Diabetes type 2, commonly called ‘onset diabetes’, is a metabolic disorder accompanied by a broad range of health complaints. In the preliminary stage of the disorder, patients develop a diminished sensitivity to the hormone insulin, which regulates the sugar metabolism. “The body tries to compensate for this by producing extra insulin”, doctoral candidate ir. Richard Jonkers explains. “In the long term, though, this results in damage to the insulin-producing cells.” As a result, the production of insulin breaks down in the end, which leads to an increased blood glucose level and damage to blood vessels and organs.

Accumulation of fat in the liver and in muscular tissue appears to be instrumental in the development of diabetes, says Jonkers. “There is a clear connection between diabetes and the amount of fat in liver and muscle cells. However, it is not yet entirely clear what causes the fat to accumulate. Is it due to the extra absorption of fat, because too little fat is metabolized, or is it a combination of those two processes?”

The question, then, is what happens to the fat we eat, and how this depends on physical exercise, for instance. In order to monitor the metabolism of fat in the body, Jonkers used magnetic resonance spectroscopy (MRS). “This is a technique akin to MRI”, he explains. “Whereas MRI produces pictures, MRS yields a spectrum.” Such a spectrum is like a fingerprint of the chemical compounds present. MRS even enables us accurately to determine the concentration of various molecules at a certain spot.

By means of MRS Jonkers researched how fat is absorbed (and broken down again) in the liver and in muscles of rats with different stages of diabetes. For this purpose he administered a specially prepared fat to the animals, containing an increased amount of the rare isotope carbon 13. “This isotope has special magnetic properties. This allows us to make the signal of this fat in the spectrum negative, so that we can distinguish it from the ordinary fat.”

Jonkers thinks that this is the first time that MRS with carbon 13 was used for this purpose. It is by no means simple to make the negative peak visible, because it is soon lost in the signal of the ‘ordinary’ fat. Nevertheless he succeeded in retracing the administered fat in liver and muscle cells. “An extra problem is that I was only interested in fat that has been absorbed into cells, and not in subcutaneous fat. This makes it necessary to measure with extreme accuracy in the right spot.”

Jonkers’ approach has great benefits over alternative ways of measuring the absorption of fat. “Although you can see many things by taking a blood sample, that is a very indirect way.” And taking a so-called biopsy also comes with its own drawbacks. “It is rather drastic. You need to make a cut and slice away a piece of tissue. Especially in the liver that is quite a serious operation.” Besides, a biopsy can only be analyzed afterwards, whereas MRS leaves everything intact so that you can measure at the same spot again later – which is exactly what Jonkers wanted.

The experiments with healthy rats showed that the administered fat had nestled in the liver after about four hours. “After 24 hours you see a decrease again in the amount of fat with carbon 13. That has then been broken down partly or transported to muscles where it is used as fuel.” Subsequently the doctoral candidate repeated the measurements in both rats with an initial stage of diabetes and in genuinely diabetic animals. Both groups proved to store much more fat in the liver than healthy animals, while the absorption of fat in muscles was only higher in rats with real diabetes. This means that things go wrong sooner in the liver than in the muscles.

The next step was physical exercise; in rats this can be stimulated easily by means of a treadmill. Regular exercise can help prevent diabetes, but it is less clear whether it also changes the metabolism of fat in the liver and the muscles. An hour’s exercise in the treadmill reduced the fat content in muscle cells of healthy and sick rats alike, Jonkers observed. That is healthy alright, but it is more important that the subsequent absorption of fat was not stimulated extra by the preceding exercise.

Jonkers did not only study rats, though. To see whether prolonged inactivity automatically results in too high a fat content in muscle cells, he examined the leg muscles of people with paraplegia. To this end he combined ‘standard’ MRS with fluorescence microscopy. “Although paraplegic people who are otherwise fit and healthy did have another distribution of fat in their muscle cells, their leg muscles did not contain more fat than in the control group. So it looks as if prolonged inactivity causes these muscles to adapt to a lower energy need.”

The MRS technique involving carbon 13 proves to be eminently suited to monitor fat in the body. In the Biomedical NMR research group the doctoral candidate had a small MR scanner at his disposal with a magnetic field of 6.3 Tesla – more powerful than the average hospital scanner and hence more accurate. In principle the new method can also be applied to humans, but a few practical problems need to be solved first. “If you convert the amount of fat you need to ingest from rats to humans, you arrive at 80 grams of pure fat. That is really a large amount; it could even generate acute insulin resistance.”

Still, Jonkers is optimistic about the possibilities of the technique. “When you use a stronger magnetic field, you do not need so much fat. Moreover, you can also label sugar with carbon 13, for example. My former roommate at Biomedical NMR, Sharon Janssens, is working on that at the moment.”