Why This Year's Nobel Prize in Medicine Matters in Understanding Diabetes

Despite a name derived from the Greek terms for "self-eating," autophagy is not harmful; rather, it is essential for insulin secretion.

Early Monday, Japan’s Yoshinori Ohsumi received the call from Sweden that his experiments with yeast in the early 1990s had brought him the Nobel Prize in Medicine, the world’s highest honor in the biological sciences. Ohsumi’s work to reveal the importance of autophagy,1 and to identify the genes responsible for this cellular process, have implications from conditions that range from cancer to Parkinson’s disease to the aging process itself.

In the last dozen years or so, researchers have examined the role of autophagy in diabetes, both type 1 (T1D) and type 2 disease (T2D). An exhaustive 2011 review paper on the topic found that elevated glucose levels appear to somehow trigger a process of stress that disrupts autophagy. Despite a name derived from the Greek terms for “self-eating,” autophagy is far from harmful; rather, it is essential to insulin secretion.

According to a statement from the Nobel committee, Ohsumi’s work was crucial in revealing the fundamental importance of autophagy, which allows cells to adapt to surroundings, respond to lack of food, or to fight infection.2

“Ohsumi’s discoveries led to a new paradigm in our understanding of how the cell recycles its content,” the Nobel Committee said in its announcement. “His discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes … Mutations in autophagy genes can cause disease, and the autophagic process is involved in several conditions, including cancer and neurological disease.”

Work that predated Ohsumi’s discoveries identified the importance of organelles, or large pieces of cellular content, that contain matter to be destroyed. Ohsumi conducted a series of experiments with yeast cells that showed that degradation took place within the cells and was, in fact, central to their functioning.

Since Ohsumi’s experiments, research in diabetes has focused on what happens when autophagy is impaired, causing organelles such as mitochondria to pile up in the cell. The 2011 review paper in the journal Autophagy2 discussed the relationships among high glucose levels, oxidative stress, and the role of autophagy in beta cell dysfunction. This begins with the role that the impaired mitochondrial function plays with the mechanisms that contribute to insulin resistance. The authors write that glucagon, which they describe as “a counter-regulatory hormone of insulin,” induces autophagy, and that many of the critical parts of the cell responsible for insulin sensitivity and beta cell survival “rely on autophagy to maintain normal cell function.”

The 2011 paper, led by authors Claudio D. Gonzalez, MD, of the University of Buenos Aires, and John W. Wiley, MD, of the University of Michigan, discusses at some length the role of the drug rapamycin, which induces autophagy and has both immunosuppressant and antitumor properties. Ironically, a different group of scientists, associated with the development of rapamycin—Michael N. Hall, David M. Sabatini, and Stuart L. Schreiber—had been predicted by some experts to win the Nobel Prize in Medicine, but it went to Ohsumi for more fundamental experiments instead.

References

1. Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biology. 1992;119(2):301-311.

2. The Nobel Prize in Physiology or Medicine 2016 [press release]. Nobel Assembly at Karolinska Institutet: Stockholm, Sweden; October 3, 2016. https://www.nobelprize.org/nobel_prizes/medicine/laureates/2016/press.html.

3. Gonzales CD, Lee MS, Marchetti P, et al. The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy. 2011;7(1):2-11.