New insights into actions of insulin and their potential impact in treating diabetes

Researchers from Ullas Kolthur’s group at the Tata Institute of Fundamental Research, in collaboration with Ranjith Padinhateeri’s group at the Indian Institute of Technology- Bombay,  have found how cells respond to fluctuating doses of the insulin hormone and its importance beyond the commonly associated role in regulating blood sugar/glucose. These are important findings since diabetes and inappropriate interventions lead to tissue damage and cause loss of kidney functions, retinopathy and neuropathy, among others. The new results not only provide fundamental insights into the actions of insulin during normal feed-fast cycles but also raise the possibility of re-evaluating insulin dosing in the clinical context and in efforts to minimize diabetes associated damage to key organs. 

This research has also revealed how continuous repeat insulin stimulation could lead to resistance with implications in metabolic disorders, aging and age-related diseases. This is relevant in the Indian context since the burden of metabolic diseases, especially of diabetes is high in the population.

In a healthy individual, the levels of insulin rise after a meal and fall during fasting, which is necessary to supply ‘normal’ levels of glucose to all the organs in the body. Loss of insulin or its action leads to uncontrolled increase in blood glucose (/sugar) ultimately leading to diabetes. In addition to its importance in regulating blood glucose, which is common knowledge, insulin is essential to ensure that cells utilize glucose for metabolism and growth/maintenance of tissues. This is brought about by a complex signaling network that is operative in all cells of the body. 

Illustration: Anugraha A

In this regard, even though decades of research identified the molecular components of insulin signaling, if or how the signaling network changes in response to varied insulin inputs was unknown until now. More importantly, the study has discovered that very high amounts of insulin inputs break the signaling network and potentially lead to resistance and cause tissue damage as seen in diabetes. This is relevant since modern lifestyles have led to intake of high calorie diets and aberrant feeding habits. The break in the signalling following high insulin inputs in the cells can be equated to uncontrolled traffic signals, which cause traffic jams and/or accidents.

Highlights of the study:

  • Illustrates robustness of information flow in the signaling cascade in response to normal and abnormal insulin inputs.
  • Demonstrates the importance of normal feed-fast cycles with the discovery of fasted insulin inputs leading to better response to fed insulin inputs. Discovery of memory of insulin signaling between fed-fast conditions.
  • Elucidates the detrimental impact of constant high insulin as in the case of uncontrolled feeding habits, without a fasting phase, and effects on signaling molecules that govern tissue maintenance and growth.
  • Identifies potential novel regulatory components and parameters whose modulation could lead to better therapeutic interventions in the future to reduce tissue damage, beyond the usual impact on blood glucose.

Researchers at TIFR are currently engaged in collaborating with clinical scientists to investigate this in humans and to also potentially evaluate the impact of insulin administration beyond glucose control in diabetic patients. It opens up avenues to explore new treatment regimes that reduce tissue damage in addition to maintaining blood glucose levels in patients.

Publication: Shukla, Namrata, Shantanu Kadam, Ranjith Padinhateeri, and Ullas Kolthur-Seetharam. “Continuous variable responses and signal gating form kinetic bases for pulsatile insulin signaling and emergence of resistance.” Proceedings of the National Academy of Sciences 118, no. 41 (2021).

Press release: 14-10-2021

This study has been highlighted in Eenadu, The Pioneer, The Hindu and Telangana Today.