Abstract
Glucose homeostasis is the tight control of glucose in the blood. This complex control is important, due to its malfunction in serious diseases like diabetes, and not yet sufficiently understood. Due to the involvement of numerous organs and sub-systems, each with their own intra-cellular control, we have developed a multi-level mathematical model, for glucose homeostasis, which integrates a variety of data. Over the last 10 years, this model has been used to insert new insights from the intra-cellular level into the larger whole-body perspective. However, the original cell-organ-body translation has during these years never been updated, despite several critical shortcomings, which also have not been resolved by other modeling efforts. For this reason, we here present an updated multi-level model. This model provides a more accurate sub-division of how much glucose is being taken up by the different organs. Unlike the original model, we now also account for the different dynamics seen in the different organs. The new model also incorporates the central impact of blood flow on insulin-stimulated glucose uptake. Each new improvement is clear upon visual inspection, and they are also supported by statistical tests. The final multi-level model describes >300 data points in >40 time-series and dose-response curves, resulting from a large variety of perturbations, describing both intra-cellular processes, organ fluxes, and whole-body meal responses. We hope that this model will serve as an improved basis for future data integration, useful for research and drug developments within diabetes.
Highlights
A dysfunctional glucose homeostasis is a hallmark for both type 1 and type 2 diabetes mellitus (T1D and Type 2 diabetes (T2D))
We have (Q1) made a new subdivision of glucose uptake between all relevant organs, to provide more reliable proportions and to include uptake in the liver (Figure 2); (Q2) improved the elimination of interstitial insulin to be tissuespecific, and included intracellular metabolism of glucose inside adipocytes, to capture an earlier peak in the glucose uptake in adipocytes compared to the corresponding peak in plasma insulin (Figure 3); and (Q3) accounted for the impact of blood flow on glucose uptake (Figure 4)
The previously published model did not include glucose uptake in the liver (Figure 2A), which is problematic since data shows that it is the biggest source of glucose clearance (Figure 2B)
Summary
A dysfunctional glucose homeostasis is a hallmark for both type 1 and type 2 diabetes mellitus (T1D and T2D). In T1D, the insulin-producing beta-cells are destroyed by the immune system. In T2D, the patient has both a reduced capacity to produce insulin and has developed a resistance to the hormone. This resistance appears in all of the three most metabolically active organs, which all respond to insulin: adipose tissue, muscle, and liver. Inside each of these organs, the response to insulin is governed by an interaction between intracellular signaling and metabolic networks. The resistance is spread between the organs, in ways which are not yet fully understood, but which involves numerous hormones, cytokines, and metabolites.
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