bluuebunny/crossref_metadata_2025 huggingface dataset:
1518-P: HMGA1 Deficiency—A Common Causal Link between Tau Pathology and Insulin Resistance?
Authors: MIRABELLI MARIA , CHIEFARI EUSEBIO D. , SAVERIO BRUNETTI FRANCESCO , PATRIZIA FOTI DANIELA , BRUNETTI ANTONIO
Published: June 2024

Consistent evidence supports a link between neurodegeneration, insulin resistance (IR) and type 2 diabetes (T2D). The molecular mechanisms for this association are unclear. It has been previously shown that the transacting factor HMGA1 is needed for proper expression of the insulin receptor. Also, IR and T2D were reported earlier in humans and mice with HMGA1 gene defects. Here, we focused on HMGA1 as a potential novel pathogenic factor of Tauopathies, including Alzheimer’s disease.

Investigations were performed in vitro, in human and mouse neuronal cell models, and in vivo, in Hmga1-/- mice. Immunoblot analyses, combined with protein-DNA interaction studies, ChIP-qPCR, and reporter gene assays in living cells were carried out, in addition to Tau immunohistochemistry in Hmga1-/- mouse brain. Also, a case-control study was used to explore the relationship between HMGA1 and Tau pathology in Tauopathy patients, carrying or not the rs146052672 variant, which negatively impacts HMGA1 protein production and increases the risk of IR and T2D.

We show that HMGA1 plays a role in controlling Tau protein expression. This function was mediated primarily through the specific repression of MAPT gene transcription. Thus, Tau mRNA and protein levels were inversely related to HMGA1 in both human neuronal cells and primary mouse neurons. This inverse relationship was confirmed in the brain of Hmga1-/- mice, in which Tau was overexpressed, compared to Hmga1+/+ mice. Furthermore, genetic analysis indicated that the rs146052672 variant was more common among patients with Tauopathy (17%) than among controls (5%). Adjusted logistic regression analysis revealed a strong association of this variant with Tauopathy (OR, 5.56 [95% CI, 2.08-14.87]; P = 0.001).

HMGA1 is a repressor of the MAPT gene. As such, HMGA1 deficiency may be a causative factor of Tauopathy. We hypothesize that a shared causal link between Tau pathology and insulin resistance is plausible, that is, via downregulation of HMGA1 function.

Disclosure

M. Mirabelli: None. E.D. Chiefari: None. F. Brunetti: None. D. Foti: None. A. Brunetti: None.
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<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<.05), particularly in T2D (ptrend<.05). Men had higher creatinine and albumin across glycemic levels (ptrend<.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<.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<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 >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<0.01). DCN, but not PBS reversed liver steatosis in diabetic MASH (p<0.001 and p>0.05 vs CTRL). Median score of ballooning was lower with DCN than with PBS treatment (p<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<0.05 vs PBS). DCN-treated livers showed increased fatty acid oxidation-linked mitochondrial respiration and reduced mitochondrial ROS production (p<0.001 and p<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 >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<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
1614-P: H2S Improves Skeletal Muscle Insulin Resistance by Inhibiting Pyroptosis via Sirt2 Pathway
Authors: QIU KANGLI , KONG WEN
Published: June 2024

Introduction & Objective: H2S is the third gaseous signaling molecule with a variety of biological effects.H2S may be involved in diabetes by modulating inflammation. The aim of this study was to determine the effects and mechanisms of H2S on high-fat diet-induced insulin resistance in skeletal muscle.

Methods: Mice were injected intraperitoneally with NaHS (50 μmol/kg/d ), the Sirt2 inhibitor AGK2 (1 mg/kg/d), or disulfiram (50 mg/kg/d). Body weight, IPGTT, ITT, calculation of skeletal muscle/body weight ratio, skeletal muscle muscle fiber cross sectional area and adipose tissue were detected. The effects of NaHS-induced sirt2 changes and the NLRP3/caspase-1/GSDMD pathway were detected.

Results: The SIRT2 inhibitor AGK2 accelerated blood glucose and body weight elevation and decreased skeletal muscle/body weight ratio in mice, and IPGTT and ITT indicated that AGK2 inhibited the recovery of blood glucose and exacerbated skeletal muscle atrophy and adiposity in mice.However, NaHS and disulfiram were effective in reversing the above changes.

Conclusion: H2S regulates skeletal muscle satellite cell proliferation and differentiation by activating sirt2 and thereby inhibiting NLRP3/caspase-1/GSDMD pathway-mediated skeletal muscle scorpioning, resulting in increased skeletal muscle mass and thus alleviating IR resistance.

Disclosure

K. Qiu: None. W. Kong: None.
1617-P: Diabetes and Bones—Unraveling the Biomarker Symphony and Density Dance
Authors: RASMUSSEN NICKLAS H. , KVIST ANNIKA V. , VAN DEN BERGH JOOP , VESTERGAARD PETER
Published: June 2024

Introduction & Aim: This study delved into essential bone biomarkers in T1D and T2D, investigating their connections with areal bone mineral density (aBMD) and volumetric BMD (vBMD).

Methods: In a cross-sectional study, 543 adults participated, including 111 with T1D, 106 with T2D, and 328 controls. Employing DXA and HR-pQCT scans, a range of biochemical bone biomarkers (CTX, P1NP, sclerostin, osteopontin, OCN, and IGF-1) were analyzed. Group comparisons and regression models, adjusting for relevant factors, were executed. Correlation analyses, utilizing Spearman with Bonferroni correction, explored associations between bone parameters and biomarkers for intergroup comparison.

Results: Results revealed significantly reduced CTX1, P1NP, IGF-1, OCN, and osteopontin in T1D and T2D (p<0.05), with T2D having the lowest (p=0.01). Conversely, sclerostin was higher in both T1D and T2D than controls (p=0.001). T2D showed elevated neck aBMD (0.85g/cm2, p=0.011) and tibial vBMD (300.6HA/cm3, p=0.004) in contrast to T1D and controls. In T2D, neck aBMD correlated negatively with CTX1 (r=-0.332, p=0.001), P1NP (r=-0.278, p=0.005), OCN (r=-0.397, p=0.001), and positively with sclerostin (r=0.229, p=0.041). In T1D, CTX1 correlated negatively, while IGF-1 correlated positively with neck aBMD (r=-0.301, p=0.002, r=0.329, p=0.001, resp). Controls exhibited positive correlations of IGF-1 (r=0.321, p=0.001) and negative correlations of sclerostin (r=-0.151, p=0.008) with neck aBMD. Tibial vBMD was negatively correlated with P1NP in T2D (r=-0.231, p=0.024) and positively correlated with IGF-1 in T1D and controls (p<0.011). Sclerostin strongly correlated with diabetes duration in both T1D and T2D (r=0.491, p=0.001, r=0.342, p=0.003, respectively). IGF-1 had a negative correlation in T1D (p=0.001).

Conclusion: Individuals with T1D and T2D present distinctive bone biomarker profiles and associations with aBMD and vBMD, emphasizing the intricate interplay between diabetes and bone health.

Disclosure

N.H. Rasmussen: Other Relationship; Boehringer-Ingelheim. Stock/Shareholder; Novo Nordisk, Eli Lilly and Company. A.V. Kvist: None. J. van den Bergh: Advisory Panel; Amgen Inc. P. Vestergaard: None.

Funding

This work was supported by a research grant from the Danish Diabetes and Endocrine Academy, which is funded by the Novo Nordisk Foundation (NNF22SA0079901)
1634-P: Changes in Bile Acid Enterohepatic Circulation in Type 2 Diabetes Mellitus Rats following Sleeve Gastrectomy
Authors: ZHAO XIANG , LIU ZITIAN , YANG GUANGWEI , GE ZHENG , DONG SHUOHUI , ZHANG XIANG , CHENG ZHIQIANG , WANG KEXIN
Published: June 2024

Introduction & Objective: T2DM can be effectively treated by sleeve gastrectomy (SG), albeit the mechanisms underlying is elusive. Postoperative changes in serum bile acid have been found contributing to metabolism improvement. This study aims to determine the overall changes of bile acid enterohepatic circulation following SG.

Methods: SG model was established in T2DM rats. Alterations of bile acids in the bile, intestine, portal vein and inferior vena cava were evaluated by liquid chromatography-mass spectrometry. Bile acid transporters were also evaluated.

Results: Metabolism was significantly improved after SG. Intraluminal bile acids were altered from the duodenum to the colon, with glycine/taurine conjugated bile acid ratio being increased. Peripheral blood total bile acids exhibited an elevation, accompanied by intricate alterations in the composition of bile acids within both the bile and the portal vein. Postoperative liver bile acid absorption transporter NTCP, OATP and efflux transporter BSEP, MDR3 were significantly decreased, whereas intestinal uptake transporter ASBT was increased and bile acid binding protein IBABP was decreased (P<0.05 all).

Conclusion: The entire pathway of bile acid enterohepatic circulation exhibited complicated changes following SG. The impact of the changes on postoperative metabolism improvement warrants further research.

Disclosure

X. Zhao: None. Z. Liu: None. G. Yang: None. Z. Ge: None. S. Dong: None. X. Zhang: None. Z. Cheng: None. K. Wang: None.

Funding

National Natural Science Foundation of China (82070852, 82270901)
164-OR: Macrophage Ucp1 Deficiency Inhibits Cold Exposure–Induced Insulin Sensitivity in High-Fat Diet Mice
Authors: SUN LIMING
Published: June 2024

Cold exposure (CE) could increase insulin sensitivity in high-fat-diet (HFD) mice, relying on adipose tissue Ucp1-induced heat release and macrophage M2 polarization. The function of thermogenic macrophages, a new subtype of macrophages that we have recently identified, has not been clearly investigated in insulin sensitivity caused by cold exposure. We used HFD wild-type (WT) mice and Ucp1 conditionally knockout in macrophages (Ucp1-cKO) mice which housed in 16°C for 2 mouths, and detected their physiological characteristics, metabolic cage, and proteome profiles of different adipose tissues based on mass spectrometry. We found that the body weights of Ucp1-cKO mice were significantly higher than that of WT mice, and the oxygen consumption and heat release were reduced in Ucp1-cKO mice, which demonstrated a weaker metabolic activity of Ucp1-cKO mice upon CE. The glucose and insulin tolerance tests indicated that Ucp1 deletion in macrophages abated insulin sensitivity caused by CE. In addition, thermogenic proteins, represented by Ucp1, were inhibited in subcutaneous adipose tissue of Ucp1-cKO mice, suggesting that the loss of macrophage thermogenesis could reduce the thermogenesis metabolism of the whole sWAT. The adipocytes in sWAT were malformed and hypertrophied, and the cytokines secreted by macrophages were no difference between each other. These conclusions confirm the important role of thermogenic macrophages in promoting adipose tissue thermogenesis and insulin resistance in HFD mice, and provide a potential strategy for cell therapies in diabetes treatment.

Disclosure

L. Sun: None.
1642-P: Metabolic Effects of Semaglutide and Resmetirom at Thermoneutrality in the Diet-Induced Obese Mouse
Authors: TOZZI MARCO , FEIGH MICHAEL , HANSEN HENRIK H.
Published: June 2024

Introduction & Objective: Semaglutide (GLP-1 receptor agonist) is currently approved for the treatment of type 2 diabetes and obesity and in late-stage clinical development for MASH. Resmetirom, a selective THR-β agonist, is waiting for approval for MASH. The present study aimed to compare the effects of semaglutide and resmetirom monotherapy on metabolic endpoints at thermoneutrality in diet-induced obese (DIO) mice. Methods: Male C57BL/6J mice were fed a high-fat diet (60 kcal-% fat) for 32 weeks. Animals were acclimatized to thermoneutrality (28◦C) for 2 weeks prior to study start and randomized into treatment groups based on body weight and whole-body fat mass. DIO mice were administered vehicle, semaglutide (10 nmol/kg, SC, QD) or resmetirom (10 mg/kg, PO, QD) for 4 weeks. Chow-fed mice served as lean controls. Endpoints included body weight, food intake, whole-body fat/lean mass (echoMRI), plasma biochemistry and energy expenditure (EE) assessed using indirect calorimetry.

Results: Both compounds induced a sustained body weight loss (semaglutide, 25%; resmetirom, 13%) mainly driven by reduced food intake and fat mass. Semaglutide, but not resmetirom, also reduced lean mass. Only resmetirom enhanced EE after 1 and 4 weeks of treatment. The compounds equally improved hepatomegaly, fasting blood glucose and plasma triglycerides. Semaglutide improved hyperinsulinemia while only resmetirom normalized plasma cholesterol levels.

Conclusion: At thermoneutrality, semaglutide and resmetirom both improve metabolic outcomes in DIO mice. Notably, metabolic benefits of resmetirom treatment are associated with increased EE, highlighting the use of indirect calorimetry for profiling mechanism of action of drugs with therapeutic potential in obesity and MASH.

Disclosure

M. Tozzi: None. M. Feigh: Employee; Gubra. H.H. Hansen: Employee; Gubra.
1643-P: P2Y14 Receptor Regulates Whole-Body Glucose Homeostasis in High Fat Diet-Induced Obese and Diabetic Mice
Authors: PRAMANIK ASMITA , JACOBSON KENNETH A.
Published: June 2024

Diverse G protein-coupled receptors (GPCRs) are expressed in different metabolic tissues and are involved in the regulation of whole-body glucose and energy homeostasis. Dysregulation of glucose homeostasis contributes to hyperglycemia in obesity and type 2 diabetes (T2D). Thus, GPCRs have emerged as important therapeutic targets for anti-obesity and anti-diabetic candidate. P2Y14 receptor (P2Y14R) is a Gi-coupled purinergic receptor stimulated by endogenous UDP-glucose and functionally expressed in adipose tissue involved in glucose and lipid homeostasis. P2Y14R plays a crucial role in adipocyte metabolism, and its selective ablation in adipocytes improves metabolic phenotypes. However, the role of P2Y14R signaling in hepatic glucose production (HGP) and insulin secretion in obese mice has remained elusive. Here, we investigated this receptor in glucose metabolism using selective P2Y14R small molecule modulators. The P2Y14R mRNA level is upregulated in mouse hepatocytes and islets isolated from high fat diet-induced obese mice compared to lean control mice. A potent synthetic P2Y14R agonist (MRS2905) was administered to lean and obese mice to selectively activate P2Y14R. Surprisingly, acute activation impaired glucose homeostasis by enhancing HGP and suppressing insulin secretion in mice consuming high fat diet as well as lean mice. In contrast, P2Y14R antagonist mono-prodrug (MRS 4779) improved HGP and protected mice from metabolic deficits. Overall, our evidence suggests that P2Y14R activation triggers defects in glucose metabolism whereas antagonist prodrugs can contribute to improve whole-body glucose homeostasis in obese mice. Hence, P2Y14R antagonists and their prodrugs might have potential for use in anti-diabetic therapy.

Disclosure

A. Pramanik: None. K.A. Jacobson: None.

Funding

National Institutes of Health (ZIADK031126)
1644-P: The Dose Makes the Poison—High-Fat Diet Based on Extra Virgin Olive Oil Leads to Increased Liver Lipogenesis and Glucose Intolerance in Mice
Authors: KELLER LENA , BOSCH ANGELA J. , LOW ANDY J.Y. , STEIGER LAURA , RACHID LEILA , DE PAULA SOUZA JOYCE C. , WUEEST STEPHAN , MEIER DANIEL T. , CAVELTI-WEDER CLAUDIA
Published: June 2024

Background & Objectives: Extra virgin olive oil (EVOO) has garnered attention for its potential anti-inflammatory and oxidative properties. However, the effect on metabolic health remains inconclusive. We previously showed that high-fat diets (HFD) based on coconut oil or lard led to glucose intolerance and inflammatory changes in gut and adipose tissue (AT). Our study aimed to investigate the metabolic and immunological consequences of an EVOO-based HFD compared to a HFD based on coconut oil.

Methods: Male mice aged 5-8 weeks were fed a coconut or EVOO-based HFD (Coco HFD, EVOO HFD) or control diet for 1 week, after which the mice underwent glucose and insulin tolerance tests. Flow cytometry was used to characterize immune cells of the colon, AT, and liver. Total liver lipids were determined by a sulfophosphovanillin reaction. qPCR was used for relative DNA quantification. Statistical analysis was performed using ordinary one-way ANOVA with multiple comparisons.

Results: Both HFDs induced hyperinsulinemia, but the EVOO HFD led to pronounced glucose intolerance and insulin resistance. Furthermore, mice fed an EVOO HFD had significantly elevated total liver lipids and increased expression of lipogenesis genes, particularly Srebp1c. However, mice on EVOO HFD showed partial protection from inflammation in the AT and colon. Neither of the HFDs resulted in systemic inflammation after 1 week.

Conclusion: Our study highlights specific metabolic and immune responses induced by different dietary fat sources. Importantly, although EVOO HFD has fewer pro-inflammatory properties compared to Coco HFD, it results in pronounced glucose intolerance. This may be related to increased hepatic lipogenesis and subsequent elevation of hepatic lipids, possibly induced by oleic acid, which accounts for approximately 70 % of EVOO.

Disclosure

L. Keller: None. A.J. Bosch: None. A.J.Y. Low: None. L. Steiger: None. L. Rachid: None. J.C. de Paula Souza: None. S. Wueest: None. D.T. Meier: None. C. Cavelti-Weder: None.

Funding

The Swiss National Science Foundation (SNSF) (32003B_204937/2)
1645-P: Metabolic and Adipogenic Effects of Di(isononyl) Cyclohexane-1,2-dicarboxylate (DINCH) In Vivo
Authors: KRUPKA SONTJE , KLÖTING NORA , BLÜHER MATTHIAS
Published: June 2024

As a substitute for phthalate plasticizers, DINCH holds significance. Human studies indicate that lipophilic xenobiotics, including DINCH, accumulate in adipose tissue, potentially disrupting adipocyte biology and contributing to metabolic disturbances like insulin resistance and obesity. In vitro experiments demonstrate the activation of PPARg in adipocytes by DINCH. To provide further clarification on the effects of DINCH, we conducted a feeding study. A total of 144 C57BL/6NTac mice (N=144; females N=72, males N=72) were randomly assigned into four groups, each receiving distinct dietary interventions: standard chow, high-fat diet (HFD), and HFD supplemented with 4,500 ppm and 15,000 ppm DINCH. Throughout the 16-week study, animals had unrestricted access to their designated diets. To explore potential washout effects, 80 animals shifted to a standard diet for an additional 10 weeks following the initial intervention. The study included routine evaluations of body weight, blood glucose, insulin tolerance, and body composition (fat mass/lean mass). At the study's conclusion, metabolic chamber analysis assessed energy metabolism, and tissues were scrutinized at both molecular and histological levels post-euthanization. In contrast to expectations, mice fed the HFD-DINCH diet exhibited lower body weights than the standard HFD group, with minimal changes in fat and lean mass distribution. The DINCH-fed mice demonstrated increased insulin resistance and dyslipidemia, which were reversible during the washout phase. These results suggest a need to reevaluate the presumed effects of DINCH on adipocyte differentiation and lipid accumulation. They provide new insights into the interplay between DINCH exposure and metabolic responses in mice.

Disclosure

S. Krupka: None. N. Klöting: None. M. Blüher: Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Speaker's Bureau; Pfizer Inc., Sanofi.

Funding

Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through CRC 1052, project number 209933838
1648-P: Opposing Roles of Sphingosine 1 Phosphate Receptors 1 and 2 in Fat Deposition and Glucose Tolerance in Obese Male Mice
Authors: ASANO MOTOCHIKA , FUWA MASAYUKI , MORI ICHIRO , MORITA HIROYUKI , KAJITA KAZUO , ISHIZUKA TATSUO
Published: June 2024

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through five cognate G protein-coupled receptors (S1P1-S1P5). However, little is known about the role of S1P in obesity formation. We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and a S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates adipogenic differentiation. In this study, we examined whether an S1P1-specific agonist SEW-2871 and VPC23019 act on obesity and glucose intolerance in ob/ob mice. The oral administration of SEW-2871 and JTE-013 induced significant reductions in body weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased mRNA levels of tumor necrosis factor-α and CD11c, whereas increased those of CD206 and adiponectin in the epididymal (not inguinal) fats isolated from ob/ob mice but not in control mice with no changes in the levels of peroxisome proliferator activated receptor gamma and its regulated genes. By contrast, VPC23019 did not cause all such alterations in these mice, however co-administration of SEW-2871 and VPC23019 abolished the effect of SEW-2871 on ob/ob mice.

In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body and improve glucose tolerance in obese mice. Therefore, endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.

Disclosure

M. Asano: None. M. Fuwa: None. I. Mori: None. H. Morita: None. K. Kajita: None. T. Ishizuka: None.
1649-P: S-309309, a Novel MGAT2 Inhibitor, Enhances Intestinal Fatty Acid Beta Oxidation and Provides Metabolic Benefits in DIO Mice
Authors: YOSHIKI RYO , TAKEMOTO KOSUKE , MORINAGA TAKUMI , TANIOKA HIDEKI , SONOYAMA TAKUHIRO , KATO HIDEAKI
Published: June 2024

Introduction & Objective: Pharmacological inhibition of Monoacylglycerol acyltransferase 2 (MGAT2) suppresses the food intake and the gain of body weight in high fat diet (HFD)-induced obesity (DIO) mice. However, the effects on metabolic abnormalities associated with obesity and detailed mechanisms of action remain unknown. In this study, we investigated the metabolic effects of S-309309, a novel selective MGAT2 inhibitor, in DIO mice and the involvement of energy consumption in the anti-obesity effects of S-309309.

Method: Mice were fed a HFD for 4 weeks to establish a DIO model. S-309309 (3 mg/kg, b.i.d.) was orally administered to DIO mice for 13 weeks. Daily body weight and weekly food intake were recorded until Week 4, and parameters of glucose and lipid metabolism were measured on Week 12. Additionally, under pair-feeding conditions, S-309309 (3 mg/kg, b.i.d.) was orally administered to DIO mice for 6 weeks with recording daily body weight. Energy expenditure was measured during the first 7 days of S-309309 treatment, and gene expression analysis was performed 4 days after the treatment.

Results: S-309309 suppressed food intake and body weight gain in DIO mice over the course of the study. DIO mice treated with S-309309 also showed decreases in insulin resistance index, hepatic triglycerides content, plasma alanine aminotransferase and aspartate aminotransferase level, and gene expression related to fibrosis. Furthermore, S-309309 suppressed body weight gain under pair-feeding conditions with enhanced energy expenditure and upregulation of intestinal gene expression related to long-chain fatty acid beta oxidation.

Conclusion: S-309309 enhanced beta oxidation in the intestine and increased energy expenditure in DIO mice. Also, S-309309 improved insulin sensitivity and fatty liver. Taken together, these results suggest that S-309309 may be a promising anti-obesity drug that improves metabolism with multiple mechanisms of action.

Disclosure

R. Yoshiki: None. K. Takemoto: None. T. Morinaga: None. H. Tanioka: Employee; Shionogi & Co., Ltd. T. Sonoyama: Employee; Shionogi & Co., Ltd. Stock/Shareholder; Shionogi & Co., Ltd. H. Kato: None.