Two investigators reviewed recent research into the progression of beta-cell failure and insulin resistance during the Scientific Sessions symposium The Banting Exchange—Diabetes Discovery—How the Past Informs the Future.
The presentation can be viewed by registered meeting attendees at ADA2020.org through September 10, 2020. If you haven’t registered for the Virtual 80th Scientific Sessions, register today to access all of the valuable meeting content.
Domenico Accili, MD, Director of the Columbia University Diabetes and Endocrinology Research Center, delivered “a message of hope” for the future of type 2 diabetes treatment.
“From what we’ve learned, we think that we can reverse beta-cell failure in a mechanistic manner,” he said. “This should lead to truly disease-modifying interventions for patients with type 2 diabetes.”
Dr. Domenico explained how a systems biology approach is being used to study the reversibility of beta-cell failure. He noted that, to date, none of the medications used to manage type 2 diabetes appears to have any effect on the progression of the disease.
“We’ve theorized three stages of progression of beta-cell failure,” he said. “Happy cells progress to metabolically challenged cells that are unable to distinguish between lipids and glucose, which in turn paves the way for dedifferentiation—the loss of features of immature beta cells and regression to a more undifferentiated phenotype.”
Dr. Domenico reviewed research looking at metabolic inflexibility and beta-cell dedifferentiation, and specifically how CRISPR technology has been used to determine drivers of this progression.
“If you look at the transcription factor BACH2, you see it’s equally adept at both driving beta-cell dedifferentiation and converting beta cells into alpha-like cells,” he explained. “In contrast, if you look at another transcription factor called AFF3, you see that it has virtually no effect on beta-cell dedifferentiation, but it is able to drive the conversion of beta cells to alpha cells. This shows different sub-phenotypes under this umbrella of beta-cell failure can be driven by different master regulators.
“This complex system analysis of human islets confirms key events in the progression of beta-cell dysfunction that we and others have identified,” Dr. Domenico continued. “The key points are dedifferentiation, metabolic inflexibility, and conversion of beta cells to alpha-like cells. It is interesting that inhibition of BACH2 can restore differentiation in diabetic beta cells and inhibition of AFF3 can reverse the transition from an alpha to a beta cell, indicating that it’s potentially possible to act mechanistically on the main driver of beta-cell dedifferentiation in a disease-modifying fashion.”
Dr. Domenico noted that a BACH1 inhibitor—a related transcription factor to BACH2—is commercially available. Dimethyl fumarate is an oral formulation approved by the U.S. Food and Drug Administration for multiple sclerosis. He said testing in both human and rodent islets is in progress to see if this BACH1 inhibitor has beneficial effects on beta-cell dedifferentiation.
Barbara Kahn, MD, Principal Investigator of the Kahn Laboratory at Beth Israel Deaconess Medical Center and Harvard Medical School, discussed research examining whether lipids can improve insulin resistance and beta-cell function.
Researchers have identified lipids that promote insulin secretion in response to a rise in glucose. Evidence shows these lipids promote glucose transport into adipocytes and are anti-inflammatory, Dr. Kahn said.
Dr. Kahn and her colleagues are investigating GLUT-4, an insulin-regulated glucose transporter.
“In patients with obesity and diabetes, GLUT-4 is reduced in adipose tissue but not in muscle,” she said. “This focused us on the question of whether the reduction in GLUT-4 in adipose tissue causes an increased risk of type 2 diabetes.”
Using animal models, Dr. Kahn and her research team determined that driving glucose into fatty acids in adipose tissue is critical for systemic insulin sensitivity. This led to further research to identify the specific fatty acids that have beneficial metabolic effects.
More than 400 fatty acid esters of hydroxy fatty acid (FAHFA) families and their multiple isomers have been identified in humans, Dr. Kahn said. Her group has focused its research on PAHSAs—FAHFAs comprised of a palmitic acid fatty acid and hydroxy stearic acid. Dr. Kahn said data show levels of PAHSA isomers are reduced in adipose tissue of insulin-resistant humans and also that PAHSAs are anti-diabetic and anti-inflammatory.
“They increase glucose transport in the adipocyte,” she said. “They decrease inflammation in the macrophages and dendritic cells. They decrease hepatic glucose production. They increase GLP-1 (glucagon-like peptide-1) in the intestine in response to glucose. And they increase insulin secretion in pancreatic islets in response to glucose. All of this improves glucose homeostasis.”