Evaluating the need for a paradigm shift in the understanding of pathogenesis of type 2 diabetes

Abstract

Earlier work from our lab has shown that type 2 diabetes mellitus (T2DM) progression is not majorly dependent on insulin-glucose deregulation. A network model by Dr. Shubhankar Kulkarni revealed that in absence of multi-organ network, impaired insulin signaling alone did not give a stable insulin resistance state. Further, the model predicted the reversal of T2DM state using behavioral and neuro-endocrine intervention, but normalization of glucose alone failed to do so (Kulkarni et al., 2017). Similarly, Dr. Manawa Diwekar-Joshi s work using multiple approaches showed that fasting glucose was independent of insulin regulation, although the postprandial curve was significantly affected (Diwekar-Joshi and Watve, 2020). The emerging view in the field supporting the above studies speculates the role of brain in regulating the insulin signaling and hyperglycemia. T2DM patients are shown to experience low brain glucose levels, with blunted brain glucose curves compared to normal healthy individuals (Hwang et al., 2017). T2DM is also known to affect vasculature, CVD (cardiovascular disease) being the most common complication of T2DM (Hu and Stampfer, 2003). A study by Hunt et al shows that subclinical atherosclerosis can predict future risk of type 2 diabetes (Hunt et al., 2003). A plausible theory gaining weight is that T2DM may be a result of vasculature changes, resulting in low glucose supply to brain and finally compensatory hyperglycemia induced by the brain. We planned to test this hypothesis using both experimental and theoretical means. The objectives of my study are listed below: Specific objectives of the project: To determine the role of brain in T2DM development in streptozotocin (STZ) induced diabetes mice models Studies on STZ induced mice models have been central to glucose-insulin theory for T2DM. STZ induces hyperglycaemia by beta cell destruction, supporting the theory that impaired insulin signals are responsible for T2DM.