Daiichi Sankyo Research Articles

1758-P: Intracellular Metabolic Change in Rodent Pancreatic ß-Cells under Diabetic Condition Is Flexible and May Compensate for Glucose Intolerance

Background: In pancreatic β-cells under diabetic conditions, metabolic stressors cause mitochondrial dysfunction and reduce oxidative phosphorylation, resulting in impaired intracellular metabolism. It has been suggested that aberrant activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a role in this impairment. However, the pathological significance of PFKFB3 activation and its flexibility are not clear. Methods: Eight-week-old ob/ob mice were fed a standard chow ad lib or the same diet restricted to 2 g/day, or tofogliflozin added chow ad lib for 4 weeks. The body mass and glucose tolerance were compared among the groups. The expression of glycolytic enzymes in the pancreatic islets was evaluated using western blotting, immunohistochemistry and DNA microarray analysis. Next, INS-1 cells were cultured in medium containing a low (5.5 mM; low-G) or a high (22 mM: high-G) glucose concentration, or high-G with PFKFB3 inhibiter (3PO) for 48 hours. The expression of mafa and pdx-1 were evaluated using real time PCR. Results: Ad lib-fed mice showed hyperglycemia and greater weight gain than food restricted mice and tofogliflozin treated mice. The expression of PFKFB3 and other glycolytic enzymes were higher in ad lib-fed mice, whereas such aberrant expression were suppressed by restricted feeding and tofogliflozin. DNA microarray analysis revealed increased expression of genes related to glycolytic pathway in ad lib-fed mice. However, these changes were corrected in a restricted diet and tofogliflozin groups. In INS-1 cells, high-G caused elevated pfkfb3 and decreased mafa and pdx-1 expression compared with low-G exposure. Inhibition of glycolytic pathway by 3PO in high-G environment did not normalize the defect of mafa and pdx-1. Conclusion: The intracellular metabolic changes in pancreatic β cells associated with obesity and diabetes are flexible and may compensate for glucose intolerance. Disclosure K.Chiba: None. H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. R.Izumihara: None. H.Kameda: None. H.Miyoshi: Research Support; Abbott, LifeScan Diabetes Institute, Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Kowa Company, Ltd., MSD Life Science Foundation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. A.Nakamura: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd.

429-P: Evaluation of Hypoglycemic Risk in Patients with Type 2 Diabetes on Hemodialysis under Tight Glycemic Control

Patients with type 2 diabetes on hemodialysis (T2HD) have unique glycemic profile resulting from hemodialysis, especially hemodialysis-related hypoglycemia, which is present in approximately 20% of them. We analyzed 48-hour sensor glucose level (SGL) on dialysis and non-dialysis days, and time in range (TIR, 70-180 mg/dL), time below range (TBR, <70 mg/dL) in 115 T2HD using continuous glucose monitoring (CGM) and evaluated the difference in clinical parameters between well-controlled group (TIR >70% and TBR <4%) and hypoglycemia group (TIR >70% and TBR ≥4%). Sixty-six patients of well-controlled group (46 males, age 62±12 years, HbA1c 6.0±0.9%, glycated albumin (GA) 18.5±4.1%) and 11 cases of hypoglycemia group (8 males, age 65±13 years, HbA1c 5.9±0.7%, GA 17.4±3.6%) were selected for retrospective analysis. There were no differences in sex, age, dry weight, body mass index, duration of diabetes, or duration of dialysis between two groups. Likewise, HbA1c and GA were not significantly different (P=0.7044, P=0.4151). Glucose levels at both the beginning and the end of dialysis were significantly lower in the hypoglycemia group (164.1±42.8 mg/dL vs. 131.0±49.2 mg/dL (P=0.0227) and 118.8±40.2 mg/dL vs. 86.8±26.1 mg/dL (P=0.0130), respectively). On the other hand, CGM data showed significantly lower mean SGL (P=0.0005) and significantly higher coefficient of variation of SGL (P=0.0014) in the hypoglycemia group. Thus, both HbA1c and GA are not sufficient to predict the presence of hypoglycemia in strict glycemic control in T2HD. Therefore, for good glycemic control without hypoglycemia in T2HD, it is important to measure glucose levels at the beginning and end of dialysis and to evaluate glucose profiles by CGM. Disclosure A.Hayashi: Research Support; Abbott Japan Co., Ltd., Roche Diabetes Care, Speaker's Bureau; Abbott Japan Co., Ltd., Medtronic, Terumo Corporation. N.Shimizu: None. A.Suzuki: None. R.Fujishima: None. K.Matoba: None. T.Masaki: None. T.Miyatsuka: Speaker's Bureau; Eli Lilly Japan K.K., Novo Nordisk, Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Sanwa Kagaku Kenkyusho, Daiichi Sankyo. Funding TERUMO Life Science Foundation (21-III-5030); Japan Association for Diabetes Education and Care (2021-YNG-028); Japan Society for the Promotion of Science (22K15674)

1585-P: MAFLD in Obesity with Deteriorating Glucose Control

The incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rising in parallel with increasing bodyweight and loss of glucose control, implicating a high risk of hepatic and extra-hepatic complications. This longitudinal observational study analysed several indicators for MAFLD in 240 overweight subjects (body mass index (BMI) > 28 kg/m²) at 2 visits within in average 16 months. Subjects were categorised according to their insulin sensitivity (HOMAIR) and diabetic status. Liver fat and liver stiffness were measured with sonographic elastography (FibroScan®), and by calculation of Fatty Liver Index (FLI), and NAFLD Fibrosis Score (NFS). Parameters indicative for liver steatosis, i.e., the controlled attenuation parameter (CAP) and the FLI, were significantly higher in the T2DM group compared to the normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) groups (p<0.05). FLI values and the HOMAIR significantly correlated with sonographic liver fat content (CAP) (r=0.53, p<0.0001; r=0.34, p<0.001, respectively). An inverse correlation was observed between serum adiponectin levels and CAP (r=-0.20; p<0.019) and adiponectin levels and FLI (r=-0.37; p<0.0001). Over 16 months, fasting insulin levels and HOMAIR score increased mainly driven by the group of obese subjects with T2DM. No significant change in liver fat or stiffness was observed that period. In subjects with a BMI ≥ 28kg/m², the prevalence of MAFLD increases in line with increasing insulin resistance and loss of glucose control. Despite some further deterioration in insulin sensitivity, liver fat content appeared relatively unchanged over 16 months. Disclosure T.Forst: Consultant; Pfizer Inc., Speaker's Bureau; Amarin Corporation, AstraZeneca, Boehringer Ingelheim Inc., Cipla Inc., Daiichi Sankyo, Eli Lilly and Company, MSD Life Science Foundation, Novo Nordisk, Sanofi. I.Botz: None. M.Berse: None. S.K.Baumann: None. A.Schultz: None.

411-P: Extended Validation of KidneyIntelXTM in Diabetic Kidney Disease

We have previously shown that plasma TNFR1, TNFR2, and KIM-1 combined with clinical variables provides effective risk stratification for kidney outcomes in individuals with diabetic kidney disease (DKD) stages 1-3. With the recommended use of a race-free eGFR and a refinement of our progression endpoint, we sought to develop and independently validate a version 2.0 of KidneyIntelX assay in a previously untested, independent, contemporary cohort of subjects from BioMe Biobank (Mount Sinai Health System, NYC, NY). The primary outcome was a composite of ≥40% sustained decline in eGFR or kidney failure (sustained eGFR<15 ml/min/1.73 m2) within 5 years from enrollment. In a training cohort of 573 patients with DKD from the Penn Medicine Biobank (PMBB), 15.4% experienced the progressive decline in kidney function over a median of 3.1 years. The following features were selected in a training model utilizing optimized random forests to predict the kidney outcome: TNFR1, TNFR2, KIM-1, baseline UACR, HbA1c, and blood urea nitrogen. The external validation cohort (BioMe, n=657) had an 11.7% event rate over a median of 3.8 years. Based on risk categorization cutoffs derived from training, 57%, 35% and 8.3% of participants were classified as low, intermediate and high-risk, respectively. The cumulative event incidence probability in the low, intermediate, and high-risk groups were 5.9% (95% CI: 3.6-9.4%), 21.2% (95% CI: 15.6-28.3%) and 66.9% (95% CI:, 49.3-83.5%). The unadjusted HRs for high vs. low and intermediate vs. low were 18.4 (95% CI: 9.4 -34.6) and 4.2 (95% CI: 2.4-7.4), respectively. After adjustment for age, sex, race, baseline eGFR, uACR, SBP, and HbA1c, the adjusted HRs were 7.7 (95% CI: 3.0-19.6) and 3.7 (95% CI: 2.0-6.8), respectively. In summary, we developed and independently validated a version 2.0 KidneyIntelX with previously established biomarkers combined with selected clinical variables and demonstrated robust prediction of progressive decline in kidney function, independent of common risk factors. Disclosure G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; Renalytix, Other Relationship; Renalytix, Speaker's Bureau; Daiichi Sankyo, GlaxoSmithKline plc., Menarini Group, Stock/Shareholder; Renalytix. F.Fleming: Employee; Renalytix. M.J.Donovan: Employee; Renalytix. S.Coca: Advisory Panel; Renalytix, Bayer Inc., Boehringer Ingelheim International GmbH, Consultant; Renalytix, Nuwellis, 3ive Labs, Reprieve Cardiovascular, Vifor Pharma Management Ltd., Stock/Shareholder; Renalytix. Funding Renalytix

101-LB: Phase 3 Trial to Evaluate Efficacy and Safety of Gemigliptin and Dapagliflozin Dual Add-on Therapy to Metformin—SOLUTION 2 Study

Background: Type 2 diabetes mellitus (T2DM) patients inadequately controlled with metformin alone require an addition of other medications with complementary mechanism of action. Gemigliptin, a dipeptidyl peptidase-4 inhibitor, and Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, can be considered as additional options. In this clinical trial, efficacy and safety of treatment of gemigliptin and dapagliflozin were evaluated in T2DM patients inadequately controlled with metformin monotherapy. Method: Total 469 T2DM patients receiving treatment with stable metformin for ≥ 8 weeks before screening were randomized to gemigliptin and dapagliflozin (n=157) or gemigliptin (n =156) or dapagliflozin (n =156), respectively. The primary endpoint was the change in HbA1c at 24 weeks from baseline. Results: At 24-week treatment, the HbA1c change from baseline in dual add-on of gemigliptin and dapagliflozin showed a significant reduction (LS Mean -1.34%) compared to gemigliptin add on (-0.90%; difference -0.44% [95% CI -0.58% to -0.31%]) and dapagliflozin add on (-0.78%; difference -0.56% [95% CI -0.69% to -0.42%]). Most of the reported adverse events were mild with no episodes of severe hypoglycemia. Conclusion: This study demonstrated that triple therapy of gemigliptin and dapagliflozin dual add-on to metformin was effective and well tolerated in T2DM patients. Disclosure K. Park: None. K. Han: None. Y. Hwang: None. S. Moon: None. H. Cho: None. H. Yoo: None. S. Choi: None. S. Chon: None. K. Kim: None. T. Kim: None. J. Kang: None. C. Park: None. J. Won: None. S. Lee: Advisory Panel; LG Chem. Speaker's Bureau; Dong-A Pharm. Advisory Panel; CKD Pharm. Speaker's Bureau; Novo Nordisk, Lilly. Advisory Panel; Daiichi Sankyo. Speaker's Bureau; Boehringer Ingelheim Inc. N. Kim: None. E. Kang: None. D. Kim: None. S. Kim: None.

787-P: Glucose and Weight Outcomes Associated with Oral Semaglutide in the Real-World—Initial Results from the Association of British Clinical Diabetologists’ (ABCD) Audit

Semaglutide is the first glucagon like peptide-1 receptor agonist (GLP1-RA) available in an oral preparation. Weight and HbA1c outcomes with injectable semaglutide in the real-world are well established. The aim of this analysis is to assess weight and HbA1c response to oral semaglutide. Methods: Data were extracted from the secure online ABCD audit tool. Individuals were included if baseline and follow-up weight and/or HbA1c data were available. Change in HbA1c, body mass index (BMI) and weight from baseline was assessed using a multivariate linear regression model and change in the numbers achieving an endpoint HbA1c≤7.5% [58mmol/mol] were assessed using Chi2 tests in Stata 16. Results: Data were available for 350 individuals with baseline mean±SD HbA1c 9.2%±1.7 [76.6mmol/mol±18.3], weight 101.8kg±21.9, BMI 34.3kg/m2±6.9, median diabetes duration 11years (IQR 6-16) and age 59 years (IQR 51-68); 63.0% were male and 79.7% were white. Median follow-up was 0.5years (IQR 0.3-0.8). Significant reductions in HbA1c of 0.7% (95%CI 0.4, 0.9; P<0.001) [7.4mmol/mol; 95%CI 4.7, 10.0; P<0.001] were observed. Weight decreased by 3.3kg (95%CI 2.3, 4.3; P<0.001) and BMI fell by 1.1kg/m2 (95%CI 0.6, 1.6; P<0.001). Twice as many people achieved a HbA1c≤7.5% at follow-up compared to baseline (28.6% [52/182] vs 14.3% [26/182]) - this change was statistically significant (P<0.001). Conclusion: In the real-world, oral semaglutide is associated with statistically significant and clinically meaningful reductions in HbA1c, weight and BMI. The numbers achieving a HbA1c≤7.5% also increased. In the light of this, further data collection and analysis should be undertaken, including comparisons between oral and injectable GLP1-RAs and analysis of switches between them Disclosure T.S.J.Crabtree: Speaker's Bureau; Abbott Diabetes, Novo Nordisk, Lilly, Sanofi, Insulet Corporation. K.Adamson: None. S.Krishnasamy: Other Relationship; Novo Nordisk, Sanofi, Eli Lilly and Company, AstraZeneca. M.Khine: None. P.De: Speaker's Bureau; Novo Nordisk, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Takeda Canada, Daiichi Sankyo, Napp Pharmaceuticals Limited, Lilly Diabetes. R.Peter: None. R.E.Ryder: Other Relationship; Novo Nordisk, Speaker's Bureau; GI Dynamics, BioQuest. Funding Novo Nordisk

1566-P: The TM6SF2 rs58542926 Polymorphism Dissociates Hepatocellular Lipids from Insulin Resistance in Recent-Onset Type 2 Diabetes

Increased hepatocellular lipid content (HCL) is generally linked to insulin resistance, which contributes to greater risk of type 2 diabetes and cardiovascular complications. Conversely, a single-nucleotide polymorphism (TM6SF2EK; rs58542926) in the transmembrane 6 superfamily member 2 gene has been associated with nonalcoholic fatty liver disease (NAFLD), but lower cardiovascular risk. Thus, this case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during the early course of diabetes. Males with recent-onset type 2 diabetes with (TM6SF2EK: n=16) or without (TM6SF2EE: n=16) the heterozygous TM6SF2 polymorphism of similar age and BMI, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body, hepatic and adipose tissue insulin sensitivity. HCL and liver fibrosis were assessed with 1H-magnetic resonance spectroscopy and non-invasive tests (FIB4, APRI, AST/ALT), respectively. A subset of both groups (n=24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2EK had similar hepatic and adipose tissue insulin sensitivity and even 27% higher whole-body insulin sensitivity than TM6SF2EE. The novel diabetes endotypes were equally distributed among both groups. After 5 years, whole-body insulin sensitivity, HCL and liver fibrosis indices were similar, while adipose tissue insulin sensitivity decreased by 87% and 55% both in TM6SF2EK and TM6SF2EE and circulating triacylglycerol increased in TM6SF2EE only. The TM6SF2 gene polymorphism rs58542926 dissociates ectopic fat content from insulin resistance in recent-onset type 2 diabetes, which is however attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over the effects of the TM6SF2 gene polymorphism during the early course of diabetes and NAFLD. Disclosure K.Bódis: None. R.Guthoff: Other Relationship; Alimera, Bayer Inc., Novartis, Allergan. V.Schrauwen-hinderling: None. H.Al-hasani: None. V.Burkart: None. J.Szendroedi: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. D.F.Markgraf: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. M.Bombrich: None. M.Schön: None. B.Knebel: None. O.P.Zaharia: None. G.J.Bönhof: None. Y.Karusheva: None. Y.Kupriyanova: None. J.Kotzka: None.

843-P: Effects of Pemafibrate on Glucose Metabolism in Adults with Type 2 Diabetes and Hypertriglyceridemia—Subanalysis of the PARM-T2D Study

Background and Aims: Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has been demonstrated to have potent effects on abnormalities of lipid metabolism in adults with type 2 diabetes (T2DM) and hypertriglyceridemia in real-world clinical practice (PARM-T2D study). However, the effects of pemafibrate on glucose metabolism have not been fully clarified. Materials and Methods: In this multicenter, open-labeled, prospective, observational study, adults with T2DM were treated with pemafibrate (PEMA group) or continued on their current therapy (CTRL group) for dyslipidemia for 52 weeks. This subanalysis consisted of participants who did not change their treatment for diabetes and who did not receive insulin or insulin secretagogues during the study period. Glycemic control, insulin secretion, and insulin resistance were assessed by HbA1c levels, HOMA2-β, and HOMA2-R, respectively. The changes of these parameters between baseline and the end of the study were compared between the groups. Results: In total, 279 of 650 participants met the criteria for this analysis. There were no statistical differences in baseline characteristics between PEMA (n = 141) and CTRL groups (n = 138). There were no significant changes in HbA1c levels and beta-cell function over 52 weeks between the groups, whereas pemafibrate significantly improved insulin resistance assessed by HOMA2-R versus the CTRL group (−0.20 vs. 0.01; estimated treatment difference, −0.23% [95% confidence interval = −0.44, −0.02]; p<0.05). Pemafibrate also ameliorated lipid profiles and liver dysfunction. Changes in serum triglyceride, HDL-cholesterol, γ-GTP, and ALP levels were significantly correlated with those in HOMA2-R (p = 0.024, p = 0.002, p < 0.001, and p = 0.032, respectively). Conclusions: Pemafibrate reduced insulin resistance and improved lipid profiles and liver dysfunction in individuals with T2DM and hypertriglyceridemia. Disclosure H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd. H.Miyoshi: Research Support; Abbott, LifeScan Diabetes Institute, Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Kowa Company, Ltd., MSD Life Science Foundation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. K.Kito: None. A.Nakamura: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. H.Kameda: None. K.Omori: None. S.Yanagiya: None. H.Iesaka: None. Y.Oe: None. S.Kawata: 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.

531-P: The Multidisciplinary Team Education for Subjects with DKD Could Affect the Prevention of eGFR Decline

Background: It still remains unclear as to whether or not multidisciplinary individual team approach (MTA) affects the decline of kidney function in persons with diabetic kidney disease (DKD). We examined the effects of MTA on 24 DKD subjects compared with effects on 24 control subjects with DKD who are managed by dietitian approach alone (DA) between January 2012 and December 2021. Methods: The team was composed of doctors, nurses (CDE, RN) and dietitians (CDE, RD). The team provided broad education, including advice on medication, medical diet therapy, management of home blood pressure, SMBG, weight measurement, self-check of edema, foot care, giving information of stage of DKD and medical examinations. Results: There was no significant difference in types of diabetes (types 1 and 2; 2/22 vs. 1/23), gender (men/women; 15/9 vs.18/6), duration of diabetes (15 ± 9 vs. 19 ± 11 yrs.), observation period (7.9 ± 1.3 vs. 7.3 ± 2.4 yrs.) between MTA and DA. MTA is significantly younger (57 ± 12 years old) than DA (67 ± 9 years old) (p=0.002). Number of interventions per year were 3.6 ± 1.4 vs. 2.6 ± 1.9 times between MTA and DA (p=0.046). Also the initial eGFR (61.0 ± 26.6 vs. 60.1 ± 19.4 mL/min/1.73m2) and albuminuria levels (246 (33-1923) vs. 382 (35-2008) mg/g•Cr) were comparable between the groups. Annual eGFR decline rate in MTA group (−1.38 ± 2.11 mL/min 1.73m2) was significantly lower than that in DA group (−3.89 ± 6.34). Two subjects were initiated hemodialysis only in the DA group (likelihood ratio 2.86, p=0.091). Four subjects died in only the DA group (likelihood ratio 5.91, p=0.015). Summary: It is possible that MTA affects the prevention of renal function decline compared with the intervention provided by DA alone. Subjects with DKD, even with normal renal function, may be recommended to have MTA to prevent the progression of renal failure. Disclosure M.Hitomi: None. N.Hiki: None. U.Sakamoto: None. Y.Usui: None. T.Miyatsuka: Speaker's Bureau; Eli Lilly Japan K.K., Novo Nordisk, Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Sanwa Kagaku Kenkyusho, Daiichi Sankyo. T.Moriya: None.

321-OR: Differential Associations of Obesity and Metabolic Syndrome with Polyneuropathy in Early Type 2 Diabetes and Normal Glucose Tolerance

There is increasing evidence for a role of the metabolic syndrome (MetS) during development of distal sensorimotor polyneuropathy (DSPN). We hypothesized that MetS components are differentially associated with measures of DSPN in individuals with normal glucose tolerance (NGT) and early type 2 diabetes (T2D). Electrophysiological and quantitative sensory testing was performed in 180 participants with NGT and 355 with recent-onset T2D (known diabetes duration <1 year) matched for age from the German Diabetes Study (NGT/T2D [mean±SD]: age: 43.9±14.0/45.1±7.7 years; sex: 61/65% male; BMI: 26.8±5.0/32.3±6.5 kg/m²; HbA1c: 5.2±0.3/6.5±1.0%). Intraepidermal nerve fiber density (IENFD) was assessed in 218 individuals (NGT/T2D: n=117/101). Subsets of participants were followed for 5 years (NGT/T2D: n=48/53). MetS was defined according to International Diabetes Federation (2006) and DSPN according to Toronto consensus criteria (2011). After adjustment for age, sex, height, smoking and HbA1c, a lower IENFD was associated with higher weight (β=-0.306), number of MetS components (NMetSC; β=-0.222) and presence of central obesity (β=-0.292), while higher malleolar vibration perception threshold was associated with weight (β=0.219) in NGT (P<0.05), but not in T2D. Median motor nerve conduction velocity and sural sensory nerve action potential were inversely associated with weight (β=-0.182/-0.286), NMetSC (β=-0.127/-0.128), presence of central obesity (β=-0.163/-0.165), and MetS (β=-0.169/-0.203) in T2D (P<0.05). Higher weight predicted the presence of DSPN at 5 years (β=0.652, P=0.001) in NGT, while increasing NMetSC and MetS prevalence predicted a decline in IENFD over 5 years (β=-0.533/-0.388, P=0.001/0.013) in T2D. This suggests that obesity indices can predict DSPN over 5 years in NGT, while MetS and its components are differentially associated with measures of DSPN in early, well-controlled type 2 diabetes compared with NGT. Disclosure G.Sipola: None. A.Strom: None. M.Bombrich: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. D.Ziegler: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. G.J.Bönhof: None. Gds group: n/a. Funding German Federal Ministry of Health; Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia; German Federal Ministry of Education and Research

1672-P: Isoxanthohumol Improves Obesity and Glucose Metabolism via Regulation of Gut Barrier and Intestinal Lipid Absorption with a Bloom of Akkermansia muciniphila

Dysbiosis is an important factor that leads to metabolic disorders via disruption of the gut barrier function. A decrease in Akkermansia muciniphila (AM) is a phenotype of obesity-induced disruption of the gut barrier. Although interventions to increase AM have been reported to improve glucose metabolism, the underlying mechanism has not been fully understood. The administration of IX suppressed weight gain and steatohepatitis and improved glucose metabolism in diet-induced obese mice. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption via decreased expression of the lipid absorption transporter, CD36, in the jejunum. Moreover, IX administration improved the gut barrier function and reduced metabolic endotoxemia. In contrast, the observed effects of IX were cancelled by antibiotics and reproduced by fecal microbiota transplantation to GF mice. 16S rRNA sequencing revealed that the microbial community structure changed with a significant increase in AM in the IX-administration group. An anaerobic chamber study showed that IX promoted the growth of AM, while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct impact of AM on lipid and glucose metabolism in monocolonized mice, we transplanted either AM or Bacteroides thetaiotaomicron to GF mice. AM monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism with decreased multiple classes of fatty acids in plasma metabolomics analysis. In summary, IX contributes to metabolic improvement by decreasing CD36 and lipid absorption in the small intestine which is associated with a bloom of AM, suggesting an important interaction between food ingredients and AM abundance in controlling metabolism. Disclosure Y.Watanabe: None. S.Fujisaka: None. S.Watanabe: None. A.Nishimura: None. T.Kado: None. M.Aslam: None. M.Bilal: None. Y.Morinaga: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. Funding Japan Society for the Promotion of Science (21K20896, 22K16424); Lotte Foundation; Yakult Bio-Science Foundation

38-LB: Ex Vivo Immune Cell Function Analysis in Patients with CKD Undergoing Dialysis Treatment Monitors Exercise Treatment Effects on Immunosurveillance

Chronic kidney disease (CKD) is marked by a pre-aging and dysfunctional immune system and chronic inflammation. Recent research indicates that chronic physical exercise training (ET) increases regulatory monocytes and T-cells thus modulating the inflammatory status associated with cardio-metabolic diseases. In particular, ET primes monocytes and T-cells towards a less inflammatory phenotype. We hypothesized that intradialytic ET is beneficial to patients with CKD by improving certain immune cell features and decreasing systemic inflammation. We isolated PBMCs from a subset of 18 patients with CKD (58-90 years, 38 % females) enrolled in the prospective intervention trial DiaTT (Dialysis Training Therapy; ClinicalTrials.gov: NCT03885102) at the beginning and after a 12-months intradialytic ET intervention (aerobic endurance + resistance training). Circulating immune cell populations were characterized by FACS. Ex-vivo basal and PMA-induced T-cell activation was determined by cell surface expression analysis of CD69. We found that ET reversed the shift towards intermediate monocytes, a known marker for CKD morbidity and mortality, and nonclassical monocytes in patients with CKD undergoing dialysis treatment. We observed an increase in naïve T-cells and Recent Thymic Emigrants (RTE) indicating an improvement of T-cell function. On T-cells, basal CD69 expression was significantly enhanced and PMA-induced CD69 expression was severely impaired in patients with CKD compared to healthy control subjects (n= 7). When patients with CKD underwent ET this specific T-cell function was restored to normal levels. Here, we show that even in these severely sick patients certain circulating immune cell functions can be regained potentially leading to an enhanced immunosurveillance. Our ex-vivo immune cell characterization and function analysis can be used to monitor exercise treatment effects on systemic inflammation. Disclosure S. M. Hofmann: None. S. M. Dinges: None. M. Walter: None. P. Vonkorn: None. G. D. Vongersdorff: None. K. Anding-rost: None. M. Halle: Advisory Panel; Abbott, Speaker's Bureau; Boehringer Ingelheim (Canada) Ltd., Daiichi Sankyo, Amgen Inc., BMS.

462-P: DPP-4 Deficiency Suppresses the Progression of Atherosclerosis via Inducing M2 Macrophage Polarization

Background: Dipeptidyl peptidase-4 (DPP4) inhibitors suppressed progression of atherosclerosis in atherosclerotic mouse models. However, the role of DPP4 on the progression of atherosclerosis is not clear. We investigated the effect of DPP4 deficiency on the progression of atherosclerosis in DPP4 and apolipoprotein-E double knockout (DPP4/ApoE-DKO) mice. Methods: Both ApoE-KO mice and DPP4/ApoE-DKO mice were fed with normal chow until 20 weeks of age. Whole aorta and aortic sinus were stained with Oil red O. Bone marrow-derived macrophages (mφ) from wildtype or DPP4-KO mice were used in in vitro study. Expression of iNOS, MCP-1, TNF-α and IL-1β (M1 markers), and arginase-1, Mgl2 and Ym1 (M2 markers) mRNA were evaluated by real-time RT-PCR, and mφ polarization was evaluated by flowcytometry. Results: There were no differences on food intake, body weight, lipid profiles and the blood glucose levels by insulin tolerance test between each group, but the blood glucose levels by glucose tolerance test were significantly decreased in DPP4/ApoE-DKO mice. Oil-Red-O staining demonstrated that the size of atherosclerotic lesions was significantly smaller in DPP4/ApoE-DKO mice. In in vitro assay, LPS+IFNγ induced the mRNA expression of M1 markers and there was no difference between wildtype mφ and DPP4-KO mφ. On the other hand, the mRNA expression of M2 markers were significantly increased in DPP4-KO mφ. Flowcytometry revealed that the number of iNOS (M1 marker)-positive cells were increased by LPS+IFNγ, which was comparable between wildtype mφ and DPP4-KO mφ. On the other hand, the number of CD206 (M2 marker)-positive cells was higher in DPP4-KO mφ than that in wildtype mφ. Conclusion: This study suggests that DPP4 deficiency suppresses the progression of atherosclerosis in apoE-KO mice. Moreover, DPP4 deficiency increases the polarization of M2 mφ. These findings may indicate the involvement of DPP4 at least in part on the development of diabetic macrovascular complications. Disclosure Y.Zhou: None. T.Matsumura: Research Support; Shimadzu Corporation, Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc. Y.Yagi: None. T.Yoshinaga: None. T.Senokuchi: None. N.Ishii: None. T.Kondo: None. E.Araki: Research Support; Eli Lilly Japan K.K., Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma Corporation, Speaker's Bureau; AstraZeneca, Merck & Co., Inc., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Sumitomo Pharma Co., Ltd., Daiichi Sankyo, Novo Nordisk Pharma Ltd.

96-OR: Liver Fibrosis Scores in Novel Subclusters of Patients at Risk for Type 2 Diabetes

Metabolic diseases such as type 2 diabetes (T2D) are linked to the development of fatty liver, steatohepatitis and liver fibrosis. We have previously described novel clusters of patients at risk for T2D. Three clusters (3, 5 and 6) either had a high risk to progress to T2D or to develop cardiorenal complications. While high-risk clusters differ in liver fat content, it remains unknown if they also harbor a different risk for hepatic fibrosis. Thus, we determined clinically applicable scores of liver fibrosis in 1115 subjects at risk for T2D from the TUEF/TULIP study, which were categorized into high-risk clusters (n=602). Liver fat content was determined by 1H-magnetic resonance spectroscopy. The AST-to-platelet-ratio index (APRI), fibrosis-4 score (FIB-4) and NAFLD fibrosis score (NFS) were used to determine fibrosis risk. ANCOVA model analysis adjusted for liver fat content was performed. Of the high-risk clusters (3: n= 83, 5: n= 203, 6: n= 316), cluster 6 had the highest BMI 44.1±9.7 kg/m² (vs. cluster 3: 29.7±3.1 kg/m², p<0.001 and cluster 5: 42.8.0±8.7, p=0.32) and cluster 5 had the highest liver fat content (13.4±8.8% vs. cluster 3: 8.0±6.5, p<0.001 and cluster 6: 9.0±6.7, p<0.001). All fibrosis scores correlated with liver fat content (e.g. FIB-4: r= 0.45, p< 0.0001). Although FIB-4, APRI and NFS were generally low, they were highest in cluster 5, but despite highest liver fat content, they did not differ from cluster 3 and 6 (e.g. FIB-4: cluster 5: 0.19±0.45 vs. cluster 3: 0.14±0.01, p=0.59 and cluster 6: 0.12±0.15, p=0.39). Interestingly, cluster 3 with the lowest liver fat content exhibited higher FIB-4 compared to cluster 6 (p=0.02). According to clinically applicable scores, the most insulin resistant cluster 5 has the highest FIB-4 score. The insulin deficient cluster 3 has a relatively high FIB-4 score despite relatively low liver fat content and BMI. Further studies are needed to investigate the clinical relevance of these findings. Disclosure V.Minelli faiao: None. A.Peter: None. A.L.Birkenfeld: None. N.Stefan: Advisory Panel; Pfizer Inc., Research Support; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Jumpertz von schwartzenberg: Other Relationship; Sanofi, Amgen Inc., Lilly, Novo Nordisk. A.Sandforth: None. S.Katzenstein: None. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. L.Fritsche: None. J.Machann: None. F.Schick: None. H.Häring: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi.

1573-P: Association of Thyroid Hormone Levels with NAFLD in Recent-Onset Diabetes

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern associated with obesity and type 2 diabetes (T2D). Thyroid hormones are important regulators of lipid homeostasis. Indeed, people with hypothyroidism are at greater risk for NAFLD and it has been suggested that humans with T2D are more likely to develop hypothyroidism. However, little is known about the relationship of thyroid function with NAFLD in type 1 diabetes (T1D) and T2D. We hypothesized that (i) low free thyroxin (fT4) and high thyroid-stimulating hormone (TSH) levels are associated with increased hepatocellular lipid content (HCL) and (ii) that fT4 and TSH can identify persons at high-risk for hepatic steatosis in people with recent-onset diabetes. We examined people with T1D (n=358) or T2D (n=596) and 175 healthy participants of the German Diabetes Study (GDS). First, validation of the fatty liver index (FLI) against quantification of HCL by 1H-magnetic resonance spectroscopy revealed a close correlation (ß=0.715, p<0.001; n=446). Second, FLI negatively correlated with fT4 in males (ß=−0.139, p<0.01), but not in females with T2D (ß=−0.086, p=0.26). Likewise, TSH associated positively with FLI in males (ß=0.116, p<0.05), but not in females with T2D (ß=−0.057, p=0.45). TSH and FLI were differently associated between males and females before (p<0.05), but not after (p=0.82) adjustment for BMI. Finally, fT4 had a low diagnostic precision for steatosis (by FLI) as derived from the respective area under the receiver operating curve (0.57, 95% CI [0.53;0.62]; p<0.001) in T2D and was not significant in other groups. TSH had no diagnostic precision for steatosis in any groups. In conclusion, FLI can be used as a surrogate measure of HCL in recent-onset diabetes. The correlation of FLI with lower thyroid function in male T2D suggests a sex-specific interaction between thyroid and liver lipid metabolism, which is mainly driven by body mass. Both, fT4 and TSH offer no relevant efficacy to detect steatosis at least in recent-onset diabetes. Disclosure N. Saatmann: None. M. Schön: None. O.P. Zaharia: None. M. Huttasch: None. K. Strassburger: None. S. Trenkamp: None. Y. Kupriyanova: None. V. Schrauwen-Hinderling: None. S. Kahl: None. V. Burkart: None. R. Wagner: Speaker's Bureau; Novo Nordisk, Sanofi. Advisory Panel; Daiichi Sankyo. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis. Consultant; TARGET PharmaSolutions, Inc. Research Support; Sanofi.

1623-P: Identification of Gut Microbes That Prevents Metabolic Syndrome in Healthy Japanese Adults

Gut microbiota is an important driver of metabolic status. Recent studies have demonstrated that dysbiosis precedes the development of metabolic disorders. However, the bacterial species associated with metabolic syndrome and their physiological role in obesity and glucose metabolism have not been fully elucidated. In this study, we performed 16S rRNA sequencing analysis on fecal samples from 49 metabolically healthy volunteers, a detailed lifestyle questionnaire survey including diet, and an analysis on metabolic parameters. We also examined the metabolic effects of some microbes by transplantation into HFD-fed mice. The average age, BMI and HbA1c were 43.5±9.0, 23.9±3.9 and 5.5±0.3, respectively. A clear correlation was observed between lifestyle and metabolic parameters. Analysis of fecal microbial structure divided the participants into three enterotypes according to their predominant phylogenic pattern; 1) Prevotella copri group, 2) Bacteroides group, and 3) others. Enterotype 1 had higher random blood glucose (BG), and lower HDL-C, while enterotype 2 had lower random BG, BMI, and waist circumference. Eleven bacterial species were identified as being positively or negatively correlated with metabolic parameters. Relative abundances of the Family Fusobacteriaceae and Prevotella stercorea were positively correlated with BMI, fasting BG, and visceral fat mass. In contrast, the Family Rikenellaceae and Bacteroides uniformis (Bu) negatively correlated with metabolic parameters. Transplantation of Alistipes indistinctus (Ali), a major bacterium of the Family Rikenellaceae, or Bu into HFD-fed C57BL/6J mice suppressed body weight gain, improved glucose tolerance and histological findings without altering food intake. In summary, our results suggest that microbial community structure can be altered by lifestyle even in good health. Moreover, maintaining microbial species such as Ali and Bu may contribute to the prevention of metabolic disorders in Japanese adults. Disclosure H. Honoki: None. S. Fujisaka: None. Y. Watanabe: None. M. Oku: None. Y. Kondo: None. A. Nishimura: None. T. Kado: None. M. Bilal: None. A. Enkaku: None. A. Takikawa: None. D. Chujo: None. Y. Morinaga: None. K. Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. Funding Japan Society for the Promotion of Science (20K10318); Japan Association for Diabetes Education and Care

479-P: Natural Course of Declining Nerve Function during the First 10 Years of Well-Controlled Type 2 Diabetes

There is a lack of evidence on the long-term changes of nerve function in individuals with type 2 diabetes (T2D) compared to those with normal glucose tolerance (NGT). Therefore, we assessed motor and sensory nerve conduction velocities (MNCV, SNCV), sensory nerve action potentials, vibration perception threshold (VPT) and thermal detection threshold of lower extremities in 45 individuals with T2D (known diabetes duration [mean±SD]: 164±95 days) and NGT from the German Diabetes Study (GDS) at baseline (BL) and 5-year follow-up. Individuals were matched pairwise for age (T2D/NGT: 52.9±10.4/52.9±10.3 years) and sex (64/64% male). In addition, 103 individuals with T2D were followed over 10 years. At BL, 1/6 indices was lower in T2D vs NGT (peroneal MNCV: 45.6±4.0 vs 47.2±2.8 m/s; P<0.05). After five years, one index deteriorated in T2D (peroneal MNCV: 45.3±4.1 vs 43.5±3.8 m/s) and one in NGT (malleolar VPT: 1.29±1.88 vs 2.25±3.06 µm) (all P<0.05). After adjustment for BL values and pairwise matching, nerve function similarly declined over the first five years in T2D and NGT (e.g. Δperoneal MNCV; figure). A comparable deterioration was observed in individuals with T2D over 10 years (figure). Parallel decline in small and large fiber function in both NGT and well controlled T2D indicates that the main events leading to impaired nerve function in well controlled T2D might occur earlier than previously assumed. Disclosure A.Strom: None. K.Strassburger: None. G.Sipola: None. D.Ziegler: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. G.J.Bönhof: None. Gds group: n/a. Funding German Federal Ministry of Health; Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia; German Federal Ministry of Education and Research

432-P: Role of Patatin-Like Phospholipase Domain–Containing 3 Gene for Kidney Dysfunction in Diabetes Endotypes

Recent studies identified distinct endotypes of diabetes with differences in metabolic features and in risk for diabetes-related comorbidities. Of note, persons allocated to the severe insulin resistant diabetes (SIRD) endotype, who show increased prevalence of nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD), are more frequently carriers of the G-allele in the single-nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase domain containing 3 (PNPLA3) gene. This SNP associates with increased risk of NAFLD yet the association between the presence of the PNPLA3 SNP and CKD remains controversial. The present study examined whether this SNP differently associates with CKD in endotypes of recent-onset diabetes. Participants with newly diagnosed diabetes (n=707) from the prospective German Diabetes Study underwent k-means clustering, genotyping, magnetic resonance spectroscopy to determine hepatocellular lipid content (HCL) and laboratory analyses to calculate the glomerular filtration rates (eGFR). SIRD had the lowest eGFR and highest HCL compared to severe insulin deficient, moderate obesity-related, moderate age-related and severe autoimmune diabetes clusters (all p<0.05). HCL was negatively associated with eGFR (r=-0.287, p<0.01) across all groups. Further stratification by PNPLA3 G-allele carrier status did not reveal any association between HCL and eGFR in any of the diabetes types, irrespective of G-allele carrier status. However, with declining eGFR the proportion of G-allele carriers increased from 44% for eGFR >60 ml/min to 52% for eGFR <60 ml/min (p<0.05). In conclusion, increased hepatic lipid content is associated with reduced kidney function across all diabetes endotypes. This association is independent of the presence of the PNPLA3 polymorphism in newly diagnosed diabetes, but there might be role for PNPLA3 for the severity of CKD. Disclosure O.P. Zaharia: None. K. Strassburger: None. B. Knebel: None. Y. Kupriyanova: None. J. Kotzka: None. K. Bódis: None. M. Schön: None. M. Bombrich: None. C. Möser: None. K. Prystupa: Other Relationship; Berlin-Chemie AG. H. Al-Hasani: None. V. Schrauwen-Hinderling: None. K. Jandeleit-Dahm: None. R. Wagner: Speaker's Bureau; Novo Nordisk, Sanofi. Advisory Panel; Daiichi Sankyo. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis. Consultant; TARGET PharmaSolutions, Inc. Research Support; Sanofi. Funding German Research Foundation; European Foundation for the Study of Diabetes; German Diabetes Association; German Federal Ministry of Education and Research; Heinrich Heine University

810-P: Do People Living with T1D Use the Dosing Flexibility of Degludec and Does This Depend on Patient Characteristics?

Flexibility in insulin degludec injection timing of 8-40 hrs between doses allows people with diabetes to adapt their treatment around daily life. This real-world multinational study explored flexible dosing (≥6hr difference in time of day [clock-time] between consecutive doses) in terms of prevalence and associated characteristics in 1136 people with T1D (mean [SD] age 31.3 [17.7] years, 54% male, median observation period 124 days [IQR 41, 234]) who were administering insulin degludec with smart pens. Of these participants, 14.4% regularly flexed dosing time (≥1 time every month). The probability of having ≥1 flexible dose in a given 2-week period was shown by a generalized linear mixed model (log link) with participant ID as a random effect and individual characteristics as fixed effects. Estimated LS-mean probability of ≥1 flexible dose in a given 2-week period was 25.0% (95% CI: 21.5%, 28.9%), with higher probability for young adults (aged 18-25), those who usually inject 9am-6pm, and those with a higher (>30 U/day) basal dose (all p<0.01). Probability decreased with time from smart pen initiation (p<0.01). In the subgroup of 455 adults with CGM data, flexibility in dosing time did not affect glycemic control. Overall, a group of people with T1D used the degludec dosing flexibility; these were most often young adults aged 18-25, those injecting 9am-6pm, and those requiring higher degludec doses. Disclosure Y.Winhofer: Speaker's Bureau; Abbott Diabetes, Amgen Inc., Boehringer-Ingelheim, Eli Lilly and Company, Novartis, Novo Nordisk, Medtronic, Sanofi-Aventis Deutschland GmbH, Daiichi Sankyo. A.Kaas: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. N.N.Knudsen: Employee; Novo Nordisk. J.H.J.Martiny: Employee; Novo Nordisk. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. Funding Novo Nordisk A/S