%0 Journal Article %A Kun Hao %A Yanguang Cao %T Modeling disease progression in newly diagnosed type 2 diabetes %D 2020 %R 10.1101/2020.05.04.076133 %J bioRxiv %P 2020.05.04.076133 %X Type 2 diabetes (T2DM) is a progressive disease, which is primarily characterized by a decline in β-cell function and worsening of insulin resistance. Unfortunately, most interventions (lifestyle, diet, and therapeutic agents) for T2DM only provide a transient restoration of β-cell function and the progression is inevitable once it starts. To understand the natural progression of T2DM, a mechanistic model was developed to quantitatively characterize the dynamic interactions among β-cell function, plasma fasting glucose (PFG), fasting insulin (FI), and the degree of insulin resistance, starting from an early stage of T2DM over up to 8 years. The model was validated using clinical data to optimize the disease parameters. The restoration and deterioration rates of β-cell function were both predicted as 84.5 %/year and 1.10 /year for early stages of T2DM. The model predicted a positive correlation between the initial level of β-cell function at diagnosis and its maximum restoration potential, underscoring the importance of early diagnosis and intervention. After the treatment, β-cell function could be temporarily restored within several months, which has a long-term benefit in glycemic control. The maximal tolerated PFG level that permits β-cell function restoration was predicted to be around 8.33 nM; and the temporal restoration of β-cell function would be unlikely at a PFG level above this threshold. The intrinsic deterioration rates of β-cell function and insulin resistance were both critical factors for long-term glycemic control. In conclusion, our model provides a quantitative analysis of the natural disease progression in T2DM and yields insights into factors that are critical for long-term glycemic control.Competing Interest StatementThe authors have declared no competing interest.BFβ-cell functionFIFasting insulinHOMA-1Homeostasis model assessment 1HOMA-2Homeostasis model assessment 2ISIInsulin sensitivity indexPFGPlasma fasting glucoseT2DMtype 2 diabetes mellitus %U https://www.biorxiv.org/content/biorxiv/early/2020/05/05/2020.05.04.076133.full.pdf