bluuebunny/crossref_metadata_2025_split huggingface dataset:
1645-P: Diabetes-Associated Variation in TCF7L2 Is Associated with a Longitudinal Decline in Glucose Tolerance Accompanied by Impaired Suppression of Postprandial Glucagon Secretion
Authors: ZEINI MAYA , MUTHUSAMY KALPANA , EGAN AOIFE M. , LAURENTI MARCELLO C. , COBELLI CLAUDIO , DALLA MAN CHIARA , VELLA ADRIAN 
Published: June 2023

Diabetes-associated alleles in TCF7L2 increase the rate of conversion from prediabetes to type 2 diabetes (T2DM). Multiple studies have shown an association of the T allele at rs7903146 with impaired β-cell function and more recently with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 140 individuals half of whom were homozygous for the diabetes-associated allele (TT) at rs7903146. The remainder were homozygous for the protective allele (CC). Subjects were studied on 2 occasions, 3 years apart using an oral 75g glucose challenge. This was labelled with 13C-glucose, in concert with intravenously infused tracers to enable measurement of endogenous glucose production, meal appearance and glucose disposal. Indices for insulin secretion and action were estimated using the oral minimal model. Fasting, peak and integrated (443 ± 27 vs. 428 ± 50 mmol/l per 6hr, p = 0.54) post-prandial glucose concentrations did not differ over time in people with the CC genotype. In contrast, post-prandial integrated glucose concentrations increased (441 ± 29 vs. 544 ± 37 mmol/l per 6hr, p &lt; 0.01) in people with the TT genotype. This was accompanied by an increase in integrated postprandial glucagon concentrations (526 ± 39 vs. 618 ± 61 pmol/l per 2hr, p = 0.04) that was not observed in the CC genotype (537 ± 50 vs. 525 ± 65 pmol/l per 2hr, p = 0.07). There were no baseline differences in β-cell function between genotype groups. Disposition Index in both TT (950 ± 130 vs. 868 ± 92 10-4 dl/kg/min per μU/ml, baseline vs. follow-up study respectively, p=0.42) and CC (896 ± 177 vs. 1062 ± 289 10-4 dl/kg/min per μU/ml, p=0.65) groups did not change. This data would suggest that α-cell dysfunction associated with the TT genotype (rs7903146) precedes β-cell dysfunction in people prior to the development of T2DM.

Disclosure
M.Zeini: None. K.Muthusamy: 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: Advisory Panel; Rezolute, Inc., Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S, Other Relationship; Novo Nordisk.

Funding
National Institutes of Health (DK116723)
1646-P: The Effect of Glucagon-Like Peptide-1 Receptor Blockade and Acute Insulin Resistance on Islet Function and Glucose Metabolism in People without Diabetes
Authors: ZEINI MAYA , FARAHANI RAHELE A. , WELCH ANDREW A. , LAURENTI MARCELLO C. , COBELLI CLAUDIO , DALLA MAN CHIARA , EGAN AOIFE M. , VELLA ADRIAN 
Published: June 2023

Intra-islet Glucagon-Like Peptide-1 (GLP-1) is increased by islet inflammation and diabetes. GLP-1 Receptor (GLP1R) blockade with exendin-9,39 impairs fasting islet function in people with and without type 2 diabetes (DM2). In addition, it decreases insulin secretion and glucagon suppression in response to hyperglycemia in people with DM2. We sought to examine if free fatty acid (FFA) elevation to induce acute insulin resistance in people without DM2 replicated the effects of GLP1R blockade seen in DM2. We studied 6 nondiabetic individuals (54 ± 4 years, 33 ± 1 kg/m2) on 4 occasions in random order. Glucose metabolism was measured after an overnight fast and during a hyperglycemic clamp (~9 mmol/l) using [3-3H] glucose. On two occasions Intralipid® and heparin were infused to raise FFA. Exendin-9,39 (300pmol/kg/min) was infused to block GLP1R in the presence or absence of FFA elevation, while on the other days saline was infused. In the absence of FFA elevation, exendin-9,39 infusion increased fasting glucose concentrations (5.0 ± 0.1 vs. 5.4 ± 0.1 mmol/l, saline vs. exendin-9,39 respectively, p = 0.01). This pattern was also observed when FFA were elevated (5.3 ± 0.1 vs. 5.7 ± 0.2 mmol/l, p = 0.02). Fasting insulin, C-peptide (without FFA: 0.9 ± 0.1 vs. 0.8 ± 0.1 nmol/l, p = 0.17; with FFA: 1.1 ± 0.1 vs. 1.0 ± 0.1 nmol/l, p = 0.08) and glucagon concentrations were unchanged, but inappropriate for the higher fasting glucose observed during exendin-9,39 infusion. Exendin-9,39 infusion did not alter islet hormone secretion during the clamp in the presence or absence of FFA elevation. The magnitude of changes induced by exendin-9,39 did not differ in the presence or absence of FFA elevation (p &gt; 0.10). These experiments confirm the effects of GLP1R blockade on fasting α- and β-cell function in people without DM2. However, FFA elevation does not replicate the abnormalities of islet function observed in people with DM2 when exendin-9,39 is infused.

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

Funding
National Institutes of Health (DK126206)
1650-P: Characterizing the Mechanism of Action of the Lipokine 12,13-diHOME
Authors: SENFELD JARED I. , LYNES MATTHEW , KODANI SEAN , SING STEPHEN LEE KIN , TSENG YU-HUA 
Published: June 2023

Lipids play an essential role in physiology. In addition to serving as an energy source, bioactive lipids, also known as lipokines, function as signaling molecules regulating metabolism and inflammation. A major source of lipokines, brown adipose tissue (BAT) has been shown to have beneficial effects on cardiometabolic health by increasing energy expenditure and improving glucose tolerance, thus providing a potential target for therapeutic interventions. Recent studies have identified 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME, produced by cytochrome P450-epoxide hydrolase metabolism of linoleic acid (C18:2n-6), as a lipokine produced by BAT that modulates fatty acid uptake (FAU) into brown adipocytes and skeletal muscle cells in response to cold stimulation or exercising, respectively. Here, we characterized the molecular mechanism and structure-activity relationship (SAR) of 12,13-diHOME in BAT fatty acid uptake. Conversion of the terminal carboxylic acid of 12,13-diHOME to ethyl acetate and changes in saturation results in decreased stimulated FAU indicating 12,13-diHOME's activity is structurally dependent. In addition, we provide insight into a novel protein target responsible for enhancing FAU in BAT, in part, by enhancing intracellular calcium mobilization and influencing the expression of lipolytic genes. Furthermore, we have determined that the 12,13-diHOME-stimulated FAU is, in part, dependent on Gq-mediated calcium mobilization as determined by the utilization of Gq inhibitor YM-254890. Thus, the receptor of 12,13-diHOME could represent a target to augment BAT activity by modulating fatty acid metabolism, which could contribute to increased energy expenditure and, consequently, to the prevention of cardiometabolic diseases.

Disclosure
J.I.Senfeld: None. M.Lynes: None. S.Kodani: None. K.Lee: None. Y.Tseng: Consultant; Cellarity, LyGenesis.
1652-P: Suppression of Plasma Angiotensin II by GLP-1 in Humans Is Independent of Changes in Plasma Angiotensinogen
Authors: JENSEN BOYE L. , ASMAR ALI 
Published: June 2023

In humans, the natriuretic effect of GLP-1 depends on GLP-1 receptor interaction, is independent of changes in renal blood flow, renin, ANP, and aldosterone but is accompanied by suppression of angiotensin II (ANGII). The mechanism by which GLP-1 reduces ANGII independently of changes in renin is not clarified. It was hypothesized that GLP-1 suppresses renin substrate, angiotensinogen, in plasma.
To test this proposal, we measured arterial angiotensinogen concentration in biobanked plasma samples from healthy males during a 3-hour GLP-1 infusion that induced natriuresis (1). Samples were from a study with fixed sodium intake where eight healthy men were examined twice in random order during a 3-hour infusion of either GLP-1(1.5 pmol kg-1 min-1) or vehicle together with an intravenous infusion of 0.9% NaCl (750 mL/hour). Arterial plasma angiotensinogen was measured in plasma by dilution (1:200) and addition of excess exogenous human renin (Inst. of Biological Standards UK). After prolonged incubation, ANGI was quantified by radioimmunoassay. Intraassay variation was 9-12%.
Arterial plasma angiotensinogen and renin levels decreased similarly and modestly (~15 and ~30%, respectively) after NaCl infusion during both studies whereas ANGII levels decreased significantly (~25%) only during GLP-1 infusion.
Suppression of plasma angiotensinogen is less likely to account for GLP-1-mediated ANGII suppression in healthy young males. In perspective, GLP-1 could enhance pathways of ANGII degradation rather than inhibit its formation.
1. Asmar A et al. Extracellular fluid volume expansion uncovers a natriuretic action of GLP-1: a functional GLP-1-renal axis in man. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519.

Disclosure
B.L.Jensen: None. A.Asmar: Research Support; Novo Nordisk A/S.
1653-P: Brown Adipocyte–Secreted Factors for Treating Type 1 Diabetes Mellitus
Authors: LEE JEONGMIN , PISTON DAVID W. 
Published: June 2023

Hyperglycemia during type 1 Diabetes (T1D) is driven not only by a lack of insulin secretion due to autoimmune destruction of the pancreatic β-cells, but also by hypersecretion of glucagon from pancreatic α-cells. Insulin therapy can replace the lack of insulin secretion, but there is no effective therapeutic tool to counter the hyperglucagonemia. Brown adipose tissue (BAT) has gained attention for treating metabolic diseases due to its role as an endocrine organ and its effect on whole-body energy metabolism. Subcutaneous transplantation of embryonic BAT into T1D mouse models reverses hyperglycemia, independent of insulin but accompanied by reduced plasma glucagon levels, which suggests that lowering plasma glucagon plays a central role in restoring euglycemia. However, the molecular mechanism(s) underlying this action remain unclear. Towards discovering these mechanisms, we have examined the effects of secretions from immortalized brown adipocytes (imBAT) on pancreatic α-cells and mouse models of T1D. We show that the large molecule fraction (&gt;100kDa) of imBAT-secreted factors suppresses glucagon secretion from both mouse and human pancreatic α-cells. Live cell fluorescence imaging shows that this fraction inhibits both intracellular Ca2+ and cAMP activities, and these inhibitions are ameliorated by blocking the insulin receptor, suggesting that imBAT-secreted factors act, at least in part, through these receptors. Injecting this imBAT-secreted fraction into the NOD mouse model reverses hyperglycemia (242 ± 47.4 to 146 ± 24.7mg/dL, n=8), suppresses hyperglucagonemia (77.6 ± 55.4 to 10.7 ± 4.75pg/mL, n=8), improves glucose tolerance (n=3), and increases thermogenic activity and differentiation of endogenous BAT (n=7). Our data provide insights into the mechanisms of long-term recovery of euglycemia by BAT transplants, and further fractionation experiments to isolate active factors are ongoing.

Disclosure
J.Lee: None. D.W.Piston: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust (2305-06050); National Institutes of Health (R01DK123301, P30DK020579)
166-OR: Developing a Fair Individualized Polysocial Risk Score (iPsRS) for Identifying Increased Social Risk of Hospitalizations in Patients with Type 2 Diabetes (T2D)
Authors: HUANG YU , ZHANG TIANXIAO , DONAHOO WILLIAM T. , SHENKMAN ELIZABETH , GUO JINGCHUAN , BIAN JIANG 
Published: June 2023

T2D is a public health crisis that must be managed by addressing patients’ unmet social needs. We aimed to develop an electronic health record (EHR)-based individualized polysocial risk score (iPsRS) of T2D, which can be used for identifying patients of high social risk and their unmet social needs. We identified T2D patients using 2015-2020 EHR data from University of Florida Health system and followed a year to record hospitalizations. We (1) used natural language processing to extract person-level social determinants of health (SDoH, e.g., employment, housing and food) from clinical notes; and (2) spatiotemporally linked 117 contextual-level SDoH (e.g., neighborhood walkability). We incorporated both contextual and person-level SDoH and used machine learning(ML) to develop an iPsRS that predicted 1-year hospitalization. We assessed iPsRS’ fairness across racial-ethnic groups (Black or Hispanic vs White) and explored different approaches to mitigate identified bias. Of 10192 T2D patients, mean age was 59±21years, and 16% were hospitalized in a year. Our iPsRS showed a good utility for predicting individuals’ risk of hospitalization (C statistic=0.70). After adjusting for clinical characteristics, iPsRS explained 41% of the increased 1-yr hospitalization risk. The naïve iPsRS was biased on Hispanic vs. White patients, that is, Hispanics (false negative rates [FNR]=0.87) were more likely to be misclassified as having low hospitalization risk compared to their White counterparts (FNR=0.77). We identified that a disparate impact remover approach reduced the bias without compromising much prediction utility, producing a final iPsRS with an optimized prediction (C-statistic=0.69) - fairness (FNR-Hispanic=0.62, FNR-White=0.64) balance. We developed a fair iPsRS that can identify T2D patients at a high risk of hospitalization due to SDoH, supporting the integration of social care with clinical care of T2D.

Disclosure
Y.Huang: None. T.Zhang: None. W.T.Donahoo: None. E.Shenkman: None. J.Guo: Consultant; Pfizer Inc., Research Support; PhRMA Foundation, NIH - National Institutes of Health. J.Bian: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK133465)
1661-P: The Myokine Irisin Is Endocytosed and Signals through an αV Integrin-Independent Mechanism in Pancreatic ß-Cells
Authors: MARRANO NICOLA , BORRELLI ANNA , BIONDI GIUSEPPINA , RELLA MARTINA , CIGNARELLI ANGELO , PERRINI SEBASTIO , LAVIOLA LUIGI , GIORGINO FRANCESCO , NATALICCHIO ANNALISA 
Published: June 2023

Irisin is a hormone secreted by skeletal muscle, able to improve metabolic homeostasis and promote energy expenditure. We have previously demonstrated that irisin protects human and rodent β-cells and pancreatic islets from lipotoxicity-induced apoptosis, increases insulin biosynthesis and glucose-stimulated insulin secretion (GSIS), and promotes β-cell proliferation, both in vitro and in vivo in mice. Irisin may also restore the defects that are characteristic of islets from T2D patients. Although it has been demonstrated that irisin mediates its effects on bone and fat via αV integrin receptors, the presence of an irisin receptor in β-cells has not been reported. In INS-1E cells, we found that irisin activates its intracellular signalling and enhances GSIS in the presence of a specific αV integrin knockdown or a chemical inhibitor of cellular integrins (RGDS), thus excluding the involvement of integrin receptors in irisin effects. Through a pull-down assay/mass spectrometry approach, we identified 102 irisin interactors in human pancreatic islets, mostly belonging to intracellular compartments (i.e., vesicles and membrane rafts), and not including canonical membrane receptors. We therefore hypothesized that irisin could be endocytosed in pancreatic β-cells and confirmed this by immunoblotting and immunofluorescence techniques. In addition, nystatin, an inhibitor of lipid-raft dependent endocytosis, reduced irisin entry into β-cells. These results suggest for the first time that irisin effects on pancreatic β-cells are independent of engaging the αV integrin receptor and may instead depend on its endocytosis. These results are important beyond irisin, as they propose a potential new mechanism of action for peptide hormones. In addition, we highlight the possibility that the same hormone, i.e. irisin, may signal through different receptors in different target tissues.

Disclosure
N.Marrano: None. A.Borrelli: None. G.Biondi: None. M.Rella: None. A.Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. S.Perrini: None. L.Laviola: Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Sanofi, Other Relationship; Medtronic, Speaker's Bureau; Abbott, Terumo Corporation. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. A.Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly.
1663-P: Estrogenic Regulation of Energy Balance in the Medial Amygdala
Authors: YE HUI , FENG BING , LUO PEI , CARRILLO-SÁENZ LESLIE , TORRES IRIZARRY VALERIA C. , IBRAHIMI LUCAS , ANTONY NIMISHA , KOTA MAYA , DIXIT DEVIN , MUN MADELINE , HE YANLIN , XU PINGWEN 
Published: June 2023

Compelling evidence has demonstrated that estradiol (E2) and estrogen receptors α/β (ERα/β) play critical roles in the central regulation of energy balance and glucose homeostasis. Our previous research proved that ERα in the medial amygdala (ERαMeA) mediates estrogenic actions to stimulate physical activity, promote energy expenditure, and prevent diet-induced obesity (DIO). Interestingly, ERβ is also highly expressed in the MeA neurons. To explore the metabolic functions of ERβMeA, we generated a mouse model with ERβ selectively deleted in the MeA (ERβKOMeA) during adulthood by using AAV virus-mediated Cre-Lox site-specific recombination. When fed on a high-fat diet (HFD) but not a standard chow diet, both male and female ERβKOMeA mice showed decreased body weight gain and fat deposition, associated with a decrease in ambulatory activity. Consistently, we also observed an increase in energy expenditure of female ERβKOMeA mice during diet switching from chow to HFD, suggesting a diet-dependent regulatory role of ERβMeA in body weight control. In addition, both electrophysiology and immunohistochemistry staining results indicated that half of the ERαMeA neurons co-express ERβ. In these ERα&β co-expressing MeA neurons, ERα agonist propyl pyrazole trio (PPT) induced ERα-dependent depolarization, while ERβ agonist diarypropionitrile (DPN) induced ERβ-dependent hyperpolarization. Further, we found that the chemogenetic activation of ERαMeA neurons promotes physical activity and stimulates body thermogenesis, while the inhibition of ERβMeA neurons downregulates physical activity and body thermogenesis. In line with this, inhibition of ERβMeA neurons impaired cold-induced brown adipose tissue thermogenesis, resulting in lower rectal temperature during acute cold exposure. Collectively, our results support a model that E2 acts on ERα/βMeA neurons to provide bidirectional regulation of body weight and resistance to DIO.

Disclosure
H.Ye: None. M.Mun: None. Y.He: None. P.Xu: None. B.Feng: None. P.Luo: None. L.Carrillo-sáenz: None. V.C.Torres irizarry: None. L.Ibrahimi: None. N.Antony: None. M.Kota: None. D.Dixit: None.

Funding
National Institutes of Health (R01DK123098, P30DK020595, P20GM135002, R01DK129548, T32AA026577, K01DK119471); U.S. Department of Agriculture (3092-51000-062-04(B)S); American Heart Association (915789, 19CDA34660335, 20POST35120600); U.S. Department of Defense (W81XWH-20-1-0075)
1664-P: High Fat High Sucrose Exposure during Lactation but Not during the Post-Weaning Period Programs Impaired Glucose Homeostasis
Authors: GOERGEN ANNE , WUEEST STEPHAN , KONRAD DANIEL 
Published: June 2023

Nutrition during critical developmental windows plays a pivotal role in shaping long-term metabolic health. Exposure to a Western diet in early life may lead to altered metabolic programing, potentially influencing the risk to develop obesity and type 2 diabetes. In particular, an early exposure to an obesogenic diet may induce a metabolic program that only emerges upon dietary challenges later in life. Accordingly, understanding the long-term impact of nutritional insults in different stages of early life may provide strategies for primary prevention. Therefore, the present study aimed to determine which time window in the post-natal period is most critical for long-term metabolic health. To this end, pups born to lean mouse dams were exposed to a high-fat-high-sucrose (HFHS) diet for 3 weeks during lactation or in the post-weaning period. Thereafter, mice were either fed a regular chow diet until the age of 30 weeks or exposed to a second bout of HFHS diet for the last 12 weeks. Metabolic health and development of obesity was assessed by regular monitoring of glucose homeostasis and body weight gain. At the age of 12 weeks, mice with lactational exposure to a HFHS diet revealed a significantly impaired glucose tolerance compared to control mice, while glucose tolerance of post-weaning exposed mice was similar to the control group. Moreover, a second bout of HFHS diet impaired glucose tolerance and increased body and adipose tissue weight in mice with lactational exposure to a significant greater extent than in post-weaning exposed mice. Preliminary data suggests that increased adipose tissue inflammation might be mechanistically involved in impaired glucose tolerance of lactation exposed mice. Hence, exposure to HFHS during lactation but not during the post-weaning period programs impaired glucose homeostasis, suggesting that the lactational window may be the most critical in terms of metabolic programing.

Disclosure
A.Goergen: None. S.Wueest: None. D.Konrad: Research Support; Novo Nordisk A/S.