Comparison of the insulin-glucose relationship in steady state and perturbed state

Abstract

Altered insulin-glucose relationship is the focus of type 2 diabetes pathophysiology and treatment. Despite decades of research on the cause and mechanisms of the disorder, there are many inconsistencies and gaps in the knowledge. I have explored these inconsistencies in detail and highlighted the need to re-examine the insulin-glucose relationship. The focus of this thesis is the difference in the glucose-insulin relationship in the steady state (fasting) versus the perturbed state (post meal/post glucose load). These distinct relationships between glucose and insulin in the two states led to the question of distinct causal roles of insulin in glucose homeostasis in the two states. This distinction in inferring the causality between homeostatic variables (not only glucose and insulin, but others as well) in these two states has not been made earlier.

In homeostatic systems, causality in a steady state can be qualitatively different from that in a perturbed state. On a broader scale there is a need to differentiate driver causality from navigator causality. A driver is essential for reaching a destination but may not have any role in deciding the destination. A navigator on the other hand has a role in deciding the destination and the path but may not be able to drive the system to the destination. The failure to differentiate between types of causalities is likely to have resulted into many misinterpretations in physiology and bio-medicine.

I have used multiple approaches to address these differences in the insulin-glucose relationship in two states. With these approaches, I have critically re-examined the causal role of insulin in glucose homeostasis. The approaches used are: 1. Systematic review of literature and meta-analysis of experiments in which the insulin levels or insulin action has been altered. I have compared the effect of this alteration on the steady and perturbed state glucose with the help of four separate meta-analyses. 2. Making differential predictions from alternative homeostasis models of glucose homeostasis and testing them in human epidemiological data. 3. Differentiating between steady state and post-meal state glucose levels in streptozotocin-treated rats in primary experiments

The results of the three approaches converge on the common inference, namely the role of insulin in determining steady state glucose is different than its role in determining the perturbed state glucose. I have then delineated the causal relations between fasting glucose, fasting insulin and insulin resistance using a novel statistical method developed in our lab. Using these results, I also make a case for the concept of driver and navigator causation with the example of insulin and glucose. The different approaches lead to the conclusion that although insulin action hastens the return to a steady state after a glucose load, there is no evidence that insulin action determines the steady state level of glucose. Thus, insulin appears to be a driver but not a navigator for steady state glucose level. The insulin-glucose example suggests that we may have to carefully re-examine causal inferences from perturbation experiments and set up revised norms for experimental design for causal inference for any homeostatic systems, or for any homeostatic variables. Thus, this study could be one more piece of evidence which will stimulate research to look for factors and therapies other than insulin to control and manage type 2 diabetes.

Since I am suggesting a new relationship between insulin-glucose, rather a new role of insulin in the glucose dynamics, I also revisited the evolutionary theories behind the causes of type 2 diabetes. The new understanding of insulin-glucose relationship has many implications to the hypotheses about evolutionary origins of type 2 diabetes. It makes the case for obesity centred hypotheses substantially weak and strengthens the behaviour and reproduction-centred hypotheses. Thus, this work could be the basis for developing new behaviour-oriented therapies to control type 2 diabetes and the related complications.