Insulin: Beyond Metabolism

Work done in the lab of Prof. Madhulika Dixit at the Laboratory of Vascular Biology, Center of Excellence in Molecular Medicine, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.

About author

Abhiram Charan Tej Mallu is a researcher in the field of molecular medicine with a Ph.D. from IIT Madras. Dr. Mallu’s doctoral research was at the interface of immunology, metabolism, and vascular biology where he studied the role of normal and impaired glucose metabolism on the function of immune cells and circulating vasculogenic progenitors. He has published several papers in reputed international journals and presented his work at multiple national and international conferences. Dr. Mallu is a passionate teacher and researcher, who aims to further understand the immune cell function in health and disease, with a long-term goal of manipulating immune cell function for therapeutic advantage.

Interview

How would you explain your research outcomes to the non-scientific community?

When you eat after fasting for a few hours, the increase in the blood glucose levels will trigger the release of insulin, a hormone that helps to bring the blood glucose levels back to normal. Since its discovery, insulin has largely been known to regulate metabolism through its action on the liver and skeletal muscle tissues. Recently, its role in immunity has been discovered. Insulin acts on activated immune cells and promotes their function to eliminate infection. However, even in the absence of infection, circulating naïve (not activated) immune cells are also continually exposed to the changes in insulin levels upon fasting and feeding. We asked a simple question: “How does insulin secretion following feeding affect circulating naïve immune cells?”

In this study, we demonstrated that feeding-induced insulin enhances the adhesion and homing functions of naïve lymphocytes (a type of immune cell). These functions are essential for the movement of lymphocytes from the circulation to various organs (called “homing”), to mediate immunity and tissue repair. We further showed that feeding enhanced the homing capability of lymphocytes to an injured blood vessel in mice. We then delineated a mechanism by which insulin acts on naïve lymphocytes by binding to the IGF-1 receptor, which is expressed on their surface. This binding of insulin leads to the activation of other cell surface proteins called integrins, which mediate the adhesion and homing functions of naïve lymphocytes.

(A) Having breakfast after overnight fasting enhanced the adhesion of healthy human lymphocytes to fibronectin. (B) In mice, immune cells isolated from recipient mice after glucose feeding showed enhanced homing and adhesion to injured mesenteric artery in recipient mice, compared to that of fasting immune cells. (C) Insulin activated the IGF-1 receptor (as opposed to insulin receptor) in naïve lymphocytes which ultimately led to the activation of integrins on the cell surface and enhanced fibronectin adhesion. The illustration was created with BioRender.com.

How do these findings contribute to your research area?

Our study identifies a fundamental physiological role of insulin in regulating lymphocyte trafficking in healthy individuals. Such a paradigm would pave the way for understanding impaired lymphocyte trafficking and compromised immunity observed during metabolic disorders such as prediabetes and diabetes.

“Our study identifies a fundamental physiological role of insulin in regulating lymphocyte trafficking in healthy individuals.”

What was the exciting moment during your research?

The most exciting moment during our research was seeing that having breakfast after overnight fasting enhanced the adhesion of healthy human lymphocytes to an extracellular matrix protein called fibronectin. This phenomenon was also reproducible in healthy mice, but it was lost in mice lacking insulin*. This ascertained that insulin does regulate circulating lymphocyte function even in the absence of infection or inflammation. It was gratifying to see this phenomenon happen in real-time in live mice, using intravital microscopy#.

*We thank our collaborators at the National Center for Cell Science, Pune, for contributing to this work.

#We thank our collaborators at the Central Drug Research Institute, Lucknow, for contributing to this work.

What do you hope to do next?

During my PhD, I understood and appreciated the versatility and plasticity of the immune system and how it contributes to homeostasis in the body. I hope to continue my research to understand how immune cells function in health and disease. My long-term goal is to understand how immune cells interact with their environment and how perturbations in the host physiology and tissue microenvironment affect immune cell function in metabolic diseases, infections, and cancer.

Where do you seek scientific inspiration from?

I believe that there is no one source of inspiration for a researcher. My foremost inspiration came from my teachers, who nurtured my enthusiasm to understand and pursue biology research. I intend to pay this forward by becoming a teacher myself. As a researcher, my inspiration comes from my desire to generate knowledge that will help in the development of sustainable and economic therapies for chronic ailments like diabetes and cancer. I am inspired by researchers who ask unorthodox questions and come up with creative ways to answer them.

How do you intend to help Indian science improve?

I intend to become a biomedical researcher in India, working on specific problems that are relevant in the Indian context, while also teaching students and encouraging them to pursue a career in science. As a researcher, I intend to initiate and sustain collaborations with clinicians, engineers, and bioinformaticians to design and execute projects with a clear potential for therapeutic translation. I will share the knowledge generated from my research not only with the scientific community but also with school and college students to foster their innovative thinking.

Reference

Mallu ACT, Sivagurunathan S, Paul D, Aggarwal H, Nathan AA, Manikandan A, Mahalakshmi M. Ravi, Ramanamurthy Boppana, Kumaravelu Jagavelu, Manas Kumar Santra and Madhulika Dixit; Feeding enhances fibronectin adherence of quiescent lymphocytes through non-canonical insulin signalling. Immunology. 2023. https://doi.org/10.1111/imm.13652

Copy Editor

Sukanya Madhwal

Ph.D. student at inStem Bangalore

Sukanya hails from a small town, kotdwara in Uttarakhand. She completed her Masters’ degree in Biotechnology from Banasthali Vidyapith, Rajasthan. After this, she served as a graduate teacher for one year at P.G. College, Kotdwara, Uttarakhand. In 2014, she qualified for the JGEEBILS exam conducted by NCBS/TIFR and joined as a Research Scholar (Ph.D. student) in Dr. Tina Mukherjee’s lab at inStem. Currently, she continued working as a bridging post-doc in Dr. Tina Mukherjee’s lab. Besides work, she loves reading non-fiction books, enjoys gardening, and cooking delicious food.

For interview related queries, write to us at interview.biopatrika@gmail.com