Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice

Michela Massollo, Cecilia Marini, Massimo Brignone, Laura Emionite, Barbara Salani, Mattia Riondato, Selene Capitanio, Francesco Fiz, Alessia Democrito, Adriana Amaro, Silvia Morbelli, Michele Piana, Davide Maggi, Michele Cilli, Ulrich Pfeffer, Gianmario Sambuceti

Research output: Contribution to journalArticle

Abstract

In the course of metformin treatment, staging abdominal cancer lesions with 18F-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 18FFDG 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 18F-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 = 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 18F-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. Conclusion: Metformin causes a selective increase in colonic 18F-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.

Original languageEnglish
Pages (from-to)259-266
Number of pages8
JournalJournal of Nuclear Medicine
Volume54
Issue number2
DOIs
Publication statusPublished - Feb 2013

Fingerprint

Metformin
Fluorodeoxyglucose F18
Glucose
Thioredoxins
Proteins
Enterocytes
Neoplasm Staging
Adenosine Monophosphate
Ileum
Pharmaceutical Preparations
Positron-Emission Tomography
Protein Kinases
Radioactivity
Fasting
Colon
Gene Expression
Messenger RNA

Keywords

  • AMPK
  • GI tract
  • Metformin
  • Positron emission tomography
  • TXNIP

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice. / Massollo, Michela; Marini, Cecilia; Brignone, Massimo; Emionite, Laura; Salani, Barbara; Riondato, Mattia; Capitanio, Selene; Fiz, Francesco; Democrito, Alessia; Amaro, Adriana; Morbelli, Silvia; Piana, Michele; Maggi, Davide; Cilli, Michele; Pfeffer, Ulrich; Sambuceti, Gianmario.

In: Journal of Nuclear Medicine, Vol. 54, No. 2, 02.2013, p. 259-266.

Research output: Contribution to journalArticle

Massollo, M, Marini, C, Brignone, M, Emionite, L, Salani, B, Riondato, M, Capitanio, S, Fiz, F, Democrito, A, Amaro, A, Morbelli, S, Piana, M, Maggi, D, Cilli, M, Pfeffer, U & Sambuceti, G 2013, 'Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice', Journal of Nuclear Medicine, vol. 54, no. 2, pp. 259-266. https://doi.org/10.2967/jnumed.112.106666
Massollo, Michela ; Marini, Cecilia ; Brignone, Massimo ; Emionite, Laura ; Salani, Barbara ; Riondato, Mattia ; Capitanio, Selene ; Fiz, Francesco ; Democrito, Alessia ; Amaro, Adriana ; Morbelli, Silvia ; Piana, Michele ; Maggi, Davide ; Cilli, Michele ; Pfeffer, Ulrich ; Sambuceti, Gianmario. / Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice. In: Journal of Nuclear Medicine. 2013 ; Vol. 54, No. 2. pp. 259-266.
@article{0fe714e7d0cd40fd87a4dc37d5fce116,
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 18F-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 18FFDG 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 18F-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 = 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 18F-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. Conclusion: Metformin causes a selective increase in colonic 18F-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.",
keywords = "AMPK, GI tract, Metformin, Positron emission tomography, TXNIP",
author = "Michela Massollo and Cecilia Marini and Massimo Brignone and Laura Emionite and Barbara Salani and Mattia Riondato and Selene Capitanio and Francesco Fiz and Alessia Democrito and Adriana Amaro and Silvia Morbelli and Michele Piana and Davide Maggi and Michele Cilli and Ulrich Pfeffer and Gianmario Sambuceti",
year = "2013",
month = "2",
doi = "10.2967/jnumed.112.106666",
language = "English",
volume = "54",
pages = "259--266",
journal = "Journal of Nuclear Medicine",
issn = "0161-5505",
publisher = "Society of Nuclear Medicine Inc.",
number = "2",

}

TY - JOUR

T1 - Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice

AU - Massollo, Michela

AU - Marini, Cecilia

AU - Brignone, Massimo

AU - Emionite, Laura

AU - Salani, Barbara

AU - Riondato, Mattia

AU - Capitanio, Selene

AU - Fiz, Francesco

AU - Democrito, Alessia

AU - Amaro, Adriana

AU - Morbelli, Silvia

AU - Piana, Michele

AU - Maggi, Davide

AU - Cilli, Michele

AU - Pfeffer, Ulrich

AU - Sambuceti, Gianmario

PY - 2013/2

Y1 - 2013/2

N2 - In the course of metformin treatment, staging abdominal cancer lesions with 18F-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 18FFDG 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 18F-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 = 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 18F-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. Conclusion: Metformin causes a selective increase in colonic 18F-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.

AB - In the course of metformin treatment, staging abdominal cancer lesions with 18F-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 18FFDG 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 18F-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 = 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 18F-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. Conclusion: Metformin causes a selective increase in colonic 18F-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.

KW - AMPK

KW - GI tract

KW - Metformin

KW - Positron emission tomography

KW - TXNIP

UR - http://www.scopus.com/inward/record.url?scp=84873553761&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873553761&partnerID=8YFLogxK

U2 - 10.2967/jnumed.112.106666

DO - 10.2967/jnumed.112.106666

M3 - Article

C2 - 23287574

AN - SCOPUS:84873553761

VL - 54

SP - 259

EP - 266

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

SN - 0161-5505

IS - 2

ER -