Donald F. Steiner MD, 1930-2014: discoverer of proinsulin.

Donald F. Steiner, the A. N. Pritzker Distinguished Service Professor Emeritus in the Departments of Medicine and Biochemistry and Molecular Biology at the University of Chicago, died at his home on Tuesday, November 11, 2014. He was 84 years old and had been a member of the faculty since 1960. Don was elected to the National Academy of Sciences in 1973. He revolutionized our understanding of the chemistry and biochemistry of polypeptide hormones. His contributions to understanding the biochemical nature of insulin production with the discovery of proinsulin and the development of C-peptide measurement have had profound scientific and clinical impact on the diagnosis and treatment of diabetes. In 1967, Don discovered that human insulin was produced as a single chain, which he termed proinsulin (1, 2). That chain was then cleaved to release the two-chain insulin molecule and a new peptide, the C-peptide. This insight solved the mystery of how the two chains of insulin, named A and B, become associated. The discovery of proinsulin was the first unambiguous demonstration of the posttranslational processing of a polypeptide precursor into the mature functional form of the hormone by specialized proteolytic enzymes. This discovery was unexpected in light of the prevailing assumptions that the A and B chains of the insulin molecule were separately synthesized and later joined. Don characterized the proinsulin processing pathway and identified and characterized proglucagon and prosomatostatin. These findings created a paradigm shift in our understanding of the biosynthetic pathway of peptide hormones. The discovery of proinsulin established the field of protein-precursor processing, paving the way to understanding how many other peptide hormones—as well as neuropeptides in the brain and endocrine system—are made and processed. Don and his colleagues later discovered the larger precursor of proinsulin, which they termed preproinsulin. This was a major advance for the understanding of peptide and prohormone processing generally. Don’s work also made major contributions to the understanding of the class of enzymes, termed prohormone convertases, that covert proinsulin to insulin along with other processing functions. His insights helped colleagues all over the world, as he traveled widely and was a frequent keynote speaker. Don had many collaborators throughout the United States, Europe, Japan, and Israel. He was an honorary member of the European Association for the Study of Diabetes. The immunoassay that Don and Arthur Rubenstein developed for the C-peptide of proinsulin provided a critical independent indicator of insulin secretion, as further developed by Kenneth Polonsky and many others (3, 4). This immunoassay has become a standard tool in the diagnosis of insulinsecreting tumors of the pancreas and the evaluation of the success of islet transplants. The discovery of proinsulin enabled the pharmaceutical industry to improve the purity of insulin preparations extracted from animals and paved the way for biosynthetic