Bristol-Myers Research Articles

1366-P: Nonalcoholic Fatty Liver Disease in Young-Onset Type 2 Diabetes Mellitus—A New Epidemic?

The prevalence of young-onset type 2 diabetes mellitus (YOT2DM), defined as T2DM diagnosed in adults <45 years old, is steadily increasing. Nonalcoholic fatty liver disease (NAFLD) is common in people with T2DM but its prevalence in YOT2DM is unknown. We therefore hypothesized that NAFLD is an emerging health concern in this population. A total of 161 adults aged 35-44 years with and without T2DM, underwent screening for NAFLD with laboratory tests and imaging by elastography (steatosis by controlled attenuation parameter [CAP]; fibrosis by liver stiffness measurement [LSM]). Of these, 25 (16%) had YOT2DM and 136 (84%) did not have diabetes mellitus (noDM). While obesity was very prevalent in the cohort (53%), those with YOT2DM had a higher BMI (35±7 vs. 31±7 kg/m2, p<0.01), and reported comorbidities more frequently: hypertension (48% vs. 24%, p=0.02) and atherogenic dyslipidemia (76% vs. 54%, p=0.04). Hepatic (HOMA-IR 4.6±2.8 vs 2.6±1.9, P<0.01) and adipose tissue (6.5±5.1 vs 3.9±3.5, p=0.01) insulin resistance were worse in people with YOT2DM. Adiponectin, a reflection of proper adipose tissue function, was lower in YOT2DM (4.2±2.3 vs 6.2±3.5 μg/mL, p=0.02). Hepatic steatosis (CAP ≥274 dB/m) was prevalent in both groups but higher in people with YOT2DM (64% vs. 47%), but much lower in people without obesity or diabetes (27%; p<0.01). Male sex was associated with a significantly higher risk of hepatic steatosis (OR 3.7, 95% CI 1.5-9.2). The frequency of any fibrosis as measured by LSM (≥7.0 kPa) was 3-fold higher in YOT2DM compared to people without diabetes (12% vs. 4%, p=0.08). Every 1 unit increase in BMI elevated the risk of both steatosis and fibrosis by 20% (OR 1.2, 95% CI 1.03-1.3). Conclusion: Hepatic steatosis is highly prevalent in young-onset type 2 diabetes (YOT2DM) and is strongly influenced by obesity. Hepatic fibrosis is relatively common and affects 1 in 8 people with YOT2DM. These results warrant the need for larger and longer follow-up studies in this population. Disclosure A. Sharma: None. E. Godinez Leiva: None. R. Lomonaco: None. E. Valdez Saenz: None. A. Ortiz Rocha: None. S.A. Marangi: None. M.A. Gonzalez: None. S. Shrestha: None. S.S. Shetty: None. J.T. Budd: None. D. Barb: None. S. Kalavalapalli: None. K. Cusi: Research Support; Echosens, Inventiva. Consultant; Poxel SA. Research Support; LabCorp, Zydus. Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns.

801-P: Short-Acting Exenatide Added Three Times Daily to Insulin Therapy Improves Fatty Liver Index in Type 1 Diabetes

Fatty liver index (FLI), a marker of hepatic fat content, has been reported as an independent risk factor for all-cause mortality and major cardiovascular events in type 1 diabetes. How short-acting glucagon-like peptide 1 receptor agonists (GLP-1RA) influence FLI in type 1 diabetes remains unknown. We analyzed FLI post-hoc in a phase 2, double-blind, randomized (1:1), clinical trial (NCT03017352) that assessed the efficacy of short-acting GLP-1RA exenatide 10 μg added three times daily to insulin therapy as compared with placebo over 26 weeks of treatment in 108 individuals with type 1 diabetes (76/32 men/women, age 50 (14) years (mean (standard deviation)), diabetes duration 21 (12) years, BMI 28 (4) kg/m2, glycated hemoglobin A1c 8.2 (0.7) % / 66 (7) mmol/mol). Exenatide significantly reduced FLI by 23 % (95 % confidence interval -44; -10, P = 0.001) (Table 1) as compared with placebo after 26 weeks’ treatment. In conclusion, short-acting exenatide reduced FLI-assessed hepatic fat content in patients with long-standing type 1 diabetes and inadequate glycemic control, alluding to potential beneficial effects of this GLP-1RA on both morbidity and mortality in type 1 diabetes. Disclosure N.Johansen: Other Relationship; AstraZeneca, Novo Nordisk, Research Support; JDRF. T.F.Dejgaard: Advisory Panel; Novo Nordisk, Research Support; Novo Nordisk, Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk, AstraZeneca. A.Lund: Speaker's Bureau; Novo Nordisk. C.K.Nielsen: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. Funding AstraZeneca

951-P: Intermittently Scanned Continuous Glucose Monitoring (isCGM) for T1DM—Subgroup Analysis from the FLASH-UK Study

The recently published1, multi-site, FLASH-UK, randomized controlled trial (n=156, males 56%, Baseline HbA1c 71±9 mmol/mol, age 44±15) showed improved HbA1c and sensor-based metrics in adults with type 1 DM and an HbA1c ≥58 mmol/mol. Here we present results from pre-specified subgroup analysis for HbA1c (Table 1) and “Time in range (TIR)” (Table 2). The effect of isCGM on both HbA1c and TIR did not differ significantly across subgroups for baseline HbA1c category, treatment modality, prior structured education, sex, deprivation status or depression category. The effect of isCGM on HbA1c was larger for younger people. Those with at least a bachelor’s degree had greater TIR improvement. Conclusion: isCGM is effective across a range of clinical and demographic factors. 1N Engl J Med. 2022 Oct 20;387(16):1477-1487 Disclosure L.Leelarathna: Advisory Panel; Abbott Diabetes, Medtronic, Insulet Corporation, Sanofi, Research Support; Abbott Diabetes, Novo Nordisk, Speaker's Bureau; Sanofi, Abbott Diabetes. V.P.Taxiarchi: None. M.Burns: None. M.E.Camm: None. H.Thabit: Advisory Panel; Dexcom, Inc., Roche Diabetes Care, Research Support; Dexcom, Inc., Speaker's Bureau; Eli Lilly and Company. E.G.Wilmot: Advisory Panel; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Roche Diabetes Care, Embecta, Consultant; Springer Healthcare, Research Support; Abbott Diabetes, Diabetes UK, Insulet Corporation, Novo Nordisk, NIH - National Institutes of Health, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Ypsomed AG, Glooko, Inc. On behalf of the flash-uk trial study group: n/a. C.J.Sutton: None. M.Evans: Advisory Panel; Zucara Therapeutics, Pila Pharma, Dexcom, Inc., Other Relationship; Novo Nordisk, AstraZeneca, Abbott Diabetes, Speaker's Bureau; Eli Lilly and Company. S.Neupane: Advisory Panel; Quin, Abbott Diabetes, Roche Diabetes Care, Insulet Corporation, Other Relationship; Abbott Diabetes. G.Rayman: Other Relationship; Diabetes UK, Novo Nordisk, Research Support; Abbott Diabetes, Speaker's Bureau; Abbott Diabetes, Lilly Diabetes, Sanofi. S.Lumley: None. I.C.Cranston: Research Support; Eli Lilly and Company, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Sanofi, Viatris Inc. P.Narendran: Advisory Panel; Omnipod, Speaker's Bureau; Abbott Diabetes, Lilly Diabetes. K.Barnard: Advisory Panel; Abbott Diabetes, Roche Diabetes Care, Sanofi, Consultant; LifeScan Diabetes Institute, Tandem Diabetes Care, Inc., Research Support; Novo Nordisk. Funding Diabetes UK (18/0005836)

123-LB: Implementing a Multidisciplinary Model of CGM Care in Real-World Pharmacy Practice—A Clinical Consensus for Canadian Pharmacists

Background: Continuous glucose monitoring (CGM) devices have transformed diabetes care, but there is a lack of guidance for pharmacists to follow when onboarding patients to begin using CGM systems. Our study aimed to develop a blueprint for best practices for pharmacists to support people living with diabetes (PWD) using CGM systems. Methods: We used a modified DELPHI process to gather insights from 11 Key Opinion Leaders (KOLs) across Canada, including two endocrinologists, one family physician, and eight pharmacists. Consensus was reached for each criterion when 75% agreement was achieved. Criteria for CGM device initiation, short-term or episodic CGM use, and best practices for CGM onboarding and monitoring were developed based on the results. Results: Amongst the ideal candidates for CGM use are PWD using insulin, those with type 1 diabetes, individuals not reaching their A1C target, those experiencing frequent hypoglycemia, pregnant individuals, and others at risk of hypoglycemia. Best practices for onboarding and monitoring included shared decision-making conversations, a comprehensive overview of cost and coverage options, customized alerts and alarms, and timely follow-up sessions. Discussion: The KOL group ensured a comprehensive and diverse perspective. The developed blueprint provides a valuable resource for pharmacists to improve the use of CGM devices and enhance diabetes management for their patients. Incorporating these best practices into clinical practice has the potential to transform diabetes care and improve outcomes. Disclosure A. S. Sihota: Consultant; Novo Nordisk Canada Inc., Other Relationship; Becton, Dickinson and Company. S. Sivapalan: Advisory Panel; Novo Nordisk, Pfizer Inc., AstraZeneca, Consultant; Pear Healthcare Solutions Inc., Other Relationship; Boehringer Ingelheim (Canada) Ltd., GlaxoSmithKline plc., Novo Nordisk, Bristol-Myers Squibb Company, Pfizer Inc., AbbVie Inc., Ferring Pharmaceuticals, AstraZeneca. T. Smith: Advisory Panel; Novo Nordisk Canada Inc., Dexcom, Inc., Emergent Biosolutions. I. Halperin: Advisory Panel; Sanofi, Speaker's Bureau; 3Boehringer Ingelheim Canada Ltd. /Ltée, Abbott Diabetes, Dexcom, Inc., Novo Nordisk. A. B. Jain: Advisory Panel; Abbott, Amgen Canada, Dexcom, Inc., AstraZeneca, Novo Nordisk, Bayer Inc., Insulet Corporation, Takeda Canada, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Research Support; Abbott, Amgen Canada, Novo Nordisk, Speaker's Bureau; Abbott, Amgen Canada, Dexcom, Inc., AstraZeneca, Novo Nordisk, Bausch Health, Canada, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Pfizer Inc. A. Chin: Other Relationship; Abbott Diabetes, BMO Bank of Montreal, Diabetes Canada, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care, Inc., Research Support; Novavax, Centricity Research. W. Chow: Advisory Panel; GlaxoSmithKline plc., Pfizer Inc., Speaker's Bureau; Abbott Diagnostics, AstraZeneca, Bayer Inc., Bausch Health, Canada, Boehringer Ingelheim (Canada) Ltd., Eisai Inc., Novo Nordisk. S. Jin: Advisory Panel; Dexcom, Inc., Eisai Inc., Novo Nordisk Canada Inc., Board Member; Wounds Canada, Consultant; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals Inc., Canadian Collaborative Research Network, Diabetes Canada, GlaxoSmithKline plc., HLS Therapeutics Inc., MDBriefcase, Novo Nordisk Canada Inc., AstraZeneca, Speaker's Bureau; Eisai Inc., Dexcom, Inc., Novo Nordisk Canada Inc. T. Molberg: None. S. Patil: None. R. Siemens: Consultant; Canadian Collaborative Research Network, Novartis Canada, AstraZeneca, Montmed, Sanofi, MDBriefcase, Other Relationship; Abbott Diabetes, Amgen Canada, Boehringer Ingelheim and Eli Lilly Alliance, GlaxoSmithKline plc., HLS Therapeutics, Novo Nordisk, Dexcom Canada, Diabetes Canada. Funding Dexcom Canada

408-P: Associations between Apolipoprotein B (apoB): Apolipoprotein A1 (apoA1) Ratio and Metabolic and Kidney Disease in Youth with Type 1 Diabetes

ApoA1 is a major protein component of high-density lipoprotein (HDL) and apoB the main protein component of low-density lipoprotein (LDL). The ratio between apoB and apoA1 (ApoB:ApoA1) is often used to measure cardiovascular disease (CVD) risk in adults, yet little is known about its relationship with insulin resistance, central adiposity and early kidney disease, important CVD risk factors, in youth with T1D. In a study of 50 youth with type 1 diabetes, glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed using iohexol and p-aminohippurate clearance, and urine albumin-to-creatinine ratio (UACR) was also measured. Central adiposity was assessed using DXA and insulin sensitivity was estimated (eIS). Intraglomerular pressure was estimated using the Gomez equations. The study participants were 16±3.0 years old, 50% were female, and their average HbA1c was 8.7±1.3%. They had an average T1D duration of 5.7±2.6 years, with UACR levels of 6[5-14] mg/g and GFR of 189±40 ml/min. Concentrations of apoA1 and apoB were quantified by targeted nuclear magnetic resonance spectroscopy. ApoA1 (185±35 vs. 150±36 mg/dl, p=0.001) and apoB (108±29 vs. 90±27 mg/dl, p=0.03) were higher in girls vs. boys, but the apoB:apoA1 ratio was similar between the sexes (p=0.59). ApoB correlated with PGLO (r: 0.42, p=0.01), log UACR (r: 0.33, p=0.02), and trunk mass (r: 0.34, p=0.02), whereas ApoB:ApoA1 correlated with GFR (r: 0.44, p=0.002), PGLO (r: 0.48, p=0.01), log UACR (r: 0.38, p=0.008), trunk mass (r: 0.45, p=0.001), BMI (r: 0.40, p=0.004) and inversely with eIS (-0.44, p=0.001). The ratio of apoB to apoA1 associated with markers of metabolic and kidney disease in youth with T1D. Further research is needed to fully understand the mechanisms behind these associations and to identify potential strategies for preventing or mitigating cardiovascular disease in young persons with T1D. Disclosure L.Remmers: None. C.Birznieks: None. D.Carrasco: None. S.Gross: None. J.K.Snell-bergeon: None. L.A.Hall: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. K.L.Tommerdahl: None.

143-OR: Prevailing Glucose Levels Alter Left Ventricular Contractions Pattern, Myocardial Performance, and Myocardial Energy Efficiency

Mechanical dispersion (MD) describes heterogeneity in ventricular contraction patterns, and myocardial work (MW) indices quantify ventricular performance. Investigating the myocardial and functional response to acute hypoglycemia and hyperglycemia may aid in identifying putative mechanisms linking glycemia and cardiovascular disease (CVD). From echocardiography performed during euglycemic, hyperglycemic and hypoglycemic clamps, we explored the relationship between glycemia and MD and MW indices in individuals with type 1 diabetes, type 2 diabetes and without diabetes. MD was measured by speckle-tracking echocardiography, and MW measures were derived from pressure-strain loop analyses. We analyzed data (mean±SD) from 84 individuals: 20 young individuals with type 1 diabetes (age: 30±8 years); 24 middle-aged individuals with type 1 diabetes (age: 53±12 years); 21 older individuals with type 2 diabetes (63±7 years), and 21 controls (62±8 years). Results for MD and MW indices are illustrated in Figure 1. In conclusion, acute hyperglycemia leads to an energy-effective myocardium with homogeneous left ventricular contractions. Hypoglycemia increases constructive myocardial work, followed by a less energy-efficient myocardium and more heterogeneous left ventricular contractions, perhaps alluding to a possible link between hypoglycemia and CVD. Disclosure C.R.Andreasen: None. A.Andersen: None. P.G.Hagelqvist: None. K.Maytham: None. M.Sengeløv: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. F.J.Olsen: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. Funding Danish Diabetes Academy (17SA0031406); Novo Nordisk Foundation (16230)

1651-P: Elevated FGF21 Levels after Total Pancreatectomy and in Response to Single-Dose Glucagon Receptor Antagonism in Humans

Fibroblast growth factor 21 (FGF21) is a liver-secreted peptide hormone reportedly improving metabolic homeostasis, partly via reduced hunger for sugar, fat, protein and alcohol. Exogenous glucagon has been shown to increase circulating FGF21 levels, but the role of endogenous glucagon for the control of FGF21 secretion remains unknown. To elucidate the relationship between endogenous glucagon and FGF21 in humans, we investigated the effect of chronic pancreatic glucagon depletion and acute glucagon receptor antagonism, respectively, on FGF21 levels. Nine totally pancreatectomized subjects (7 men, 2 women, age 61.3 ± 10.3 years, BMI 22.6 ± 4.8 kg/m2) and 9 matched control subjects (6 men, 3 women, age 65.9 ± 8.8 years, BMI 23.9 ± 2.7 kg/m2) underwent two randomized, double-blinded test days 24 hours after single-dose oral administration of either the glucagon receptor antagonist LY2409021 (300 mg) or placebo. FGF21 levels were measured both in the fasting state and in response to an oral glucose tolerance test (OGTT). The pancreatectomized patients exhibited significantly increased mean fasting FGF21 levels compared to the control subjects (493 ± 429 vs 108 ± 58 pg/mL, P=0.02). In the control subjects, administration of LY2409021 significantly increased mean fasting levels of FGF21 (216 ± 117 vs 108 ± 58 pg/mL, P=0.004) whereas fasting FGF21 levels in the pancreatectomized patients were unaffected by LY2409021. In both groups, FGF21 levels increased in response to the OGTT, with no significant treatment effect of LY2409021. Our results suggest that both chronic glucagon depletion and acute antagonism of the glucagon receptor mediate an increase in FGF21 levels in humans, pointing to direct or indirect effects of glucagon as important regulators of FGF21 secretion. Disclosure M.F.G.Grøndahl: Speaker's Bureau; Novo Nordisk A/S. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. C.T.Juel: None. A.Lund: Speaker's Bureau; Novo Nordisk. S.Haedersdal: Consultant; Novo Nordisk. M.M.Andersen: None. J.S.Svenningsen: None. M.Gillum: None. B.Hartmann: Stock/Shareholder; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. Funding Aase and Ejnar Danielsen's Foundation; Novo Nordisk Foundation (LY2409021); Eli Lilly and Company

1751-P: SERCA2 Regulates ER Lipid Composition and Proinsulin Processing

Endoplasmic reticulum calcium (ER Ca2+) levels are primarily maintained through the sarco-ER Ca2+ ATPase (SERCA) pump. We have demonstrated reduced SERCA2 expression in islets from human cadaveric donors with Type 2 Diabetes (T2D) compared to normoglycemic controls and linked β-cell specific deletion of SERCA2 with impaired proinsulin processing. To test mechanisms of how reduced ER Ca2+ and SERCA2 deficiency regulate proinsulin processing, a SNAP-tagged human proinsulin adenovirus (SNAP-proinsulin) was overexpressed in rat insulinoma β-cells where SERCA2 had been deleted (S2KO INS-1) using CRISPR/Cas9 and in islets from C57BL/6 mice with SERCA2 haploinsufficiency fed a high fat diet or treated ex vivo with glucolipotoxicity (GLT). Immunoblotting SNAP-tagged cleavage products showed reduced proinsulin processing in SERCA2 deficient models compared to wildtype (WT), these defects were exacerbated by GLT treatment. To determine whether reduced processing could be related to impaired trafficking of proinsulin within the β-cell secretory pathway, SNAP-proinsulin was fluorescently labelled in C57BL/6 mouse islets treated with GLT. The colocalization of SNAP-proinsulin with Golgi immuno-marker, Giantin, suggested an accumulation in this compartment. The ER is the main site of lipid synthesis and lipid remodeling is known to regulate β-cell function. Preliminary mass spectrometry data revealed that loss of SERCA2 increases ER levels of phosphatidylcholine and decreases ceramide and sphingomyelin in S2KO INS-1 cells compared to WT cells. Taken together, these results demonstrate that ER Ca2+ deficiency changes ER lipid composition, which may affect proinsulin processing and trafficking. Characterizing this novel mechanism could provide valuable insight into β-cell dysfunction in T2D. Disclosure M.Hartley: Employee; Eli Lilly and Company. M.J.Pearson: None. F.Syed: None. H.Bui: None. T.Kono: None. K.D.Roth: Employee; Eli Lilly and Company. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK093954, R01DK127308, R01DK127236)

1342-P: Are Plasma Aminotransferases of Value in Screening Patients with T2DM for NAFLD or Fibrosis?

The ADA recommends to screen for NASH and liver fibrosis individuals with type 2 diabetes (T2DM), obesity (OB) and/or elevated alanine aminotransferase (ALT). However, recent studies have questioned the clinical value of measuring ALT and AST for the detection of patients at risk of nonalcoholic fatty liver disease (NAFLD) or advanced liver fibrosis or cirrhosis. The aim of this study was to assess the clinical value of ALT and AST ≥40 IU/L, or their lower cut-offs ≥30 IU/L as recommended by recent AACE guidelines, to screen populations at risk. To this end, we recruited 714 participants (age: 56 ± 11 years, male: 42%; BMI: 30.8 ± 6.5 kg/m2; T2DM: 35%; A1c: 6.0 ± 1.2%) from primary care or endocrinology clinics, unaware of having NAFLD/fibrosis. Screening for NAFLD included laboratory tests and imaging with elastography (steatosis by controlled attenuation parameter [CAP]; fibrosis by liver stiffness measurement [LSM]). Elevated transaminases were more common in patients with vs. without T2DM, with ALT ≥40 IU/L occurring in 13% vs. 8% and AST in 9% vs. 3% of patients (both p<0.05). If using a cutoff of ≥30 IU/L: 25% vs. 18% and 20% vs. 13%; respectively (both p<0.05). Elevated ALT ≥30 IU/L was the highest in patients with T2DM and OB (n=164) vs. controls (without T2DM or OB; n=269; 27% vs 15%; p=0.02). The sensitivity for diagnosing steatosis by ALT or AST was very low, with ALT and AST ≥40 IU/L present in only 16% and 9%, respectively. However, steatosis by imaging (CAP) was often present if ALT or AST were high (81 and 90%, respectively). An ALT ≥40 IU/L was also not useful for diagnosing patients with fibrosis of any stage (LSM ≥7.0), missing the diagnosis in 63% of patients, and this did not improve when examining only those with more advanced fibrosis (≥F3) being elevated in only 40%. Conclusions: Plasma aminotransferases are of limited diagnostic value when screening patients with T2DM for NAFLD or fibrosis. This supports the ADA recent guidelines for using FIB-4 and additional noninvasive testing for screening. Disclosure A. Ortiz Rocha: None. E. Godinez Leiva: None. S. Kalavalapalli: None. R. Lomonaco: None. S.S. Shetty: None. S.A. Marangi: None. E. Valdez Saenz: None. S. Shrestha: None. M.A. Gonzalez: None. X. Chi: None. M.J. Gurka: None. D. Barb: None. K. Cusi: Research Support; Echosens, Inventiva. Consultant; Poxel SA. Research Support; LabCorp, Zydus. Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns. Funding National Institutes of Health (R01120331-01A1)

31-OR: Sex-Specific Differences in Subcutaneous Adipose Tissue in Persons with HIV May Contribute to Diabetes Risk

Background: Men with HIV have greater visceral adipose tissue (VAT) accumulation compared to women, which contributes to insulin resistance and derives, in part, from a failure to sequester lipids in subcutaneous adipose tissue (SAT). We assessed whether sex-specific differences in SAT composition are associated with measures of VAT volume and insulin resistance. Methods: Adults with HIV and consistent viral suppression on antiretroviral therapy had SAT and VAT measured by CT imaging, HOMA2-IR using fasting plasma glucose and insulin, and a subset had abdominal SAT lipoaspirates for single-cell RNA-sequencing to define proportions of CD4 and CD8 T effector memory cells (TEM), perivascular (PVM) and intermediate (IM) macrophages, and fibroblasts. Adjusted ordinal regression models and partial Spearman’s assessed the interaction between sex and cell proportions. Results: We enrolled 111 participants (24% female) with a median age of 48 years, BMI of 31.5 kg/m2, and HOMA2-IR of 3.0. VAT volume was significantly associated with HOMA2-IR. Women had lower VAT volumes and higher proportions of SAT PVMs and lower IMs, as well as fewer cytotoxic CD4 and CD8 T cells compared with men (p ≤ 0.05 for all). The proportions of SAT CD4 TEM, CD8 TEM, myofibroblasts, MYOC fibroblasts, and IMs were associated with VAT volume (p ≤ 0.05 for all), but an interaction by sex was not observed. The proportions of CD4 and CD8 TEM cells were significantly associated with HOMA2-IR and there was evidence of an interaction by sex status (interaction term p = 0.09 & p = 0.06, respectively). Conclusions: Women with HIV have a greater adjusted proportion of PVMs and lower cytotoxic CD4 and CD8 T cells in SAT. While the relationship between immune cell proportions and HOMA-IR only appeared to differ for CD4 and CD8 TEM cells, lower ectopic fat deposition in the context of reduced SAT inflammatory cells in women suggests the sex difference in diabetes risk among persons with HIV may relate to adipose tissue cellular composition. Disclosure S.Bailin: None. M.Mashayekhi: None. C.L.Gabriel: None. L.Hannah: None. S.Kalams: None. S.A.Mallal: None. J.A.Kropski: Advisory Panel; APIE Therapeutics, Research Support; Boehringer Ingelheim Inc., Bristol-Myers Squibb Company, Genentech, Inc. C.N.Wanjalla: None. J.Koethe: Advisory Panel; Merck Sharp & Dohme Corp., Janssen Pharmaceuticals, Inc., Gilead Sciences, Inc., Theratechnologies, Research Support; Merck Sharp & Dohme Corp. Funding National Institutes of Health (R01DK112262, UL1RR024975, T32AI007474, P30AI110527)

20-OR: Loss of Characteristic ß-Cell Function in Autoantibody-Positive (Ab+) Individuals during the Progression to Type 1 Diabetes (T1D)

We used correlations of C-peptide secretion between follow-up time points (autocorrelation) of Ab+ relatives in the TrialNet Pathway to Prevention study to assess the loss of characteristic β-cell function during progression to T1D. Measures of β-cell function: AUC C-peptide; C-peptide Index (30-0 min C-peptide)/(30-0 min glucose); and Index60 (composite of glucose and C-peptide during first 60 minutes of OGTT)] were assessed (table 1). Spearman correlations of AUC C-peptide from baseline to pre-diagnosis (6 months before) OGTTs of progressors (Pro; Age=8.7±3.6 yrs; n=182) were lower than correlations of AUC C-peptide from baseline to last OGTTs of non-progressors (NPro; Age=9.6±3.8 yrs; n=3,137; p<0.001 for all). Among Pro, correlations of AUC C-peptide from baseline to diagnosis OGTTs were considerably lower than correlations of AUC C-peptide from baseline to pre-diagnosis OGTTs (p=<0.001 for all). In conclusion, the lower C-peptide autocorrelation from baseline to last OGTTs of Pro compared to NPro indicates that β-cell function is already appreciably altered 6 months before diagnosis. Among Pro, the substantial decline of C-peptide autocorrelation from 6 months before diagnosis to diagnosis suggests a marked loss of β-cell function in that interval. Autocorrelation offers another approach for providing insight into β-cell compromise. Disclosure H.M.Ismail: Consultant; Rise Therapeutics. D.D.Cuthbertson: None. J.S.Skyler: Advisory Panel; Adocia, Altheia Sciences, Arecor, Avotres Inc., Bayer Inc., COUR Pharmaceuticals, Dance Biopharm/Aerami, Diasome, Enthera, Immnomolecular Therapeutics, Kriya Therapeutics, Oramed Pharmaceuticals, Orgenesis Inc., Precigen, Inc., ViaCyte, Inc., Board Member; Applied Therapeutics Inc., Dexcom, Inc., Consultant; Novo Nordisk, Sanofi, Signos, 4Immune, Other Relationship; Imcyse, Provention Bio, Inc. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. J.Sosenko: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK129799-01A1)

165-LB: Circulating Metabolomic Biomarkers of Glycemic Control in Youth with Type 2 Diabetes (T2D)

There are few biomarkers of glycemic response among youth with T2D, despite increasing disease prevalence and suboptimal response to approved therapies. We hypothesized that plasma metabolites may predict glycemic outcomes in youth-onset T2D. We measured 480 metabolites in fasting plasma samples in the Treatment options for T2D in Adolescents and Youth (TODAY) study (n=391), in which youth with T2D aged 10-17 years were randomized to metformin alone, metformin + rosiglitazone, or metformin + intensive lifestyle intervention. Metabolite associations with loss of glycemic control (defined as HbA1c ≥8% for 6 months or need for insulin therapy) were modeled using Cox proportional hazards regression adjusted for baseline age, sex, race/ethnicity, BMI, treatment group, and fasting glucose. Loss of glycemic control was observed in 150 of 391 youth (mean 2.6 years). Baseline levels of 11 metabolites were associated with loss of glycemic control (FDR<0.05, Fig. 1A). Treatment group modified the association of hexose and xanthurenic acid levels with glycemic control. For both compounds, youth with higher baseline levels had a lower risk of treatment failure when randomized to metformin therapy alone (Fig. 1B). Thus, metabolomics provides insight into circulating analytes associated with loss of glycemic control, and may highlight different effects of specific treatments in youth with T2D. Disclosure Z. Chen: None. C. Lu: None. X. Shi: None. S. Zheng: None. D. Wolfs: None. P. Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. R. E. Gerszten: None. E. M. Isganaitis: None. Funding National Institutes of Health (K23DK127073)

1367-P: Type 2 Diabetes Mellitus and Obesity Amplifies Nonalcoholic Fatty Liver Disease Risk with Age

Nonalcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent in the general population with multiple known metabolic risk factors. There is limited evidence on the impact of age on the prevalence of hepatic steatosis and fibrosis, and their relationship to cardiometabolic risk factors. To this end, we recruited 761 patients 35-75 years of age, with and without T2DM, who underwent screening for NAFLD with laboratory tests and imaging by elastography (steatosis by controlled attenuation parameter [CAP]; fibrosis by liver stiffness measurement [LSM]). Patients were divided into 3 age groups: <45 years (young), 45-64 years (middle age), and ≥65 years old (older age), with results reported in this order. Of the 761 patients included, 21% (n=161) were young, 52% (n=397) middle age, and 27% (n=203) older. In the older age group, prevalence of obesity was lower (53% vs. 53% vs. 40%, p=0.01) but T2DM was higher (15% vs. 39% vs. 44%; p<0.01). Similarly, hypertension, atherogenic dyslipidemia, and use of antihypertensives and statins were more frequent in the older age group. Despite this, there were no differences in steatosis (CAP ≥274 dB/m: 50% vs. 54% vs. 52%, p=0.7). A marker of NAFLD disease activity (NIS4) worsened with increasing age (p<0.01). There was a trend for fibrosis (LSM≥7.0 kPa) to be higher in middle (11%) and older (8%) vs. younger (5%) age. After multivariable analysis (sex, race, ethnicity, BMI, A1c, cardiometabolic risk factors), BMI was associated with both steatosis and fibrosis in all age groups (p<0.01). There was a significant association between A1c as a continuous variable and steatosis only in the older age group (OR 2.8, 95% CI 1.6-4.9), while its association with fibrosis started at middle age (OR 1.3, 95% CI 1.1-1.7) and was stronger in older age (OR 1.8, 95% CI 1.01-3.2). Conclusion: Age was not associated with steatosis or fibrosis. BMI was the strongest predictor of hepatic steatosis and synergizes with T2DM for the development of fibrosis with age. Disclosure A. Sharma: None. E. Godinez Leiva: None. R. Lomonaco: None. E. Valdez Saenz: None. A. Ortiz Rocha: None. M.A. Gonzalez: None. S.A. Marangi: None. S. Shrestha: None. S.S. Shetty: None. J.T. Budd: None. S. Kalavalapalli: None. D. Barb: None. K. Cusi: Research Support; Echosens, Inventiva. Consultant; Poxel SA. Research Support; LabCorp, Zydus. Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns.

187-LB: Preclinical Biomarkers of Alzheimer's Disease Neuropathology in Young Adults with Youth-Onset Diabetes (YDM)—A Proof-of-Concept Study

Adult-onset diabetes increases one's risk for Alzheimer's disease and its related dementias (AD/ADRD). However, little is known about the risk for AD/ADRD in young adults with YDM. The current study quantified preclinical plasma and imaging biomarkers of AD/ADRD in a subset of young adults with YDM from the SEARCH for Diabetes in Youth study cohort (type 1 diabetes [T1D], n=20; type 2 diabetes [T2D], n=21; mean [SD], age=27.4 years [2.2], diabetes duration=13.6 years [2.4], 59% female). Plasma biomarkers were assayed from stored samples at two timepoints: within 1-year of YDM diagnosis (baseline) and in young adulthood via the Quanterix Simoa platform including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), amyloid beta (Aβ)40, and Aβ42. Seven participants from the SEARCH subset (T1D=6, T2D=1; age=30.7 years [2.4], 87% female) and four age-similar controls (age=26.5 years [4.4], 50% female) underwent [18F]PI-2620 tau positron emission tomography (PET) to quantify brain tau density. Tau standardized uptake value ratios (SUVRs) with partial volume correction were derived in AD/ADRD sensitive brain regions. From baseline to young adulthood, plasma pTau181 significantly increased in both YDM-T1D and YDM-T2D (mean change=9.5 pg/mL [3.8] and 12.4 pg/mL [6.3], respectively; p<0.001). Average tau SUVRs in the middle temporal poles (SUVR=1.26 [0.14] vs 1.17 [0.04]) and parahippocampal gyri (SUVR=1.01 [0.33] vs 0.92 [0.05]) were greater in YDM vs. controls. However, these differences were not statistically significant. Our preliminary results suggest that YDM may increase the risk of AD/ADRD via accelerated accumulation of soluble phosphorylated tau. Additional measurement of AD/ADRD neuropathology, including amyloid PET scans, is currently underway to further understand the trajectory of preclinical AD/ADRD pathology in YDM. Disclosure A. Shapiro: None. K. K. Harrall: None. R. A. Barcus: None. J. Tan: None. B. Bettcher: None. A. Thaker: None. K. A. Walker: None. A. D. Liese: None. D. Dabelea: None. C. T. Whitlow: Consultant; Biogen, Genentech, Inc. C. Coughlan: None. J. Kim: None. H. Potter: None. P. Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. M. E. Pauley: None. B. S. Rajic: None. J. Truong: None. D. H. Glueck: None. Funding American College of Radiology

1148-P: Glycoprotein Acetyls (GlycA) Associate with Intraglomerular Hemodynamic Dysfunction, Albuminuria, Central Adiposity, and Insulin Resistance (IR) in Youth with Type 1 Diabetes (T1D)

GlycA is a biomarker of systemic inflammation and cardiovascular disease, yet little is known about this biomarker in T1D. We examined the associations among GlycA, central adiposity, IR, and early kidney injury in adolescents with T1D. Glomerular filtration rate (GFR) and renal plasma flow (RPF) by iohexol and p-aminohippurate clearance, respectively, urine albumin-to-creatinine ratio (UACR), central adiposity by dual-energy x-ray absorptiometry (DXA), and estimated insulin sensitivity (eIS) by the CACTI equation were assessed in youth with T1D (n=50, 16.0±3.0 years, 50% female, HbA1c 8.7±1.3%, T1D duration 5.7±2.6 years, UACR 6 [5-14] mg/g, GFR 189±40 mL/min). Intraglomerular pressure (PGLO) was estimated by the Gomez equations. Concentrations of GlycA were quantified by targeted nuclear magnetic resonance spectroscopy. Correlation and multivariable linear regression analyses were performed. GlycA was higher in girls vs. boys (1.05±0.26 vs. 0.84±0.15 mmol/L, p=0.001), and in participants who were overweight or obese vs. normal weight (1.12±0.23 vs. 0.87±0.20, p=0.0004). GlycA correlated positively with estimated PGLO (r=0.52, p=0.001), UACR (r=0.53, p<0.0001) and trunk mass (r=0.45, p=0.001) and negatively with eIS (r=-0.36, p=0.01). All relationships remained significant after adjustment for age, sex, and HbA1c. In youth with T1D, GlycA, a biomarker of inflammation, was found to be higher in girls with T1D and those of overweight/obese habitus, compared to boys with T1D. Additionally, GlycA associated with parameters of early kidney dysfunction, central adiposity, and IR. Disclosure T.Reinicke: None. S.Gross: None. D.Cherney: Other Relationship; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. T.B.Vigers: None. L.Pyle: None. L.Driscoll: None. F.H.Mahmud: None. A.Dart: None. M.E.Pavkov: None. R.G.Nelson: None. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. A.Caldwell-mcgee: None. C.Birznieks: None. D.Carrasco: None. M.Marcovecchio: None. K.J.Nadeau: None. K.L.Tommerdahl: None. M.Pauley: None. J.K.Snell-bergeon: None. Funding Junior Research Fellowship Award

1771-P: STIM1 Maintains Beta-Cell Identity and Function

Impairments in endoplasmic reticulum (ER) Ca2+ homeostasis have been linked to β cell dysfunction and diabetes development; however, the pathways mediating these effects are not fully understood. Store-operated Ca2+ entry (SOCE) replenishes ER Ca2+ levels through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). We found that female, but not male, mice with β cell-specific STIM1 deletion (STIM1Δβ) had reduced β cell mass, increased α cell mass, and reduced expression of markers of β cell identity. To determine the mechanisms underlying this sexually dimorphic phenotype, RNA sequencing, immunofluorescent staining, and Ca2+ imaging experiments were performed using islets from control and STIM1Δβ mice and WT and STIM1 KO INS-1 cells. RNA sequencing of islets from STIM1Δβ mice identified 55 pathways that were significantly modulated (P<0.05), including “estrogen receptor signaling”, “mitochondrial dysfunction”, and “endocytosis”, and “estrogen receptor signaling”. Consistent with a role for SOCE in mitochondrial function, STIM1 KO cells decreased mitochondrial Ca2+ levels. Furthermore, we used the novel fluorescent time construct, syncollin-dsRedE5TIMER, to demonstrate an abnormal accumulation of aged insulin granules in STIM1 KO cells. Lastly, to test the relationship between STIM1 expression and glucose regulation in humans, we queried a publicly available NCBI GEO dataset derived from organ donors with and without type 2 diabetes (T2D). In this dataset, islet STIM1 expression was negatively correlated with HbA1c levels in female organ donors (n=35, r=-0.38, p=0.035), while there was no correlation in male donors. Together, these data highlight a novel role for STIM1 in the maintenance of mitochondrial function and insulin granule turnover. These findings confirm the importance of Ca2+ regulation within the β cell and highlight the significant role of sex as a biological variable in diabetes pathogenesis. Disclosure T.Kono: None. M.Slak rupnik: None. P.Krishnan: None. P.Sohn: None. M.Mclaughlin: None. W.Wu: None. S.Postic: None. P.Krishnan: None. C.Lee: None. M.Slak rupnik: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. Funding National Institutes of Health (R01DK093954, R01DK127236, U01DK127786, R01DK127308, UC4DK104166); U.S. Department of Veterans Affairs (I01BX001733)

193-LB: Refining Diabetes Risk for Individuals with Prediabetes

Rate of progression from prediabetes to diabetes varies greatly, and better risk stratification would help guide prevention efforts. We evaluated predictors of incident diabetes in the placebo arm (n=1212) of the vitamin D and type 2 diabetes (D2d) study. At baseline, participants met 2 or 3 ADA glycemic criteria for prediabetes (fasting glucose, FPG, 100-125mg/dL; 2-hour glucose during a 75-g OGTT, 2hPG, 140-199 mg/dL; HbA1c, 5.7-6.4%). Diabetes was diagnosed based on semiannual testing. After a median follow up of 2.5 years, 27% met criteria for diabetes. Among those who did and did not develop diabetes, mean BMI (±SD) was similar (32.1 kg/m2 ± 4.4), as well as other demographic factors including age, race, and ethnicity. More men than women developed diabetes (29% vs 23%, p=0.02). Incident diabetes rates differed by prediabetes subgroups (Figure); and those meeting all three prediabetes criteria at baseline (35.4%) were most likely to develop diabetes (log-rank p <0.001). There were no differences in the incident diabetes rate among those people meeting only 2 of the prediabetes criteria (Figure). Also, area under the receiver operator characteristic curves for incident diabetes at 36 months increased when all 3 criteria were used in the diagnosis (0.736) vs only FPG and HbA1c (0.686). We conclude that ‘prediabetes’ is heterogeneous, and the 2hPG may refine diabetes risk and guide intervention strategies in adults with high-risk prediabetes. Disclosure S. H. Kim: Advisory Panel; GI Dynamics, Consultant; Aligos, Research Support; Fractyl Health, Inc. D. S. Hsia: None. E. S. Leblanc: Other Relationship; Dexcom, Inc. M. Staten: None. R. Chatterjee montgomery: Research Support; Bristol-Myers Squibb Company, Epigenomics AG. N. Rasouli: Research Support; Novo Nordisk, Eli Lilly and Company, Somalogic. V. R. Aroda: Consultant; Applied Therapeutics Inc., Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Applied Therapeutics Inc., Eli Lilly and Company, Fractyl Health, Inc., Novo Nordisk, Sanofi. A. G. Pittas: None. Funding National Institutes of Health (U01DK098245)

1349-P: People with Type 2 Diabetes Have a High Prevalence of Nonalcoholic Steatohepatitis with Significant Fibrosis When Screened by NIS4 or Elastography

Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Diagnosis remains challenging as a liver biopsy is usually not feasible. NIS4 is a novel plasma diagnostic test combining the measurement of A1c and 3 biomarkers (miR-34a-5p, A2M, YKL-40) linked to NASH disease activity and higher cirrhosis risk. The aim of this study was to assess the prevalence of high-risk NASH (NASH with significant fibrosis [≥F2]) as estimated by NIS4 or elastography in the outpatient setting. A total 400 participants (age: 55±11 years; BMI: 31.6±6.6 kg/m2; T2DM: 32%; obese without T2DM [OB]: 33%), unaware of having NAFLD, were recruited from PCP and endocrine clinics and screened by: a) Elastography (Fibroscan®) for steatosis (controlled attenuation parameter or CAP ≥274 dB/m) and for fibrosis (liver stiffness measurement or LSM ≥7.0 kPa); and b) NIS4 for high-risk NASH (defined as a NIS4 >0.63; low-risk: <0.36). Among patients with T2DM or OB, 68% had steatosis compared to 35% without obesity or T2DM (CON) (p<0.01), while fibrosis (LSM≥7.0 kPa) was present in 14% of patients with T2DM (CON = 1%; p=0.02). High-risk NASH by NIS4 occurred frequently among patients with T2DM, either with (30%) or without (26%) obesity, and rare in those without T2DM (3%; p<0.001). NIS-4 correlated with steatosis (CAP) (r = 0.35) and fibrosis (LSM) (r = 0.32; both p<0.001). Patients with high-risk NASH by NIS4 compared to those with low-risk NASH, more often had steatosis (82% vs 46%), fibrosis (16% vs 4%), AST≥30 IU/L (41% vs. 8%) and ALT≥30 IU/L (36% vs. 15%), hepatic (HOMA-IR: 68% vs. 25%) and adipose tissue (adipo-IR: 80% vs 56%) insulin resistance (all p<0.01). NIS4 correlated with having metabolic syndrome (r=0.41; p<0.01) and was more often increased in people from endocrine vs. PCP clinics (34% vs. 9%; p<0.05). Conclusion: NASH with significant fibrosis is common in T2DM. Patients with elevated NIS4 often have NAFLD with fibrosis and an unfavorable cardiometabolic profile. Disclosure S.Kalavalapalli: None. T.R.Prezant: None. M.A.Connelly: Employee; LabCorp, Stock/Shareholder; LabCorp. D.Barb: None. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. E.Godinez leiva: None. R.Lomonaco: None. S.A.Marangi: None. E.Valdez saenz: None. A.Ortiz rocha: None. J.T.Budd: None. Y.Mohseni: None. K.Y.Chun: None. Funding National Institutes of Health (R01120331-01A1)

1441-P: Index60 Stratification Enhances Current Staging for Type 1 Diabetes by Identifying At-Risk Single Islet Autoantibody Positive (Ab+) Individuals

The current staging system for T1D development is used for participant selection in prevention trials. This system is based on multiple Ab+ and the presence or absence of dysglycemia, but does not address C-peptide measures or single Ab+ individuals. Since a limited number of Ab+ individuals are available for trials, we used TrialNet Pathway to Prevention (TNPTP) study data to assess whether a composite glucose and C-peptide measure, Index60, could identify single Ab+ individuals (designated as Stage 0) with comparable risk to those in Stages 1 or 2 for progression to Stage 3. Table 1A compares normoglycemic Stage 0 individuals with Index60 values above the median (>-0.045) of the full TNPTP cohort (n=6107) vs. those at Stage 1 with Index60 below the median (< -0.045). Table 1B compares those at Stage 0 with dysglycemia and higher Index60 vs. those at Stage 2 with lower Index60. In both comparisons, Index60 stratification identified Stage 0 individuals with metabolic features characteristic of T1D (e.g., lower C-peptide with higher glucose) and comparable 5-year risk to Stage 1 or Stage 2 individuals. Thus, by considering individuals with 1 Ab and C-peptide measures, the current staging system could be improved for risk discernment and to identify appropriate eligibility for prevention trials. Disclosure E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. D.D.Cuthbertson: None. E.Bosi: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. M.J.Redondo: None. B.M.Nathan: None. H.M.Ismail: Consultant; Rise Therapeutics. L.M.Jacobsen: None. J.Sosenko: None.

389-P: Glycemia and Cardiac Arrhythmias in People with Type 1 Diabetes

The impact of hypoglycemia, hyperglycemia and glycemic variability on cardiac arrhythmia susceptibility in people with type 1 diabetes is uncertain. We performed a 12-month prospective observational study employing continuous glucose monitoring and implantable loop recorders to investigate potential associations between glycemia and cardiac arrhythmias. Thirty adults with type 1 diabetes ([mean ± SD] age 63 ± 8 years, BMI 26 ± 5 kg/m2, HbA1c 7.3 ± 1.1% [56.9 ± 11.9 mmol/mol]) and without any history of cardiac arrhythmias were included. Daytime and nighttime incidence rate ratios (IRR) of arrhythmias were determined for hypoglycemia (interstitial glucose (IG) < 3.9 mmol/L), hyperglycemia (IG > 10.0 mmol/L), and glycemic variability (standard deviation and coefficient of variation). Hypoglycemia was not associated with an increased risk of cardiac arrhythmias in comparison with euglycemia (IG 3.9 - 10.0 mmol/L) and hyperglycemia. However, during daytime, a trend of increased risk of arrhythmias was observed when comparing hypoglycemia with euglycemia (IRR 1.08 [95% CI 0.99 - 1.18]). Furthermore, during daytime both the occurrence of hyperglycemia and time spent in hyperglycemia within the same hour of an arrhythmia were associated with an increased risk of arrhythmias compared to euglycemia (IRR 2.03 [95% CI 1.21 - 3.40] and IRR 1.07 [95% CI 1.02 - 1.13], respectively). Nighttime hypoglycemia and hyperglycemia were not associated with increased risk of arrhythmias. Increased glycemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during nighttime. In conclusion, daytime hypoglycemia and hyperglycemia may contribute to an increased risk of cardiac arrhythmias compared to euglycemia, in people with type 1 diabetes. No associations were found between glycemic levels and cardiac arrhythmias during nighttime, indicating diurnal differences in arrhythmogenic susceptibility. Disclosure P.G.Hagelqvist: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. A.Andersen: None. K.Maytham: None. C.R.Andreasen: None. S.Engberg: Employee; Novo Nordisk A/S. T.B.Lindhardt: None. J.Forman: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. Funding Novo Nordisk Foundation (28300)