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Introduction: Glucagon plays a role in the pathogenesis of type 2 diabetes. Yet, little is known about the effect of interventions aimed at preventing progression from prediabetes to diabetes on glucagon concentrations. We examined the effects of dapagliflozin, metformin or exercise on plasma glucagon concentration in individuals with HbA1c-defined prediabetes. Methods: 120 individuals were randomized to a 13-week intervention with dapagliflozin (10 mg once daily), metformin (850 mg twice daily), exercise (interval training 30 min 5 days/week) or control (habitual living). A 75 g oral glucose tolerance test (OGTT; 0, 30, 60 and 120 min) was administered at baseline, at 13 weeks (end of intervention) and at 26 weeks (end of follow-up). Linear mixed-effects models were used to assess effects on fasting concentration, early (0-30 min) area under the curve relative to the fasting level (rAUC0-30 min) and full rAUC0-120 min for glucagon. Results: At baseline, the median (Q1;Q3) age was 62 (54;68) years, HbA1c 5.9% (5.7;6.1%), fasting glucagon 11 (7;15) pmol/L, and 56% were men. No differences in the glucagon measures between groups from baseline to 13 or 26 weeks were observed (Table 1). Conclusions: 13 weeks of treatment with dapagliflozin, metformin or exercise was not associated with changes in fasting or post-OGTT glucagon concentrations in individuals with prediabetes. Disclosure K.K.B. Clemmensen: Research Support; Self; AstraZeneca, Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. M.B. Blond: None. H. Amadid: None. L.B. Nielsen: None. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. K. Karstoft: Employee; Spouse/Partner; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. M. Ried-Larsen: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. S.S. Torekov: Research Support; Self; Novo Nordisk Inc. J.S. Quist: None. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. K. Færch: None. Funding Novo Nordisk Foundation; AstraZeneca; University of Copenhagen; Innovation Foundation

Background: Plasma levels of liver enzymes are elevated in prediabetes but may improve in response to weight loss and glucose-lowering interventions. We examined the effects of dapagliflozin, metformin, or exercise on plasma levels of alanine transferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) in people with prediabetes. Methods: 120 adults with prediabetes (30-70 years, BMI≥25 kg/m2, HbA1c 5.7-6.4%) were randomized to 13 weeks of dapagliflozin (10 mg once daily), metformin (850 mg twice daily), exercise (30 min, 5 days/week) or control (habitual living). Fasting plasma levels of ALT, AST, and GGT were measured at baseline and after 6 and 13 weeks of intervention and after 26 weeks of follow-up. Linear mixed-effects models were performed. Results: At baseline, median (Q1;Q3) HbA1c was 5.9% (5.7; 6.1). 17% had elevated ALT levels, 3% elevated AST levels, and 6% elevated GGT levels. ALT and AST levels did not change in response to the interventions (Table 1). Small within-group changes in GGT were observed in the active groups after 6, 13 or 26 weeks, but they did not differ from the control group (P≥0.09 for all comparisons). Conclusions: 13 weeks of treatment with dapagliflozin, metformin or exercise was not associated with changes in liver function markers compared with habitual living in people with prediabetes. Disclosure M.B. Blond: None. K.K. Clemmensen: Research Support; Self; AstraZeneca, Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. H. Amadid: None. L.B. Nielsen: None. M. Ried-Larsen: None. K. Karstoft: Employee; Spouse/Partner; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. K. Faerch: None. Funding Novo Nordisk Foundation; AstraZeneca; University of Copenhagen; Innovation Foundation

Introduction: We assessed the efficacy of three glucose-lowering interventions in persons with HbA1c-defined prediabetes. Methods: 120 participants were randomised 1:1:1:1 to 13 weeks of 1) dapagliflozin (DAP, 10 m/day); 2) metformin (MET, 1700 mg/day); 3) exercise (EXE, 5 x 30 min/week); or 4) control (CON, no treatment). Continuous glucose monitor (CGM) was used for 6 days before, during (6 weeks) and after (13 weeks) the intervention. Treatments were stopped the day before the last visit (two days before in EXE). Primary outcome was 13-week change in mean amplitude of glycaemic excursions (MAGE). Intention-to-treat analysis was conducted. Results: At baseline, median (Q1;Q3) HbA1c was 5.9 (5.7;6.1)%; BMI 30.8 (28.6;34.3) kg/m2; age 62 (54;68) years; 44% were men. No within- or between-group changes were observed for MAGE. Mean CGM glucose (MG) was slightly reduced in MET and DAP at 6 weeks (Table 1). The 6-week change in MG in DAP was different from that in CON (mean diff. (95% CI): -0.3 mM (-0.5;0.0), P=0.031). At 13 weeks, MG had increased in MET and CON, and the change in MET was different from those in EXE (0.2 mM (0.0;0.5), P=0.041) and DAP (0.2 mM (0.0;0.5), P=0.039). Conclusion: 13 weeks of treatment with MET, DAP or EXE did not change MAGE. Treatment with DAP or MET for 6 weeks slightly reduced MG; these improvements disappeared immediately after treatments were stopped at 13 weeks. Disclosure K. Færch: Research Support; Self; Ascensia Diabetes Care, AstraZeneca, Unilever. Stock/Shareholder; Self; Novo Nordisk A/S. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. M.B. Blond: None. L.B. Nielsen: None. H. Amadid: None. T.F. Dejgaard: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Boehringer Ingelheim International GmbH. M. Ried-Larsen: Other Relationship; Self; Novo Nordisk A/S. K. Karstoft: Employee; Self; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. M.E. Jørgensen: Research Support; Self; Amgen Inc., AstraZeneca, Danish Diabetes Association, Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Novo Nordisk Foundation; AstraZeneca

Introduction: We assessed the effects of dapagliflozin, metformin or exercise on glucose metabolism in individuals with prediabetes. Methods: 120 participants were randomized to 13 weeks of either: 1) dapagliflozin (DAP, 10 mg once daily); 2) metformin (MET, 1700 mg daily); 3) exercise (EXE, 5x30 min/week); or 4) control (CON, no treatment). Participants were tested at baseline and after 6 and 13 weeks of intervention with oral glucose tolerance tests with 0, 30, 60, 120 min samples performed at baseline and at 13 weeks. Treatments were stopped the day before the last visit (two days before in EXE). Intention-to-treat analyses were conducted (baseline-adjusted). Results: 44% were men. At baseline, the median (Q1;Q3) age was 62 (54;68) years, BMI 30.8 (28.6;34.3) kg/m2, HbA1c 41 (39;43) mmol/mol (5.9 (5.7;6.1)%), fasting plasma glucose (FPG) 5.6 (5.2;5.8) mmol/L, and fasting serum insulin (FSI) 72 (47;99) pmol/L. HbA1c decreased in DAP at 6 weeks (Table 1). All groups showed reductions of around 1 mmol/mol at 13 weeks. MET, and to a lesser extend DAP, decreased FPG. FSI was reduced by 19-25% in all treatment groups, except for EXE at 13 weeks. The iAUCglucose increased by 66% in MET, and iAUCinsulin decreased somewhat in DAP and EXE. Conclusion: All treatments slightly improved HbA1c and fasting measures. Only DAP and EXE showed signs of improvements in postprandial glucose metabolism. Disclosure K. Færch: Research Support; Self; Ascensia Diabetes Care, AstraZeneca, Unilever. Stock/Shareholder; Self; Novo Nordisk A/S. M.B. Blond: None. H. Amadid: None. L.B. Nielsen: None. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. K.K. Clemmensen: None. C.H. Pedersen: None. K. Karstoft: Employee; Self; Novo Nordisk A/S. M. Ried-Larsen: Other Relationship; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen Inc., AstraZeneca, Danish Diabetes Association, Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. Funding Novo Nordisk Foundation; AstraZeneca

Chronic hyperglycemia promotes oxidative stress and advanced glycation end product (AGE) formation, leading to recognition by the AGE receptor (RAGE). AGE-RAGE binding and inflammation perpetuates diabetic complications, however the study of these phenomenon present inherent challenges in vivo. Therefore, our purpose was to evaluate the effects of acute experimental hyperglycemia on AGEs, oxidative markers, and RAGE expression in healthy, obese subjects (n=10; 31.2±1.2 kg/m2; 56±3 y) subjected to hyperglycemic clamps (+5.4 mM above basal). Plasma was assayed at baseline, 2, and 24 h post glucose-infusion for well-known AGE-free adducts (CML, CEL, G-H1, MG-H1, 3DG-H) and oxidative markers (MethSO, AAA) via LC-MS/MS as well as soluble RAGE (sRAGE) isoforms via ELISA. Urine was also assayed (basal and 24 h) for AGEs and oxidative markers (normalized to creatinine) and skeletal muscle biopsies were used to study RAGE expression via Western blot. Most circulating factors (MethSO, AAA, CEL, MG-H1, and G-H1) decreased (p0.05). In urine, only MethSO was seen to increase at 24 h (p0.05). In skeletal muscle tissue, there was a trend (p Disclosure R. Perkins: None. E.R. Miranda: None. K. Karstoft: None. P.J. Beisswenger: Employee; Self; PreventAGE Health Care, LLC.. T.P. Solomon: None. J.M. Haus: None.