Lipoatrophic (lipodystrophic) diabetes is a disorder in which insulin resistance and hyperglycaemia are associated with a reduced body-fat mass1, in contrast to the usual association of diabetes with obesity. Transgenic mice with differing degrees of fat loss can be used as models for lipoatrophy2,3,4. Using the aP2-SREBP-1c mouse3, which has a moderate fat deficiency, Shimomura et al. showed that leptin treatment reverses the diabetes, concluding that insulin resistance in congenital generalized lipodystrophy can be explained by a leptin deficiency5. However, we have used a more severe model of lipoatrophy, the A-ZIP/F-1 mouse2,6, in which we find that leptin treatment is only slightly effective in correcting diabetes.