Abstract

Worldwide, diabetes has reached epidemic proportions, with type 2 diabetes accounting for ~90% of all cases. One of the earliest disturbances in the etiology of type 2 diabetes is insulin resistance in major metabolic tissues, such as the liver and skeletal muscle. It has been well established that high-energy, high-fat diets and a sedentary lifestyle are important factors leading to an increased risk of developing type 2 diabetes. Whole-body insulin resistance is generally accompanied by ectopic lipid deposition in liver and skeletal muscle tissue.

The mechanistic link between intracellular lipid overload and insulin resistance is believed to reside in the accumulation of lipid derived intermediates, such as diacylglycerols and ceramides, which trigger activation of novel protein kinases C leading to impairments in insulin signaling. A key issue that remains to be determined is whether the excess storage of lipids in insulin-resistant muscle and liver is a consequence of greater lipid uptake from the circulation, decreased lipid utilization, or a combination of both. To identify the exact origin of lipid handling derangements in insulin resistant tissues, direct in vivo measurements of lipid storage dynamics are essential.

Lipid handling in insulin-resistant liver and skeletal muscle has previously been determined using radioactive or stable-isotope labeled fatty acid tracers in arterio-venous balance methods or by determining the specific uptake of these tracers in biopsies, collected tissues, cultured liver and muscle cells, or giant vesicles obtained from muscle. However, these methods are either indirect, invasive, or only performed in vitro. Localized 1H magnetic resonance spectroscopy (MRS) is a powerful tool for the noninvasive detection of intracellular lipid storage in vivo, but it cannot discriminate between disturbances in lipid uptake on one hand and lipid utilization on the other.

Defence date: 20/12/12

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Jonkers, R.A.M.
Jonkers, R.A.M.
Principal Clinical Research Specialist
Medtronic