Olanzapine-induced hyperglycemia: role of humoral insulin resistance-inducing factors.

To the Editors: Second-generation antipsychotic agents such as olanzapine are increasingly replacing older antipsychotic drugs because of their superior activity against the negative symptoms of schizophrenia, decreased extrapyramidal symptoms, and the better overall tolerability. However, second-generation antipsychotic agents are associated with several adverse metabolic effects: clozapine and olanzapine induce the most significant weight gain, olanzapine mainly by increasing body fat; and both of these antipsychotics have been associated with disturbances of glucose metabolism (for review, see Ref. 3). The pathogenesis of olanzapineand clozapine-induced disturbances of glucose homeostasis is unclear. It has recently been demonstrated that several antipsychotics including olanzapine, clozapine, and risperidone do not impair pancreatic h-cell function in vitro. In vivo, neither olanzapine nor risperidone altered h-cell function in healthy volunteers studied in hyperglycemic clamp experiments. Thus, it seems unlikely that these antipsychotics cause a disturbance of glucose homeostasis via a direct effect on the h cells. In a prospective study of schizophrenia patients and a control group, we confirmed and extended these results. In these subjects, h-cell function remained unaltered, but the index representing peripheral insulin resistance increases significantly. The insulin resistance induced by olanzapine treatment is induced within days, suggesting that potent factors that are distinct from weight gain induce insulin resistance directly. Likely candidates include tumor necrosis factor-a (TNF-a), free fatty acids (FFAs), leptin, adiponectin, and resistin. These adipocytokines interfere with the insulin signaling cascade and thus induce insulin resistance and— for some of these adipocytokines—their soluble receptors regulate the biologically active, free fraction of the respective adipocytokines. It is conceivable that olanzapine interferes either directly or indirectly with the insulin signaling pathway. As new assays for some of these adipose tissue–derived insulin resistance–inducing factors have recently become available, we were able to further explore the pathogenesis of olanzapine-induced peripheral insulin resistance, by reassessing the blood samples from our previous study. Consequently, TNF-a, FFAs, adiponectin, and resistin plasma levels were analyzed in schizophrenia patients and healthy controls. Ten patients fulfilling International Classification of Diseases, Tenth Revision diagnostic criteria for schizophrenia, consecutively admitted to 1 of the psychiatric department’s inpatient units, who were assigned to a monotherapy with olanzapine (7.5–20 mg/d) were included in this study (for details, see Refs. 2,6). Plasma FFA concentrations were measured using an enzymatic colorimetric assay (WAKO, NEFA-C, Neuss, Germany), TNF-a using the Quantikine HS human TNF-a immunoassay kit (R&D Systems, Minneapolis, Minn, USA), plasma adiponectin concentrations using a radioimmunoassay method (Linco Research, St Charles, MO, USA), and plasma resistin concentrations using an enzyme immunoassay (Phoenix Pharmaceuticals, Belmont, CA, USA). As previously reported, weight increased by 3.3 kg in olanzapine-treated patients during the medication period of 8.1 weeks, whereas it remained stable in the comparison group. Fasting serum glucose, fasting serum insulin, and the insulin resistance index as calculated by the homeostasis model assessment for insulin resistance was significantly increased in olanzapinetreated patients. TNF-a is expressed and secreted from adipocytes and enlarged adipocytes from obese animals, and humans overexpress this cytokine. Also, neutralizing antibodies against TNF-a increase insulin sensitivity. In a previous prospective study, olanzapine did not change TNF-a plasma levels, whereas the levels of TNF receptors increased significantly, suggesting a regulation of biologically active TNF-a by its soluble receptor. In this study, TNF-a plasma levels also remained stable over the observation period, arguing against a role of TNF-a in olanzapineinduced glucose homeostasis dysregulation (Table 1). FFA levels increase as adipose depots expand. Elevated FFAs impair the ability of insulin to suppress hepatic glucose output and to stimulate glucose uptake into skeletal muscle by increasing the inhibitory insulin receptor substrate-1 serine phosphorylation. Thus, FFAs were analyzed in our blood samples. Results revealed stable FFA levels suggesting that olanzapine does not increase FFA levels (Table 1). Adipose tissue–secreted adiponectin levels are lower in obese than in lean humans and particularly low in diabetic patients. In a cross-sectional pilot study, Togo et al found higher adiponectin levels in olanzapineand risperidone-treated patients and concluded that increased adiponectin levels might have a normalizing effect on glucose dysregulation. In our study, adiponectin concentrations increased by approximately 25%, which confirms part of the observations made by Togo et al (Table 1). Letters to the Editors