bluuebunny/crossref_metadata_2025 huggingface dataset:
1626-P: Activation of Cardiac Mitochondrial Akt1 Enhanced Myocardial Fatty Acid Utilization, Protected against Diabetic Cardiomyopathy, and Improved Whole Body Fat Distribution
Authors: TA ALBERT , CHEN YUMAY , LI JUNFENG , SALEM ESAM , WANG PING H.
Published: June 2023

Insulin stimulates Akt1 translocation to cardiac mitochondria, and we have recently shown that inhibition of cardiac mitochondria Akt1 led to mitochondrial dysfunction and cardiomyopathy. However, whether activation of mitochondrial Akt1 in cardiac muscle can protect against the development of diabetic cardiomyopathy is not known. To this end, we have generated an inducible heart-specific transgenic mouse harboring a mitochondria-targeting constitutively active Akt1 (CAMCAKT). Long-term high fat-high fructose diet (HFFD) caused myocardial hypertrophy, fibrosis and ventricular dysfunction in control mice, but the impact of HFFD were attenuated in the CAMCAKT mice. After just two months on HFFD, expression of Col1a1 and Col3a1 in CAMCAKT mice were lower than controls (p<0.01). After five months on HFFD, ejection fraction in CA mice was 17 % higher than in controls while fractional shortening was 22% higher (p<0.05). This indicated that activation of mitochondrial Akt protected myocardium against the development of cardiomyopathy in diet-induced diabetes. Metabolically, cardiac mitochondrial Akt1 increased fatty acid uptake in the cardiac muscle, which resulted in redistribution of whole-body fatty acid metabolism. Dynamic PET scans revealed a 65% increase (p<0.001) in heart uptake of fatty acid reporter [18F]fluoro-4-thia-oleate in CAMCAKT mice. CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and expended 13% more energy, compared to controls (p<0.05). Interestingly, fatty liver was reduced in the CAMCAKT mice (p<0.05), suggesting that cardiac mitochondrial Akt modulated fat deposition in the liver by higher myocardial fatty acid metabolism. In summary, activating cardiac mitochondrial Akt protected against diabetic cardiomyopathy, attenuated fatty liver, and induced whole body metabolism in this murine model of diet-induced diabetes.

Disclosure

A.Ta: None. Y.Chen: None. J.Li: None. E.Salem: None. P.H.Wang: Research Support; ViaCyte, Inc.

Funding

National Institutes of Health (R01HL096987); Ko Family Foundation
1632-P: Effects of MTOR Signaling in Muscle-Specific Irs1/2 Knockout Mice
Authors: STOEHR OLIVER , COPPS KYLE D. , TAO RONGYA , WHITE MORRIS F.
Published: June 2023

Disruption of Irs1 and Irs2 expression in skeletal and cardiac muscle (MDKO mice) caused death from dilated cardiomyopathy within the first 30 days of life. MDKO showed muscle atrophy but were not glucose intolerant, despite impaired muscle glucose uptake. Beiging of white adipose fat increased glucose uptake into white adipose tissue of MDKO mice, and glucose uptake into brown adipose was also increased. Knockout of atrophy-driving genes FoxO1 and FoxO3a in MDKO mice (MQKO mice) extended life span to 70 days, when MQKO mice died with cardiomyopathy. High fat diet feeding increased life span in both MDKO and MQKO mice; however, genetic activation of the MTOR pathway in muscle of MDKO mice by Tsc1 knockout (MTKO mice) increased life span to 220 days. Regardless, MTKO mice developed cardiac hypertrophy with reduced ejection fraction by 24 weeks. Cardiac glucose uptake in MTKO mice was impaired during non-insulin as well as during insulin-stimulated conditions. Moreover, fat mass of MTKO mice decreased over time, implying a shift in consumption by MTKO hearts from glucose to fatty acids as source for cardiac energy. Tracing of radiolabeled palmitic acid did not support increased cardiac fatty acid uptake in MTKO mice; however, expression of lactate transporters was significantly elevated in MTKO hearts and circulating lactate generated by skeletal muscle was significantly reduced, indicating a potential use of lactate in MTKO hearts. These results show more robust effects of activating the MTOR pathway in insulin resistant hearts of MDKO mice rather than manipulating atrophy-related genes FoxO1/3a to counter early death from cardiomyopathy. Furthermore, activated MTOR signaling potentiated a metabolic switch in MDKO hearts.

Disclosure

O.Stoehr: None. K.D.Copps: None. R.Tao: None. M.F.White: Board Member; Housey Pharma.
1634-P: Brown Adipose Tissue and Muscle Responses to Tolerable Cold in Black and White Young Lean Men
Authors: THOMAS REED J. , BRYCHTA ROBERT , COURVILLE AMBER B. , MCGEHEE SUZANNE , CYPESS AARON M. , CHEN KONG Y.
Published: June 2023

There has been a renewed interest in brown adipose tissue (BAT) as a therapeutic target for diabetes and obesity treatments due to its ability to consume glucose and expend energy in response to cold temperatures and Beta-adrenergic stimulation. However, comparisons of BAT in different races are limited. To address this knowledge gap, we directly compared healthy, young, lean Black and White men in a controlled inpatient study using a whole-room indirect calorimeter.

12 Black and 12 White men completed a 6-13-day protocol with randomized calorimeter temperatures between 18-31°C for 5 hours. Resting metabolic rate (RMR) was measured under reclined, fasted conditions with standard clothing. Body composition was measured by dual x-ray absorptiometry and BAT and muscle glucose uptake activity was quantified using 18-F Fluorodeoxyglucose (18-F FDG) PET-CT following the last chamber study where each individual's coldest tolerable temperature (Tct) was used. Basal metabolic rate (BMR) was defined as minimum RMR and the cold-induced thermogenesis (CIT) was calculated as the percentage increase of RMR above BMR in the cold.

The groups were similar in age (23.8±4.7 yrs) and BMI (23.1±1.5 kg/m2) and their Tct (21.0±1.4°C; p=0.54) and CIT (12.1±8.1 kcal/h; p=0.8) were not different. While White males had significantly higher BAT volume (334 ± 188mL vs 242 ± 89mL; p=0.045), BAT volume was comparable between the groups after normalizing to body volume. BAT activity was similar between the groups. Among all muscle activity measured, the intercostal muscles in the Black males had significantly higher activity (p=0.002) and activity was present in all 12 Black participants but only 4 of 12 White males. Individual BAT or muscle activity did not correlate with each other nor with Tct or CIT.

Our data suggest that the cold-induced BAT activity was comparable in Black and White young, lean men. The surprising difference in intercostal muscle activity warrants further investigation.

Disclosure

R.J.Thomas: None. R.Brychta: None. A.B.Courville: None. S.Mcgehee: None. A.M.Cypess: None. K.Y.Chen: None.
1637-P: Acute Hyperinsulinemia Alters Intramuscular 1,2-DAG Species across Metabolic Phenotypes
Authors: MCKENNA COLLEEN , ZEMSKI BERRY KARIN , ZARINI SIMONA , KAHN DARCY , PERREAULT LEIGH , NEWSOM SEAN A. , SNELL-BERGEON JANET K. , BERGMAN BRYAN C.
Published: June 2023

Intramuscular lipid levels are linked to obesity and type 2 diabetes (T2D). Annotation of the lipid profile is necessary to elucidate the relevance of this association, as certain lipids are more potent in their pathogenic role in insulin resistance. Despite the relationship between insulin action and intramuscular lipid composition, the effect of acute hyperinsulinemia on the myocellular lipid profile is unknown. Basal and insulin-stimulated vastus lateralis muscle was sampled in sedentary lean adults (n = 12), endurance athletes (n = 12), and individuals with obesity with (n = 7) or without T2D (n = 13). A hyperinsulinemic-euglycemic clamp was performed at 40 mU/m2/min insulin with variable dextrose to maintain 90 mg/dL blood glucose. An insulin-stimulated muscle biopsy was performed 1 h into the insulin clamp. Muscle was dissected of extramuscular adipose tissue and then flash frozen. Whole muscle lipidomics analysis was performed by LC-MS/MS. Hyperinsulinemia decreased whole muscle cell total acylcarnitine (AC) levels (p = 0.001) regardless of group. However, only athletes exhibited a decrease in AC C6:0, C14:0, and C16:1 during the insulin clamp (p < 0.001). Triacylglycerol concentrations also decreased during the clamp regardless of group (p = 0.041). There was no significant effect of the clamp on total 1,2-diacylglycerol (DAG). However, many 1,2-DAG species were elevated with acute hyperinsulinemia, such that the change in various long-chain 1,2-DAGs were inversely related to insulin sensitivity (r = -0.35 - -0.45, p < 0.050). Moreover, di-C18:1 and C16:0/20:0 1,2-DAGs were elevated with acute hyperinsulinemia in T2D alone (p < 0.010). Acute hyperinsulinemia did not affect muscle 1,3-DAG, ceramide, nor sphingomyelin total concentrations. While 1,2-DAGs have been implicated in muscle insulin resistance, our results suggest that differential handling of 1,2-DAGs during acute hyperinsulinemia across metabolic phenotypes may further promote decreased insulin sensitivity.

Disclosure

C.Mckenna: None. K.Zemski berry: None. S.Zarini: None. D.Kahn: None. L.Perreault: Advisory Panel; Sanofi, Consultant; Novo Nordisk A/S, Speaker's Bureau; Novo Nordisk A/S, Boehringer Ingelheim Inc., Lilly, Bayer Inc. S.A.Newsom: None. J.K.Snell-bergeon: None. B.C.Bergman: Research Support; Eli Lilly and Company.

Funding

National Institutes of Health (R01DK089170, T32DK007658)
1641-P: C-C Motif Chemokine Ligand 2 Promotes Myogenesis Recovery, Muscle Strength, and Muscle Performance In Vivo and Has Clinical Relevance for Muscle Performance in Human
Authors: HONG EUN-GYOUNG , SUK HA EUN , LEE JIWOO , MI CHOI YUN , LEE KWANWOO , CHUL WON JONG , KYUNG KWAK MI
Published: June 2023

Muscle mass decreases with aging, while the C-C motif chemokine ligand 2 (CCL2) increases with aging. In our previous study, CCL2 positively affects in vitro myogenesis. In this context, CCL2 can be considered a potential aging-promoting factor. To further confirm the relationship between muscle and CCL2, we sought to establish the role of CCL2 in vivo and in humans. It was divided into Dimethyl Sulfoxide (DMSO) control, dexamethasone (Dexa) intraperitoneal treatment group, and Dexa with the CCL2 treatment group. As a result, grip power and exercise endurance were reduced in the Dexa treatment group compared to the control group but recovered with the CCL2 treatment. In muscle mass, there was no significant difference in mass between groups. We examined the cross-sectional area distribution (CSA) with the tibialis anterior muscle. The Dexa treatment group was distributed between CSA 1000-3000 µm² and was left-shifted. However, the Dexa and CCL2 group was similar or slightly higher than the DMSO group; it was right-shifted and distributed in the 2000-5000 µm². In humans, the median value was 303.8 pg/ml in the no sarcopenia group and 321.7 pg/ml in the sarcopenia group. Subsequently, the CCL2 level was checked by dividing the groups into whether there was sarcopenia, low mass, low strength, or low speed. The CCL2 level was statistically significantly higher in the group showing low speed. In conclusion, CCL2 promotes myogenesis recovery, muscle strength, and muscle performance in vivo and has clinical relevance for muscle performance in humans.

Disclosure

E.Hong: None. E.Ha: None. J.Lee: None. Y.Choi: None. K.Lee: None. J.Won: None. M.Kwak: None.

Funding

Ministry of Education, Republic of Korea (2020R1I1A3073230)
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 < 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 > 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 (>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.
1679-P: L-arginine Ameliorates Polycystic Ovary Syndrome and Attenuates Intestinal Oxidative Stress by Regulating Gut Microbiota
Authors: DILIMULATI DILIQINGNA , CAI MEILI , ZHANG YUQIN , QU SHEN , ZHANG MANNA
Published: June 2023

More than half of Polycystic ovary syndrome (PCOS) women are overweight or obese, and weight gain amplifies and worsens the symptoms of PCOS. Hence, it is essential to further understand and treat PCOS women with obesity. Therefore, this study tried to use a multi-omics approach that integrates the gut microbiome, serum metabolomics, serum transcriptomics, and clinical indicators to distinguish obese PCOS from obese non-PCOS women. The stool and blood samples from 33 obese PCOS patients and 30 obese control women were collected. The sequencing results suggested there were significant differences in gut microbiome and metabolites between obese PCOS women and obese women. Of which, the level of L-arginine (Arg) in obese PCOS patients was significantly lower than that in the control group and associated with gut microbiota alterations. Further correlation analysis between metabolite and clinical phenotype showed that Arg was significantly correlated with the clinical phenotype of obese PCOS patients. In this study, C57BL/6 mice were treated with dehydroepiandrosterone (DHEA) with a high-fat diet (HFD) to induce obese PCOS mice models for 3 weeks. PCOS mice were randomly divided into four groups: Arg group, Arg + antibiotic cocktail (ABX) group, PCOS group, and PCOS + ABX group. After 3 weeks of Arg supplementation, the estrous cycle, ovarian morphology, intestinal oxidative stress and intestinal barrier integrity were improved in Arg group PCOS mice, while testosterone levels and insulin resistance levels were decreased. However, these improvements were not observed in the Arg plus ABX group, suggesting that ABX-mediated depletion of the gut microbiome would eliminate these improvements. Then the 16s rRNA sequencing was performed to determine the gut microbiota of the four groups. The results showed that Arg can ameliorate reproductive characteristics of PCOS and attenuate intestinal oxidative stress by regulating gut microbiota.

Disclosure

D.Dilimulati: None. M.Cai: None. Y.Zhang: None. S.Qu: None. M.Zhang: None.
1689-P: Macrophage SUCLA2-Coupled Glutamine Metabolism Drives Obesity
Authors: JIANG HAOWEN
Published: June 2023

Activation and infiltration of macrophages in adipose tissue are closely linked to obesity and are implicated in the pathogenesis of metabolic diseases. Glutamine is an essential energy resource that supports the inflammatory activation of macrophages, however, the underlying mechanism remains unknown. We found that AMP-activated protein kinase (AMPK) was the key regulator for mitochondrial glutamine metabolism. Once inflammatory activation of macrophages, increased ATP production from glutaminolysis inhibited the activity of AMPK, then removed its inhibitory effect of glutamine metabolism, resulting in the succinate accumulation derived IL-1β production and secretion. Mechanically, macrophage AMPK phosphorylated at Ser60 of succinyl-CoA synthetase β subunit (SUCLA2) that was responsible for catalyzing the succinate production, decreases its activity resulting in the reduction of the succinate accumulation derived IL-1β production and secretion correspondingly. Moreover, myeloid cell-specific knockout of the α subunit of AMPK exacerbated obesity and insulin resistance through IL-1β production and secretion in macrophages. Both the obstruction of the IL-1β signaling pathway by the neutralizing antibody and the decreasing of IL-1β production and secretion by myeloid cell-specific knockout of IL-1β could repair insulin resistance and obesity derived by AMPK deficiency in macrophages. Our study revealed that AMPK-mediated SUCLA2 phosphorylation drove the mitochondrial glutamine metabolism and the IL-1β production and secretion in macrophages, and targeting macrophage AMPK-SUCLA2 pathway might be a potential strategy for obesity and insulin resistance therapy.

Disclosure

H.Jiang: None.
1694-P: Impact of Bariatric Surgery on Increased Circulating Levels of Several Biomarkers for Neurodegenerative Diseases in Obese Chinese
Authors: YANG RANYAO , LI HUIXIN , YANG WAH , WU QIUPING , JIN LEIGANG , SONG ERFEI , WANG CUNCHUAN , XU AIMIN
Published: June 2023

Background: Increasing studies have shown a strong association of obesity with neurodegenerative disorders. However, there is scarce evidence for the direct link between obesity and neurodegeneration. In addition, although bariatric surgery is well-known to be an effective therapy for obesity-related metabolic dysfunctions, its impact on cognitive function remains uncertain. This study aims to address these questions by monitoring several well-established circulating biomarkers for neurodegeneration in morbidly obese subjects receiving bariatric surgery.

Methods: The single molecule array, an ultra-sensitive enzyme-linked immunosorbent assay technique, was used for measurement of plasma levels of p-tau 181, tau, Aβ42 and Aβ40 in 36 morbidly obese individuals (BMI=39.46±7.87) before and after bariatric surgery for 12 months and 55 lean subjects (BMI=21.79±2.84).

Results: Plasma levels of p-tau 181, tau, Aβ42 and Aβ40 in obese individuals, were significantly elevated compared to lean individuals, and positively correlated with several indices of obesity, including body weight, BMI and waist circumference. In obese subjects who received bariatric surgery, significant improvements on many metabolic parameters were observed, such as BMI, HOMA-IR and triglyceride. However, circulating p-tau 181 levels in obese individuals kept unchanged before and after treatment, while tau, Aβ42 and Aβ40 levels increased from 4.34±0.74 to 6.06±0.38 pg/ml, 4.37±0.51 to 8.47±0.41 pg/ml, and 98.89±11.53 to 174.14±8.99 pg/ml, respectively.

Conclusions: Circulating levels of several neurodegenerative biomarkers are elevated in obesity but such changes cannot be reversed by bariatric surgery. These findings implicate the adverse effects of obesity at the early stage of life on neurodegeneration may be last-lasting and hardly repairable, highlighting the importance of maintaining a healthy weight in prevention of neurodegenerative diseases.

Disclosure

R.Yang: None. H.Li: None. W.Yang: None. Q.Wu: None. L.Jin: None. E.Song: None. C.Wang: None. A.Xu: None.

Funding

Hong Kong Research Grants Council (AoE/M/707-18)
1697-P: Waist Circumference, Hippocampal Volume, and Cognitive Impairment—A Mendelian Randomization
Authors: ZHANG JINYAN , LUAN SISI , ZHOU JIANBO
Published: June 2023

The Relationship Between Central Obesity, Cognitive Function, Structural Brain Outcomes: A Mendelian Randomization Study

We investigated the relationship between central obesity and cognitive function, brain structure using a Mendelian randomisation (MR). Our exposures were genetic instruments for waist circumstance (WC, 65 variants) and our outcomes were cognitive performance and hippocampal volumes. We used conventional inverse-variance weighted (IVW) MR as the primary analysis method, alongside MR sensitivity analyses. Using IVW, genetic liability to WC was associated with cognitive performance (exponentiated ß=-0.16, 95%CI=0.07; 0.24), volume of left hippocampus (expß=-0.15, 95%CI=0.02; 0.27) and volume of right hippocampus (c=-0.14, 95%CI=0.01; 0.27). Furthermore, we found two variants in hippocampal volume that were also associated with WC, these two variants were associated with cognitive function (expß = 0.006, 95%CI=0.003; 0.009). Overall, we observed evidence of causal association between genetic instruments for WC and cognitive performance, and volume of hippocampus may be a mediator linking WC with cognitive function.

Table 1 MR estimates of the effect of WC on cognitive function and left or right hippocampus volume.

Disclosure

J.Zhang: None. S.Luan: None. J.Zhou: None.
17-OR: ADA Presidents' Select Abstract: CGM Initiation within Six Months of T1D Diagnosis Associated with Lower HbA1c at 3 Years
Authors: MANN ELIZABETH A. , ROMPICHERLA SAKETH , NOOR NUDRAT , MIYAZAKI BRIAN , GOLDEN LAUREN , SARHIS JENNIFER , AKTURK HALIS K. , LEE JOYCE M. , DESALVO DANIEL , GOMEZ PATRICIA , EBEKOZIEN OSAGIE , PRAHALAD PRIYA
Published: June 2023

Background: Early initiation of CGM after T1D diagnosis has been associated with lower HbA1c in the years following diagnosis in single-institution studies. This multi-institution study evaluated the association between the timing of CGM initiation and HbA1c at 3 years post-diagnosis.

Methods: Data were obtained from the T1D Exchange QI Collaborative, representing 52 centers across the US. Of the 33,942 youth ≤18 years with T1D >12 months in the Collaborative data set, those who started CGM within 12 months of diagnosis were included. LOESS plots evaluated the relationship between timing of CGM initiation and HbA1c.

Results: Of the 5,339 youth included in this analysis, median age was 9 (IQR 6) and 26% had public health insurance. Initiation of CGM occurred within 3-months of diagnosis for 43%, between 3-6 months for 27%, and 6-12 months for 30%. There was no significant difference in CGM initiation based on insurance or the social construct of self-identified race and ethnicity, used as an indicator of systemic racism. Median HbA1c at 3 years was lower for those who initiated CGM within 3 months and between 3-6 months of diagnosis compared to those starting CGM at 6-12 months (7.3 ± 1.7 and 7.5 ± 1.7 vs. 7.9 ± 1.7; Figure 1).

Conclusion: In summary, early initiation of CGM within the first 6 months of diagnosis is related to improved A1c outcomes at 3 years post-diagnosis.

Disclosure

E.A.Mann: None. P.Gomez: None. O.Ebekozien: Advisory Panel; Medtronic, Research Support; Eli Lilly and Company, Dexcom, Inc. P.Prahalad: None. S.Rompicherla: None. N.Noor: None. B.Miyazaki: None. L.Golden: None. J.Sarhis: None. H.K.Akturk: Advisory Panel; Senseonics, MannKind Corporation, Research Support; Medtronic, Tandem Diabetes Care, Inc., Dexcom, Inc., REMD Biotherapeutics, Eli Lilly and Company, IM Therapeutics. J.M.Lee: Advisory Panel; GoodRx, Consultant; Tandem Diabetes Care, Inc. D.Desalvo: Consultant; Dexcom, Inc., Research Support; Insulet Corporation.
170-LB: Do Telemedicine vs. In-Person Outpatient Type 1 Diabetes Visits Immediately Improve Glycemic Control?
Authors: FERBER CHRISTOPHER J. , WILHALME HOLLY , MITTELMAN STEVE , MOIN TANNAZ , HICKS REBECCA A.
Published: June 2023

Background: Children with type 1 diabetes (T1D) require frequent outpatient evaluation to assess glucose trends, modify insulin doses, and stay up to date with screening. Continuous glucose monitoring (CGM) has become more prevalent in recent years and provides a detailed glycemic control assessment. Telemedicine is increasingly utilized in lieu of in-person visits, especially since the onset of the COVID-19 pandemic.

Objective: To assess a difference in CGM profile parameters in the periods immediately before and after T1D follow-up visits and determine whether being seen by telemedicine versus in-person impacts this difference.

Methods: A dual center retrospective chart review was conducted including outpatient T1D follow up visits for patients aged 5-21 years old utilizing Dexcom CGM during the 2021 calendar year. CGM profile parameters assessed were Time in Range (TIR) and Glucose Management Indicator (GMI) during the period 4-weeks leading up to each outpatient visit, compared to the 2-week and 4-week period immediately following.

Results: A total of 269 outpatient visits (41.2% telemedicine) among 135 patients were included from both study sites. Mean TIR increased by 1.63 and 1.35% during the 2-week and 4-week period after each visit, respectively (p = 0.003, 0.013). Mean GMI also improved, decreasing by 0.07% and 0.06% during the 2-week and 4-week period after each visit, respectively (p = 0.003, 0.021). These changes in TIR and GMI were not statistically different between telemedicine versus in-person visits (p = 0.40, 0.29).

Conclusions: This study detected a small, but statistically significant improvement in CGM profile parameters immediately after outpatient visits. Telemedicine versus in-person visits were comparable. These findings suggest that multiple visits over time are needed to obtain a sustainable, clinically relevant change in glycemic control, and telemedicine can be utilized just as effectively as traditional visits to achieve this goal.

Disclosure

C. J. Ferber: None. H. Wilhalme: None. S. Mittelman: None. T. Moin: None. R. A. Hicks: None.
170-OR: Hyperglycemia in Patients without Diabetes in the Emergency Department and Subsequent Cascade of Care
Authors: MASHOUF KIMIA , JOHNSON ARIANNE , WILSON MARK
Published: June 2023

Introduction: Hyperglycemia in patients without a history of diabetes (DM) is common in the Emergency Department (ED). Data describing how this is routinely managed is lacking. In this study, we report how often patients in the ED without a history of diabetes and hyperglycemia (blood glucose (BG) > 200 mg/dL) receive a HbA1c and diabetes education (DE).

Methods: This retrospective study evaluates patients in our ED with a random BG ≥ 200 mg/dL and no prior history of DM based on medical record review. In total, 110 charts were analyzed. These patients were divided into two groups: admitted for inpatient treatment (AD) and discharged from the ED (DCED). 90-day endpoints included: HbA1c performed and completion of DE. We also compared the frequency of diabetes diagnosis in these populations.

Results: Of the 110 patients studied, 62 (56%) were AD and 48 (44%) were DCED. Within 90 days from the ED visit, 40 (65%) of AD had an HbA1C performed compared to 18 (38%) of DCED. Of AD patients, 25 (63%) were diagnosed with DM based on HbA1c ≥ 6.5%, compared to 13 (72%) of those DCED. Of patients with a new diagnosis of DM, 22 (88%) of AD received DE, while only 4 (31%) of DCED patients received DE.

Conclusion: We have determined that patients with hyperglycemia without a history of DM in our ED are inadequately screened for DM. 53% of this population received HbA1c evaluations within 90 days. Of patients who had a HbA1c performed, 66% were diagnosed with diabetes. AD patients were approximately twice as likely as those DCED to have a HbA1c performed. AD patients with a diagnosis of diabetes were three times as likely to have met with a diabetes educator relative to those DCED. Hyperglycemia in our ED is an opportunity to diagnose DM that is currently underutilized.

Disclosure

K.Mashouf: None. A.Johnson: None. M.Wilson: Stock/Shareholder; Novo Nordisk, Dexcom, Inc.