Discussion
The current study has confirmed associations of AT-IR with fasting glucose and triglycerides as previously reported by us,14 and demonstrated that AT-IR but normal weight was associated positively with resting pulse rate and hsCRP, a marker of systemic low-grade inflammation through mechanisms unrelated to adiposity. Normal weight young Japanese women with the high AT-IR tertile were indeed in the adipose insulin-resistant state because their AT-IR (6.3±3.4, table 1) was equivalent to or even higher than AT-IR (4.3±2.4) in overweight Japanese women.14
Suppression of hepatic glucose production by insulin is critical for maintenance of normal glucose homeostasis, and impairment in this process plays an important role in the pathogenesis of type 2 diabetes. There is general agreement that the acute suppression of hepatic glucose production by insulin is mediated by both a direct (hepatic) and an indirect (extrahepatic) effect on the liver.20 As reviewed by Lewis et al,20 there is abundant evidence that insulin’s effect on adipose tissue lipolysis is a key signal mediating insulin’s extrahepatic effect to inhibit hepatic glucose production. These findings may be related to the independent association of AT-IR but normal weight with fasting glucose concentrations in the present study since hepatic glucose production has been shown to correlate with fasting glucose concentrations.21 22
Fat cell lipolysis results in the release of FFA to the circulation, which is used for hepatic production of very low-density lipoprotein triglycerides.23 Consequently, high spontaneous subcutaneous fat cell lipolysis activity and resistance to the antilipolytic effect of insulin have been reported to be associated with elevated triglyceride and low HDL cholesterol concentrations.24 As AT-IR is the product of fasting insulin and FFA, adipose tissue insulin-resistant but normal weight women had elevated FFA, suggesting that they had high spontaneous subcutaneous fat cell lipolysis activity, which may be associated with elevated triglyceride in the present study.
Facchini et al studied whether insulin-resistant individuals had a higher heart rate than insulin-sensitive subjects.25 Insulin sensitivity was measured using insulin-mediated glucose disposal quantified by the insulin suppression test in apparently healthy normotensive individuals without diabetes. Heart rate was continuously monitored during sleep by an electronic device measuring RR intervals. They found that insulin-resistant individuals, with compensatory hyperinsulinemia, had a higher nocturnal heart rate, suggesting that the increased nocturnal heart rates are secondary to insulin-induced sympathetic activity.25 These observations may be in line with the present finding that adipose tissue insulin-resistant but normal weight women had elevated resting pulse rate, which may be associated with heart rates in young healthy women.
CRP is a hepatic acute phase protein largely regulated by circulating levels of interleukin-6. Although the activated leukocyte is widely assumed to be the major source of circulating interleukin-6 in clinical inflammation, it was demonstrated that human subcutaneous adipose tissue secreted interleukin-6 in healthy subjects.26 Studies including ours showed that total body fat and abdominal/central fat were associated with hsCRP,27–32 whereas we have shown an association between abdominal/central fat and AT-IR in Japanese women.14 Therefore, it is likely that abdominal fat may be a link of association between hsCRP and AT-IR in adipose tissue insulin-resistant but normal weight women in the present study.
Adipose tissue and the liver are major sites of storage for carotenoids, which are vital antioxidants and rich in vegetables, green-yellow vegetables in particular, and fruits.33 Harari et al measured serum and adipose tissue carotenoids concentrations and tissue-specific insulin resistance in subjects without diabetes with a wide range of BMI and insulin resistance.34 They found that serum carotenoids were correlated inversely with insulin resistance in the liver evaluated by hepatic glucose production and adipose tissue evaluated by AT-IR. Because serum carotenoids concentrations were correlated positively with consumption of green-yellow vegetables,35 the latter finding may be in line with the present finding that women with the high AT-IR tertile had lower intake of green-yellow vegetables (87 g/day), which was lower than the recommended dose in adults (120 g/day) by the Ministry of Health, Labor and Welfare, Japan.36
Studies are limited on adipose insulin resistance in normal weight people. Dumesic et al37 compared 10 normal weight women with polycystic ovary syndrome and 18 control women matched for age and BMI and found that AT-IR was higher in women with polycystic ovary syndrome (4.5 vs 2.8, p=0.007) and positively correlated with serum androgen. Kim et al studied normal weight versus obese adolescents with and without pre-diabetes or type 2 diabetes.38 They found that AT-IR was 2.2-fold higher in obese normal glucose tolerance, 4.3-fold higher in impaired glucose tolerance, and 4.6-fold higher in type 2 diabetes compared with normal weight adolescents (approximately 3.8, calculated by 15 μU/mL×0.25 mEq/L, figure 1), which is comparable with AT-IR (3.4) found in normal weight Japanese women.
The strength of the present study includes the accurate and reliable measures of general and central fat accumulation by DXA and the homogeneous study population with few confounding factors.15 It is well known that socioeconomic status is associated with resting heart rate and systemic inflammatory markers.39 40 Participants are female university students, in whom more than 95% of grade 1 students are 18 years old. This may decrease the interference of age and environmental factors, such as smoking, alcohol, educational, and socioeconomic status. Further, in almost all students, almost all school expenses for 4 years were covered by their parents, suggesting that socioeconomic status appears to be less heterogeneous even among parents. There are several limitations of this study that include the cross-sectional design, relatively small sample size, and a single measurement of biochemical variables. We did not measure daily physical activity, which may influence resting pulse rates. Statistical power and sample size were not calculated. As participants were young Japanese women, the results may not be generalized to other gender, age populations, races or ethnicities.
In conclusion, adipose insulin-resistant but normal weight young Japanese women consumed less green-yellow vegetables and had higher hsCRP and resting pulse rate in addition to higher fasting glucose and triglycerides through mechanisms unrelated to adiposity. Studies are needed to see if increased consumption of green-yellow vegetables ameliorates increased cardiometabolic risk.