Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes

OBJECTIVE

Leptin therapy improves insulin sensitivity in people with leptin deficiency, but it is not known whether it improves insulin action in people who are not leptin deficient. The purpose of the current study was to determine whether leptin treatment has weight loss–independent effects on insulin action in obese subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We conducted a randomized, placebo-controlled trial in obese subjects (BMI: 35.4 ± 0.6 kg/m²; mean ± SE) with newly diagnosed type 2 diabetes. Subjects were randomized to treatment with placebo (saline), low-dose (30 mg/day), or high-dose (80 mg/day) recombinant methionyl human (r-Met hu) leptin for 14 days. Multiorgan insulin sensitivity before and after treatment was evaluated by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions to measure glucose, glycerol, and fatty acid kinetics.

RESULTS

Low-dose and high-dose leptin treatment resulted in a threefold (P < 0.01) and 150-fold (P < 0.001) increase in basal plasma leptin concentrations, respectively. However, neither low-dose nor high-dose therapy had an effect on insulin-mediated suppression of glucose, glycerol, or palmitate rates of appearance into plasma compared with placebo. In addition, leptin treatment did not increase insulin-mediated stimulation of glucose disposal compared with placebo (14.3 ± 3.1, 18.4 ± 3.6, 16.7 ± 2.4 vs. 17.5 ± 2.5, 20.7 ± 3.0, 19.1 ± 3.3 μmol/kg body wt/min before vs. after treatment in the placebo, low-dose, and high-dose leptin groups, respectively).

CONCLUSIONS

r-Met hu leptin does not have weight loss–independent, clinically important effects on insulin sensitivity in obese people with type 2 diabetes.Data from studies conducted in animal models indicate that leptin has beneficial effects on insulin action on glucose metabolism (1–3). Leptin also has profound metabolic effects in people. Leptin deficiency is associated with increased body weight and insulin resistance (4), and leptin replacement therapy improves insulin sensitivity in people with congenital leptin deficiency and leptin deficiency as a result of lipodystrophy or HIV-induced lipoatrophy (5–8). In contrast, obesity is commonly associated with insulin resistance despite high plasma leptin concentrations (9–11). Moreover, obesity is associated with resistance to many of the metabolic effects of leptin (12), which has led to the notion that resistance to leptin is involved in the pathogenesis of obesity-related insulin resistance. We hypothesized that increasing plasma leptin concentrations by exogenous leptin administration can improve insulin sensitivity in obese, insulin-resistant subjects. Accordingly, we conducted a randomized, placebo-controlled trial (NCT01207934) to evaluate the effect of low-dose and high-dose leptin treatment on insulin action on glucose production, glucose uptake, and lipolysis (by using a two-stage euglycemic-hyperinsulinemic clamp in conjunction with stable isotopically labeled tracer infusions) in obese subjects with newly diagnosed type 2 diabetes.