Another limitation of this study

Another limitation of this study relates to how metabolic change in response to fasting differs among species. For example, in a recent report, lipidomic analysis of human and animal plasma showed that lipid metabolism differed markedly between humans and rats during fasting (Ishikawa et al., 2015). In our study, we examined the regulatory mechanism of first-phase GSIS only in rats, and did not confirm our findings in humans. Species-dependent variation in whole-body Bindarit cost metabolism during fasting may influence the regulatory mechanism of first-phase GSIS differently in humans and rodents, although both showed a significant decrease in first-phase GSIS after fasting. The following are the supplementary data related to this article.
Funding Sources This work was supported by the SUMS President\'s Grant for the Encouragement of Young Researchers (to S.K.). The funder had no role in any process of this work, including study design, data collection, data analysis, interpretation, and writing of the manuscript.
Conflicts of Interest
Author Contributions
Acknowledgments
Introduction Recently, China faces an increasing burden of type 2 diabetes and its vascular complications with approximately 11.6% of overall prevalence in adults (Xu et al., 2013). People with diabetes impose about 3.38 times higher cost than those with normal glucose intolerance, while the cost will be 3.75 times higher for patients with longer duration of diabetes (≥10years) compared with those with shorter duration (≤5years) due to its complications (Yang et al., 2012). Therefore, it\'s important to conduct precise strategies to treat patients with diabetes effectively. Actually, clinical trials demonstrated that more intensive blood pressure lowering and glucose control yielded evident clinical benefits for diabetes patients with vascular endpoints (Zoungas et al., 2014). On the other hand, inter-individual variation of drug response was observed in prophylactic medications for diabetes and its comorbidities (Tkac, 2015), which may be partially explained by accumulating the pharmacogenetics evidence. However, the influence of common genetic variations on the individual difference in drug response or clinical endpoints need to be confirmed by large and long-term follow-up studies, because of the progressive feature of type 2 diabetes mellitus (T2DM), and the mechanisms in molecular levels that related to clinical heterogeneity phenotype remains unclear. Human tribbles homolog 3 (TRIB3, also called NIPK, SINK, TRB3, SKIP3) is a pseudokinase that can inhibit Akt by physically occupying its phosphorylation sites, which plays a pivotal role on subsequent insulin signaling (Du et al., 2003). Previous reports indicated that TRIB3 has a ubiquitous cellular functions by interacting with a host of molecules establishing a mechanic link between metabolic phenotypes and cardiovascular risk traits (Wang et al., 2012; Ti et al., 2011), renal diseases (Ding et al., 2014), tumor progression (Hua et al., 2015) in T2DM. Interestingly, in vitro study data showed TRIB3 genetic variation (c.251 A>G, Gln84Arg, rs2295490) does not affect its protein level, but impacts on insulin-stimulated Akt (Thr308, Ser473) and eNOS (Ser1177) phosphorylation, which results in 2 to 3 times of decreased eNOS activity and nitric oxide production (Andreozzi et al., 2008). On another hand, valsartan (an antihypertensive drug), could significantly down-regulate the expression of TRIB3 mRNA levels and improve the cardiac functions in rats with diabetic cardiomyopathy (Zhang et al., 2006). Moreover, The presence of the gain-of-function mutation in TIRB3(rs2295490) is one of a leading cause of TRIB3 over-activity and subsequent Akt inhibition, which has linked to increased risk of cardiovascular diseases by metabolic syndrome, endothelial and/or cardiac dysfunction (Prudente et al., 2012). Therefore, we considered that TRIB3 may have an impartible role in mediating the development of the diabetic vascular complications by regulating insulin signal transduction pathway and (or) by regulating blood pressure homeostasis in patients with type 2 diabetes. And the relationship between TRIB3 genetic variation and diabetes and its vascular complications merits further attention.