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Fasting glucose levels: Beyond the insulin-centric paradigm   Jan 27, 2021

In a recent paper in the journal PeerJ—Life and Environment, through a systematic review and analysis of studies from literature, IISER Pune researchers propose a reinterpretation of the glucose-insulin relationship.

Authored by IISER Pune PhD student Manawa Diwekar-Joshi with Prof. Milind Watve, previously at IISER Pune and now at Deenanath Mangeshkar Hospital and Research Centre, Pune, this study has important implications to our understanding of and to our approach towards treating type 2 diabetes.

The team first studied the evidence for the premise that insulin decided the fasting level of glucose. Diwekar-Joshi interpreted experiments from over 40 published papers coming independently from different research groups. Additionally, Diwekar-Joshi performed experiments wherever there were gaps in the published literature. The team then developed a mathematical model which accounts for the experimental results and population data in a way that the classical models have not been able to.

“All the evidence converged on the finding that the role of insulin is only like that of a driver,” says Diwekar-Joshi. “If you want to reach a destination, you need a driver. But the driver does not decide where to go. Similarly, insulin level and insulin action does not decide what the fasting blood glucose should be. But it only helps attaining the level faster,” she adds.

Article Citation:

Driver versus navigator causation in biology: the case of insulin and fasting glucose. Manawa Diwekar-Joshi​ and Milind Watve​. Peer J e10396. 


More on the insulin-glucose relationship
by Manawa Diwekar-Joshi

In 2012, the journal Diabetes Care published two papers back-to-back, both sharing the first part of the title, Diabetes: Have we got it all wrong? Both papers by eminent diabetes researchers raised doubts whether the classical textbook relationship between obesity, insulin and glucose regulation was correct. Working along with Prof. Watve as a PhD student, I chose to probe this deeper. 

After an overnight fast, the blood sugar is known to be in a steady state and, by classical belief insulin action decides the glucose level in this steady state. The reason why blood sugar is often high in type 2 diabetes in spite of normal or higher levels of insulin is said to be “insulin resistance”.
Contrary to this belief, whenever insulin resistance was induced in muscle, fat or liver cells of experimental animals, it did not affect fasting blood glucose. When insulin levels were stably raised or suppressed in experiments, fasting glucose did not change. Such experiments have been performed in rodents as well as in humans by several laboratories independently and the results are quite consistent. So far, no experiment has demonstrated a change in steady state blood sugar by changing insulin levels or insulin action on cells.

The reason why the role of insulin in glucose regulation was interpreted the way it has been for several decades is a basic flaw in the methodology of determining cause-effect in biology. For example, if salt is added to water and stirred vigorously, salt dissolves faster but the saturation level of salt in water does not change. If an experimenter only sees that stirring increases dissolution of salt, without waiting for the saturation point, they may conclude that stirring always dissolves more salt in water. Insulin action is like stirring in this metaphor. It increases the rate at which glucose returns to the basic level after a meal. But it does not decide what the basal level should be. All experiments critically examining glucose insulin relationship converge on this conclusion.

If not insulin, then what decides the basal sugar level? Our paper does not focus on this question, but an increasing number of researchers are now pointing to the brain as the true decision maker of what fasting blood sugar should be. The new interpretation is likely to alter the direction of research as well as will reflect on the treatment of type 2 diabetes in the long run.