Metformin and FDG-positron emission tomography

FDG positron emission tomography

18F-FDG is a radiolabelled glucose analogue that provides a key tool in the diagnosis and monitoring of tumors1. Many tumors have a high metabolic rate and require large amounts of glucose to satisfy their energy demands. Consequently, when 18F-FDG is injected into a person with a cancerous lesion it will become concentrated at the site of the tumor. The radiolabel can then be visualized using positron emission tomography (PET) to determine the presence of a tumor and allows calculation of the rate of glucose uptake by the tumor to give an indication of how aggressive it is.

FDG positron emission tomography and diabetes

The accuracy of this technique, however, can be challenged in patients with diabetes as a consequence of the differences in the way glucose is handled. Most importantly, low blood glucose is needed to conduct the test and this can be difficult to achieve in patients with diabetes, especially since anti-diabetic medication needs to be discontinued prior to imaging2. High glucose levels can reduce the sensitivity of PET imaging and the accuracy of glucose uptake measurements3.

Drugs affecting glucose metabolism that are used to manage type 2 diabetes (and therefore are taken by a significant proportion of patients requiring tumor imaging) also interfere with 18F-FDG PET. In particular, the oral anti-hyperglycemic treatment metformin tends to cause 18F-FDG to accumulate in the bowel rather than just at the site of a tumor. This can be seriously detrimental to interpretation of 18F-FDG PET images. Radioactivity observed in the bowel may be attributed to metformin when in fact there is a tumor present or, conversely, be reported as a tumor when there is none.

Metformin diabetes drug (biguanide class), chemical structure. Atoms are represented as spheres with conventional color coding: hydrogen (white), carbon (grey), nitrogen (blue)
Metformin diabetes drug (biguanide class), chemical structure. Atoms are represented as spheres with conventional color coding: hydrogen (white), carbon (grey), nitrogen (blue). Image Credit: Copyright: molekuul.be via Shutterstock - Image ID: 148126673

Effect of metformin on glucose metabolism

Metformin helps control blood sugar levels by suppressing glucose production in the liver. It is known that metformin reduces the amount of glucose from food that reaches the blood and increases the amount of glucose consumed by cells of the intestinal mucosa. However, it was not clear how this led to high levels of 18F-FDG retention in the large intestine.

Elucidation of metformin mode of action

Recent research using whole-body 18F-FDG PET imaging (performed using Albira; Bruker Corporation.) in mice models has provided the answer4. Images were made of mice who had received either short- or long-term treatment with metformin and of mice who were metformin-naive.

The PET images showed greatly increased glucose uptake in the gut of mice exposed to long-term metformin. This effect was observed even when metformin treatment was stopped two days before testing. No effect on gut glucose uptake was observed in mice receiving metformin for a short period or not at all.

18F-FDG levels were determined for each of the different intestinal compartments. This showed that the increased gut glucose uptake was restricted to the colon. Further evaluation of intestinal enzyme levels and gene expression provided insight into the mode of action of metformin. It appears that metformin inhibits mitochondrial production of adenosine triphosphate (ATP). Since ATP is required by the transporters that take up glucose from the gut, this process is reduced and glucose accumulates in the gut. In addition, expression of a protein that regulates cell growth and metabolism and was reduced. These effects were restricted to colon tissue, reflecting the colon-specific increase in glucose uptake. No such changes were observed in tissue from the small intestine.

Clinical relevance

The increase in 18F-FDG in the bowel of patients who have been taking metformin is thus explained by a biological response to chronic metformin treatment. This confirms that colonic lavage, which has been used in an attempt to obtain clearer PET images in diabetic patients, is unlikely to achieve this goal. The only way to prevent interference during 18F-FDG PET imaging is by withholding metformin treatment long enough for this response to have subsided.

References

  1. Kelloff GJ, et al. Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development. Clin Cancer Res 2005;11:2785–2808.
  2. Surasi DS, et al. 18F-FDG PET and PET/CT Patient Preparation: A Review of the Literature. J Nucl Med Technol 2014; 42:5–13.
  3. Büsing KA, et al. Impact of blood glucose, diabetes, insulin, and obesity on standardized uptake values in tumors and healthy organs on 18F-FDG PET/CT. Nucl Med Biol. 2013;40:206–213.
  4. Massollo M, et al. Metformin Temporal and Localized Effects on Gut Glucose Metabolism Assessed Using 18F-FDG PET in Mice. J Nucl Med 2013; 54:259–266.

About Bruker

Bruker is market leader in analytical magnetic resonance instruments including NMR, EPR and preclinical magnetic resonance imaging (MRI). Bruker's product portfolio in the field of magnetic resonance includes NMR, preclinical MRI, EPR and Time-Domain (TD) NMR. In addition.

Bruker delivers the world's most comprehensive range of research tools enabling life science, materials science, analytical chemistry, process control and clinical research. Bruker is also the leading superconductor magnet and ultra high field magnet manufacturer for NMR and MRI solutions.


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Last updated: Jun 9, 2015 at 8:25 PM

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