Nuclear Medicine, Department of Internal Medicine, University of Genoa and IRCCS San Martino-IST, 16132 Genoa, Italy.
J Nucl Med. 2013 Feb;54(2):259-66. doi: 10.2967/jnumed.112.106666. Epub 2013 Jan 3.
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.
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).
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.
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.
在二甲双胍治疗过程中，由于肠道放射性高，常妨碍用（18）F-FDG PET 图像对腹部癌症病灶进行分期。本研究旨在验证这一现象的机制。
53 只小鼠在空腹状态下进行（18）F-FDG 动力学的动态采集。在 4 个月的研究期间进行了 3 次小动物 PET 扫描。根据以下二甲双胍给药方案将动物分为 4 组：第 1 组，未治疗的小鼠（n = 15）；第 2 组，在每次 PET 研究前 48 小时暴露于二甲双胍治疗（脉冲，n = 10）；第 3 组，整个研究期间接受治疗（延长，n = 10）；第 4 组，在 PET 前 48 小时中断延长治疗（中断，n = 8）。通过 Patlak 分析估计（18）F-FDG 摄取的速率常数。研究结束时，收获回肠和结肠，洗涤并进行离体计数。还包括另外两组，每组 5 只，以评估延长二甲双胍治疗对硫氧还蛋白相互作用蛋白（TXNIP）的磷酸化腺苷单磷酸（AMP）激活蛋白激酶（pAMPK）形式和基因表达的影响。
脉冲治疗与未治疗组相比并未改变肠道示踪剂的保留。相反，延长治疗会导致（18）F-FDG 摄取逐渐增加，这种增加仅涉及结肠壁，而不会使肠内容物受到任何明显污染。在中断组中完全停药后，这种作用仍然存在。这些反应伴随着结肠细胞中 pAMPK 可用性的增加和长期二甲双胍治疗下 TXNIP 信使 RNA 表达的降低。
二甲双胍会导致结肠（18）F-FDG 摄取增加。这种作用在相对较长的治疗期后出现，并在停药后不久仍然存在。因此，肠道葡萄糖代谢增加反映了对慢性二甲双胍治疗的生物学反应，其特征是 pAMPK 水平升高和 TXNIP 水平降低。
