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The Continuing Saga of Genes, Pathophysiology and Diabetes Mellitus

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Among the most rapidly expanding areas of knowledge in the diabetes arena are the relationships among genetic variables and the risk of developing diabetes mellitus. Several general sessions and the two major scientific research awards were related to understanding how genetic studies are beginning to unravel the heterogeneity of Type 2 diabetes mellitus (T2DM). I will discuss the general session issues only briefly, but the presentations by two ADA awardees on one form of monogenic diabetes were very insightful.

When the Human Genome Project got underway, Dr. Francis Collins (current director of the NIH) was its lead. At many national meetings, including the AHA and ADA, he described diabetes mellitus as the classic example of a complex disorder. He posited that the Human Genome Project might not provide immediate clear evidence of causal genetic relationships for diabetes risk. This view has turned out to be prescient. Whereas now, GWAS analyses have reported hundreds of genes associated with T2DM, and genetic risk scores have been developed, there is, as yet, no genetic panel that can be used in clinical practice to predict future T2DM. But the story is unfolding as investigators now seek to understand whether genes are associated with specific protein products, modulate the effects of other genes, or may involve pathways associated with known pathophysiologic features of diabetes such as insulin secretion or insulin resistance. Methods are now available to determine whether the genes have exposed chromatin and thus may be functional or whether they represent comparatively “silent” associations.

One area of genetic and clinical success is in the area of monogenic diabetes. In 1974, Dr. Robert Tattersall from the U.K. noted that there were families in which early-onset diabetes mellitus occurred in multiple siblings and over multiple generations. The disease pattern was consistent with an autosomal dominant form of T2DM. Early confirmation for these observations in the U.S. was made by Dr. Stefan Fajans at the University of Michigan. The terms currently applied to this familial diabetes have been monogenic diabetes or maturity-onset diabetes of youth (MODY). Over the past several decades, at least 14 different genes have been associated with MODY. Among these genes are ones that modulate insulin secretion by the beta-cell and the function of ATP channels necessary for insulin secretion.

The lecture by the Banting Medal recipient, Prof. Francis Ashcroft, was entitled “Metabolic Regulation of Insulin Secretion in Health and Disease.” Prof Ashcroft has devoted her career to understanding electrical activity in the beta-cell, as well as factors that modulate insulin secretion from the beta-cell. Insulin secretion is dependent on a pancreatic ATP-sensitive potassium (KATP) channel, and much of her work is in this area. Genetically determined alterations in this channel can result in both over or under secretion of insulin and, in turn, both neonatal hyperinsulinemia or diabetes mellitus. One such alteration in persons with monogenic diabetes results in a KATP channel, which is responsive to sulfonylureas. A quote from one of her publications succinctly captures the problem: “The data demonstrate that tiny changes in KATP channel activity can alter beta cell electrical activity and insulin secretion sufficiently to cause diabetes.” The Outstanding Scientific Achievement Award awardee was Dr. Anna L Goyn. Her lecture was entitled, “Mining the Genome for Gold—Drilling Down on Mechanisms for Pancreatic Islet Cell Dysfunction in Diabetes. Her presentation included clinical applications of these KATP channel abnormalities. A key theme in her lecture was the clinical impact of treating children whose diabetes had been (inappropriately) treated with insulin before the diagnosis of the monogenic form of diabetes, which was responsive to the sulfonylureas was made. In addition to elegant science she showed smiling pictures of groups of children whose diabetes was more easily managed with a sulfonylurea pill after having been on insulin therapy.

These two lectures were one of the highlights of the ADA 2022 scientific sessions. They included both elegances of the science and clear clinical impact in children who develop diabetes. The data presented also indicate that as diligent scientists and clinician-scientists continue to evaluate the relationships between genetics, pathophysiology and clinical features of T2DM, the extensive heterogeneity in T2DM will ultimately be much more well characterized.

Dr. Hoogwerf was formerly employed by Eli Lilly. He has received consulting fees from MannKind Corp and Zealand Corp and payments for reviewing material from Merck Manual.

Image by GoodStudio / shutterstock

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