Bi-stability in type 2 diabetes mellitus multi-organ signalling network.

Shubhankar Kulkarni,Sakshi Sharda,Milind Watve,Corentin Cras-Méneur

doi:10.1371/journal.pone.0181536

Shubhankar Kulkarni, Sakshi Sharda + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0181536

Copy DOI

Abstract

Type 2 diabetes mellitus (T2DM) is believed to be irreversible although no component of the pathophysiology is irreversible. We show here with a network model that the apparent irreversibility is contributed by the structure of the network of inter-organ signalling. A network model comprising all known inter-organ signals in T2DM showed bi-stability with one insulin sensitive and one insulin resistant attractor. The bi-stability was made robust by multiple positive feedback loops suggesting an evolved allostatic system rather than a homeostatic system. In the absence of the complete network, impaired insulin signalling alone failed to give a stable insulin resistant or hyperglycemic state. The model made a number of correlational predictions many of which were validated by empirical data. The current treatment practice targeting obesity, insulin resistance, beta cell function and normalization of plasma glucose failed to reverse T2DM in the model. However certain behavioural and neuro-endocrine interventions ensured a reversal. These results suggest novel prevention and treatment approaches which need to be tested empirically.

Highlights

The classical thinking about the pathogenesis of Type 2 diabetes mellitus (T2DM) can be summarized in the form of five postulates: (i) Obesity results when net energy intake exceeds net energy expenditure. (ii) Obesity leads to insulin resistance. (iii) To compensate for the insulin resistance, more insulin is produced by the pancreatic β-cells. (iv) Chronically increased rate of insulin synthesis leads to ‘exhaustion’ or some form of dysfunction of β-cells which causes relative insulin insufficiency
This combination of insulin resistance and relative insulin insufficiency results in hyperglycaemia. (v) The pathophysiological complications of T2DM are a consequence of chronically elevated glucose levels in the blood [1,2]
We started with the classical theory of T2DM involving the 3 main variables classically believed to be central to T2DM namely plasma insulin level, insulin resistance and plasma glucose level

Summary

Introduction

The classical thinking about the pathogenesis of Type 2 diabetes mellitus (T2DM) can be summarized in the form of five postulates: (i) Obesity results when net energy intake exceeds net energy expenditure. (ii) Obesity leads to insulin resistance. (iii) To compensate for the insulin resistance, more insulin is produced by the pancreatic β-cells. (iv) Chronically increased rate of insulin synthesis leads to ‘exhaustion’ or some form of dysfunction of β-cells which causes relative insulin insufficiency. (iv) Chronically increased rate of insulin synthesis leads to ‘exhaustion’ or some form of dysfunction of β-cells which causes relative insulin insufficiency. This combination of insulin resistance and relative insulin insufficiency results in hyperglycaemia. The inability to cure diabetes can be attributed to these flaws and the clinical approach that uses this classical thinking in patient treatment. Since hyperglycemia was assumed to be the primary cause of the macrovascular and microvascular complications, treating hyperglycemia was the major course of treatment for T2DM patients. It was observed in many large scale

Methods

Results

Conclusion