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Type 2 diabetes (T2D) is a complex and polygenic disease yet in need of a complete picture of its development mechanisms. To better understand the mechanisms, we examined gene expression profiles of multi-tissues from outbred mice fed with a high-fat diet (HFD) or regular chow at weeks 1, 9, and 18. To analyze such complex data, we proposed a novel dual eigen-analysis, in which the sample- and gene-eigenvectors correspond respectively to the macro- and micro-biology information. The dual eigen-analysis identified the HFD eigenvectors as well as the endogenous eigenvectors for each tissue. The results imply that HFD influences the hepatic function or the pancreatic development as an exogenous factor, while in adipose HFD’s impact roughly coincides with the endogenous eigenvector driven by aging. The enrichment analysis of the eigenvectors revealed diverse HFD impact on the three tissues over time. The diversity includes: inflammation, degradation of branched chain amino acids (BCAA), and regulation of peroxisome proliferator activated receptor gamma (PPARγ). In particular, we reported remarkable pancreatic angiogenesis as downstream of the HIF signaling pathway in the T2D development. The discoveries provide new thinking in T2D prevention and therapy.
By integrating our discoveries and other relevant reports in the literature, we propose a scheme of earlier detection and treatment of prediabetes. We suggest that hyperinsulinemia rather than hyperglycemia is an “early warning signal” of T2D. Therefore, only testing the blood glucose levels is not enough whereas testing and monitoring the blood insulin levels is much needed. We also suggest that metformin, as an agent directly acting against insulin resistance, shall be administrated as early as in the prediabetes stage, and sufficient dose of this medication shall be applied upon correcting hyperinsulinemia. To examine and prove the above hypothesis, further comprehensive basic research and clinical study, with the assistance of computational and systems biology to analyze big data, are recommended. Once such studies provide sufficient evidences supporting the above suggestions, the current clinical guidelines should be updated and modified. These efforts may make a breakthrough in tackling the problems of curing T2D and in reducing its incidences.