Discussion
The present study has demonstrated that increased ORM was associated with increased glucose excursion (AUCg) and 30 min postload glucose in non-obese, young Japanese women. These associations were not related to sophisticated measures of general and abdominal adiposity (FMI, the percentage of body fat, trunk/leg fat ratio) and serum leptin. Associations observed were not related to insulin secretion, insulin sensitivity/resistance, adiponectin and other investigated markers of inflammation. Glucose excursion (AUCg) and 30 min postload glucose explained >90% of variations of ORM. The present results in young women confirmed positive associations of ORM with fasting and 2-hour glucose as previously reported in general population, and in overweight and obese people.19–21
Metabolomics now seeks to identify early biomarkers which are predictive of the development of dysglycemia and type 2 diabetes. A Finnish metabolic profiling study22 demonstrated that branched-chain and aromatic amino acids and orosomucoid referred to as α1-acid glycoprotein, were predictors of both fasting and 2-hour glucose at 6.5-year follow-up in a general population setting of middle-aged men and women.
Since the prevailing insulin concentrations over the first 30 min of the OGTT, a direct estimate of insulin secretion during the OGTT, were not associated with ORM, insufficient insulin secretion was possibly not the primary factor. Studies from Asia have reported an independent association between elevated 30 min glucose and incident diabetes.23 24 However, this was associated with decreased β-cell function in those studies.23 24 An incremental 30 min glucose concentration may reflect the ability of endogenous insulin secretion to suppress hepatic glucose production.25 It is suggested that hepatic IR during early phase insulin secretion may be related to early phase hyperglycemia.25 Although there was no association between ORM and HOMA-IR, a more reflective surrogate of hepatic IR,16 the possibility cannot be ruled out that hepatic IR may be involved in ORM-early phase hyperglycemia association because majority of circulating ORM is produced in the liver.21
In above-mentioned studies,19–22 serum ORM concentrations were considered a marker of low-grade chronic inflammation, which links obesity to IR and β-cell failure resulting in dysglycemia.26 However, in the present study, there was no association of ORM with FMI, trunk/leg fat ratio, hsCRP and adiponectin, the last of which is known to stimulate glucose uptake through AMPK or peroxisome proliferator-activated receptor α activation.27 Since IR and β-cell failure are known to be causative in the development of diabetes, this might suggest that ORM could be related to the glucose levels independently of the muscle insulin signaling: insulin-independent glucose uptake via skeletal muscle.
It is reported that contraction-stimulated, insulin-independent glucose transport in skeletal muscle may be mediated by AMPK.28 29 Studies in mice have demonstrated that contraction-stimulated elevation of muscle ORM increases muscle glycogen and enhances muscle endurance,30 which is mediated through activation of AMPK by ORM in skeletal muscle.10 Taken together, it seems reasonable to speculate that ORM per se may stimulate glucose uptake by myocytes and hence may lower blood glucose. Indeed, exogenous ORM improved glucose and insulin tolerance in diabetic db/db mice.21 However, in the present study, higher serum ORM was associated with higher, but not lower glycemia. It may be that sustained increase in circulating ORM might cause ORM resistance.21
Increased ORM may be a consequence of increased plasma glucose in the present study as it is reported that adipose ORM levels were elevated by high glucose31 and it has been suggested to modulate immune responses to protect adipose tissue from inflammation and metabolic dysfunction.21 However, this explanation appears to be unlikely in the present study because differentiated adipocytes were incubated with extremely high glucose (450 mg/dL)31 and because another study reported repressed adipose ORM expression in diabetic ob/ob mice, although ORM was expressed in adipose tissue at high levels.32 The biology underlying the association between high serum ORM concentrations and increased glucose excursion found in the present study is not known.
The strengths of the present study include homogeneous study population with scarce confounding factors, and accurate and reliable measures of body composition by dual-energy X-ray absorptiometry (DXA). Several limitations of this study warrant consideration. The cross-sectional design of the present study complicates the drawing of causal inferences, and a single measurement of biochemical variables may be susceptible to short-term variation, which would bias the results towards the null. We used crude measures of insulin sensitivity/IR and insulin secretion, which may be less accurate. Statistical power was not calculated. As we studied young Japanese women only, results may not be generalized to other gender, age populations, races or ethnicities.
In conclusion, elevated circulating orosomucoid was associated with elevated 30 min glucose and glucose excursion in non-obese young Japanese women independently of general and abdominal adiposity, insulin secretion, insulin sensitivity/resistance, other investigated markers of inflammation and adiponectin. Further research is needed to determine the public health and clinical significance of these results. But these results may suggest a clue to identify novel pathways that may have utility in monitoring glucose dysmetabolism within NGT.