How will diabetes be treated in 2021, 100 years after the discovery of insulin? With selective insulin sensitizers, and by preventing beta-cell dedifferentiation in type 2 diabetes and producing insulin in the gut for type 1. All are basic research areas ripe for translation, according to Domenico Accili, MD, this year’s winner of the Banting Medal for Scientific Achievement.
Dr. Accili, the Russell Berrie Foundation Professor of Diabetes and Director of the Diabetes Research Center at Columbia University College of Physicians and Surgeons, laid out the course of future diabetes treatment Sunday morning during his Banting lecture.
“Early in my career, I matured the belief that research is a continuation of clinical care, driven by the realization that diseases won’t disappear of their own account,” Dr. Accili said. “Current treatments don’t modify or reverse the two key causes of the disease—insulin resistance and beta-cell dysfunction. We are now positioned to design new classes of drugs that will tackle the root causes of diabetes and consign the disease to the realm of medical curiosities, much the same way as polio or smallpox.”
When Dr. Accili, began his medical career, insulin action was a black box. He helped open the box, shifting the focus of insulin action research from the plasma membrane to the nucleus.
The discovery of the FOXO gene, which regulates insulin, leptin, hepatic glucose production, triglyceride synthesis, bile acid composition, beta-cell function, gut cell progenitor differentiation, atherogenesis, and endothelial function, provided the key. It was an obvious target.
Inhibiting FOXO decreases hepatic glucose production, but it also increases triglyceride synthesis with adverse effects on the heart, kidney, bone, and other systems. Dr. Accili’s lab screened a million small molecules to identify 15 FOXO inhibitors. Cellular assay found several that selectively increase insulin sensitivity without increasing de novo lipogenesis.
“We now know that selective reversal of insulin resistance should be possible,” Dr. Accili said. “This research is now ripe for transformative drug discovery.”
FOXO also regulates beta-cell function. What distinguishes individuals with insulin resistance who develop diabetes from those who do not is the innate susceptibility of beta cells to functional exhaustion. FOXO makes the difference.
Dr. Accili said beta-cell function in diabetes shows at least three abnormalities: impaired insulin response, a reduction in the number of beta cells, and an inappropriate glucagon response. FOXO links all three abnormalities, he said.
Under stress from hyperglycemia, beta cells lose their ability to shift between glucose, amino acids, and lipids as substrates for mitochondrial oxidative phosphorylation. If fatty acid oxidation increases, FOXO is activated to prevent excessive lipid utilization and the resulting accumulation of toxic metabolites.
But FOXO is rapidly depleted if hyperglycemia is not resolved quickly. When hyperglycemia is chronic, beta cells increasingly turn to lipid oxidation, which eventually impairs insulin secretion.
Long-term lipid utilization also causes beta cells to lose their differentiated features, Dr. Accili said. They revert to a dedifferentiated state. Some beta cells convert to glucagon-producing cells, which may explain the hyperglucagonemia seen in diabetes, he explained.
The good news is that hyperglycemia does not kill beta cells, it simply silences them. It should be possible to revive and redifferentiate quiescent beta cells to restore normal biological activity.
“There’s a gene that has turned up in nearly every human genetic association study of diabetes and in virtually every ethnic group investigated,” Dr. Accili said. “We don’t know whether this is the key gene predisposing to beta-cell failure, but we need to identify pharmacologically actionable pathways for intervention.”