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Volume 15, Issue 7, Pages 1394-1400 (May 2016) Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes Adam R. Konopka, Raul Ruiz Esponda, Matthew M. Robinson, Matthew L. Johnson, Rickey E. Carter, Michele Schiavon, Claudio Cobelli, Fredric E. Wondisford, Ian R. Lanza, K. Sreekumaran Nair Cell Reports Volume 15, Issue 7, Pages 1394-1400 (May 2016) DOI: 10.1016/j.celrep.2016.04.024 Copyright © 2016 The Authors Terms and Conditions

Cell Reports 2016 15, 1394-1400DOI: (10.1016/j.celrep.2016.04.024) Copyright © 2016 The Authors Terms and Conditions

Figure 1 Metformin Improves Fasting and Postprandial Indices of Insulin Sensitivity (A and B) HOMA-IR (A) and insulin-to-glucagon ratio (B). (C) Whole-body SI. (D and E) β Cell responsivity (D) and disposition index (E) modeled after a mixed-meal challenge. (F–I) Basal and postprandial plasma values and area above baseline (AAB) after 2 weeks of metformin compared with placebo for glucose (F), C-peptide (G), insulin (H), and glucagon (I). Postprandial glucagon was decreased with metformin at 120, 180, and 240 min. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 metformin versus placebo. Data are presented as mean ± SEM. Cell Reports 2016 15, 1394-1400DOI: (10.1016/j.celrep.2016.04.024) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Endogenous Glucose Production after Metformin Treatment in Prediabetic Individuals (A) EGP under basal, glucagon-deficient (somatostatin), and glucagon-stimulated conditions (glucagon). (B) Fasted plasma glucagon. (C) Relationship between the change in basal EGP to basal, fasting glucagon after metformin treatment. (D) The difference in EGP (Δ EGP) under glucagon-deficient (somatostatin) and glucagon-stimulated (glucagon) conditions versus basal EGP. ∗p < 0.05 metformin versus placebo. Data are presented as mean ± SEM. Cell Reports 2016 15, 1394-1400DOI: (10.1016/j.celrep.2016.04.024) Copyright © 2016 The Authors Terms and Conditions