Adiponectin, also referred to as Acrp30, AdipoQ, and GBP28, is a plasma protein exclusively produced by adipose tissue and a possible insulin-sensitizing agent (1–6). Serum adiponectin levels are negatively correlated to BMI in healthy individuals and decreased in type 2 diabetic patients (1–6). However, serum adiponectin levels in type 1 diabetes have not been elucidated.
We examined the serum adiponectin concentrations in 46 type 1 diabetic patients (21 males and 25 females) and compared them with those of BMI-matched healthy control subjects (17 males and 19 females). Mean age was 33 ± 3 and 33 ± 4 years, BMI was 19.8 ± 0.5 and 19.9 ± 0.6 kg/m2, HbA1c level was 9.7± 0.7 and 10.4 ± 0.6%, duration of diabetes was 3.2 ± 0.9 and 3.4 ± 1.3 years, and urinary C-peptide excretion was 18.4 ± 4.3 and 18.0 ± 2.4 μg/day in male and female patients, respectively. High prevalence of GAD antibody or islet cell antibodies (91.3%) indicated autoimmune-associated β-cell destruction in those patients. Two patients suffered from simple diabetic retinopathy, and two other patients had microalbuminuria, but no patient suffered from macroalbuminuria, continuous proteinuria, or elevated serum creatinin. All patients revealed normal electrocardiogram at rest. In the control group, mean age was 34 ± 1 and 33 ± 2 years and BMI was 20.8 ± 0.4 and 20.2 ± 0.5 in males and females, respectively. There were no significant differences in age and BMI between type 1 diabetic patients and control subjects, in either males or females. Informed consent was obtained from all patients and healthy control subjects. Serum adiponectin levels were determined by enzyme-linked immunosorbent assay (2). Intra- and interassay variation in our laboratory was 3.3 and 7.4%, respectively. Unexpectedly, serum adiponectin levels were markedly higher in type 1 diabetic patients (13.6 ± 1.8 μg/ml in males, and 16.1 ± 1.6 μg/ml in females) than in healthy control subjects (6.9 ± 0.7 μg/ml in males and 10.0 ± 0.8 μg/ml in females, respectively; P < 0.01).
Serum adiponectin levels also were determined before and during the insulin replacement therapy in seven patients. Exogenous insulin (0.49 ± 0.10 units · kg−1 · day−1) had been injected for 1.9 ± 0.7 years after the onset of overt diabetes. HbA1c levels before and during insulin therapy were 10.7 ± 1.3 and 8.2 ± 1.1%, and BMI was 18.3 ± 0.5 and 20.0 ± 0.6 kg/m2, respectively. There was no significant difference in serum adiponectin levels before (11.5 ± 1.3 μg/ml) and during insulin therapy (14.3 ± 3.7 μg/ml) .
Our results have demonstrated that serum adiponectin levels, which have been reported to decrease in type 2 diabetes (3,4), surprisingly increased in type 1 diabetes. Plasma glucose or insulin concentration is a possible regulator of circulating adiponectin level. Among them, hyperglycemia is a common feature of type 1 and type 2 diabetes. Therefore, hyperglycemia itself is not a critical determinant for circulating adiponectin level in vivo.
Chronic exposure of insulin decreased the gene expression of adiponectin in the cultured 3T3-L1 adipocytes (7), suggesting that absolute insulin deficiency may contribute to elevated level of serum adiponectin in type 1 diabetes. However, our longitudinal study showed insulin therapy did not change serum adiponectin levels in type 1 diabetic patients. Berg et al. (6) demonstrated that circulating levels of adiponectin did not change before or after the onset of overt diabetes in NOD mice, although serum insulin levels dramatically decreased after the onset of diabetes. Therefore, factors other than plasma glucose and insulin levels must play a significant role in controlling the serum adiponectin concentration in type 1 diabetes.
Recently, it has been reported that leptin, another adipocyte-derived protein, modulates T-cell immune response (8) and accelerates the development of autoimmune diabetes in NOD mice (9). We have previously reported that adiponectin modulates the expression of endothelial adhesion molecules in vitro (10), which were dysregulated in the pancreas of type 1 diabetic patients (11). Our present results have indicated that serum adiponectin levels increased in type 1 diabetes, suggesting that adiponectin, an adipocyte-derived protein, might influence immune responses as leptin does in autoimmune diabetes.
This study was supported in part by a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology (14013038), a grant from Kanae Foundation for life and socio-medical science, and a grant from Senri Life Science Foundation.
Address correspondence to Akihisa Imagawa, MD, FACP, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2-B5 Yamadaoka, Suita 565-0871, Japan. E-mail: firstname.lastname@example.org.