Advances in Understanding Insulin

Dr Ronald Kahn, Chief Academic Officer at the Joslin Diabetic Center and Professor of Medicine at Harvard Medical School

100th Anniversary Dinner Celebrating the Nobel Prize to Banting and Macleod, November 27, 2023

Good evening. What a great day we have had hearing about the discovery of insulin and all of the impacts it has had upon science. 

We have heard about the classic work of Banting, McLeod, Best, and Collip that led to the discovery that changed the face of type 1 diabetes from a disease of wasting and cachexia and early death to routine, immediate, and effective treatment as described already in 1923 by Elliot Joslin, and as recognized by the Karolinska with a Nobel Prize to Banting and McLeod in 1923. 

Insulin not only itself received a Nobel Prize, insulin was also the pacesetter for the shape of scientific research for the next 50 or more years. For example, in 1958, Fred Sanger received the Nobel Prize for the discovery of techniques to sequence proteins, and the first protein he sequenced was insulin. In 1969, Dorothy Hodgkin received the Nobel Prize for her work using x-ray crystallographic structures to determine the structure of vitamin B12, but she, with her student Guy Dodson, also solved the structure of insulin. In 1977, Roslyn Yalow, and if he had survived, probably Sol Berson, received a Nobel Prize for the first radioimmunoassay to measure a hormone in blood, and that first hormone to be measured was insulin. In 1980, Wally Gilbert along with Paul Berg and Fred Sanger, received the Nobel Prize for recombinant DNA, and again, the first recombinant protein therapeutic was human insulin. 

Moving to the present, however, now a big challenge is understanding how insulin works. The insulin receptor was not discovered until 50 years after the molecule. And, although that was 50 years ago, there is still much we don’t know about it, although you can see the very pretty structure of the insulin receptor and its extracellular domain solved using cryo-EM. We also know that this receptor signals through a complex series of kinase reactions. These are enzymatic reactions that stimulate cell metabolism through stimulating chemical reactions called phosphorylation. For insulin, this involves the insulin receptor substrate (IRS) proteins, PI3 kinase and AKT. These result in all of the classic metabolic effects of insulin on glucose uptake and lipid synthesis, and glycogen synthesis. In type 2 diabetes, these steps of insulin action are altered indicating insulin resistance. Thus, there is decreased stimulation of AKT, GSK3 and FoxO, and decreased glucose uptake. This is important, since type 2 diabetes accounts for 95% of patients with the disease, and most are insulin resistant. Insulin resistance is present also in individuals with obesity, hypertension, dyslipidemia, atherosclerosis, fatty liver disease, polycystic ovarian disease, even cancer and Alzheimer’s disease. Insulin resistance is also linked to longevity. So as we think about insulin’s role in metabolism, it still continues to drive research – with the biggest current challenge being. 

Thus, since the discovery of insulin, we’ve made tremendous progress in making better insulins and more sophisticated and physiologic delivery systems. In addition, again and again, studies of insulin have provided models for advancement in diabetes and many other fields. These include glucose-sensitive insulins for therapy of diabetes, which are now in development, and even new viral insulin-like molecules, which have certain inhibitory properties that may help cancel cancer therapeutics. But it is insulin resistance, which is the primary driver of type 2 diabetes and metabolic syndrome, diseases which affect now almost 30% of the population of adults in developed countries, that remains the challenge of this century. Using new models created from human stem cells converted to muscle and liver, we are now beginning to understand this insulin resistance at a molecular level, and thus hope to provide a new tool for unraveling this challenge in future therapeutics. Thanks to the organizers of this wonderful symposium, and thanks to all of you for your attention and good night.

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