title: Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice.
abstract: In the course of metformin treatment, staging abdominal cancer lesions with (18)F-FDG PET images is often hindered by the presence of a high bowel radioactivity. The present study aimed to verify the mechanism underlying this phenomenon.
  
  
  METHODS
  Fifty-three mice were submitted to dynamic acquisitions of (18)F-FDG kinetics under fasting conditions. Three small-animal PET scans were obtained over a 4-mo study period. The animals were subdivided into 4 groups according to the following metformin administration protocol: group 1, untreated mice (n = 15); group 2, mice exposed to metformin treatment (750 mg/kg/d) for the 48 h before each PET study (pulsed, n = 10); group 3, mice treated for the whole study period (prolonged, n = 10); and group 4, mice in which prolonged treatment was interrupted 48 h before PET (interrupted, n = 8). The rate constant of (18)F-FDG uptake was estimated by Patlak analysis. At the end of the study, the ileum and colon were harvested, washed, and counted ex vivo. Two further groups, of 5 animals each, were included to evaluate the effect of prolonged metformin treatment on phosphorylated adenosine monophosphate (AMP)-activated protein kinase (pAMPK) form and gene expression for thioredoxin-interacting protein (TXNIP).
  
  
  RESULTS
  Pulsed treatment did not modify gut tracer retention with respect to the untreated group. Conversely, prolonged treatment induced a progressive increase in (18)F-FDG uptake that selectively involved the colonic wall, without any significant contamination of bowel content. This effect persisted after a complete drug washout in the interrupted group. These responses were paralleled by increased pAMPK availability and by reduced expression of TXNIP messenger RNA in colonic enterocytes exposed to prolonged metformin treatment.
  
  
  CONCLUSIONS
  Metformin causes a selective increase in colonic (18)F-FDG uptake. This effect appears after a relatively long period of treatment and persists soon after drug washout. Accordingly, the increased bowel glucose metabolism reflects a biologic response to chronic metformin treatment characterized by increased levels of pAMPK and reduced levels of TXNIP.
authors.affiliation: Nuclear Medicine, Department of Internal Medicine, University of Genoa and IRCCS San Martino-IST, 16132 Genoa, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Massollo
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marini
authors.forename: Massimo
authors.initials: M
authors.lastname: Brignone
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.forename: Barbara
authors.initials: B
authors.lastname: Salani
authors.forename: Mattia
authors.initials: M
authors.lastname: Riondato
authors.forename: Selene
authors.initials: S
authors.lastname: Capitanio
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiz
authors.forename: Alessia
authors.initials: A
authors.lastname: Democrito
authors.forename: Adriana
authors.initials: A
authors.lastname: Amaro
authors.forename: Silvia
authors.initials: S
authors.lastname: Morbelli
authors.forename: Michele
authors.initials: M
authors.lastname: Piana
authors.forename: Davide
authors.initials: D
authors.lastname: Maggi
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
authors.forename: Gianmario
authors.initials: G
authors.lastname: Sambuceti
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology*; D041981:Gastrointestinal Tract / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000494:pharmacology; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D019275:Radiopharmaceuticals; C445672:Txnip protein, mouse; D019788:Fluorodeoxyglucose F18; D013879:Thioredoxins; D008687:Metformin; D005947:Glucose