Multi-Omics Comparison of the Spontaneous Diabetes Mellitus and Diet-Induced Prediabetic Macaque Models.

Zhu Yang,Dianqiang Yang,Zongwei Cai,Da Zhou,James Y Yang,Chi Wai Wong,Fancheng Tan,Shu-Hai Lin

doi:10.3389/fphar.2021.784231

Zhu Yang, Dianqiang Yang + Show 6 more

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https://doi.org/10.3389/fphar.2021.784231

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Abstract

The prevalence of diabetes mellitus has been increasing for decades worldwide. To develop safe and potent therapeutics, animal models contribute a lot to the studies of the mechanisms underlying its pathogenesis. Dietary induction using is a well-accepted protocol in generating insulin resistance and diabetes models. In the present study, we reported the multi-omics profiling of the liver and sera from both peripheral blood and hepatic portal vein blood from Macaca fascicularis that spontaneously developed Type-2 diabetes mellitus with a chow diet (sDM). The other two groups of the monkeys fed with chow diet and high-fat high-sugar (HFHS) diet, respectively, were included for comparison. Analyses of various omics datasets revealed the alterations of high consistency. Between the sDM and HFHS monkeys, both the similar and unique alterations in the lipid metabolism have been demonstrated from metabolomic, transcriptomic, and proteomic data repeatedly. The comparison of the proteome and transcriptome confirmed the involvement of fatty acid binding protein 4 (FABP4) in the diet-induced pathogenesis of diabetes in macaques. Furthermore, the commonly changed genes between spontaneous diabetes and HFHS diet-induced prediabetes suggested that the alterations in the intra- and extracellular structural proteins and cell migration in the liver might mediate the HFHS diet induction of diabetes mellitus.

Highlights

Diabetes mellitus (DM) is a metabolic malfunction, characterized by a prolonged high blood glucose level, the prevalence of which has been steadily elevating in the past decades (Martins, 2014; Zhang et al, 2020)
The two values of the spontaneous DM (sDM) macaques (17.9 ± 1.0 mM fasting blood glucose and 10.4 ± 1.6% HbA1c) were much higher than these standards both levels of non-human primates (NHPs) are typically lower than humans (Lei et al, 2020)
The genes commonly regulated in both high-fat high-sugar (HFHS) and sDM groups included a bunch of genes encoding proteins functioning in the lipid metabolism, such as LIPG, APOA5, ACAA2, and fatty acid binding protein 4 (FABP4) (Figure 3E). These results demonstrated the similarity in lipid metabolism between the sDM and HFHS groups, as those observed from the metabolomes (Figure 2)

Summary

Introduction

Diabetes mellitus (DM) is a metabolic malfunction, characterized by a prolonged high blood glucose level, the prevalence of which has been steadily elevating in the past decades (Martins, 2014; Zhang et al, 2020). Because animals of other orders do not fully recapitulate metabolic changes of primates, non-human primates (NHPs) are of value in DM study with genetic and physiological similarity to humans (Yasuda et al, 1988; Hansen, 2010; Bauer et al, 2011; Harwood et al, 2012; Pound et al, 2014; Havel et al, 2017; Lei et al, 2020; Cox et al, 2021). With the datasets representing the cellular and molecular alterations at various levels in NHPs of spontaneous DM (sDM), researchers can project the data from clinical and experimental studies to the picture of the correlated metabolic and gene expression profiles

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