Carmella Evans-Molina, MD, PhD, Eli Lilly Professor of Pediatric Diabetes, Indiana University (IU) School of Medicine, and Director, IU Center for Diabetes and Metabolic Diseases, received the 2023 Outstanding Scientific Achievement Award from the American Diabetes Association® (ADA) on Monday morning.
“This award actually belongs to the many members of my lab over the years,” Dr. Evans-Molina said. “They are the ones who did the work helping us to understand the role of the failing B-cell in diabetes.”
Dr. Evans-Molina’s lecture, The Ailing Beta Cell in Diabetes—Insights from a Trip to the ER, can be viewed by registered meeting participants at ADA2023.org. If you haven’t registered for the 83rd Scientific Sessions, register today to access the valuable meeting content through August 28.
Her original interest lay in understanding the beta-cell pathways that drive the transition from normoglycemia to dysglycemia to diabetes. Calcium ions play similar roles in insulin secretion as they do in muscular contractions, regulating a signaling cascade that results in the release of insulin.
Intracellular calcium ion (Ca2+) stores regulate the heavy biosynthetic burden of insulin production, powered by a steep gradient from high concentrations in the extracellular matrix to increasingly lower concentrations in secretory granules, Golgi bodies, and the endoplasmic reticulum (ER). The membrane pump sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) moves Ca2+ through the cell to facilitate maturation of proinsulin to insulin and insulin section, among other functions.
Other members of the SERCA family regulate calcium activity in other cell types, including muscle.
In animal models of diabetes, reduced SERCA2 expressing dysregulates ER calcium release, a common pathway of beta-cell dysfunction in diabetes, Dr. Evans-Molina said.
In animal models, this impaired glucose secretion is accompanied by an increase in proinsulin in the pancreas and in serum. Ca2+ signaling regulates the activation of prohormone convertases. A SERCA deficiency leads to reduced production of prohormone convertase, reduced conversion, and an accumulation of proinsulin in the ER-Golgi intermediate compartment and in Golgi bodies.
Increased circulating proinsulin precedes the first symptoms of type 1 diabetes by about 12 months, Dr. Evans-Molina continued. Impaired proinsulin processing may be a useful biomarker or predictor of diabetes.
Knocking out SERCA2 reduces ER calcium and accelerates the onset of diabetes in non-obese diabetic (NOD) mice. These same mice also show progressive mitochondrial dysfunction, likely the result of Ca2+ exchange from ER to the closely linked mitochondria.
The molecular pathways that link mitochondrial calcium and type 1 diabetes pathogenesis are not clear, Dr. Evans-Molina said. In broad terms, reduced SERCA appears to create weaker and more immunogenic beta cells, leading to accelerated antibody development. There may also be mitochondria-mediated immune activation in play.
On the other side, activation of SERCA2 reduces the incidence of diabetes in NOD wild-type and SERCA knockout mice.
“This could be a useful target for disease-modifying therapy, at least in preclinical models,” Dr. Evans-Molina said.
The U.S. Food and Drug Administration (FDA) has already approved teplizumab-mzwv to delay the progression of type 1 diabetes, she noted. Approving the first disease-modifying therapy may ease other approvals.
For now, Dr. Evans-Molina is focusing on ways to leverage beta-cell stress to inform type 1 diabetes biomarker development. Stressed beta-cells moving into type 1 diabetes upregulate all the usual suspect proteins and pathways, she said, but her lab has uncovered new players, including protein disulphide isomerase A1 (PDIA1) and nucleobindin 2 (NUCB2).
PDIA1/prolyl 4-hydroxylase subunit beta (P4HB) is needed for efficient proinsulin maturation and beta-cell health in diet-induced obesity in animal models and PDIA1 expression is increased in human diabetes. Early animal and human data suggest that circulating PDIA1 may be a useful type 1 diabetes biomarker.
“I love the beta-cell, but the beta-cell is not everything in diabetes, and one biomarker is not likely to be sufficient,” Dr. Evans-Molina said. “I see multiple biomarkers to monitor and improve beta-cell health.”