bluuebunny/crossref_metadata_2025_split huggingface dataset:
152-OR: Sex Differences in Metabolomics and Risk of Coronary Heart Disease in Type 2 Diabetes
Authors: YOSHIDA YILIN , LI DANTING , LI XIANG , FONSECA VIVIAN , MAUVAIS-JARVIS FRANCK , QI LU 
Published: June 2024

Aim: We compared circulating metabolites and their associations with coronary heart disease (CHD) in men and women across glycemic status.
Method: We used metabolomic data (amino acids, glycolysis, ketone bodies, inflammation, fluid balance, fatty acids, lipids, lipoproteins) for 95,108 CHD-free UK Biobank participants. We used linear regressions to examine the association of sex and metabolites (log) in newly diagnosed T2D (diagnosis&lt;2 yrs from baseline), prediabetes (A1c 5.7-6.5%), and euglycemia, accounting for age, race, Deprivation Index, income, smoking, obesity, medications for hypertension, hyperlipidemia & diabetes. We used Cox models to evaluate the association of metabolites and CHD risk by sex, adjusting the same covariates & menopausal status. All analyses were FDR-adjusted.
Results: We included 1328 individuals with new T2D, 6204 with prediabetes, and 87,576 with euglycemia. In adjusted linear regressions, glycoprotein acetyls (GlycA, inflammation), fatty acids (total, polyunsaturated, saturated fatty acids [SFA]), lipids (phosphoglycerides, cholines, sphingomyelins, phospholipids), atherogenic lipoproteins (total cholesterol, non-HDL-c, remnant-c, LDL-c, cholesteryl esters, ApoB) were higher in women than in men across glycemic status (pinteraction&lt;.05), particularly in T2D (ptrend&lt;.05). Men had higher creatinine and albumin across glycemic levels (ptrend&lt;.05). In a 10-year follow-up, an SD higher GlycA (W HR 16.1, 95%CI 2.1-137.8 vs M 0.5, 0.1-1.7), SFA (W 4.5, 1.5-13.8 vs M 0.9, 0.5-2.8), triglycerides (TG)/phosphoglycerids ratio (W 3.0, 1.4-6.8 vs M 1.3, 0.7-2.3), and total TG (W 2.5, 1.3-4.9 vs M 1.1, 0.7-1.7) was associated with CHD risk in women with T2D, but not in men (p-interaction&lt;.1).
Conclusions: With advancing glycemic status, women had higher levels of markers of inflammation, fatty acids, and atherogenic lipids, while men had higher levels of renal markers. Women with T2D are at a higher risk of CHD associated with GlycA, SFA, and TG than men with T2D.

Disclosure
Y. Yoshida: None. D. Li: None. X. Li: None. V. Fonseca: Consultant; Abbott, Bayer Inc. Stock/Shareholder; BRAVO4HEALTH, LLC. Consultant; Corcept Therapeutics. Speaker's Bureau; Eli Lilly and Company. Research Support; Fractyl Health, Inc. Consultant; Sun Pharmaceutical Industries Ltd. Stock/Shareholder; Amgen Inc. F. Mauvais-Jarvis: None. L. Qi: None.

Funding
American Diabetes Association (7-23-JDFWH-10)
1521-P: Carnosic Acid Protects against Diet-Induced Insulin Resistance
Authors: TSAKIRIDIS NICOLE , M NIAZUR RAHMAN S , TSIANI EVANGELIA , GIACCA ADRIA 
Published: June 2024

Background: Obesity and type 2 diabetes (T2D) are associated with elevated plasma free fatty acids (FFA). In vivo exposure to FFAs, such as palmitate, by lipid infusion results in insulin resistance as observed in obesity and T2D. In recent years, compounds found in herbs and plants have attracted attention for prevention and treatment of insulin resistance and T2D. In recent studies by our group, carnosic acid (CA), found in rosemary, increased glucose uptake and attenuated the FFA (palmitate)-induced insulin resistance in muscle cells and adipocytes. In addition, CA caused a robust activation of AMP-activated protein kinase (AMPK). Our present study aimed to examine the effects of CA on mice fed a high-fat high sucrose diet (HFSD), which mimics the Western-style diet.
Material and Methods: C57Bl/6J mice (4 week old) were given control diet (CTD) or HFSD for 8 weeks, which we have seen induces fasting and fed hyperglycemia and insulin resistance during an insulin tolerance test (ITT). CA (70 mg/kg/day) or vehicle were administered orally (incorporated into the diet) for 8 weeks in combination with HFSD. Results: Mice underwent intraperitoneal insulin tolerance test (ipITT) and intraperitoneal glucose tolerance test (ipGTT). Preliminary data from the ipITT revealed that the HFSD+CA group had similar insulin tolerance to that of the CTD group. Indeed, the AUC of the ipITT of the CA HFSD (mean + SEM, 632 + 75) group was significantly lower than that of the HFSD (1000 + 118) group (p&lt;0.05) and similar to CTD (623 + 57) group. In contrast, the ipGTT revealed that the HFSD+CA group had a tendency to better glucose tolerance than the WT HFSD group, but the effect was not significant.
Conclusions: Our data indicate that CA has the potential to counteract diet-induced insulin resistance but is less effective on diet-induced glucose intolerance.

Disclosure
N. Tsakiridis: None. S. Rahman: None. E. Tsiani: None. A. Giacca: None.
1523-P: Anorexia Induced by the Central Action of Fibroblast Growth Factor 1 (FGF1) Is Dependent on Activation of Parabrachial CGRP Neurons
Authors: SCARLETT JARRAD M. , BRYAN CAELEY , REDFORD INGRID K. , ALONGE KIMBERLY M. , MORTON GREGORY J. , SCHWARTZ MICHAEL W. 
Published: June 2024

Intracerebroventricular (icv) injection of FGF1 induces remission of hyperglycemia that is sustained for weeks across multiple rodent models of type 2 diabetes. However, in addition to sustained remission of hyperglycemia, we and others have shown that icv FGF1 injection also induces a transient but potent anorexic response that has hindered efforts to translate these findings towards the clinic. Recently, our group reported that the activity of orexigenic AgRP neurons is inhibited following icv FGF1 injection, both in vivo and after bath application of FGF1 in an ex vivo brain slice preparation. Previous work by other groups has established that neurons located in the parabrachial nucleus (PBN) that express calcitonin gene-related peptide (CGRPPBN neurons) are highly anorexigenic when activated and are innervated by and tonically inhibited by GABAergic projections from AgRP neurons. Based on these findings, we hypothesized that FGF1-induced anorexia involves CGRPPBN neuron activation. To test this hypothesis, we employed CalcaCre:GFP/+ transgenic mice, which express GFP fused to Cre recombinase driven by the CGRP-encoding gene Calca. We first found that CGRPPBN neurons are robustly activated following icv FGF1 injection (based on detectable c-Fos staining). We next found that the anorexic response to icv FGF1 injection was blunted by &gt;50% by continuous subcutaneous infusion of the GABAA receptor agonist Bretazenil via osmotic minipump at a dose that does not affect intake in control mice. Finally, we bilaterally infected CGRPPBN neurons with either AAV1-DIO-hM4Di:mCherry or AAV1-DIO-mCherry control virus and observed that inhibition of CGRPPBN neurons following administration of CNO fully reversed FGF1-induced anorexia in hM4Di-bearing mice, while anorexia remained intact in the mCherry control group. Together, these data suggest that FGF1-induced anorexia results from reduced GABAergic inhibition of CGRPPBN neurons.

Disclosure
J.M. Scarlett: None. C. Bryan: None. I.K. Redford: None. K.M. Alonge: None. G.J. Morton: Research Support; Novo Nordisk A/S. M.W. Schwartz: None.

Funding
NIH (DK114474, DK128383DoD, W81XWH2110635); GJM (DK089056, DK124238MWS, DK101997, DK083042)
153-OR: Gut Microbiota, Blood Metabolome, and Incident Type 2 Diabetes in U.S. Hispanics
Authors: LUO KAI , PETERS BRANDILYN , WANG ZHENG , WANG TAO , YU BING , BOERWINKLE ERIC , ISASI CARMEN R. , KAPLAN ROBERT , QI QIBIN 
Published: June 2024

Introduction & Objective: Current evidence on the relationship between the human gut microbiota and incident type 2 diabetes (T2D) is limited. We sought to identify gut bacteria and related blood metabolites associated with incident T2D.
Methods: Using gut microbiome data from the Hispanic Community Health Study/Study of Latinos (HCHL/SOL), we assessed the associations of bacteria species (spp.) with incident T2D (n=1877; 245 incident cases). In a subset of HCHS/SOL (n=804), we examined cross-sectional associations between species and plasma metabolites. In a larger subset of HCHS/SOL (n=4725), we evaluated associations of identified microbial-related metabolites with incident T2D.
Results: We identified 19 out of 516 predominant bacteria associated with incident T2D, with the majority showing lower risk, including 3 Akkermansia spp. and 5 Clostridium spp., a group of potentially beneficial bacteria related to insulin/glucose homeostasis. 99 metabolites were associated with the identified T2D-related spp., 41 of which were associated with incident T2D, including many microbial-derived metabolites from aromatic amino acids, bile acids, and branched-chain amino acids. Further analyses with these metabolites as proxies confirmed the observed prospective associations of 10 spp. with T2D.
Conclusions: This study supports the potential role of gut microbiota and microbial metabolites in the development of T2D.

Disclosure
K. Luo: None. B. Peters: None. Z. Wang: None. T. Wang: None. B. Yu: None. E. Boerwinkle: None. C.R. Isasi: None. R. Kaplan: None. Q. Qi: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK119268; R01-DK126698); National Institute on Minority Health and Health Disparities (R01-MD011389); AHA Postdoctoral Fellowship Award (23POST1020455)
1537-P: GPSM1-Mediated Astroctyte-Secreted IGFBP5 Regulates Glucose Metabolism via AgRP Neurons
Authors: ZHANG YI , HU CHENG 
Published: June 2024

Genome-wide association studies (GWASs) have identified that genetic variations in G-protein-signaling modulator 1 (GPSM1) are strongly associated with type 2 diabetes mellitus (T2DM) in Asians, but the specific mechanism remains largely unknown. Here, we found that GPSM1 is abundantly expressed in the hypothalamus, and its expression in astrocytes is significantly increased in HFD-fed mice. Mice with astrocyte-specific GPSM1 knockout (KO) protect against high-fat diet-induced glucose dysfunction by regulating whole-body glucose uptake and production, while mice with GPSM1 overexpression in astrocytes exhibit glucose and insulin intolerance. Mechanistically, GPSM1 in astrocytes promotes IGFBP5 secretion via the mTOR-HIF1α pathway. Subsequently, IGFBP5 blocks the effects of IGF1 on decreasing AgRP neuron activity, leading to sustained activation of AgRP neurons and ultimately resulting in T2DM.

Disclosure
Y. Zhang: None. C. Hu: None.
1550-P: Changes in Beta-Cell Function during Dapagliflozin Therapy in Combination with Exenatide in Type 2 Diabetes Patients (T2D)
Authors: DEFRONZO RALPH A. , BASKOY GOZDE , TRIPLITT CURTIS L. , CERSOSIMO EUGENIO , SOLIS-HERRERA CAROLINA , ADAMS JOHN M. , HANSIS-DIARTE ANDREA A. , GASTALDELLI AMALIA , CHAVEZ ALBERTO 
Published: June 2024

Introduction & Objective: To examine the effect of sodium-glucose co-transporter-2 inhibitor [SGLT2i] therapy alone or in combination with glucagon-like peptide-1 receptor agonist [GLP-1 RA] on beta-cell function [BCF] in T2D. HYPOTHESIS: the improvement in BCF with GLP-1 RA plus SGLT-2i would be superior to that with either agent alone.
Methods: Ninety patients received 3-hour OGTT: (i) before and after a single dose of drug (ACUTE study): placebo [PCB, n=15]; dapagliflozin [DAPA, n=25]; exenatide [EXE, n=25]; or both [DAPA/EXE, n=25], and (ii) after 1 and 4 months of therapy (CHRONIC study) with PCB, DAPA, EXE or DAPA/EXE. Matsuda Index [MI], Insulin Secretion [ΔI/ΔG)0-3h) and Disposition Index [DI=IS x MI] were calculated using standard formulae. MI was corrected for urinary glucose excretion.
Conclusion: Dapagliflozin and exenatide as monotherapy improve beta cell function (DI) acutely and chronically (4 months). Combination therapy with dapagliflozin plus exenatide leads to superior and sustained improvement in beta cell function (DI) compared to either drug alone. These data suggest that combination therapy with GLP-1 RA plus SGLT2i may enhance long-term preservation of beta-cell function in T2D patients.

Disclosure
R.A. DeFronzo: Advisory Panel; AstraZeneca, Novo Nordisk, Boehringer-Ingelheim, Intarcia Therapeutics, Inc., Aardvark, Renalytix, Corcept Therapeutics, Alnylam Pharmaceuticals, Inc. Research Support; Boehringer-Ingelheim, AstraZeneca, 89bio, Inc., Amgen Inc., Medality, Corcept Therapeutics. Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Renalytix. G. Baskoy: None. C.L. Triplitt: Speaker's Bureau; Novo Nordisk. Consultant; Eli Lilly and Company. Other Relationship; American Diabetes Association. E. Cersosimo: None. C. Solis-Herrera: Advisory Panel; Novo Nordisk, Bayer Inc. J.M. Adams: None. A.A. Hansis-Diarte: None. A. Gastaldelli: Consultant; Boehringer-Ingelheim. Other Relationship; Pfizer Inc., Eli Lilly and Company. Consultant; Merck Sharp & Dohme Corp. Advisory Panel; Novo Nordisk. Speaker's Bureau; Merck Sharp & Dohme Corp., Eli Lilly and Company. Advisory Panel; Pfizer Inc. Speaker's Bureau; Novo Nordisk. A. Chavez: None.
1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis
Authors: SAKUMA IKKI , GASPAR RAFAEL C. , NASIRI ALI , KAHN MARIO , ZHENG JIE , GUERRA MATEUS , YIMLAMAI DEAN , MURRAY SUE , PERELIS MARK , BARNES WILLIAM , VATNER DANIEL F. , PETERSEN KITT , SAMUEL VARMAN , SHULMAN GERALD I. 
Published: June 2024

Metabolic dysfunction-associated steatohepatitis (MASH) is a frequent complication of type 2 diabetes. However, the molecular mechanisms responsible for the development of MASH are unknown. Loss of function mutations in the lipid droplet proteins Comparative Gene Identification-58 (CGI-58) and Cell Death-inducing DNA fragmentation factor-like effector B (CIDEB) promote and protect against MASH, respectively. We hypothesized that the discrete impact of these proteins on MASH is due to the alteration of lipid droplet morphology followed by cholesterol content. We tested these hypotheses using antisense oligonucleotides (ASO) to knock down the expression of CGI-58 or CideB in the liver of a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) mouse MASH model. CGI-58 ASO treatment increased plasma ALT, macrophage crown-like structures, and liver inflammation/fibrosis marker expression, which were associated with increased lipid droplet size and liver lipid droplet cholesterol content. Co-treatment with an ASO against glycerol-3-phosphate acyltransferase, mitochondrial (Gpam) decreased liver lipid droplet cholesterol and prevented CGI-58 ASO-induced MASH. In contrast, CideB ASO treatment in CDAHFD mice prevented liver inflammation and fibrosis and reduced liver lipid droplet size and lipid droplet cholesterol content. These protective effects of the CideB ASO were all abrogated with cholesterol supplementation to the diet.
Conclusions: Knockdown of CGI-58 promotes liver inflammation and fibrosis by increasing liver lipid droplet size and lipid droplet cholesterol content, whereas knockdown of CideB protects against the development of liver inflammation and fibrosis by reducing liver lipid droplet size and cholesterol content. Furthermore, CIDEB and GPAM are potential therapeutic targets for MASH.

Disclosure
I. Sakuma: None. R.C. Gaspar: None. A. Nasiri: None. M. Kahn: None. J. Zheng: None. M. Guerra: None. D. Yimlamai: None. S. Murray: Employee; Ionis Pharmaceuticals. M. Perelis: Employee; Ionis Pharmaceuticals. W. Barnes: Employee; Ionis Pharmaceuticals. D.F. Vatner: None. K. Petersen: None. V. Samuel: None. G.I. Shulman: None.
1578-P: Recombinant Decorin Improves Features of Diabetes-Related Steatotic Liver Disease in Mice
Authors: DEWIDAR BEDAIR , YAVAS ASLIHAN , GRANATA CESARE , TRINKS NINA , MASTROTOTARO LUCIA , ESPOSITO IRENE , REINADOFUNDO MICHELLE , RODEN MICHAEL 
Published: June 2024

Although type 2 diabetes closely associates with metabolic dysfunction-associated steatotic liver disease (MASLD) and accelerates its progression to steatohepatitis (MASH), fibrosis and hepatocellular carcinoma (HCC), still no treatment has been approved for MASLD. The extracellular matrix proteoglycan, decorin (DCN) may protect against fibrosis and HCC, but its role in MASLD is yet unclear.
Thus, we treated mice for 8 w with recombinant human DCN (200 μg/kg/day) or phosphate-buffered saline (PBS) via subcutaneous osmotic pumps. Diabetes-related MASH was induced by injecting two-day old male C57BL/6j mice with 200 µg streptozotocin and subsequent feeding a high-fat diet from 4 w on. Control mice (CTRL) received vehicle and standard diet. Hepatic steatosis, inflammation, ballooning, and fibrosis were quantified by histology. Liver mitochondrial respiration and mitochondrial ROS were assessed by high-resolution respirometry. Plasma metabolites and liver protein and gene expression levels were quantified by colorimetric assays, ELISA and qPCR.
MASH treated with PBS showed greater hepatic steatosis and ballooning, along with 3.28fold rise in blood glucose as compared to CTRL (p&lt;0.01). DCN, but not PBS reversed liver steatosis in diabetic MASH (p&lt;0.001 and p&gt;0.05 vs CTRL). Median score of ballooning was lower with DCN than with PBS treatment (p&lt;0.05). Compared to PBS, DCN lowered hepatic expression of genes involved in lipid synthesis, e. g. Fasn and Srebf, and increased plasma HDL-cholesterol. DCN also downregulated specific inflammation- and fibrogenesis-related genes, e. g. Il6 and Tgfβ (both p&lt;0.05 vs PBS). DCN-treated livers showed increased fatty acid oxidation-linked mitochondrial respiration and reduced mitochondrial ROS production (p&lt;0.001 and p&lt;0.05 vs PBS).
In conclusion, DCN improves biomarkers of hepatic cellular injury in MASH, likely by enhancing hepatic mitochondrial capacity, and may therefore represent a promising concept for treating MASLD in diabetes.

Disclosure
B. Dewidar: None. A. Yavas: None. C. Granata: None. N. Trinks: None. L. Mastrototaro: None. I. Esposito: None. M. ReinaDoFundo: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca.

Funding
German Center for Diabetes Research (82DZD02E1G)
1585-P: Changes in Metabolic Health following COVID-19 in Persons with Type 2 Diabetes Mellitus
Authors: YURCHENKO IRYNA , KUPRIYANOVA YULIYA , BOBROV PAVEL , BURKART VOLKER , WAGNER ROBERT , SCHRAUWEN-HINDERLING VERA , RODEN MICHAEL 
Published: June 2024

Objective: COVID-19 can affect various organs beyond the respiratory system with unclear potential long-term effects. This study aimed to assess the effect of COVID-19 infection on insulin sensitivity, lipid metabolisms and features of metabolic dysfunction-associated steatotic liver disease (MASLD) in type 2 diabetes mellitus (T2D).
Methods: Participants with T2D from the prospective German Diabetes Study (GDS) with recent history of mild (no hospital admission, O2 saturation &gt;90%) PCR-confirmed COVID-19 (COVID+: n=14, age 58±12 years, BMI 30.9±5.2 kg/m2) were invited to a follow-up visit with comprehensive phenotyping. They were compared to GDS participants with similar baseline age- and body mass index (BMI), but without history of COVID-19 (COVID-: n=15, 61±6 years, 30.0±4.6 kg/m2). Investigations comprised clinical examination, fasting blood sampling and magnetic resonance (MR) imaging (MRI) and MR elastography (MRE). Adipose tissue volumes, hepatic lipid contents and hepatic stiffness were compared with ANCOVA, adjusted for the respective baseline values and sex, revealing whether parameters evolved differentially in COVID+ vs COVID-.
Results: COVID- and COVID+ did not differ in BMI, HOMA-IR, triglycerides-glucose index and HOMA-B, while high-density lipoprotein was lower in COVID+. Liver lipid content did not significantly change in the COVID- group (-8%, CI [-20; 15%]), but increased by 80% (CI [30; 149 %], pdifference-by-group=0.01) in the COVID+ group. Surrogate indices of liver fibrosis (FIB-4, APRI, NAFLD score, FLI, Forns index) and MRE-based hepatic stiffness were not different. Likewise, hepatic, whole body, subcutaneous and visceral adipose tissue volumes were comparable between the groups. There was no correlation between history of COVID-19 and high-sensitivity C-reactive protein (hsCRP) levels.
Conclusion: A history of COVID-19 is associated with higher hepatic lipid content long after recovery from infection.

Disclosure
I. Yurchenko: None. Y. Kupriyanova: None. P. Bobrov: None. V. Burkart: None. R. Wagner: Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk. V. Schrauwen-Hinderling: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca.
1595-P: Differential Effects of Carbohydrate Overfeeding on Postprandial Glucose Metabolism in Individuals with Low Compared with Normal Birthweight
Authors: ENGELHARD LEONIE M. , OHRT ELINGAARD-LARSEN LINE , JUSTESEN LOUISE , HANSEN TORBEN , VAN HALL GERRIT , VAAG ALLAN A. , BRØNS CHARLOTTE 
Published: June 2024

Introduction & Objective: Individuals born with low birthweight (LBW) are at elevated risk of developing type 2 diabetes (T2D). We studied postprandial (pp) glucose metabolism during a mixed meal-test in healthy LBW compared with normal birthweight (NBW) men before and after carbohydrate overfeeding (CO).
Methods: Twenty-two non-obese, middle-aged LBW men (BW 2797±175g) and 21 age- and BMI-matched NBW controls (BW 3807±176g) were included. Glucose kinetics were assessed by [U-13C]Glucose (meal) and [6,6-D2]Glucose continuous forearm venous infusion during a 5-hour liquid mixed meal-test before and after 4-week CO (+25% energy). Data were analyzed assessing change in pp area under the curve (AUC). Subgroup analysis was performed for five cases of screen-detected non-alcoholic fatty liver disease (NAFLD) among LBW men measured by magnetic resonance spectroscopy.
Results: CO resulted in increased weight (P&lt;0.0001) and liver fat content (P=0.009) in both groups. LBW men responded to CO with an increase in pp insulin AUC (P=0.04), with no differences in pp glucose AUC, compared with NBW men. In response to CO, the pp total glucose rate of appearance (Ra) decreased paradoxically by 4.5% in the LBW group (with and without NAFLD), whereas it increased by 6.3% in the NBW group (P=0.03). This, in turn, was explained by a decrease of oral glucose Ra (P=0.01), and not endogenous (hepatic) Ra, in the LBW group. In response to CO, the pp glucose disposal rate (reflecting insulin action) decreased by 26% in the LBW group, whereas it increased by 40% in the NBW group (P=0.08).
Conclusion: LBW compared with NBW subjects respond to CO with increased plasma insulin levels, peripheral insulin resistance, and a decline in postprandial Ra of ingested glucose in the main circulation possibly caused by an increased hepatic retention of ingested glucose contributing to increased hepatic lipogenesis, fat storage and NAFLD risk in LBW subjects.

Disclosure
L.M. Engelhard: None. L. Elingaard-Larsen: None. L. Justesen: None. T. Hansen: None. G. van Hall: None. A.A. Vaag: None. C. Brøns: Stock/Shareholder; Novo Nordisk A/S.

Funding
NNF, EFSD Organ Crosstalk Program, Trygfonden, Augustinus Fonden and Aase and Ejnar Danielsens Fond