Metabolically obese, normal-weight (MONW) subjects (BMI <25 kg/m2) are characterized by an excess (≥100 cm2 by abdominal computed tomography scanning) visceral fat area (VFA), insulin resistance, and hyperinsulinemia (1,2). The criteria for MONW subjects and the insulin resistance syndrome are very similar, and the pathophysiological events occurring in MONW subjects have recently been the focus of many investigators (1–4).
Several studies have reported the association of oxidative stress with insulin resistance and hyperinsulinemia in obese subjects (5,6). However, the degree of oxidative stress and its correlation with insulin resistance and insulin secretion have not yet been evaluated in MONW subjects.
The present study comprised 18 Japanese MONW (aged 34.7 ± 1.7 years, BMI 23.9 ± 0.3 kg/m2, and VFA 146.3 ± 5.8 cm2 [means ± SE]) and 18 age-matched normal (BMI <25 kg/m2 and VFA <100 cm2) men (aged 33.8 ± 1.4 years, BMI 21.9 ± 0.5 kg/m2, and VFA 59.3 ± 5.3 cm2).
According to the American Diabetes Association’s diagnostic criteria, all subjects had normal glucose tolerance based on the 75-g oral glucose tolerance test (OGTT) (7).
The plasma levels of free 8-epi-prostaglandin F2α (8-epi-PGF2α) were measured as marker of oxidative stress using a commercially available enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI).
8-epi-PGF2α plasma levels in MONW men (40.4 ± 6.2 pg/ml; P < 0.01) were significantly increased compared with normal subjects (8.5 ± 1.5 pg/ml). The glucose infusion rates (index of insulin resistance during the euglycemic-hyperinsulinemic clamp study) in MONW subjects (53.9 ± 3.2 μmol · kg−1 · min−1; P < 0.02) were significantly decreased compared with normal subjects (65.0 ± 2.5 μmol · kg−1 · min−1). Fasting serum levels of insulin (49.1 ± 4.1 pmol/l; P < 0.01), insulin area under the curve (AUC) during the 75-g OGTT (44721.7 ± 3811.3 pmol/l; P < 0.02), and serum levels of triglycerides (1.6 ± 0.1 mmol/l; P < 0.01) were significantly increased in MONW subjects compared with normal subjects (fasting insulin levels 29.9 ± 2.9 pmol/l, insulin AUC 31341.7 ± 3388.9 pmol/l, and serum levels of triglyceride 0.9 ± 0.1 mmol/l).
The 8-epi-PGF2α plasma levels were significantly correlated with the glucose infusion rate (r = −0.513, P < 0.05), VFA (r = 0.868, P < 0.01), serum levels of triglyceride (r = 0.658, P < 0.02), fasting serum levels of insulin (r = 0.502, P < 0.05), and the insulin AUC (r = 0.655, P < 0.01) only in MONW subjects.
Bakker et al. (8) have previously reported that elevated concentration of cytosolic long-chain acyl-CoA, which is associated with increased cytosolic triglyceride stores, induces mitochondrial oxygen free radical production due to intramitochondrial ADP deficiency. Therefore, increased trigylceride content in nonadipose tissue together with increased serum levels of trigylcerides may play an important role in the production of oxidative stress in Japanese MONW subjects.
8-epi-PGF2α plasma levels were significantly correlated with insulin resistance in MONW men. This relationship was also observed in obese men (6). Although correlation does not prove causation, these findings suggest that oxidative stress may contribute to the development of insulin resistance in obese and MONW men.
The results of the present study are in agreement with a previous study (9,10) that showed increased cytosolic long-chain acyl-CoA and oxidative stress lower glucose-induced insulin secretion from pancreatic β-cells. On the other hand, it has been reported that hyperinsulinemia reduces oxidative stress production (11,12). Hyperinsulinemia may also have a protective role against increased oxidative stress in MONW men.
