In all clinical studies to date, type 2 diabetic patients treated with thiazolidinediones tend to gain weight and accumulate adipose tissue (55). It would appear paradoxical that a drug which improves insulin sensitivity and glucose and lipid profiles would at the same time increase adiposity and body weight. Considerable research has focused on the reasons for this paradox, especially the sites and nature of thiazolidinedione-induced weight gain. The thiazolidinediones, through PPAR-y activation cause preadipocytes to differentiate into mature fat cells and also induce key enzymes involved in lipogenesis (56). However, in vitro studies demonstrate that the thiazolidinediones specifically promote the differentiation of pre-adipocytes into adipocytes only in subcutaneous fat and not in omental fat (57). Thiazolidinedione-associated increase in fat mass occurs predominantly in the more insulin responsive subcutaneous fat depots and not in the insulin-resistant visceral body compartments which secrete increased quantities of cytokines. Early clinical studies with CT scans confirmed that thiazolidinedione treatment produces a shift in adipose tissue distribution from the more deleterious omental depot to the more insulin sensitive subcutaneous compartment (58,59). Recent studies with determinations of fat distribution using abdominal magnetic resonance imaging (MRI) and dual energy x-ray absorptiometry (DEXA) after rosiglitazone and pioglitazone therapy confirm that there is greater accumulation in the subcutaneous adipose tissue compartment as compared to a decrease or no change in visceral fat (60). In these and other studies, thiazolidinedione treatment is also associated with a decrease in hepatic lipid content (measured by CT or MRI) and this is consistent with a shift in fat storage not only away from omental/visceral fat, but also away from ectopic storage sites such as the liver to subcutaneous fat tissue.
This putative mechanism is elegantly demonstrated in a study which examined the effects of rosiglitazone treatment in nine subjects with type 2 diabetes (61). After 3 months of rosiglitazone treatment, there were significant improvements in insulin-stimulated glucose metabolism by 68% and 20% during low- and high-dose insulin clamps, respectively. This was associated with significant reductions in plasma FA concentration and hepatic triglyceride content, a 39% increase in extramyocellular lipid content and a 52% increase in the sensitivity of peripheral adipocytes to the inhibitory effects of insulin on lipolysis (as assessed by glycerol release in microdialysis from SQ fat). These results support the hypothesis that thiazolidinediones enhance insulin sensitivity in patients with type 2 diabetes by promoting increased insulin sensitivity in peripheral adipocytes, which results in lower plasma FA concentrations and a redistribution of intracellular lipid from insulin responsive organs into peripheral adipocytes.
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