1 Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: Results from a randomized clinical trial  Jukka P. Koffert, Kirsi Mikkola, Kirsi A. Virtanen, Anna-Maria D. Andersson, Linda Faxius, Kirsti Hällsten, Mikael Heglind, Letizia Guiducci, Tam Pham, Johanna M.U. Silvola, Jenni Virta, Olof Eriksson, Saila P. Kauhanen, Antti Saraste, Sven Enerbäck, Patricia Iozzo, Riitta Parkkola, Maria F. Gomez, Pirjo Nuutila  Diabetes Research and Clinical Practice  Volume 131, Pages (September 2017) DOI: /j.diabres Copyright © 2017 The Authors Terms and Conditions

2 Fig. 1 Study design. [18F]-fluoro-2-deoxy-d-glucose tracer (FDG) combined with positron emission tomography (PET) imaging (FDG-PET), magnetic resonance imaging (MRI). Diabetes Research and Clinical Practice  , DOI: ( /j.diabres ) Copyright © 2017 The Authors Terms and Conditions

3 Fig. 2 Intestinal glucose uptake (GU) after metformin intervention. Panels A–H: experimental animals, I–K human data, green (metformin) and white (control) symbols indicate interventions. Metformin treated rats showed higher [18F]-fluoro-2-deoxy-d-glucose (FDG) uptake in the small intestine in the biodistribution analysis (A). B–E: representative images of radiotracer accumulation in the mucosal layer (black arrows). Autoradiography confirmed radiotracer accumulation only in the mucosal layer of the intestinal sections (D and E, between white lines). In the metformin treated group (C) this accumulation was higher compared to control group (B) 239 (65.4) PSL/mm2 vs. 185 (47.7), P=0.002, respectively. The PET examinations (F) showed increased FDG uptake in vivo in small intestine in animals following metformin intervention compared to controls. There was also an increase in FDG uptake in the colon, although from a lower basal level. White arrows demonstrating increased FDG uptake in red areas. Small animal CT and PET images for control and metformin groups (G and H). Human data, show GU in the small bowel was increased by 2-fold and in the colon by 3-folds compared to baseline (I) after 26weeks of metformin treatment. Fused PET/MRI images for same study subject in the baseline (J) and after metformin treatment (K). Region of interest drawn in fused PET-MRI (white line). Data are shown with median (A and F), *P<0.05, **P<0.01 and ***P< vs. control (for animal study) and baseline (for human study). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Diabetes Research and Clinical Practice  , DOI: ( /j.diabres ) Copyright © 2017 The Authors Terms and Conditions

4 Fig. 3 Tissue specific glucose uptake. Panel (A) showing small intestine and (B) colon GU (C) M-value (D) skeletal muscle GU in different intervention groups. Metformin significantly increased GU in the small intestine (2-fold) and in the colon (3-fold). Rosiglitazone treatment caused 22%, 44% and 25% incremental increases in the small intestine GU, M-value and skeletal muscle GU, respectively. *P<0.03, **P<0.05 and ***P<0.001 vs. baseline. Diabetes Research and Clinical Practice  , DOI: ( /j.diabres ) Copyright © 2017 The Authors Terms and Conditions

5 Fig. 4 Relationship between intestinal metabolism and glycemic control. Increased glucose uptake (GU) in colon correlated with decrease in fasting plasma glucose in metformin group (A). Increased whole body GU correlated with postintervention intestinal GU in metformin (B)group. Diabetes Research and Clinical Practice  , DOI: ( /j.diabres ) Copyright © 2017 The Authors Terms and Conditions