Response to Fukui et al.

In response to the letter by Fukui et al. (1) in this issue of Diabetes Care, we first must comment on the possible interaction between leptin and insulin, independent of body fatness. Leptin is mainly an adipocyte-secreted protein. Leptin, the obese (ob) gene product, is an adipose tissue hormone that has been closely linked to the amount of body-fat stores. Most of the research following the discovery of leptin was focused on the role it plays in body weight regulation, aiming to illuminate the pathophysiology of human obesity. However, more data are emerging that show that leptin is not only important in the regulation of food intake and energy balance, but that it also has a function in metabolism, as well as in normal sexual maturation and reproduction. Leptin may thus be considered a new endocrine mediator, besides its obvious role in body weight regulation. A possible interaction between leptin and insulin was first suggested by the strong correlations between fasting serum leptin and insulin levels observed in human studies, independent of body fatness (2). Convincing evidence has shown that insulin can regulate leptin expression. This is most evident from studies with isolated adipocytes, which all showed that in vitro insulin clearly stimulates the mRNA expression and secretion of leptin in cultured rat and human adipocytes. Leptin probably acts at different intracellular levels, from transcription to membrane permeability, to inhibit insulin synthesis as well as secretion. Leptin can impair insulin production, and some data indicate that leptin could also play a role in the development of peripheral insulin resistance (3).

In our study, 44 consecutive eligible patients with chronic hepatitis C virus (HCV) infection were studied. The study group had a BMI of 22.6 ± 1.3 kg/m² and were aged 27.3 ± 6.8 years. The control group was matched for age, sex, and BMI. All study patients were evaluated to rule out other causes of chronic liver disease such as hepatitis B virus (HBV) infection, alcohol abuse, autoimmune hepatitis, and primary biliary cirrhosis. There was no evidence of decompensated liver disease. No patient received any antiviral, immunomodulatory, or immunosuppressive therapy. Patients with any other causes of peripheral insulin resistance were excluded. Therefore it is impossible to determine whether the correlation between fasting serum leptin and insulin levels/HOMA-estimated insulin sensitivity in the whole group depends on the effect of BMI and any other causes of peripheral insulin resistance.

In the letter by Fukui et al., it was mentioned that leptin reverses insulin resistance (1,4). We think that this reversal is the result of leptin in physiological levels because previous studies showed that the high serum leptin levels cause desensitization of the receptor and thus defective leptin receptor signaling in β-cells, which leads to chronic hyperinsulinemia and may thus contribute to the pathogenesis of diabetes (3).

Fukui et al. also mentioned that the mechanism of insulin resistance in patients with chronic HCV infection may be due to HCV-induced inflammation. Yet, it is impossible to say that the only mechanism of insulin resistance in these patients was HCV-induced inflammation and that leptin played no role. Leptin receptors are present on human hepatocytes, and leptin was shown to modulate several insulin-induced activities in these cells. Leptin antagonizes insulin signaling by decreasing insulin-induced tyrosine phosphorylation of insulin receptor substrate-1. It increases PEPCK and decreases glucokinase expression, leading to increased gluconeogenesis and decreased glycogenolysis. The hepatic effects of high leptin levels may thus contribute to hepatic insulin resistance (5). Leptin also plays an important role in liver fat storage. Steatosis is a common finding in chronic HCV infections. Overaccumulation of lipids in nonadipose tissues may lead to lipotoxic complications such as diabetes (6). Previous studies reported that the serum leptin levels were significantly higher in patients with steatohepatitis, and elevated serum leptin levels may promote hepatic steatosis and steatohepatitis (7).

There are also several pathogenetical mechanisms to explain the insulin resistance in patients with chronic HCV infection. Bonora et al. (8) reported that the peripheral hyperinsulinemia observed in subjects with chronic hepatic disease was due to diminshed insulin removal by the diseased liver rather than pancreatic hypersecretion. Bonora et al. also reported that both hyperinsulinemia and high concentrations of counterregulatory substances might play a role in the pathogenesis of insulin resistance in subjects suffering from chronic liver disease (9). So, we cannot say that the only mechanism of insulin resistance in such patients was hypersecretion of insulin-resistant cytokines and decreased liver carbohydrate metabolism. For these reasons, we believe that high serum leptin levels are an important etiological factor of insulin resistance in patients with chronic HCV infection.