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Figure S1 Acute oral glucose tolerance test in normoglycaemic Wistar rats with two representative N-pyridinylbenzamide compounds and piragliatin reveals different insulin secretion and hypoglycemic profiles. Rats were catheterized at the jugular vein 3 days before glucose administration. The day of OGTT, rats were fasted for 4 h, and compounds were given orally at 45 mg kg−1, 1 h before the administration of 1 g kg−1 glucose at time 0. Blood was sampled at the jugular vein 10, 20, 40, 60 and 120 min after glucose administration; and glucose and insulin concentrations were measured using the accucheck glucometer from Roche and the high-range rat elisa kit from Mercodia. (A) Glycaemia profiles. (B) Glycaemia areas under curves (AUC) between 0 and 60 min. (C) Insulinaemia profiles. (D) Insulinaemia AUC between 0 and 60 min. Data are means ± SEM of 8 to 12 animals per group. Significance was determined for glycaemia (B) and insulinaemia (D) exposures by Student's t test. *P < 0.05, **P < 0.01.

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Figure S2 Oral glucose tolerance test performed at week 5 of the 6 week chronic study in db/db mice. The OGTT was performed under fasting conditions 16 h after the last compound administration, in order to examine the impact of chronic treatment rather than an acute effect. Glucose was given orally at 1.5 g kg−1 at time 0. Blood was sampled at the tail 10, 25, 60 and 120 min after glucose administration; and glucose and insulin concentrations were measured using the accucheck glucometer from Roche and a mouse elisa kit from Mercodia. Doses expressed as mg kg−1 correspond to equimolar concentrations for GKA50 and N00236460 (80 and 130 μmol kg−1 for the low-dose and high-dose groups respectively). (A) Glycaemia profiles with an inset depicting basal glycaemia values just before glucose administration. (B) Glycaemia AUC between 0 and 120 min. (C) Insulinaemia profiles. (D) Insulinaemia AUC between 0 and 60 min. Data are means ± SEM of 11 to 12 animals per group. Significance was determined for glycaemia exposure (B) and insulinaemia exposure (D) by anova and Dunnett's multiple comparison test to analyse the dose-dependent effect of GKA50 and N00236460, and by Student's t-test for metformin. **P < 0.01, ***P < 0.001.

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Figure S3 Body weight and plasma parameters after oral administration of GKA50, N00236460 or metformin for 6 weeks in db/db mice. Doses expressed as mg kg−1 correspond to equimolar concentrations for GKA50 and N00236460 (80 and 130 μmol kg−1 for the low-dose and high-dose groups respectively). (A) Differences in body weight between day 1 and day 42. (B) Total cholesterol concentration after 6 weeks. (C) HDL-cholesterol concentration after 6 weeks. (D) Alkaline phosphatase concentration after 6 weeks. (E) LDH concentration after 6 weeks. Significance was determined by anova and Dunnett's multiple comparison test to analyse the dose-dependent effect of GKA50 and N00236460, and by Student's t-test for metformin. Data are means ± SEM of 11 to 12 animals per group. *P < 0.05, **P < 0.01.

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Figure S4 Body weight and plasma parameters after oral administration of GKA50 or N00236460 for 2 weeks in db/db mice. On the day of killing, groups of 20 mice receiving similar treatment throughout the study were separated into two groups of 10 mice fasted for 4 h and 10 mice fed ad lib. The doses expressed as mg kg−1 correspond to equimolar concentrations (130 μmol kg−1) for GKA50 and N00236460. (A) Differences in body weight between day 1 and day 14. (B) Total cholesterol concentration after 2 weeks. (C) HDL-cholesterol concentration after 2 weeks. (D) Alanine aminotransferase levels and (E) aspartyl aminotransferase levels after 2 weeks. (F) Alkaline phosphatase concentration after 2 weeks. (G) LDH concentration after 2 weeks. Data are means ± SEM of 10 animals per group. Significance was determined by Student's t-test. *P < 0.05 for comparison between GKA50- and N00236460-treated groups with control groups.

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Figure S5 Body weight and plasma parameters after oral administration of GKA50 and N00236460 for 4 weeks in ZDF and Wistar rats. Left panels, ZDF rats. Right panels, Wistar rats. (A, B) Differences in body weight between day 1 and day 28. Doses expressed as mg kg−1 correspond to equimolar concentrations for GKA50 and N00236460 (30 and 80 μmol kg−1 for the low-dose and high-dose groups respectively). (C, D) Total cholesterol concentration after 4 weeks. (E, F) HDL-cholesterol concentration after 4 weeks. (G, H) Alkaline phosphatase concentration after 4 weeks. Data are means ± SEM of 10 animals per group. Significance was determined by anova and Dunnett's multiple comparison test to measure the dose-dependent effect of GKA50 and N00236460. *P < 0.05, **P < 0.01.

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