A growing body of evidence points to changes in beta cell function and mass as central elements in the pathogenesis and progression of type 2 diabetes. Preclinical models and early clinical work point to amyloid deposition in the islets as a mechanism contributing to beta cell dysfunction and death, leading to progressive loss of glycemic control.

“We  have learned that islet amyloid is a mechanism for loss of beta cells in type 2 diabetes and that reducing amyloid formation preserves beta cells by decreasing oxidative stress and inflammation,” said Steven E. Kahn, MB, ChB, Professor of Metabolism, Endocrinology and Nutrition, University of Washington (UW) and the VA Puget Sound Health Care System, and Director of the UW Diabetes Research Center and VA Puget Sound Health Care System Diabetes Research Group. “The development of amyloid inhibitors may reduce the progression of the type 2 diabetes process.”

Dr. Kahn was awarded the Banting Medal for Scientific Achievement for research focused on beta cell function and dysfunction in type 2 diabetes. He described the journey during his Banting Award lecture, “Revisiting the β-cell: The Key to the Type 2 Diabetes Puzzle,” on Sunday morning, June 22, at the 85^th Scientific Sessions. His lecture was featured in the session, President, Medicine & Science Address and Banting Medal for Scientific Achievement.

Beta cell dysfunction in type 2 diabetes was documented in 1960 and loss of beta cell mass even earlier, in 1955, Dr. Kahn noted. It has long been known that feedback between insulin-secreting cells and insulin-sensitive tissues such as liver, muscle, and adipose regulate insulin secretion and glucose homeostasis.

Dr. Kahn’s lab identified a hyperbolic relationship between beta cell response and insulin sensitivity in the early 1990s. Higher insulin sensitivity is associated with higher beta cell response. As insulin sensitivity declines, so does beta cell response. And as beta cell response declines, fasting glucose levels increase.

One of the realities of type 2 diabetes is declining response to medication over time. Dr. Khan’s lab found that different classes of glucose-lowering agents, incretins and glucagon-like peptide-1 (GLP-1) receptor agonists all had decreased response over time that was associated with increasing beta cell dysfunction. More rapid loss of beta cell function in youth compared to adults also accounts for the more rapid progression of type 2 diabetes in young people, he noted.

One reason beta cell function decreases is loss of beta cell mass over time, Dr. Khan explained. There are multiple potential contributors to beta cell loss, but amyloid deposition in islets is a prime candidate. Islet amyloid polypeptide (IAPP) is co-secreted with insulin and, for unknown reasons, deposits as fibrils in type 2 diabetes. Islet amyloid deposition is strongly associated with beta cell loss in humans, but not in mice.

Dr. Kahn’s label developed a transgenic mouse model with human islet cells and found that islet amyloid deposits contribute to oxidative stress. Blocking oxidative stress reduced amyloid deposition and beta cell loss.

Islet amyloid formation also enhanced macrophage infiltration and accumulation in mouse islets as well as enhancing inflammatory gene expression. Adding physiologic concentrations of interleukin-1 beta (IL-1β) increased amyloid deposition and beta cell death.

“We believe a vicious cycle gets established whereby amyloid begets oxidative stress, which in turn can increase amyloid production,” Dr. Kahn explained. “The data support a feed forward mechanism in which amyloid formation begets inflammation, which, through IL-1β, increases amyloid.”

Human cell culture work showed reducing amyloid formation could preserve beta cells and beta cell function. Amyloid inhibitors under development for use in Alzheimer’s disease might also find use in type 2 diabetes, Dr. Kahn noted

A proof of principle study of CT/PET Florbetapir imaging of pancreatic amyloid in humans confirmed excess amyloid deposition in individuals with type 2 diabetes. Dr. Kahn said confirmatory imaging is planned if the long-term follow-up study of the National Diabetes Prevention Program (DPP) is restarted later this summer as planned following intense pressure from members of Congress and the diabetes community. Federal funding for the Diabetes Prevention Program Outcomes Study (DPPOS) was cancelled earlier this year.

On-demand access to recorded presentations will be available to registered participants following the conclusion of the 85th Scientific Sessions, from June 25–August 25.