A special symposium at the 81st Scientific Sessions showcased current research by young investigators supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
NIDDK Symposium—Heterogeneity in Diabetes Mellitus—Developing a More Stratified Medical Approach from the Bench to Bedside, which was originally presented Saturday, June 26, can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.
Six early-career scientists—three investigating beta cell biology and three investigating gene-driven physiology and population heterogeneity in the management of glucose metabolism—provided updates on their research that’s made possible thanks to support from the NIDDK.
Beta cell biology and implications for the bedside
Emily K. Sims, MD, Assistant Professor of Pediatrics, Indiana University School of Medicine, reviewed her work using circulating proinsulin relative to C-peptide as a marker of beta cell stress and applying this marker to type 1 diabetes prevention studies. Dr. Sims shared preliminary research into the significance of elevations of the proinsulin to C-peptide (PI:C) ratio, especially in those 10 years old or younger.
“Since beta cell stress is ongoing, could prevention approaches be improved by repeated dosing of immunomodulatory drugs or the addition of an agent that directly targets beta cell health in people with high PI:C ratios?” Dr. Sims asked. “Additionally, could PI:C be useful as a predictor of responders to immunotherapies in this population?”
Emilyn U. Alejandro, PhD, McKnight Presidential Fellow and Associate Professor of Integrative Biology and Physiology, University of Minnesota Medical School, discussed research into the role of O-linked N-acetylglucosamine (GlcNAc) transferase, or OGT, in pancreas and beta cell development and OGT’s role in survival, insulin secretion and processing, and beta cell adaptation in response to obesity.
“This endogenous, highly expressed nutrient sensor protein in the pancreas, specifically in the islets, can regulate pancreas development. In the beta cell, it regulates multiple aspects, from survival to functions such as processing, as well as the level of insulin content,” said Dr. Alejandro, who also noted that islet O-GlcNAcylation of specific OGT targets, such as sarco/endoplasmic reticulum Ca2+ ATPase, can improve beta cell function.
Rafael Arrojo e Drigo, PhD, Assistant Professor of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, and his colleagues are developing ways to identify and quantify cell age in situ without disrupting the tissue microenvironment. His lab wants to reverse-engineer long-living cells or the mechanisms that maintain cell longevity to repair or protect tissues from age-related functional decline.
“So far, we think that PDX1 (pancreatic and duodenal homeobox 1) is linked to a long-lived beta cell phenotype. However, we’re still trying to determine what the mechanism is that is linking PDX1 with beta cell longevity. We’re really interested in what is the functional and metabolic profile of these caloric-restricted beta cells. Are they changing the way they metabolize different types of nutrients?” Dr. Arrojo e Drigo said.
Gene-driven physiology and population heterogeneity in management of glucose metabolism
Camille E. Powe, MD, Assistant Professor of Medicine, Obstetrics, Gynecology & Reproductive Biology, Harvard Medical School, has worked to improve the understanding of hyperglycemia in pregnancy and has developed a longitudinal cohort study titled Study of Pregnancy Regulation of Insulin and Glucose (SPRING), which is collecting DNA and looking at physiology across pregnancy using oral glucose tests. Dynamic longitudinal changes in glycemic physiology in pregnancy include lower fasting glucose and higher postprandial glucose, but the hormonal mediators of these changes are largely unknown.
“We are hoping to use genomic approaches to better uncover what’s mediating these changes in physiology,” Dr. Powe said. “We have identified cluster polygenic scores that are associated with gestational diabetes, and we have ongoing work to try to identify genetic determinants of longitudinal changes in pregnancy glycemic physiology.”
Rochelle N. Naylor, MD, Assistant Professor of Pediatrics, University of Chicago, discussed management approaches for glucokinase–maturity-onset diabetes of the young (GCK-MODY) in pregnancy and fetal and maternal outcomes of GCK-MODY in pregnancy.
GCK-MODY management must be based on the known or suspected fetal genotype. If insulin is used when the fetus is affected, there’s a risk for a small-for-gestational-age baby, Dr. Naylor noted, but not using insulin when the fetus isn’t affected brings the risk of a large-for-gestational-age baby. While there are risks for neonatal and maternal adverse outcomes, there do not appear to be long-term impacts, she said.
“Cell-free fetal DNA diagnostics has the potential to greatly improve GCK-MODY pregnancy outcomes by allowing us to know the fetal genotype early in the pregnancy,” Dr. Naylor said.
Joshua J. Joseph, MD, MPH, FAHA, Assistant Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, Ohio State University Wexner Medical Center, discussed his research group’s work examining the role of aldosterone in type 2 diabetes.
Current research looks at the role of the renin-angiotensin aldosterone system, the protein-coding gene ARMC5, and neprilysin in glucose metabolism among African Americans with prediabetes. Dr. Joseph said that aldosterone could offer a path to more structured and precise approaches for diabetes prevention and treatment.
“Aldosterone is associated with higher insulin resistance, higher odds of prevalent diabetes, increased risk of diabetes over seven to 10 years, depending on the study we have done, and it’s a mediator of the association of Life’s Simple 7 with incident diabetes,” said Dr. Joseph, referring to seven risk factors for cardiovascular disease defined by the American Heart Association.