Leptin is an important regulator of insulin action; both leptin deficiency and leptin resistance are associated with insulin-resistant glucose metabolism (4
). Furthermore, leptin replacement improves insulin sensitivity in subjects with leptin deficiency (5
). Part of the beneficial effect of leptin replacement therapy could be a result of reductions in body weight in both leptin-deficient rodents and rodents with high-fat diet–induced obesity (3
). However, leptin therapy increases insulin sensitivity in the absence of a significant decrease in body weight or causes a greater reduction in blood glucose concentration after leptin-induced weight loss than after weight loss induced by pair-feeding alone in wild-type and leptin-deficient rodent models (1
) and improves insulin sensitivity in leptin-deficient subjects, even in the absence of significant changes in body weight (7
). In contrast, our data demonstrate that increasing leptin availability above normal plasma concentrations by treatment with r-Met hu leptin does not have weight-loss–independent, clinically important effects on insulin sensitivity in obese people with type 2 diabetes. These results are consistent with data from previous leptin weight loss trials, which found that 8–12 weeks of leptin therapy and a low-calorie diet did not cause a greater change in plasma glucose or insulin concentrations than placebo therapy and a low-calorie diet (18
The reason(s) for the discrepancy in results from our study and those conducted in leptin-deficient subjects and rodent obesity models is unclear. We studied only subjects with newly diagnosed, and presumably more reversible, type 2 diabetes and used sensitive measures to evaluate insulin sensitivity in vivo to increase our ability to detect an effect of leptin therapy on insulin action. Furthermore, we gave low and high doses of r-Met hu leptin to our subjects to ensure adequate plasma leptin concentrations were achieved and to evaluate potential dose-dependent effects. It is unlikely that the 2-week intervention in our study was not long enough to affect insulin action, because leptin administration alters glucose metabolism within several hours in rodents (11
) and the beneficial metabolic effects of leptin replacement therapy in subjects with leptin deficiency occur within 1 week of treatment (20
). In addition, current treatment strategies in obese insulin-resistant subjects, such as weight loss and pharmacotherapy, demonstrate improved insulin sensitivity can occur within days (13
). Therefore, our data demonstrate that leptin treatment has different metabolic effects in subjects with leptin deficiency (who have almost no body fat) than in obese subjects (who have high plasma leptin concentrations and large amounts of body fat). However, we cannot exclude the possibility that leptin treatment would affect insulin action in overweight or obese subjects who have a lower BMI than our cohort.
In addition, our results demonstrate that leptin does not worsen insulin sensitivity, which has been suggested because of data obtained from studies conducted in obese people and isolated adipocytes. At any given BMI, increased plasma leptin concentration is associated with greater insulin resistance (9
), and withdrawal of chronic leptin therapy in leptin-deficient subjects improves insulin sensitivity (23
). Furthermore, large doses of leptin decrease insulin signaling and metabolic actions of insulin in isolated rat adipocytes (24
). In our study, however, even remarkably high plasma leptin concentrations did not cause insulin resistance.
Although our study was conducted in a small number of subjects, it is unlikely we missed an important therapeutic effect of leptin as a result of inadequate statistical power, because there was not even a trend in leptin-induced changes in substrate kinetics with either dose of leptin therapy compared with placebo. In contrast, current treatment strategies for insulin resistance, such as weight loss and pharmacotherapy, improve insulin-mediated glucose uptake by ~25% or more (13
In summary, we found that short-term treatment with either low-dose or high-dose r-Met hu leptin did not improve liver, skeletal muscle, or adipose tissue insulin sensitivity in weight stable, obese subjects with type 2 diabetes. The absence of a therapeutic effect of leptin in our study, within the context of the observed beneficial effects of leptin replacement therapy in subjects with leptin deficiency (4
), suggests that a small amount of leptin is important for normal insulin action, but increasing leptin availability above normal plasma concentrations does not have weight loss–independent effects on insulin action.