The finding that circulating leptin concentrations exhibit a diurnal pattern (1,2), with peak nocturnal concentrations up to two times higher than nadir levels, raised the hypothesis that the evaluation of fasting leptin levels might have underestimated the effect of food secretagouges on postpradial leptin regulation and action. This variation in diurnal leptinemia is related to insulin excursions in response to meals (2), and shifting mealtime by 6.5 h without changing the light and sleep cycles will shift plasma-leptin rhythm by 5–7 h (3). In a recent study (4), it was reported that meals with high fat content result in the production of lower 24-h leptin concentrations compared with meals high in carbohydrates, a phenomenon attributed to lower insulin excursions after fatty meals. However, the impact of reduced insulin sensitivity on short-term leptin production in response to meals has not been investigated in subjects with similar degrees of obesity. We hypothesize that patients with type 2 diabetes (a well-established insulin-resitant state) show lower postprandial incremental leptin production in response to an oral fat tolerance test.

A total of 18 type 2 diabetic male patients and 14 control subjects were matched for age and anthropometric parameters. After a 14-h fast, a test meal of 700 kcal/m2 (consisting of 4.75 g protein, 24 g carbohydrates, and 65 g fat) (5) was ingested. Blood samples were drawn at fasting and at 2-, 4-, 6-, and 8-h after the meal to determine the levels of glucose, total cholesterol, triglycerides, HDL-C, insulin, and leptin.

Triglycerides increased significantly from baseline only in diabetic patients (P = 0.001 vs. P = 0.066, respectively), with peak concentrations attained at 6-h. Postprandial total cholesterol, LDL cholesterol, and HDL cholesterol levels did not differ significantly between groups or from levels at fasting. Insulin levels increased postprandially in both groups (P = 0.001 and P = 0.002), with peak values observed at 2 h. Compared with control subjects, diabetic patients displayed a prolonged insulin response, with 4-h values being significantly different from fasting insulin levels (P = 0.008). Although we could not legitimately evaluate the significance of differences at each time point (P > 0.05) (Fig. 1), leptin levels tended to decrease postprandially in both groups, with nadir levels observed at 4 h in diabetic patients and at 2 h in control subjects. Leptin levels at 4 h were significantly lower in diabetic patients compared with control subjects (4.12 ± 0.45 vs. 5.85 ± 0.47 ng/ml, P = 0.015).

Although we did not observe significant variations of leptin concentrations in the two groups, some points need particular consideration. The initial decrease in leptin concentration observed at 2 h was common in both groups. Interestingly, in type 2 diabetic patients, leptin continued to decline contrary to control subjects, with nadir levels observed at 4 h. Regardless of feeding, this early waning appears to be a continuation of decline from peak nocturnal levels. The same tendency was observed in another study (1), where the 24-h profiles of circulating leptin levels were studied using isocaloric diet. No such decrease was observed after lunch, supper, or evening snack.

Although there was no interaction between time and postprandial leptin performance, leptin concentrations continued to decline at 4 h in type 2 diabetic patients, reaching values significantly lower compared with those of control subjects, in whom leptin tended to increase after the initial drop. A similar time difference regarding leptin increase was observed during hyperinsulinemic clamp studies, where a significant increase in leptin concentration was observed after 6 and 8.5 h in control subjects and type 2 diabetic patients, respectively (6). It is reported that an insulin-mediated increase in leptin levels is dependent on glucose entry and metabolism in adipocytes (7). We hypothesize that the delayed response of leptin observed in diabetic patients might be related to impaired-insulin sensitivity at the level of adipose tissue. Indirect evidence of insulin resistance (8,9) in our study arises from the enhanced triglyceride response exhibited only by diabetic patients. Although we cannot exclude the contribution of relative insulin deficiency in impaired leptin response found in diabetic patients, the comparable insulin concentration in the two groups does not favor this hypothesis.

In conclusion, we found that a lipid load does not have a short-term effect on leptin levels in both type 2 diabetic patients and healthy control subjects. The tendency of a delayed postprandial leptin response in diabetic subjects might be related to impaired insulin sensitivity at the level of adipose tissue. Further studies are needed to confirm this observation and to address the corresponding metabolic significance.

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Address correspondence to Andreas Melidonis, MD, PHD, Vizandiou 90, Terpsithea, Glyfada, Athens, Greece. E-mail: