Effect of TGRL modifications on insulin resistance

Insulin resistance is a major pathophysiological feature of type-2 Diabetes Mellitus (DM). The factors involved in the development of insulin resistance have not been identified, yet, evidence is accumulating that lipids, in particular non-esterified fatty acids (NEFAs) play an important role in the development of this state. A recent study from our lab has demonstrated that postprandial triglyceride-rich lipoproteins (TGRL), i.e. chylomicrons and VLDL, are also capable of inducing insulin resistance in L6 skeletal muscle cells, as evidenced by an impairment of glycogen synthesis, glycogen synthase activity, glucose uptake and several insulin signaling steps. A comparative analysis regarding the potential of postprandial TGRL versus NEFAs has not been conducted, nor has been investigated whether major steps in the metabolism of these lipoproteins affect their potential to induce insulin resistance. Therefore, the objective of this study is to answer these important questions. The major steps in the metabolism of TGRL are triglyceride-hydrolysis by lipoprotein lipase (LPL) and lipid exchange by cholesteryl-ester transfer protein (CETP). To mimic these physiologically occurring steps in the metabolism of postprandial lipoproteins, we will in vitro co-incubate highly purified TGRL with LPL and/or with CETP together with HDL3. For this purpose, unprocessed TGRL were isolated by pleural puncture of a chylothorax from one of our patients. Lipoprotein fractions will be purified by zonal ultracentrifugation followed by gel filtration or dialysis. For the second part of this study, various NEFAs, known to be abundant in Western diet, will be compared with TGRL regarding their potential to induce insulin resistance. To assess insulin sensitivity in skeletal muscle cells, we have decided to study the regulation of glycogen synthesis, the impairment of which is considered the biochemical basis of insulin resistance in type-2 DM. The specific experiments planned may provide a conceptual advance towards understanding the pathophysiology of insulin resistance and, thus, represent the basis for novel strategies in preventing and/or treating insulin resistant states including type-2 DM.

Insulin resistance is a major pathophysiological feature of type-2 Diabetes Mellitus (DM). The factors involved in the development of insulin resistance have not been identified, yet, evidence is accumulating that lipids, in particular non-esterified fatty acids (NEFAs) play an important role in the development of this state. A recent study from our lab has demonstrated that postprandial triglyceride-rich lipoproteins (TGRL), i.e. chylomicrons and VLDL, are also capable of inducing insulin resistance in L6 skeletal muscle cells, as evidenced by an impairment of glycogen synthesis, glycogen synthase activity, glucose uptake and several insulin signaling steps. A comparative analysis regarding the potential of postprandial TGRL versus NEFAs has not been conducted, nor has been investigated whether major steps in the metabolism of these lipoproteins affect their potential to induce insulin resistance. Therefore, the objective of this study is to answer these important questions. The major steps in the metabolism of TGRL are triglyceride-hydrolysis by lipoprotein lipase (LPL) and lipid exchange by cholesteryl-ester transfer protein (CETP). To mimic these physiologically occurring steps in the metabolism of postprandial lipoproteins, we will in vitro co-incubate highly purified TGRL with LPL and/or with CETP together with HDL3. For this purpose, unprocessed TGRL were isolated by pleural puncture of a chylothorax from one of our patients. Lipoprotein fractions will be purified by zonal ultracentrifugation followed by gel filtration or dialysis. For the second part of this study, various NEFAs, known to be abundant in Western diet, will be compared with TGRL regarding their potential to induce insulin resistance. To assess insulin sensitivity in skeletal muscle cells, we have decided to study the regulation of glycogen synthesis, the impairment of which is considered the biochemical basis of insulin resistance in type-2 DM. The specific experiments planned may provide a conceptual advance towards understanding the pathophysiology of insulin resistance and, thus, represent the basis for novel strategies in preventing and/or treating insulin resistant states including type-2 DM.