The innate immune response and type 2 diabetes: evidence that leptin is associated with a stress-related (acute-phase) reaction

OBJECTIVE: Leptin is produced by adipose tissue and controls food intake and body weight. Although blood levels of leptin reflect energy stores, cytokines also stimulate leptin production from fat. Because we have proposed that type 2 diabetes mellitus is associated with a cytokine-mediated acute-phase or stress response, part of the innate immune system, we sought evidence that leptin is increased in type 2 diabetes partly as a stress response, independently of obesity and sex. DESIGN: We selected two groups of type 2 diabetic patients with either a low acute-phase response (< 2.30 mmol/l serum concentration of the acute-phase marker sialic acid) or high response (> 2.30 mmol/l sialic acid), but pair-matched for body mass index (BMI) and sex. PATIENTS: Twenty type 2 diabetic subjects (11 male, 9 female) in each group, whose body mass index (BMI) and age were comparable (mean +/- SD: 28.8 +/- 3.8 vs. 28.9 +/- 3.8 kg/m2, and 60.7 +/- 8.9 vs. 61.9 +/- 12.3 years, low vs. high acute-phase responders, respectively). The glycaemic control was also similar in each group (glycated haemoglobin: 9.1 +/- 2.2 vs. 8.9 +/- 1.9%). MEASUREMENTS: Serum concentrations of sialic acid, leptin, interleukin-6 (IL-6) (the major cytokine mediator of the acute-phase response) and cortisol were assayed in fasting venous blood samples from patients and the results compared. RESULTS: Serum leptin concentration was increased in the high compared to the low acute-phase group (median 13.2 (range 3.6-55) vs. 8.1 (2.0-22.5) microg/l, P = 0.004). IL-6 and cortisol concentrations were also higher in the high-stress group (1.9 (1.0-6.4) vs. 1.4 (0.4-7.5) ng/l, P = 0.02; and 409 (180-875) vs. 290 (157-705) nmol/l, P = 0.02, respectively). Leptin was strongly correlated with BMI (r = 0.61, P < 0.001), but also with sialic acid (r = 0.40, P = 0.01) and IL-6 (r = 0.38, P = 0.04). CONCLUSIONS: Serum leptin concentrations in type 2 diabetes are partly related to an acute-phase or stress response, independent of BMI and sex. The association of hyperleptinaemia with elevated serum cortisol provides a mechanism for leptin resistance in type 2 diabetes (glucocorticoids inhibit the central action of leptin). This study provides further support for the theory that type 2 diabetes is asociated with chronic innate immune activation.