HR=0.86) . In contrast, despite links with better lipids, higher C-III2/III1 was associated with increased risk of CVD (HR=1.09) . No CVD events were related to total apoC-III. Our data indicate differences in clinical and demographic determinants of total apoC-III concentrations and apoC-III proteoforms and highlight the importance of apoC-III proteoform distribution in predicting future lipid concentrations and CVD risk.

Disclosure
J.Koska: None. S.Sinari: None. Y.Hu: None. J.Furtado: Research Support; Eli Lilly and Company, Pfizer Inc. D.Billheimer: None. D.Nedelkov: None. R.Mcclelland: None. P.Reaven: Research Support; AstraZeneca, Dexcom, Inc.

Funding
National Institutes of Health (R01-HL138969)
209-LB: Evidence Thathypothalamic Glucoregulatory Neurons Sense and Respond to Changes of Glycemia in Conscious, Free-Living Mice
Authors: DEEM JENNIFER D. , TINGLEY DAVID , BJERREGAARD ANNE-METTE , FABER CHELSEA L. , DOAN TAMMY P. , PHAN BAO ANH N. , NASIR ZAINAB , WU BRANDON , HWANG MATTHEW K. , KUMAR ASMIT , SCARLETT JARRAD M. , MORTON GREGORY J. , SCHWARTZ MICHAEL W. 
Published: May 2022

The brain’s capacity to normalize the defended blood glucose level in diabetic animals is now well established. We hypothesized that for this to occur, the brain, like the pancreas, must detect and respond to changes in circulating glucose, but whether and how this occurs remains unknown. To identify specific neuronal subsets that are responsive to changes in glycemia in conscious, free-living mice, we combined continuous arterial glucose monitoring (CGM) with fiber photometry (FP) to measure the calcium activity of neurons located in the hypothalamic ventromedial nucleus that express the peptide, Pacap (VMHPacap neurons) . CGM and FP data from each of six mice were obtained during both a 1-h baseline monitoring period (without access to food) and over a 2-h intervention period in which the blood glucose (BG) level was elevated by either chow or a high-sucrose meal consumption, or by IP glucose injection. Cross-correlation analysis revealed that following a 60-80 s delay, interventions that raise the BG level are reliably associated with significantly reduced VMHPacap neuron activity (p &lt; 0.01) . Interestingly, levels of BG and VMHPacapneuron calcium activity were also significantly correlated under baseline conditions (i.e., in the absence of any intervention) , but unlike what occurs following an intervention, these two variables were positively correlated with a ∼25 min offset, suggestive of an oscillatory pattern. We conclude that after a short delay, physiological stimuli that raise the BG level are coupled to reduced activity of VMHPacap neurons in vivo. In the basal state, levels of these two variables are positivity correlated in a delayed manner suggestive of an oscillatory control mechanism. These findings identify hypothalamic glucoregulatory neurons that are capable of sensing and responding to changes of glycemia in conscious, free-living mice.

Disclosure
J. D. Deem: None. A. Kumar: None. J. M. Scarlett: None. G. J. Morton: Research Support; Novo Nordisk A/S. M. W. Schwartz: None. D. Tingley: None. A. Bjerregaard: Employee; Novo Nordisk. C. L. Faber: None. T. P. Doan: None. B. N. Phan: None. Z. Nasir: None. B. Wu: None. M. K. Hwang: None.

Funding
NIDDK:P30 DK035816 K01 DK126793 R01 DK124238 R01 DK83042 NIDA:P30 DA048736; Novo Nordisk Research Agreement:CMS-431104
209-OR: Ceramide-Based Lipid Profiles and the Prevalence of Type 2 Diabetes Differ between Patients with Coronary Artery Disease and Those with Peripheral Artery Disease
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , BRANDTNER EVA MARIA , SAELY CHRISTOPH H. , VONBANK ALEXANDER , MADER ARTHUR , SPRENGER LUKAS , MAECHLER MAXIMILIAN , LARCHER BARBARA , JYLHA ANTTI , LAAPERI MITJA , LAAKSONEN REIJO , MAERZ WINFRIED , FRAUNBERGER PETER , KLEBER MARCUS , DREXEL HEINZ 
Published: May 2022

Serum lipids and metabolic diseases, in particular type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) , predict the atherosclerotic diseases coronary artery disease (CAD) and peripheral arterial disease (PAD) . However, it is not known in how far a more detailed characterization including serum lipids improves discrimination of PAD from CAD. A cohort of 274 statin-naïve patients with either PAD (n = 89) or stable CAD (n = 185) were referred to metabolic screening and were characterized using nuclear magnetic resonance- and liquid chromatography-tandem mass spectrometry based advanced lipid and lipoprotein analysis. Results were validated in an independent cohort of 1239 patients with PAD or CAD. We found a significant difference in T2D prevalence and in the ceramide-based lipid profile between PAD and CAD patients. However, neither cholesterol-based markers (including LDL-C, HDL-C) and detailed lipoprotein profiles nor the NAFLD status differed significantly between PAD and CAD patients (figure) . The difference between ceramide-based lipid profiles of CAD and PAD remained significant also after adjusting for body composition, smoking, inflammatory parameters, and T2D. We conclude that PAD and CAD differ in ceramide-based lipid profiles and T2D status, but not in other lipid characteristics or metabolic diseases.

Disclosure
A.Leiherer: None. A.Jylha: None. M.Laaperi: None. R.Laaksonen: None. W.Maerz: None. P.Fraunberger: None. M.Kleber: None. H.Drexel: None. A.Muendlein: None. E.Brandtner: None. C.H.Saely: None. A.Vonbank: None. A.Mader: None. L.Sprenger: None. M.Maechler: None. B.Larcher: None.
210-LB: Central Regulation of Peripheral Adiposity by Nos1PVHNeurons
Authors: FAULKNER LATRICE D. , LEWIS KENNETH , MEEK THOMAS H. , MERCER AARON J. , MACDOUGALD ORMOND A. , OLSON DAVID 
Published: May 2022

Within the CNS, the paraventricular nucleus of the hypothalamus (PVH) is critical for energy homeostasis, as developmental or mechanical lesions targeting the PVH lead to massive obesity. The PVH is composed of multiple cell types expressing an assortment of neuropeptides, receptors, and enzymes, including a subset of neurons expressing nitric oxide synthase-1 (Nos1PVH) . Nos1PVH neurons project to the nucleus of the solitary tract and the intermediolateral column of the spinal cord suggesting a neural substrate through which Nos1PVH neurons might directly modulate sympathetic output and energy balance [1]. To understand the necessity of Nos1PVH neurons in basal energy balance regulation, we bilaterally injected the PVH of Nos1-iCre mice with an AAV expressing a Cre-dependent tetanus toxin (Nos1TT) . Chronic silencing of the Nos1PVH resulted in acute onset of subcutaneous and visceral obesity without changes in food intake. Surprisingly, metabolic analyses indicated no significant changes in energy expenditure, although Nos1TT treated animals preferred to utilize fat as the predominant fuel source. Pair feeding experiments also confirmed that the obesity observed in Nos1TT animals was not secondary to increased caloric intake. Adipose tissues receive input from CNS cell groups that are part of the general SNS outflow from the brain [2, 3]. Analysis of subcutaneous white adipose tissue of Nos1TT animals revealed a significant decrease in tyrosine hydroxylase (TH) immunoactivity within WAT suggesting decreased capacity for sympathetic activation of lipolysis. These data indicate that Nos1PVH neurons regulate energy homeostasis possibly through changes in peripheral aspects of energy balance without the influence of energy consumption. Therefore, the main goal of this project is to clarify the physiological roles of Nos1PVH neurons in the regulation of peripheral adiposity, which may lead to the development of more refined anti-obesity therapies. 1. PMID: 25392498 2. PMID: 9688991 3. PMID: 15142857

Disclosure
L. D. Faulkner: n/a. K. Lewis: None. T. H. Meek: Employee; Novo Nordisk. A. J. Mercer: Employee; Novo Nordisk. O. A. Macdougald: None. D. Olson: Research Support; AstraZeneca, Novo Nordisk A/S.

Funding
American Diabetes Association (7-21-PMF-020) ; Novo Nordisk A/S; National Institutes of Health (5R01DK104999-05)
211-LB: The Islet Tester Mouse, a Stable and Reproducible In Vivo Model to Study Human Islet Function
Authors: WAITE ERIC , MAY CATHERINE L. , PANCREAS ANALYSIS PROGRAM (HPAP) HUMAN , KAESTNER KLAUS H. 
Published: May 2022

The current gold standard for assessing the function of human islet in vivo, is to engraft islets under the kidney capsule of hyperglycemic, immunodeficient mice. Current models, such as Streptozotocin (STZ) treatment or NSG-Akita mice, are limited due to instable hyperglycemia and/or morbidity of the mouse strain. The glycemia in STZ treated mice is variable and can even result in death or spontaneous recovery of normoglycemia, making it difficult to discern small differences in human islet function. The NSG-Akita mouse is difficult to breed and maintain, and thus has reduced practicality. To address these limitations, we developed a stable, highly reproducible immunodeficient Islet Tester mouse via CRISPR-Cas9 mediated gene editing of glucokinase (GCK) directly in NSG zygotes. Islet Tester mice are heterozygous for the Arg345-&gt;stop variant and present with stable hyperglycemia (∼250mg/dl) , without the severe age-dependent morbidity of the NSG-Akita mice. This mouse will allow us to study human islet biology over time and under different physiological conditions and could provide a useful preclinical platform to investigate drugs targeting islet cells.

Disclosure
E. Waite: None. C. L. May: None. Human pancreas analysis program (hpap) : n/a. K. H. Kaestner: None.