Fat as a target of antidiabetic drugs

November 12, 2000

Obesity is well known as a risk factor for diabetes mellitus, but curiously, the complete absence of adipose tissue is not protective, but actually causes diabetes. In humans with lipoatrophy, as well as in mouse models of this condition, blood glucose is abnormally high and physiological responses to insulin are blunted. Chao et al. have pursued this paradox by studying the responses of lipoatrophic and obese mice to thiazolidinediones (TZDs), antidiabetic drugs that heighten insulin responsiveness. They report here that mice lacking adipose tissue differ from obese diabetic animals in that they do not benefit from the glucose lowering effects of TZDs. Nevertheless, some of the other effects of these drugs-- increased lipid oxidation and lowered circulating lipid levels‹still occur in these animals. The authors note that both obese and lipoatrophic animals accumulate abnormal quantities of lipid in their livers, and they show that expression of the transcription factor PPARg, the known target for TZD action, is greatly increased in such steatotic liver. Moreover, some TZDs greatly exacerbate this steatosis, which may in part account for their beneficial effects on circulating lipid levels. These findings suggest a possible link between steatosis and diabetes, but it is unclear how lipid accumulation in the liver could affect glucose metabolism in other tissues. The present evidence that adipose tissue is essential for TZDs' antidiabetic effect conflicts with earlier findings that relied on a different, and less severely affected, mouse model of lipoatrophy. Which of these models best matches human lipoatrophic diabetes remains an open question.
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JCI Journals

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