Type 2 diabetes has reached epidemic proportions and affects more than 170 million individuals worldwide. The number of people affected by diabetes is expected to have increased by almost 50% in the year 2010. Insulin resistance is an early event in the pathogenesis of type 2 diabetes. However, the exact processes leading to insulin resistance are still not known.
Excessive ectopic lipid storage inside muscle cells has been linked to insulin resistance, as the amount of these so-called intramyocellular lipids (IMCL) negatively correlates with insulin sensitivity. This association is unlikely to be causal, as also insulin sensitive subjects may have high IMCL levels, e.g. well-trained endurance athletes.
Acute lipid infusion studies have identified an important role for lipid derived intermediates, such as long chain acyl-CoA, diacylglycerol and ceramides, which are likely to induce defects in the insulin signaling cascade. These insulin desensitizing intermediates are only transiently present and high levels of these compounds may result from an imbalance between lipid availability, storage and oxidation.
In recent years, it has become clear that mitochondrial dysfunction is another common phenotype of type 2 diabetes. Mitochondrial dysfunction might lead to increased levels of lipid derived intermediates, as it reduces the capacity for fat oxidation, and thereby induce insulin resistance. On the other hand, mitochondrial dysfunction might also be a consequence of insulin resistance, e.g. by downregulation of oxidative genes. Based on data of current cross-sectional studies, these different mechanisms cannot be distinguished.
In our research, we investigate the causality of the relationship between IMCL accumulation and mitochondrial dysfunction by measuring longitudinal changes in IMCL content and muscle oxidative capacity in rat models of insulin resistance and type 2 diabetes with the use of in vivo magnetic resonance spectroscopy (MRS).
MRS is a non-invasive technique, which allows repeated measurements and is therefore uniquely suited for longitudinal studies of changes in metabolism during the development of a disease. In addition to static IMCL levels, it is of relevance to study the dynamics of incorporation of endogenous fatty acids in, and the liberation of stored fatty acids from IMCL’s, as this will determine the level of insulin desensitizing lipid intermediates. In addition to our longitudinal animal studies, we apply the same MRS methods to measure IMCL content and muscle oxidative capacity in human (intervention) studies. As an example, we investigated the effect of a 5-month exercise training program on these parameters in long-standing, insulin-treated type 2 diabetic subjects.
H.M.M.L. De Feyter, N.M.A. van den Broek, S.F.E. Praet, K. Nicolay, L.J.C. van Loon, and J.J. Prompers. Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction. Eur. J. Endocrinol. 158, 643-653 (2008).
H.M.M.L. De Feyter, S.F.E. Praet, N.M.A. van den Broek, H. Kuipers, C.D. Stehouwer, K. Nicolay, J.J. Prompers, and L.J.C. van Loon. Exercise training improves glycemic control in long-standing, insulin-treated type 2 diabetes patients. Diabetes Care 30, 2511-2513 (2007).
N.M.A. van den Broek, H.M.M.L. De Feyter, L. de Graaf, K. Nicolay, and J.J. Prompers. Intersubject differences in the effect of acidosis on phosphocreatine recovery kinetics in muscle after exercise are due to differences in proton efflux rates. Am. J. Physiol. Cell Physiol. 293, C228-C237 (2007).
S.F.E. Praet, H.M.M.L. De Feyter, R.A.M. Jonkers, K. Nicolay, C. van Pul, H. Kuipers, L.J.C. van Loon, and J.J. Prompers. 31-P MR spectroscopy and markers of oxidative capacity in type 2 diabetes patients. 19, 321-331 (2006).
J.J. Prompers, J.A.L. Jeneson, M.R. Drost, C.C.W. Oomens, G.J. Strijkers, and K. Nicolay. Dynamic MRS and MRI of skeletal muscle function and biomechanics. NMR Biomed. 19, 927-953 (2006).
H.M.M.L. De Feyter, G. Schaart, M.K.C. Hesselink, P. Schrauwen, K. Nicolay, and J.J. Prompers. Regional variations in intramyocellular lipid concentration correlate with muscle fiber type distribution in rat tibialis anterior muscle. Magn. Reson. Med. 56, 19-25 (2006).