Astellas Research Articles

1852-PUB: The Effect of Lactic Acid Fermented Sake Lees in a NASH-HCC Mouse Model

Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by fatty liver and cirrhosis that van lead to hepatocellular carcinoma. Although NASH prevalence is increasing worldwide, no cure has yet been established. Sake-lees, which are a by-product of sake refinement, have liver-protecting properties. Lactic acid fermented sake lees (FSL) is a food made by lactic acid fermentation of lees, which are then dealcoholized. Although FSL is regarded as a pro-health supplement, whether it has hepatoprotective effects remains unclear. To address this, we used a murine model of NASH to determine whether FSL could suppress progression of the disease. FSL supplementation significantly suppressed the increase in blood glucose impeded the progression of NASH. Protein analysis revealed that FSL also attenuated the increased expression of inflammatory markers. We infer that dietary FSL has anti-inflammatory and anti-hyperglycemic effects that contribute to the inhibition of NASH progression. Disclosure H. Suzuki: None. K. Watanabe: None. S. Arumugam: None. M. Afrin: None. Y. Matsubayashi: None. H. Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. Funding Japan Society for the Promotion of Science (22K17772)

871-P: Study of Glucagon Response and Its Association with Glycemic Control and Ketogenesis after Administration of Ipragliflozin as an Adjunctive Treatment in Patients with Type 1 Diabetes (Suglat-AID)—A Multicenter, Open-Label, Prospective Exploratory Trial

Objective: SGLT2 inhibitors including ipragliflozin have been used as adjunctive to insulin therapy for the treatment of type 1 diabetes (T1D) in Japan. Previous studies showed glucagon levels increased after initiating SGLT2 inhibitors, however, the effects of increased glucagon on glycemic control and ketogenesis in T1D remains unclear. Methods: Twenty-five patients with T1D with HbA1c >7.5% were administered ipragliflozin 50 mg as an add-on to insulin therapy. The patients underwent a mixed-meal tolerance test (MMTT) twice before (1st-MMTT) and 12 weeks after administration of ipragliflozin (2nd-MMTT) to evaluate glucagon responses and its associations with glycemic parameters including CGM data. Results: The values of area under the curve from fasting to 120 min (AUC0-120min, pg/mL) of plasma glucagon in 2nd-MMTT were significantly increased than 1st-MMTT (75±37 vs. 66±37, p=0.044), but fasting glucagon levels were not changed. The levels of fasting β-OHBA and AUC0-120min of β-OHBA were significantly elevated in 2nd-MMTT compared to 1st-MMTT, but there were no correlations between glucagon and β-OHBA levels. In CGM analyses, the values of glycemic variability (SD, CV% and MAGE) significantly ameliorated and the percentage of time in range (70-180 mg/dL) significantly increased from baseline to 12 weeks (46±14% vs. 54±20%, p=0.005) without an increase of the time below range (TBR, <70 mg/dL). A negative correlation between TBR% and fasting glucagon levels (r=-0.45, p=0.048) was found at 12 weeks but not at baseline. No severe adverse events including ketoacidosis developed in the participants during the study. Conclusion: Adjunctive treatment of ipragliflozin was found to increase postprandial glucagon secretion and might contribute to prevention of hypoglycemia via mitigating glycemic variability in T1D. Disclosure Y.Nakamura: Research Support; Astellas Pharma Inc. Y.Maeda: None. M.Minami: None. T.Matsui: None. A.Kawakami: Research Support; Astellas Pharma Inc. I.Horie: Research Support; Astellas Pharma Inc. N.Abiru: None. T.Kitamura: None. Y.Kusunoki: None. K.Nishida: None. A.Yamamoto: None. Y.Hirota: Other Relationship; Lilly, Sanofi K.K., Terumo Corporation, Sumitomo Dainippon Pharma Co., Ltd., Research Support; Sumitomo Dainippon Pharma Co., Ltd. T.Fukui: None. Funding Astellas Pharma Inc.

850-P: The Efficacy of Imeglimin in Diabetes Subgroups Stratified by Data-Driven Cluster Analysis—A Post Hoc Analysis of Imeglimin Clinical Trial Data

Objectives: We performed a post-hoc analysis of clinical trial data with the goal of investigating whether diabetic subgroups identified by data-driven clustering respond differently to imeglimin. Methods: Data from randomized, double-blind clinical trials of imeglimin as monotherapy or add-on to insulin therapy were included in the analysis. For monotherapy, 1) duration of type 2 diabetes, 2) baseline BMI, 3) baseline HbA1c, and 4) baseline HOMA-β, and for add-on to insulin therapy, the first three and 4) insulin total daily dose were applied as coordinates to form clusters by the non-hierarchical k-means method. The efficacy of imeglimin were examined for each cluster. Results: We identified four clusters of patients with diabetes, which had significantly different patient characteristics. Cluster 1 was a group with lower values of all four indices compared to the total patient population before cluster segregation, cluster 2 was a group with longer duration of diabetes, cluster 3 was a group with higher baseline BMI and higher HOMA-β (for monotherapy) or higher insulin total daily dose (for add-on to insulin therapy), and cluster 4 was a group with higher baseline HbA1c. The improvement in HbA1c with imeglimin differed significantly among the four clusters. The mean change differences versus placebo for imeglimin in monotherapy ranged from -0.64% to -1.27%, and add-on to insulin therapy ranged from -0.31% to -0.82%. In all clusters except for cluster 3 in the add-on to insulin therapy, imeglimin showed statistically significant HbA1c improvement compared to placebo. Conclusion: Data-driven clustering of patients with type 2 diabetes allowed us to identify subgroups that respond differently to imeglimin in improving HbA1c. This new stratification might help to tailor and target the imeglimin treatment to patients who would benefit most. Disclosure K.Hagi: Employee; Sumitomo Pharma. K.Kochi: Employee; Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Pharma Co., Ltd. H.Watada: Research Support; Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, LifeScan Diabetes Institute, Eli Lilly Japan K.K., Sun Pharmaceutical Industries Ltd., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Sanwa Kagaku Kenkyusho, Speaker's Bureau; Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Novo Nordisk, Abbott Japan Co., Ltd., Astellas Pharma Inc., Merck Sharp & Dohme Corp., Kissei Pharmaceutical Co., Ltd., AstraZeneca, Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Eli Lilly Japan K.K. K.Kaku: Advisory Panel; Novo Nordisk, Consultant; Sanwa Kagaku Kenkyusho, Speaker's Bureau; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd. K.Ueki: Advisory Panel; Abbott Japan Co., Ltd., Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk, Sanofi K.K., MSD Life Science Foundation, Takeda Pharmaceutical Co., Ltd., Speaker's Bureau; Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Astellas Pharma Inc., AstraZeneca, Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk, Taiho Pharmaceutical Co. Ltd., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd.

1381-P: Effect of Dietary Potassium Intake and Its Interaction with Sodium Intake on Risk of Developing Cardiovascular Disease (CVD) in Persons with Type 2 Diabetes (T2D)—Japan Diabetes Complication and Its Prevention Prospective Study (JDCP Study)

Many guidelines recommend increased potassium intake. However, the relationship between dietary potassium intake and incidence of CVD in persons with T2D has not been explored, nor is it known if this relationship varies with sodium intake in such persons. Therefore, we investigated these relationships as part of the JDCP study, a nationwide study launched in 2007. A total of 1477 persons with T2D aged 40-75 years completed a brief self-administered Diet History Questionnaire at baseline, and resultant data were analyzed. Primary outcome was the 7-year risk of a CVD event. Hazard ratios (HRs) for CVD according to tertiles of dietary potassium and sodium intake were estimated by Cox regression adjusted for confounders in addition to a stratified analysis of tertiles of sodium intake. Mean daily potassium and sodium intakes in tertiles 1 to 3 were 1.9, 2.6, and 3.5 g and 3.3, 4.2, and 5.3 g, respectively. HbA1c, BMI, triglycerides, and blood pressure were well controlled. No significant associations between potassium and sodium intakes and incidence of CVD were shown for the second and third tertiles relative to the first tertile (potassium: 0.64 [95% CI, 0.34-1.23] and 0.59 [0.28-1.25]; sodium: 1.02 [0.51-2.04] and 1.15 [0.58-2.30]). In the stratified analysis of tertiles of sodium intake, in the high sodium intake groups (T2 and T3) HRs for CVD in the high potassium intake group were significantly lower compared to the low potassium intake group (T2: 0.40 [0.12-1.35] and 0.06 [0.01-0.69]; T3: 0.23 [0.07-0.82] and 0.26 [0.07-0.88]). Associations of potassium intake with CVD in those with low sodium intake (T1) were not significant. Findings suggested that high potassium intake under high sodium intake is associated with a deceased incidence of CVD in persons with T2D although potassium intake under low sodium intake was not associated with incident CVD. Disclosure C.Horikawa: None. H.Shimano: None. J.Satoh: None. Y.Hayashino: Advisory Panel; Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Speaker's Bureau; Boehringer Ingelheim Japan, Inc., Sumitomo Dainippon Pharma Co., Ltd., Santen, Daiichi Sankyo, Kowa Company, Ltd. N.Tajima: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck & Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca. Y.Yamasaki: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. Jdcp study group: n/a. M.Takahara: None. N.Katakami: Speaker's Bureau; Abbott Japan Co., Ltd., Daiichi Sankyo, MSD, Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Ono Pharmaceutical Co., Ltd., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Bayer Inc., Lilly, Teijin Pharma Limited, Kyowa Kirin Co., Ltd., Boehringer Ingelheim Japan, Inc., Sanofi. Y.Takeda: None. M.Takeuchi: None. K.Fujihara: None. H.Suzuki: None. K.Tsuda: None. N.Yoshioka: None.

1440-P: Single Islet Antigen 2 Antibody–Positive (IA2A Ab+) Children Exhibit Significant Metabolic Abnormalities and 5-Year Type 1 Diabetes (T1D) Risk

Current T1D staging defines multiple Ab+ as the start of T1D (Stage 1 or 2 depending on presence of dysglycemia). However, single Ab+ individuals are considered low-risk and are typically not considered for inclusion in prevention trials. We hypothesized that single IA2A+ children exhibit metabolic compromise with appreciable Stage 3 (clinical diabetes) risk. To test this, we evaluated 2163 confirmed single Ab+ children (IA2A, glutamic acid decarboxylase [GADA], or insulin [IAA]) with available OGTT data in the TrialNet natural history study. With and without age and BMI adjustment (Table), IA2A+ children had higher area under the curve (AUC) glucose, lower AUC C-peptide, and higher diabetes risk indices (Diabetes Prevention Trial Type 1 Risk Score [DPTRS] and Index60). Cox regression demonstrated that IA2A+ children were most likely to have progressed to Stage 3 (50.9% vs. 12.0% or 9.6% over 5 years). Of single Ab+ children who did not progress to Stage 3, GADA+ most frequently progressed to multiple Ab+ (34.0% over 5 years). In conclusion, amongst single Ab+ children, IA2A+ children have greater metabolic dysfunction and rates of progression to Stage 3. These findings suggest that single IA2A+ children exhibit substantial T1D risk, should also be considered as having Stage 1 T1D, and be considered for eligibility in prevention studies. 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.

896-P: Effectiveness of Newly Prescribed SGLT2 Inhibitors as Second-Line Therapy following DPP-4 Inhibitors or Metformin as First-Line Therapy in Type 2 Diabetes Patients

Prescriptions of SGLT2 inhibitors (SGLT2i) for patients with type 2 diabetes (T2DM) are increasing. In this study real-world data were used to evaluate the long-term benefits of SGLT2i as a second-line drug for glycemic control in people with T2DM being treated with DPP-4 inhibitor (DPP4i) or metformin (MET) monotherapy. People with T2DM patients on DPP4i or MET monotherapy were followed for at least 12 months after receiving a new SGLT2i prescription. Patients were divided into DPP4i and MET groups, and patient background factors were controlled for using propensity score matching (PM). Changes in HbA1c and other indexes during the 12 months after the new prescription were compared using t-tests, and the factors affecting changes in HbA1c were examined using multiple regression analysis. After PM, there were 192 patients in the DPP4i (n=96) and MET (n=96) groups, with no significant differences in patient backgrounds. HbA1c levels 12 months after a new SGLT2i prescription were significantly lower in both groups compared to base line (8.1% to 7.0%, p<0.001; 8.1% to 7.1%, p<0.001), but there were no significant differences between the two groups in the change in HbA1c level (p=0.271), body weight (p=0.371), systolic blood pressure (p=0.828), eGFR (p=0.642), and Fib-4 index (p=0.674). The change in HbA1c was greater for those with initially higher HbA1c levels (-0.629 [-0.722-0.536], p<0.001) and those with shorter diabetes histories (0.024 [0.001-0.048], p=0.044), but it was not significantly different between the two groups (p=0.236). After controlling for patient background, there was no significant difference in the long-term effects of a new SGLT2i prescription between those previously receiving either DPP4i or MET monotherapy, but higher previous HbA1c levels and a shorter diabetes history may be prediction of better HbA1c 12 months after a new SGLT2i prescription, regardless of prior medication. Disclosure H.Takahashi: Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Medtronic, Novo Nordisk. Y.Suganuma: None. T.Ohno: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck & Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca.

1604-P: DPP-4 Inhibitor and SGLT2 Inhibitor Additively Ameliorate Hepatic Steatosis in NAFLD Model Mice through Different Action Mechanisms

Nonalcoholic fatty liver disease (NAFLD) is closely associated with the development and pathogenesis of type 2 diabetes mellitus (T2DM). Luseogliflozin (Luseo) has been reported to improve NAFLD in T2DM model mice by affecting factors related to fatty acid synthesis and beta oxidation. Anagliptin (Ana) improves NAFLD in mice by altering the M1/M2 macrophage ratio. The aim of this study is to assess the molecular mechanisms of DPP4 and SGLT2 inhibitors, which are often used in combination clinically, on NAFLD. Six-week-old male C57BL/6J mice were fed a high fat diet (HFD) to create a diet-induced NAFLD model, and at 14 weeks of age, the mice were divided into 4 groups: control, Luseo (15 mg/kg/day: mixed diet), Ana (300 mg/kg/day: mixed water), and combination group. After the 4 weeks intervention, various metabolic parameters were evaluated. In addition, the expression of mRNAs was analyzed by qPCR. Luseo and combination groups showed a significant reduction in body weight. HE and Oil-Red-O staining demonstrated an improvement of hepatocyte ballooning and decreased fat staining area in the combination compared to the control. Liver qPCR showed that the expression levels of genes related to lipid synthesis and glycogenesis such as SCD1 and PEPCK in Luseo were decreased and inflammatory response such as IL6 were decreased in Ana. The expression levels of chemokine-related genes including CCL3, CCL4, and CCL5 were also decreased in Ana. Those findings observed in Luseo and Ana groups were also confirmed in the combination. In summary, Luseo improved lipid synthesis and glycogenesis in addition to body weight reduction, and reduced inflammation-related factors, while Ana suppressed inflammatory cytokines and chemokine-related pathways. Combination of two drugs markedly ameliorated hepatocyte fat deposition. Thus, it is likely that both DPP-4 inhibitor and SGLT2 inhibitor contributed to the improvement of NAFLD through different action mechanisms. Disclosure Y. Iwamoto: Speaker's Bureau; Kowa Company, Ltd. T. Kimura: Speaker's Bureau; Sanwa Kagaku Kenkyusho, Kowa Research Institute, Inc., Taisho Pharmaceutical Holdings Co., Ltd., Boehringer Ingelheim Japan, Inc., Sumitomo Dainippon Pharma Co., Ltd., Sanofi, MSD Life Science Foundation, Lilly, Daiichi Sankyo, Novo Nordisk. H. Iwamoto: None. Y. Fushimi: None. J. Sanada: Speaker's Bureau; Lilly, Kowa Company, Ltd. Y. Katakura: Speaker's Bureau; Abbott. M. Shimoda: Speaker's Bureau; Sanofi, Lilly, AstraZeneca, Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., MSD Life Science Foundation, Mitsubishi Tanabe Pharma Corporation. T. Mune: None. K. Kaku: Speaker's Bureau; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Novo Nordisk. Consultant; Sanwa Kagaku Kenkyusho. Speaker's Bureau; Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd. H. Kaneto: Research Support; Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan, Inc. Speaker's Bureau; Lilly, Sanofi, Boehringer Ingelheim Japan, Inc., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd. Research Support; Abbott.

1725-P: The Role of miR-146a-5p on Cytokine-Induced ß-Cell Mitochondrial Dysfunction and Death

MicroRNAs are small non-coding RNAs with ~22 nucleotides in size involved in the modulation of gene expression. Previously, we observed that miR-146a-5p is upregulated during inflammatory stress in pancreatic islets and pancreatic tissue sections from T1D donors. Although others have linked overexpression of miR-146a-5p to β cell death and impaired insulin secretion, the molecular mechanisms mediating these effects remain unclear. To further understand miR-146a-5p role in β cell health and disease, we have generated stable cell lines that are either overexpressed (OE) or inhibited (ZIP) for miR-146a-5p and assessed for β cell function under inflammatory (IL-1β, IFN-γ, and TNF-α) conditions to model T1D in vitro. Treatment of OE cells with or without pro-inflammatory cytokines increased expression of cleaved caspase-3 and Annexin-V-positive cell death and reduced insulin secretion in both untreated and cytokine treatment. However, ZIP cells are protected from inflammatory stress showing decreased apoptosis and improved insulin secretion. Furthermore, ZIP cells were found to have increased mitochondrial DNA copy numbers, mitochondrial membrane potential, and basal and maximal respiration rate. Notably, cytokines-treated OE cells showed reduced basal respiration rate and ATP production compared to cytokines-treated ZIP cells. In addition, mitochondria isolated from MIN6 cells showed enriched miR-146a-5p under cytokine treatment, suggesting inflammation-mediated enrichment of miR-146a-5p. Finally, RNA sequencing analysis of OE and ZIP cells identified the RNA transcripts regulated by miR-146a-5p, including MAPT, MYRIP, NRG1, and GPX1; pathway enrichment analysis showed pathways related to insulin secretion, apoptosis, and mitochondrial function. Taken together, findings from our study show for the first time that miR-146a-5p upregulation promotes β cell dysfunction and death by suppressing mitochondrial function during T1D pathogenesis. Disclosure P.Krishnan: None. R.C.S.Branco: None. S.A.Weaver: Employee; Eli Lilly and Company. C.Lee: None. F.Syed: 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 JDRF (2-SRA-2019-834-S-B, 2-SRA-2018-493-A-B); National Institutes of Health (DK127308, U01DK127786, UC4DK104166)

1092-P: sRAGE—A Biomarker of Kidney Disease in Youth-Onset Type 2 Diabetes (T2D)

The circulating soluble receptor for advanced glycation end products (sRAGE) has been proposed as a biomarker of diabetes complications in adults. In the TODAY study of youth with T2D, we measured sRAGE 3 times at: randomization (T1), glycemic failure (HbA1c≥8%) on randomized treatment or midpoint in study (T2), and end of follow-up (T3). Of TODAY subjects, 165 lost glycemic control with HbA1c ≥ 8% (G1) and 135 maintained HbA1c < 8% (G2)]. Controls [n=99, HbA1 5% (4.9, 5.2), with similar obesity, sex (60% female), race-ethnicity, median age 24 (21, 27) years as the TODAY cohort at T3] had sRAGE measured once. Multivariable models examined the relationship of sRAGE with nephropathy [urine albumin: creatinine (UACR) ≥30 mg/g, hyperfiltration (eGFR ≥135 ml/min/1.73m2)] and vascular measures [pulse wave velocity (PWV), augmentation index (AI)], adjusting for treatment, diabetes duration, HbA1c, BMI, age, sex, and race-ethnicity. At T1, the T2D youth groups had similar age (13.9 yrs), diabetes duration (0.7 yrs), and sex (60% female). sRAGE concentrations were lower in T2D vs. controls (752.8±308.3 vs. 954.4 ± 356.7 pg/ml, p<0.0001) at T3. By T3 (mean duration 7 yrs), sRAGE levels decreased compared with T1 and T2 in G1 vs. G2 (p<0.05). sRAGE concentrations were 711.9±294.1 vs. 802.7±318.9 pg/ml, p=0.0032 in G1 vs. G2 at T3, with no significant difference by treatment. HbA1c was inversely related with sRAGE. Higher sRAGE concentrations were associated with a lower risk of hyperfiltration (HR=0.93, 95% CI 0.86-0.99, p=0.03) and inversely related to eGFR (p<0.001); no relationships were observed with UACR, PWV, or AI. sRAGE levels decline overtime in youth with T2D, are inversely related to glycemia, and may serve as a biomarker of kidney function. Disclosure F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. E.M.Urbina: Advisory Panel; Astellas Pharma Inc., Other Relationship; Targus Medical, Inc. S.Gidding: Consultant; ESPERION Therapeutics, Inc. V.M.Monnier: None. L.El ghormli: None. K.Drews: None. B.H.Braffett: None. Funding National Institutes of Health (5U01DK061230-16)

1501-P: Deletion of miR-494 Induces Adipocyte Browning and Slows Aging in Mice

Adipocyte browning is a potent therapeutic strategy for obesity and metabolic disorders. We previously reported that miR-494 served as a negative regulator of mitochondrial biogenesis during browning in cultured adipocytes. However, the in vivo evidence has not been provided. In this study, we examined the role of miR-494 in adipocyte browning and aging using miR-494 knockout (KO) mice. KO mice were generated using CRISPR/Cas9 system. KO mice had equivalent energy expenditure, physical activity, food intake and body weight compared to wild-type (WT) mice; had lower resting respiratory quotient (0.95±0.006 vs 0.91±0.004), less visceral fat (16.3±1.08 vs 13.4±0.96 g/kg body weight) and 3.7-fold increased expression of Ucp1 in subcutaneous fat. In addition, KO mice showed cold tolerance during 3 hours exposure to 4ºC and increased oxygen consumption than WT mice after administration of a β3 agonist in thermoneutral condition, indicating an increase in non-shivering thermogenesis. In adipose tissues of KO mice, increased expression of Pgc-1α, a target gene of miR-494, and tendency to increase in mitochondrial DNA were observed. Primary adipocytes derived from KO mice showed enhanced mitochondrial respiration driven by fatty acids as determined by extracellular flux analysis. Finally, KO mice showed an extended median lifespan 29% relative to WT mice (from 113.7 to 146.7 weeks). Aged KO mice (≥ 2 years old) showed reduced age-related changes, such as hair graying and low physical activity. In conclusion, deletion of miR-494 demonstrated increased adipocyte browning and survival advantage in mice. Although there are numerous studies that focused on promoting adipocyte browning, its long-term effect has not been well evaluated. Thus, our data showing the association among miR-494, adipocyte browning and longevity provide a novel insight into adipocyte biology and aging study. The gene sequence of miR-494 and its binding site to Pgc-1α are conserved from mice to humans; it is expected to be applied to human research. Disclosure L.Sugawara: None. K.Morino: Research Support; AstraZeneca, Astellas Pharma Inc., Sanwa Kagaku Kenkyusho, Ono Pharmaceutical Co., Ltd. H.Iwasaki: None. S.Ida: None. T.Yanagimachi: None. M.Lemecha: None. H.Maegawa: None. Y.Fujita: Research Support; Terumo Corporation, Boehringer Ingelheim Japan, Inc., Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd. S.Kume: Research Support; Boehringer Ingelheim International GmbH, Japan Society for the Promotion of Science. Funding Grants-in-Aid for Scientific Research (22K08650)

1231-P: Influence of Diabetes on the Progression of Preclinical Stage B Heart Failure Phenotypes to Heart Failure

Introduction: The extent to which diabetes influences progression from preclinical heart failure (HF) stage B phenotypes (2021 Universal Definition) to overt HF or death is unknown. Methods: We included 4,264 adults with preclinical HF (stage A [n = 1,174] or B [n = 3,090]) who attended the Atherosclerosis Risk in Communities (ARIC) Study Visit 5 (2011-2013). Stage A was defined by HF risk factors only. Stage B1: echocardiographic abnormalities but no biomarker elevation; Stage B2: elevated NT-pro-BNP ≥125 pg/mL and/or hscTnT>14 ng/L but no echocardiographic abnormality; Stage B3: echocardiographic and biomarker abnormalities. We assessed the associations of diabetes and each preclinical stage B phenotype with incident HF and HF or death. Results: Among the participants (mean age 76 years, 62% women, 24% Black), there were 383 HF events and 730 deaths during 8.6 years of follow-up. Diabetes conferred a high absolute risk of HF across all preclinical stages B HF, but more so for the Stage B3 phenotype (Table). In cross-categories of preclinical HF stages (A and B) and diabetes status, participants with diabetes and Stage B3 had the highest risks of HF or HF and death combined, compared to those in stage A without diabetes. Conclusion: Addressing diabetes appears to be critical in stage B individuals with both echocardiographic and biomarkers abnormalities for preventing the progression to HF. Disclosure J.Echouffo tcheugui: None. C.E.Ndumele: None. S.Zhang: None. K.Matsushita: Consultant; Fukuda Denshi, Akebia Therapeutics, Inc., AMGA, Other Relationship; Kowa Company, Ltd. V.Nambi: Research Support; Amgen Inc., Kowa Pharmaceuticals America, Inc. H.Skali: Consultant; Astellas Pharma Inc., Elsevier, Wolters Kluwer Health, APM Tunisia / Hikma. E.Selvin: None. Funding National Institutes of Health (K23HL153774)

884-P: Decentralized N=1 Study—A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin

Background: The SGLT2 inhibitor dapagliflozin reduces kidney function decline and urine albumin:creatinine ratio (UACR) on a population level. However, there is marked heterogeneity in the efficacy among individual patients. We conducted a decentralized (i.e. at home) N=1 trial to assess the effect of dapagliflozin in individual patients and the feasibility of remote data collection. Methods: Twenty patients with type 2 diabetes, UACR >20 mg/g and eGFR >30 mL/min/1.73m2 entered the randomized placebo-controlled double-blind N=1 trial. Patients were randomly assigned to two periods of 1-week treatment with dapagliflozin 10 mg/day and two periods of 1-week treatment with placebo in random order with 1-week wash-out periods in between. Patients collected and sent their own data with automatic uploading to an online platform and sent early morning urines 5 times/week to the laboratory for albumin and creatinine assessment. Primary outcome was UACR change from baseline (mixed effects model). The study had 80% power to detect a correlation in UACR change between first and second dapagliflozin period of 0.6. Results: Patients had a mean eGFR of 70.2 mL/min/1.73m2 and median UACR of 94.7 mg/g. During the study, dapagliflozin compared to placebo reduced albuminuria by 15.1% (95%CI 3.3 - 28.2; p=0.013). There was a marked variation in the change from baseline in UACR during dapagliflozin treatment periods (range first and second exposure -26.9 to -4.7% and -30.5 to -5.8%, respectively). The individual change in UACR during the first and second exposure correlated in the dapagliflozin periods (r=0.50; p=0.026) but not in the placebo periods (r=0.09; p=0.69). Of all scheduled urine collections (N=816), only 5 collections (0.61%) were not delivered in the laboratory. Conclusion: The individual UACR response to dapagliflozin varies among individual patients and is consistent upon re-exposure. Remote data collection was very reliable with nearly any missed urine collection. Disclosure J.Beernink: None. G.D.Laverman: Advisory Panel; AstraZeneca, Vifor Pharma Management Ltd., Boehringer Ingelheim Inc., Astellas Pharma Inc., Lilly, Other Relationship; Sanofi, AstraZeneca. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. N.Jongs: Speaker's Bureau; AstraZeneca.

551-P: Healthy Lifestyle Behaviors as Predictors of Initiation of Hemodialysis (HD) in People With and Without Diabetes Mellitus (DM)

Breslow’s Health Practice Index (HPI) includes recommendations for a healthy lifestyle and is composed of 7 simple lifestyle factors (never smoking, regular physical activity, moderate or no use of alcohol, 7-8 hours sleep regularly, maintaining proper weight, eating breakfast, and not eating between meals). Cardiovascular health metrics (CVHMs), defined by the American Heart Association are composed of lifestyle factors and clinical laboratory values (smoking, weight, physical activity, diet, cholesterol, blood pressure, and blood glucose). To clarify the impact of HPI or CVHMs on incident HD according to DM, we analyzed a nationwide claims-based database of 294,647 people included from 2008-16 (DM- 277,935, DM 16,712). Risk for HD were analyzed according to DM and HPI/CVHMs based on the number of unfavorable lifestyle factors in the HIP and unfavorable lifestyle factors and clinical values in the CVHM (Table). Multivariate Cox regression analysis showed that DM increased the risk of dialysis 5- to 6-fold and DM and CVHMs synergistically increased the risk of HD. Results indicated that factors similar to those used to predict cardiovascular disease would also be useful to predict HD. These approaches might be helpful in clinical practice and patient education. Disclosure T.Osawa: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. M.H.Yamada: None. Y.Yaguchi: None. T.Sato: None. M.Kitazawa: None. Y.Matsubayashi: None. T.Yamada: None. S.Kodama: None.

405-P: ROCK2 Activation and Its Role in Folic Acid–Induced Murine Model of Nephropathy

Over 2 million people currently receive treatment with dialysis or a kidney transplant throughout the world. Thus, developing a new strategy to treat chronic kidney diseases is significant from the perspective of a health economic and the prevention of cardiovascular death. The small GTPase Rho and its effector Rho-kinase (ROCK) are involved in the pathogenesis of diabetic nephropathy. In chronic kidney diseases including diabetic nephropathy, tubulointerstitial fibrosis is known to be highly associated with renal outcome. We have previously reported that ROCK inhibition prevented the progression of diabetic nephropathy in murine models. With regards to ROCK, there are two isoforms, which are ROCK1 and ROCK2. ROCK1 has been shown to be involved in the endocytosis of albumin in tubular epithelial cells via megalin/cubilin-dependent mechanism. However, the role of renal tubular ROCK2 remains to be elucidated. The aim of this study is to reveal the role of renal tubular ROCK2 in the pathogenesis of chronic kidney disease. To this end, we used a tubulointerstitial injury model known as folic acid-induced nephropathy (FAN). Importantly, ROCK2 was elevated at protein levels in FAN group compared with vehicle-treated group. We next generated tubular specific ROCK2 knockout mouse (TR2KO) by crossing Ksp-Cre mice with mice containing two loxP sites flanking in Exon 3 of ROCK2. In the Ksp-Cre transgenic mice, Cre recombinase has been demonstrated to be expressed in tubules, collecting ducts, and thick ascending limbs. Compared with vehicle-treated group, collagen deposition in the kidneys of FAN group was highly elevated as revealed by Masson’s trichrome staining. The increased collagen deposition was significantly improved in TR2KO. Our findings indicate that ROCK2 regulates the progression of tubulointerstitial fibrosis. ROCK2 may be a potential therapeutic target for the prevention of chronic kidney disease. Disclosure K.Sekiguchi: None. K.Matoba: None. S.Ohashi: None. E.Mitsuyoshi: None. Y.Nagai: None. Y.Takeda: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck & Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca.

360-OR: Continuous Glucose Monitoring–Guided Insulin Administration in Subjects with Type 2 Diabetes in Long-Term Care Facilities—A Randomized Clinical Trial

The efficacy of real-time continuous glucose monitoring (rt-CGM) in adjusting insulin therapy in long-term care facilities (LTCF) has not been evaluated. Accordingly, we randomized 100 insulin-treated subjects with T2D in LTCF. All subjects underwent point-of-care (POC) capillary glucose testing before meals and bedtime. Patients in the standard of care (POC group) wore a blinded Dexcom G6 CGM with treatment adjusted based on POC results; while in the rt-CGM group (Dexcom G6), treatment adjustment was based on daily CGM profile. Treatment adjustment was performed by the LTC medical team, with a target glucose of 140-180 mg/dL, and a duration of intervention up to 60 days. Primary endpoint was difference between groups in time in range (TIR, 70-180 mg/dL). Results: There were no significant differences in TIR (53.38%±30.16 vs 48.81%±28.03, p=0.40), mean daily glucose (185±44 vs 191 ±47 mg/dL, p=0.72), patients with % CGM values <54 mg/dL (0.23±0.8% vs 0.56±2.2 %, p=0.88), with a trend in reducing time below range (TBR <70 mg/dL) (0.83±2.6 % vs 1.18±3.5%, p= 0.51), between CGM and POC group. Conclusion: The results of this pilot randomized study indicate that the use of Dexcom G6 rtCGM is safe and effective in guiding diabetes therapy in long-term care facilities, resulting in a similar improvement in glycemic control (TIR) without differences in hypoglycemia. Disclosure T.Idrees: None. T.M.Johnson: Consultant; Astellas Pharma Inc., Research Support; Dexcom, Inc. L.Peng: None. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. I.A.Castro-revoredo: None. H.Oh: None. M.D.Gavaller: None. Z.Zabala: None. E.M.Moreno: None. B.Moazzami: None. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. E.Cabb: None. Funding Dexcom, Inc. (IIS-2020-119_6X)

463-P: Risk Stratification of Coronary Artery Disease (CAD) according to LDL-C, HDL-C Levels, and Glucose Status

Whereas elevated LDL-C is a major risk factor for CAD, the inverse association between HDL-C levels and risk of CAD is well-known. Although insulin resistance, and glucose intolerance are associated with low HDL-C levels, it is not clear whether the association of LDL-C with CAD differs depending on glucose status and HDL-C values. We examined associations of LDL-C with the incidence of CAD according to HDL-C and glucose status using a nationwide claims database on 1,524,289 individuals during 2008-2019 with no history of CAD or familial hypercholesterolemia. Cox proportional hazards model identified risks of CAD events among combinations of 3 levels of HDL-C and 7 levels of LDL-C according to glucose status. During a mean follow-up period of 5.5 years, 8,301 CAD events occurred. CAD risk increased from lower LDL-C levels accompanied by lower HDL-C levels regardless of glucose status (Table). Even in people with LDL-C <80mg/dl, HDL-C <40mg/dl conferred 2.5-fold increased risk of CAD all glucose status. HDL-C and LDL-C values had a synergistic effect on the incidence of CAD in people with normoglycemia, whereas an addictive effect in people with prediabetes and diabetes. Although more strict LDL-C target need to be achieved as worsening of glucose status, results demonstrated that the necessity of modulating the LDL-C target according to HDL-C levels is not affected by glucose status. Disclosure M.H.Yamada: None. M.Iwanaga: None. T.Yamada: None. S.Kodama: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. K.Fujihara: None. T.Osawa: None. M.Kitazawa: None. Y.Yaguchi: None. T.Sato: None. Y.Mitsuma: None. M.Yamamoto: None. Y.Matsubayashi: None.

631-P: Development of Noninvasive Diabetes Management Method Using Glycated Albumin in Tears

Aims/Background: Several clinical trials have demonstrated that strict glycemic control is important to minimize the risk of diabetic complications. Although frequent measurement of blood glucose levels by the invasive finger prick method is useful to achieve strict glycemic control, this method is invasive and burdensome to the patients. Glycated albumin (GA) is a biomarker which reflects the glycemic control status over the previous 2 weeks. We demonstrated GA levels in tears correlated those in blood. We hypothesized that regular GA tests in tears caused behavior change and improved glycemic control. Methods: Participants with type 2 diabetes were recruited and randomly divided to two groups. One group (intervention group) was performed tear GA tests every 2 weeks and reported the results, while the other group (control group) was not. After 8 weeks of intervention, the two groups were compared. GA levels in tears were measured by Liquid Chromatography / Mass Spectrometry. Results: We enrolled 56 participants to the study. Compared with the control group, the intervention group showed improvement in fasting blood glucose, HbA1c, GA, non-HDL cholesterol. Conclusions: Levels of GA, as a diabetes-related biomarker, in tears can be measured noninvasively. Regular measurement of the GA levels in tears could allow smoother management of diabetes mellitus and reduce the risk of complications noninvasively. Disclosure M.Aihara: None. N.Kubota: None. T.Yamauchi: Other Relationship; Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Novo Nordisk, Astellas Pharma Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim, Kyowa Kirin Co., Ltd., Kowa Company, Ltd., Merck & Co., Inc., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Tosoh Corporation, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., NTT Docomo Inc., Aero Switch, Asahi Mutual Life Insurance Company, NIPRO Medical Corporation, Abbott Japan Co., Ltd., Bayer Inc., Kyorin Pharmaceutical Company, Limited.

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)

329-OR: Accuracy of Dietary Records (DR) Using a Smartphone App Is Greatly Improved by User’s Adjustments Compared with Artificial Intelligence (AI) Alone

Although DR are important in managing diabetes, the traditional method, such as weighing foods and calculating nutrients, is burdensome to both patients and medical care providers. Although photo DR with smartphones using AI to identify the dish and calculate nutrients can be expected to reduce this burden, accuracy not been clarified. Furthermore, it is not clear to what extent accuracy improves when users and dietitians adjust the name of the dish and the portion consumed compared with AI only. In this study, photo DR taken with the smartphone app were analyzed by AI only, then adjusted by the users followed by further adjustments by a dietitian. We compared the nutrients calculated by AI, users, and dietitians to those by the traditional weighing method. Analyzed were 180 participants (mean age 58.7 y, BMI 26.7 kg/m2, 94/86 women/men, 22 with diabetes, energy intake [EI] 1640 kcal/day) The EIs (kcal/day) were calculated as 1502, 1619, and 1674 for AI, users, and dietitians, respectively, those were lower than that with the weighing method Spearman's rank correlation coefficients compared to the weighing method were 0.48, 0.88, and 0.88 for AI, users and dietitians, respectively, showing a weak correlation for AI and a strong correlation for users and dietitians. The user's adjustments greatly improved accuracy without increasing the burden on the dietitians. Disclosure M.Kitazawa: None. H.Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd. C.Horikawa: None. I.Ikeda: None. Y.Takeda: None. E.D.Ferreira: None. M.Takeuchi: None. S.Y.Morikawa: None. K.Fujihara: None. S.Kodama: None. Funding Grants-in-Aid for Scientific Research (21K17637)

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)