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 & 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 & 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. But it is shown that beta cells recover quickly after STZ treatment, but hyperglycemia continues. This challenges the classical theory. My experiments show that not all STZ animals develop hyperglycemia and the hypoglycemia that develops within 6-12 hours of STZ treatment is a good predictor of later hyperglycemia. STZ is also known to affect FGF expression, vascularization of brain and reduced glucose transport to the brain so my hypothesis was that infusion of glucose to brain would reduce peripheral hyperglycemia. Experiments on these lines could not be completed due to repeated pandemic lockdowns. So, I expanded the theoretical lines of work. Historical analysis of the field to study the emergence of various hypotheses and examine the anomalies accumulating in the field I analyze various evidences and anomalous findings in the field in perspective of two prominent philosophies of science, Karl Popper and Thomas Kuhn (Kuhn, 1970; Popper, n.d.). This part of the work examines which parts of the current T2DM paradigm are challenged by experiments, whether the current status of the field resembles the crisis state described by Kuhn, that precedes a paradigm shift and from Kuhn’s analysis can a paradigm shift be predicted? The anomalies include multi-species variability across animal kingdom in the obesity-insulin-glucose relationship and why simple biochemical explanations don’t work. Collective analysis of clinical trial towards normalization of glucose in type 2 diabetes patients The failure of glucose normalization treatment to arrest diabetic complications is also an anomaly but literature on it is contradictory. So, I did a meta-analysis of major non-pharma driven clinical trials. I also examined the scientific rigor of these trials. The emerging picture is that glucose normalization does not reduce the incidence of complications or mortality. Development of an alternative paradigm model I modelled a brain centered glucose homeostasis model to address the question whether the anomalies can be satisfactorily explained by the hypothesis that reduced glucose supply to the brain is the cause of fasting hyperglycemia. The model is used to test whether its predictions match with the anomalous empirical patterns qualitatively. The results suggest that this hypothesis works substantially better than the insulin resistance model. The model also predicts additional testable predictions (Ojha & Watve, 2022). The historical, meta-analytical and modeling exercise converge to indicate that the insulin resistance centered view held currently has several anomalies pointing to a need for paradigm.