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Home Projects 2nd call (2009) 8. Quantitative and reproducible measurement of the glucose metabolic rate

8. Quantitative and reproducible measurement of the glucose metabolic rate

Dr. R. Schibli (ETHZ), Dr. S-D. Krämer (ETHZ), Dr. R. Grütter (EPFL) - PhD student: Malte Alf

Project finished in May 2013.

The measurement of the glucose metabolic rate is recognized as an important diagnostic tool not only in cancer research but also in studying physiological processes, and is finding increasingly widespread use also in animal research, mainly by using autoradiography of e.g. 3H or 14C labeled deoxy-glucose. Animal PET, an emerging modality, offers the ability to non-invasively image the glucose metabolic rate in rats and mice using FDG. However, this modality has not found widespread application although in the brain the potential to combine its measurement with e.g. measurements of BOLD fMRI, arterial spin labeling (ASL) of cerebral blood flow (CBF) and 13C NMR measures of oxygen consumption may yield unprecedented insight into the regulation of energy metabolism in rodents.

A standard application of FDG PET is to image the distribution of 18F signal 45 minutes after a bolus administration. At this time point it is assumed that the free (tissue and blood) FDG is negligible and all radioactivity is in the phosphorylated pool. The uptake of the analogue is converted to absolute cerebral metabolic rate of glucose (CMRglc) e.g. by means of the lumped constant (the factor between FDG and glucose metabolic rate), which was only just recently reported for rat brain.

Most labs to date express the tissue radioactivity such imaged in terms of percent injected dose per g tissue (%ID/g). However, this procedure does not easily permit the quantitative measurement of metabolic rates. Some labs thus have resorted to normalization, e.g. by expressing local activity in terms of whole-brain activity. This approach assumes that overall brain activity has not changed and may be suitable for detecting profound changes in a small brain area such as during activation. However, when studying brain glucose metabolism, it is important not only to contend with cerebral metabolic rates but also peripheral glucose levels. Following a bolus of FDG, the duration and amount of FDG remaining in the blood and thus entering the brain for phosphorylation depends on peripheral and hepatic glucose metabolism, the plasma glucose concentration and hormonal factors affecting the endocrine system, such as insulin and glucagon.

While much quantitative information can be gleaned by measuring the plasma arterial input function, a critical factor in obtaining quantitatively reliable measures of glucose metabolic rate, it adds to the experimental complexity of the scan and may require blood sampling, which is problematic, especially in mice. It would thus be desirable to establish highly reproducible protocols that obviate this need and/or scan procedures where the measurement of glucose metabolic rate does not depend on a precise characterization of the arterial input function by blood sampling. Therefore, a highly reproducible administration protocol (and thus the quantitative measurement of CMRglc in vivo depends on tight physiological control.

It is the overall aim of this project to establish reproducible physiological conditions, as well as controlling the conditions governing the conversion of radiotracer glucose uptake into quantitative rates. It is a major challenge to understand the factors influencing the rate of radiotracer incorporation and to accomplish this in the context of studying the effect of hypoglycemia on the cerebral metabolic rate. The rationale for studying insulin-induced acute hypoglycemia is two-fold: First, hypoglycemia is an important complication of the treatment of patients with diabetes with insulin and an understanding of the factors governing the ability of the brain to sustain energy metabolism is crucial in understanding the role of glucose supply across the BBB. In past research we have shown that the increase in CBF occurs when glucose content becomes rate-limiting for metabolism, and that glycogen metabolism accounts for the majority of glucose supply deficit during moderate hypoglycemia. Second, we will study insulin-induced hypoglycemia (and as a secondary aim hyperglycemia), an extreme case of glycemic alteration, in which the lumped constant is substantially altered, and this will lead to a major advance in our understanding how insulin and glucose among others affect reproducible PET scanning.

The hypotheses to be tested are that (a) CMRglc is unchanged until CBF is globally increased during hypoglycemia and (b) that glucose metabolism remains tightly coupled to oxygen metabolism above 3mM in plasma glucose in lightly anesthetized animals and (c) glucose metabolism is decreased only when glucose concentration becomes rate-limiting for metabolism.

Contact: Malte Alf