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Modeling results reveal that glucose and insulin may not be central to type 2 diabetes  Aug 03, 2017

The glucose-insulin connection in type 2 diabetes mellitus is well established and the treatment regime is centered on lowering glucose levels through insulin. With the best available treatment being a combination of medication and changes in lifestyle, a cure for diabetes has been eluding us. Prof. Milind Watve’s group at IISER Pune has studied the condition through network modeling. Their recently published research in PLOS ONE indicates there may be players other than glucose and insulin that could help reverse the condition.         

The group has considered various known signals, including metabolic, hormonal, neuronal, immunological, and behavioral signals involved in type 2 diabetes mellitus in a computer model to make a complex network with over 70 signals.

Describing one of their first exciting observations in this work, PhD student Shubhankar Kulkarni said, “The network is like a giant cobweb in which perturbing one thread perturbs the entire network. But the effects, though complex, were far from being chaotic: the perturbations made the system either insulin sensitive or insulin resistant, both the states being stable in their own way.”  

The network model could successfully mimic many known patterns and processes of type 2 diabetes mellitus. As was observed previously in clinical trials, the model showed that even when glucose levels are controlled without hypoglycemia, the progress of diabetes pathology could not be arrested. This suggested that changes in glucose and insulin levels might be only symptoms, and not primary causes, of the condition.

The rationale described by the study is that none of the steps in the known pathophysiology of type 2 diabetes mellitus is irreversible. Therefore, unlike the widely held belief in clinical practice, it should be possible to find ways to reverse the effects of diabetes.

Analysis of the network showed that this apparent irreversibility is contributed by the structure of the network which is dominated by multiple positive feedback loops, where outputs return to the system as inputs and lead to even higher levels of the output. The model also showed that while it was not possible to overcome insulin resistance by regulating insulin and glucose levels, it was possible to do so by regulating a few other targets including signals in the brain and behavior.

Prof. Watve said, “This implies that diabetes can be curable, but certainly not by targeting glucose and insulin. To find the right targets that are central to pathophysiology of type 2 diabetes mellitus, there needs to be a paradigm shift. We need to give up the current insulin centered thinking and be open to other possibilities.”

This work titled “Bi-stability in type 2 diabetes mellitus multi-organ signalling network” has been published in PLOS ONE and was authored by Shubhankar Kulkarni, Sakshi Sharda, and Milind Watve.

- by Shanti Kalipatnapu with inputs from Milind Watve