bluuebunny/crossref_metadata_2025_split huggingface dataset:
1547-P: The Differential Effect of Glucagon-Like Peptide-1 Receptor Blockade on Glucose Metabolism in People With and Without Type 2 Diabetes
Authors: WELCH ANDREW A. , FARAHANI RAHELE A. , ZEINI MAYA , EGAN AOIFE M. , LAURENTI MARCELLO C. , COBELLI CLAUDIO , DALLA MAN CHIARA , VELLA ADRIAN 
Published: June 2023

Glucagon-Like Peptide-1 (GLP-1) is present within the islet but the effects of GLP-1 Receptor (GLP1R) blockade on islet function in humans remains unknown. To address this, we studied 12 nondiabetic individuals (54 ± 2 years, 33 ± 1 kg/m2) and 11 people with type 2 diabetes (DM2 - 58 ± 2 years, 34 ± 2 kg/m2) on 2 occasions in random order. On each occasion, after an overnight fast, [3-3H] glucose was used to measure glucose turnover during fasting and a hyperglycemic clamp (~9 mmol/l) using the tracer dilution technique. On one occasion exendin-9,39 (300pmol/kg/min) was infused to block GLP1R, while on the other saline was infused. Exendin-9,39 increased fasting glucose concentrations in those without (4.6 ± 0.4 vs. 5.5 ± 0.1 mmol/l, saline vs. exendin-9,39 respectively, p = 0.04) and in those with DM2 (7.3 ± 0.5 vs. 8.3 ± 0.6 mmol/l, p = 0.03). Fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed during exendin-9,39 infusion. The same pattern was seen in people with DM2 except that fasting glucagon concentrations increased (8.3 ± 0.5 vs. 10.2 ± 0.6 pmol/l, p &lt; 0.01) and remained elevated throughout hyperglycemia (4.7 ± 0.4 vs. 7.7 ± 0.6 pmol/l, p &lt; 0.02). Insulin secretion rate calculated by deconvolution of C-peptide concentrations was also decreased in DM2 (0.54 ± 0.08 vs. 0.51 ± 0.08 nmol/min, p = 0.02). Consequently, suppression of endogenous glucose production by hyperglycemia was impaired in people with DM2 (2.9 ± 0.4 vs. 5.7 ± 0.3 μmol/kg/min, p &lt; 0.01). Intriguingly, 1st phase response to hyperglycemia was decreased in those without DM2 (3.5 ± 0.6 vs. 2.5 ± 0.5 nmol per 10 min, p = 0.04). These data show that in humans, GLP1R blockade impairs fasting α- and β-cell function resulting in fasting hyperglycemia. Subtle effects are also present in response to hyperglycemia. This implies that intra-islet GLP1R activation sustains islet responses to glucose and it does so to a greater degree in people with DM2.

Disclosure
A.A. Welch: None. R.A. Farahani: None. M. Zeini: None. A.M. Egan: None. M.C. Laurenti: None. C. Cobelli: None. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126206)
1550-P: A Gain-of-Function Maturity-Onset Diabetes of the Young (MODY)–Associated TALK1 Mutation Impairs Glucose Metabolism in Mice
Authors: TSAI WEN-HAO , YANG SHI-BING 
Published: June 2023

A Leu substitution with Pro at position 114 (L114P) of TALK1 K+ channels has recently been identified in a MODY (maturity-onset-diabetes-of-the-young) family. Previous in vitro studies have shown this gain-of-function TALK1-L114P mutant may attenuate Ca2+ homeostasis and inhibit insulin secretion; nevertheless, how this mutant induces diabetes in vivo remains elusive. In this study, we have generated a transgenic mouse line that carries a TALK1-L114P mutation. About three-quarters of TALK1L/P and TALK1P/- mice died within ten days after birth due to hyperglycemia. Interestingly, those survival mice till adulthood exhibited diverse levels of glucose intolerance with islet morphology that is commonly observed in patients with type 2 diabetes. Electrophysiological recording further indicated that only a portion of the beta cells is glucose responsive, and high glucose challenge often yielded in low-frequency action potential bursting. According to our results, we hypothesized that despite the augment of membrane K+ conductance by the TALK1-L114P channel, high glucose might still be enough to depolarize beta cells and generate action potential bursting. This dampened beta cell excitation may result in a weakened Ca2+ influx and insufficient insulin secretion to cause glucose intolerance. In conclusion, this study has revealed a vital role of the TALK1 channel in regulating glucose homeostasis and a plausible diabetogenic mechanism of TALK1-L114P mutation.

Disclosure
W.Tsai: None. S.Yang: None.

Funding
National Science and Technology Council, Taiwan (111-2320-B-001-008-MY3)
1555-P: Novel Imaging Platform Highlights the Disconnect between ß-Cell Mass and Glucose Control in the Onset of Type 1 Diabetes
Authors: CRAS-MÉNEUR CORENTIN , SEELEY RANDY J. , ARVAN PETER 
Published: June 2023

The age of onset of Type 1 Diabetes (T1D) presents considerable variation from patient to patient. Some become insulin dependent in a just few weeks, while others may take months or years. In either, immune system-β-cell interactions conspire to lead to loss of β-cells and insulin secretion. The molecular and cellular events involved have been the focus of intense research efforts, but most longitudinal studies during the onset of T1D have been limited to biomarkers (circulating autoantibodies, C-peptide⋯), without direct β-cell assessment. Despite data indicating that patients can retain functional β-cells years after the onset of the disease, one school of thought is that there is a precipitous loss of β-cells just preceding the time of clinical onset, triggering the hyperglycemia observed in T1D patients. A counter-view supported by recent studies suggests that insulin secretion is reduced even before β-cell loss. These assessments are traditionally performed through histo-morphometry. The process is time-consuming, prone to errors and costly. Using an NOD line with a SfGFP reporter attached to the C-peptide, we have designed a platform allowing the in toto imaging of β-cell mass in a model of T1D. After a 15-minute IPGTT to capture the peak of insulin secretion, pancreata were harvested and imaged on a cohort of animals at a time of early onset of T1D. A comparison of classical histo-morphometry and in toto imaging revealed a tight correlation between both approaches. Using the new platform allowed the rapid classification of large cohorts of animals based on the β-cell mass and glucose response. The results highlighted a significant disconnect between mass and function in a subset of mice: Some animals presenting near-normal mass while being glucose intolerant while others displaying a drastically reduced mass but still responding normally to a glucose challenge. These findings emphasize the role of islet dysfunction during the onset of T1D even before β-cell death.

Disclosure
C.Cras-méneur: None. R.J.Seeley: Board Member; Fractyl Health, Inc., Consultant; Novo Nordisk, Eli Lilly and Company, Research Support; Novo Nordisk, Fractyl Health, Inc., AstraZeneca, Eli Lilly and Company. P.Arvan: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)
1561-P: Dietary Proteins Impact Glucose Tolerance and Hepatic Insulin Resistance in Mice through Modulation of the Urea Cycle
Authors: BÉGIN FRÉDÉRIC , CARON ALEXANDRE , MARETTE ANDRE 
Published: June 2023

We recently reported that dietary proteins (DP) modulate diet-induced obesity and insulin resistance in mice (Nat Commun 12: 3377, 2021). We posit that these metabolic alterations are caused by differential activation of the hepatic urea cycle in response to different amino acid (AA) compositions and total nitrogen load.
Objective: To test whether DP sources alter hepatic metabolism and insulin resistance through the urea cycle.
Methods: Metabolic phenotypes, hepatic urea cycle and insulin resistance were measured in mice fed low-fat, low-sucrose (LFLS) or high-fat, high-sucrose (HFHS) diets containing either pork (PP), soy (SP) or casein (CP) protein for 12 weeks. Based on their AA composition, PP had the highest nitrogen load, followed by SP and CP.
Results: When compared to SP and CP, feeding PP to HFHS mice induced more glucose intolerance which was correlated with higher post-prandial AA-derived nitrogen load in the portal vein. PP feeding in HFHS mice induced hepatic insulin resistance, revealed by impaired insulin-induced Akt phosphorylation on Ser473. Mice fed the LFLS diet were, however, protected from PP-induced glucose intolerance and insulin resistance, and this was associated with robust increase in the protein levels of urea cycle enzymes (CPS1, OTC) in the liver. In starked contrast, induction of urea cycle enzymes was blunted in the liver of PP-fed HFHS mice. PP feeding also increased the expression of inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) as showed by DHE staining of liver sections.
Conclusion: Dietary PP increases total nitrogen load activating the urea cycle, which may protect against metabolic dysfunction and hepatic insulin resistance in LFLS mice. This protective mechanism is lost in PP-fed HFHS mice, likely by downregulation of urea cycle activity, when the liver is overloaded with dietary fat. iNOS induction could be acting as an alternative nitrogen handling pathway, causing a build-up of mitochondrial ROS.

Disclosure
F.Bégin: None. A.Caron: None. A.Marette: Advisory Panel; Valbiotis, Amancia, Plexus, Acasti.
1563-P: Hepatic PHD3 Stimulates Gluconeogenesis and Aggravates Hyperglycemia and Type 2 Diabetes by Hydroxylating CRTC2 at Pro129 and Pro615
Authors: XUE YAQIAN , CUI AOYUAN , WEI SHUANG , MA FENGGUANG , LIU ZHENGSHUAI , FANG XIA , LI WENJING , LIU YUXIAO , CAI GENXIANG , SU WEITONG , ZHAO JIUXIANG , GAO CHENLIN , WEN JIAN , XU YONG , FU WENGUANG , FANG JING C. , LI YU 
Published: June 2023

Hepatic gluconeogenesis is critical for metabolic adaption in response to fasting, and its abnormal elevation contributes to the pathogenesis of hyperglycemia and type 2 diabetes. However, whether and how protein hydroxylation regulates hepatic gluconeogenesis and glucose metabolism remains largely unknown. Here we report that PHD3 is identified as a fasting-induced factor and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its nuclear translocation and association with CREB, and enhanced binding to promoters of gluconeogenic target genes in response to fasting or the cAMP activator forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) mice or prolyl hydroxylase-deficient knockin mice with alanine mutation in PHD3 at Pro196 (PHD3 KI) show significant attenuated gluconeogenic genes, glycaemia and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. The efficacies of glucagon or adenylyl cyclase activator forskolin on stimulating the expression of gluconeogenic enzymes, such as PEPCK and G6Pase, and on glucose output are abolished in PHD3-/- mouse primary hepatocytes. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice and humans with diabetes. Together, these findings increase our understanding of the molecular mechanisms linking protein hydroxylation to gluconeogenesis under physiological and insulin resistant conditions, and may offer therapeutic potential for treating sustained gluconeogenesis, hyperglycemia and type 2 diabetes.

Disclosure
Y.Xue: None. W.Su: None. J.Zhao: None. C.Gao: None. J.Wen: None. Y.Xu: None. W.Fu: None. J.C.Fang: None. Y.Li: None. A.Cui: None. S.Wei: None. F.Ma: None. Z.Liu: None. X.Fang: None. W.Li: None. Y.Liu: None. G.Cai: None.

Funding
National Key R&D Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008, 82073061, 82170587, 32100943); Ministry of Science and Technology of China (2020YFA0803301); Open Project Program of Metabolic Vascular Diseases Key Laboratory of Sichuan Province (2022MVDKL-K2); Shandong Natural Science Foundation (ZR2020MH206); China Postdoctoral Science Foundation (2021M693273)
1565-P: Relationship between Glycemic Control, Body Weight, and Nonalcoholic Fatty Liver Disease in Patients with Type 1 Diabetes
Authors: DHAVER SHILTON E. , SALAH TAREQ , AL-BADRI MARWA , KIBAA KARIM , KHATER ABDELRAHMAN , MCCARRAGHER RYAN , AL-ROOMI FATIMAH , DEMATTOS LILY , HAMDY OSAMA 
Published: June 2023

Increased body weight is a common risk factor for nonalcoholic fatty liver disease (NAFLD). Although the prevalence of overweight and obesity among patients with type 1 diabetes (T1D) is rising, most patients are still lean. Currently, little is known about the relationship between glycemic parameters, body weight and NAFLD in patients with T1D.
In this study, we evaluated glycemic parameters in 200 participants with T1D (mean age 46.9±16.5 years, 55.5% females, mean diabetes duration 27.4±15.7 years, mean BMI 26.9±5.0 kg/m2) who underwent screening for NAFLD. We used transient elastography to measure controlled attenuation parameter (CAP) as an indicator of hepatic steatosis, and liver stiffness measurement (LSM) as an indicator of hepatic fibrosis. We assessed glycemic parameters by measuring A1C and collecting 3 months of continuous glucose monitoring (CGM) data.
CAP score was found to be positively correlated with A1C (p=0.009) and BMI (p&lt;0.001). Participants with NAFLD (CAP≥274 dB/m) had significantly higher A1C (p=0.025). Using CGM parameters, CAP positively correlated with average blood glucose (p=0.029) and Glucose Management Indicator (GMI) (p=0.008). CAP positively correlated with coefficient of glucose variability (CV) only in lean individuals (BMI≤25 kg/m2) (p=0.031), suggesting a link between blood glucose variability and hepatic steatosis in the absence of overweight or obesity. LSM score positively correlated with BMI (p&lt;0.001), but not with A1C or CGM parameters.
We conclude that poor glycemic control is associated with hepatic steatosis while high BMI is associated with increased risk of hepatic fibrosis in patients with T1D. Blood glucose variability is particularly associated with hepatic steatosis in lean patients with T1D. These results may suggest the need of evaluating uncontrolled patients with T1D for NAFLD, specifically those with high BMI and those with high glucose variability.

Disclosure
S.E.Dhaver: None. T.Salah: None. M.Al-badri: None. K.Kibaa: None. A.Khater: None. R.Mccarragher: None. F.Al-roomi: None. L.Demattos: None. O.Hamdy: Advisory Panel; Abbott Nutrition, Nemaura Medical, L-Nutra Inc., Twin Health, Consultant; Sanofi, Research Support; Novo Nordisk, Eli Lilly and Company, Gilead Sciences, Inc., Stock/Shareholder; Healthimation.
1566-P: The TM6SF2 rs58542926 Polymorphism Dissociates Hepatocellular Lipids from Insulin Resistance in Recent-Onset Type 2 Diabetes
Authors: BÓDIS KÁLMÁN , BOMBRICH MARIA , SCHÖN MARTIN , KNEBEL BIRGIT , ZAHARIA OANA P. , BÖNHOF GIDON J. , KARUSHEVA YANISLAVA , KUPRIYANOVA YULIYA , KOTZKA JORG , GUTHOFF RAINER , SCHRAUWEN-HINDERLING VERA , AL-HASANI HADI , BURKART VOLKER , SZENDROEDI JULIA , WAGNER ROBERT , MARKGRAF DANIEL F. , RODEN MICHAEL 
Published: June 2023

Increased hepatocellular lipid content (HCL) is generally linked to insulin resistance, which contributes to greater risk of type 2 diabetes and cardiovascular complications. Conversely, a single-nucleotide polymorphism (TM6SF2EK; rs58542926) in the transmembrane 6 superfamily member 2 gene has been associated with nonalcoholic fatty liver disease (NAFLD), but lower cardiovascular risk. Thus, this case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during the early course of diabetes. Males with recent-onset type 2 diabetes with (TM6SF2EK: n=16) or without (TM6SF2EE: n=16) the heterozygous TM6SF2 polymorphism of similar age and BMI, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body, hepatic and adipose tissue insulin sensitivity. HCL and liver fibrosis were assessed with 1H-magnetic resonance spectroscopy and non-invasive tests (FIB4, APRI, AST/ALT), respectively. A subset of both groups (n=24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2EK had similar hepatic and adipose tissue insulin sensitivity and even 27% higher whole-body insulin sensitivity than TM6SF2EE. The novel diabetes endotypes were equally distributed among both groups. After 5 years, whole-body insulin sensitivity, HCL and liver fibrosis indices were similar, while adipose tissue insulin sensitivity decreased by 87% and 55% both in TM6SF2EK and TM6SF2EE and circulating triacylglycerol increased in TM6SF2EE only. The TM6SF2 gene polymorphism rs58542926 dissociates ectopic fat content from insulin resistance in recent-onset type 2 diabetes, which is however attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over the effects of the TM6SF2 gene polymorphism during the early course of diabetes and NAFLD.

Disclosure
K.Bódis: None. R.Guthoff: Other Relationship; Alimera, Bayer Inc., Novartis, Allergan. V.Schrauwen-hinderling: None. H.Al-hasani: None. V.Burkart: None. J.Szendroedi: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. D.F.Markgraf: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. M.Bombrich: None. M.Schön: None. B.Knebel: None. O.P.Zaharia: None. G.J.Bönhof: None. Y.Karusheva: None. Y.Kupriyanova: None. J.Kotzka: None.
1567-P: Hepatic ALKBH5 Regulation of Glucose and Lipid Metabolism
Authors: AAMODT KRISTIE , POLAY MADISON , SALERNO GONZALES VALERIA R. , KULKARNI ROHIT 
Published: June 2023

Obesity is a worsening global health crisis leading to increased risk of long-term complications such as type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH), dyslipidemia and cardiovascular disease. Identifying novel molecular mechanisms regulating the connection between obesity, hepatic insulin resistance and progression of NASH is critical to develop new therapeutic options for these patients. Previous work has shown that reversible N6-methyladenosine (m6A) RNA methylation patterns are altered in and regulate metabolic disease in the pancreatic beta cell and liver. However, these studies have primarily focused on the m6A writer proteins that direct placement of m6A methyl groups, while our study explores the role of m6A eraser protein AlkBH5 in regulating metabolic pathways in the liver.
To test the hypothesis that hepatic ALKBH5 is required to maintain normal glucose homeostasis, insulin sensitivity and lipid metabolism under physiologic conditions and in response to metabolic stress we used liver-specific Alkbh5 knockout (A5KO) mice and evaluated changes in weight gain, body composition, glucose tolerance, insulin sensitivity, fasting insulin levels, and gluconeogenesis in response to a chow versus Western diet (WD). In physiologic conditions (chow), A5KO mice have decreased glucose tolerance with no other significant phenotypic changes compared to controls. Exposure to metabolic stress (WD) caused (1) greater weight gain with increased visceral fat in control compared to A5KO mice, (2) decreased glucose tolerance compared to chow in both genotypes, (3) decreased glucose mobilization in A5KO mice on WD compared to chow, with no significant differences in controls, and (4) no significant differences in global insulin sensitivity. These studies demonstrate that A5KO mice are protected against weight gain upon exposure to metabolic stress with decreased glucose tolerance and mobilization compared to controls, establishing a role for hepatic ALKBH5 in regulating glucose and lipid metabolism.

Disclosure
K.Aamodt: None. M.Polay: None. V.R.Salerno gonzales: None. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK007699-39, 5T32DK007260-45); Pediatric Endocrine Society
1568-P: Identification of Stage-Specific Hepatocytes That Contribute to Nonalcoholic Steatohepatitis Progression
Authors: XIAO YANG , ZHU KUN , LIU YIFAN , LAZAR MITCHELL A. 
Published: June 2023

Current therapeutic strategies for treating an advanced form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. To identify potential novel therapeutic targets, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during the progression from nonalcoholic fatty liver (NAFL) to NASH in mice and humans. We found that the hepatocyte trajectory switched from metabolic adaptation to cell adhesion and migration when the NAFLD stage transited from NAFL to NASH. The trajectory switch was conserved between mouse and human. The hepatocyte trajectory leading to NASH was enriched for a receptor tyrosine kinase, EphB2. The transcription of EphB2 in hepatocytes was activated by Notch signaling pathway and sufficient to induce cell-autonomous inflammatory response in mouse and human induced pluripotent stem cell (hiPSC) derived-hepatocytes. EphB2 loss-of-function specifically in hepatocytes ameliorated inflammation and fibrosis in mouse models of NASH. Thus, NASH-stage specific hepatocytes were demarcated by EphB2 and may serve as a potential therapeutic target.

Disclosure
Y. Xiao: None. K. Zhu: None. Y. Liu: None. M.A. Lazar: Board Member; Pfizer Inc. Consultant; Novartis. Board Member; Flare Therapeutics, Inc. Consultant; Third Rock Ventures, Inc, Madrigal Pharmaceuticals, Inc.

Funding
American Heart Association (827529); National Institutes of Health (R01DK125573)