An expert panel explained several ways that diet and environmental factors can affect beta cell function, metabolic disease, and diabetes during the Scientific Sessions symposium What’s for Dinner? Dietary Interventions and Beta-Cell Function.
The session was originally presented Sunday, June 27, and 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.
Maria S. Remedi, PhD, Assistant Professor of Medicine and Cell Biology & Physiology, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, shared unpublished data from her lab, where researchers are using mouse models to investigate the effect of intermittent fasting on beta cell autophagy and endoplasmic reticulum (ER) stress. Autophagy maintains cellular homeostasis during nutrient deprivation or cellular stress, and defective autophagy has been linked to many human diseases. In diabetes, it regulates function in pancreatic beta cells and insulin-target tissues, while also protecting beta cell toxicity from ER stress.
In animal models, intermittent fasting increases autophagy, decreases ER stress, improves glucose tolerance and adipose tissue function, decreases advanced glycation end products and weight, and increases lifespan in some, Dr. Remedi said. In one study using non-diabetic mice, ad libitum feeding for 25 days showed increased ER stress and autophagosome accumulation, with decreases in autophagic flux and adipose tissue function, she said. Intermittent fasting—24 hours feeding followed by 24 hours no feeding—for 25 days showed decreased ER stress and autophagosome accumulation, with increases in autophagic flux and adipose tissue functions.
Richard O’Brien, PhD, Professor, Vanderbilt University School of Medicine, discussed research focused on the protein-coding gene G6PC2, part of the glucose 6-phosphate system in the ER predominantly expressed in beta cells. G6PC2 is identified as a major locus in the control of fasting blood glucose.
In the context of ketogenic diets and prolonged fasting, G6PC2 protects against hypoglycemia, Dr. O’Brien said. In mouse models using G6PC2 knockout and wild type mice, both became hypoglycemic after one day on a ketogenic diet, with a compensatory increase in fasting plasma glucagon levels, he said.
“These data suggest that G6PC2 inhibitors are likely to be beneficial for lowering fasting blood glucose levels, and potentially reducing the risk of type 2 diabetes and cardiovascular-associated mortality. But hypoglycemia might be a concern under specific physiological conditions,” Dr. O’Brien said.
Aleksey Matveyenko, PhD, Consultant, Department of Physiology & Biomedical Engineering, Mayo Clinic, presented his lab’s work on the physiological and molecular effects of time-restricted feeding. Circadian disruption (CD)—associated with shift work, night work, and circadian misalignment—disturbs normal feeding cycles and profoundly affects the beta cell function and beta cell survival in the islet. Restoration of normal fasting-feeding cycles through time-restricted feeding prevents metabolic derangements associated with CD, he said.
“We identified that the PAR bZIP (proline- and acidic amino-acid-rich basic leucine zipper) circadian transcription factor family, likely DBP (D-box binding PAR bZIP transcription factor), plays an important and perhaps previously underappreciated role in mediating the beta cell’s circadian response to time-restricted feeding and is required for glucose-stimulated insulin secretion,” Dr. Matveyenko said.
Jennifer Bruin, PhD, Carleton University, Canada, closed the session with a look at unpublished data from her lab’s research into how environmental pollutants impact the metabolic effects of a high-fat diet.
Using CYP1A1 as a sensitive biomarker for exposure to aryl hydrocarbon receptor (AhR) ligands, Dr. Bruin’s lab is investigating how dioxins, through the dioxin-like research chemical TCDD, impact islet physiology and diabetes risk. Reviewing research into early-life and adult TCDD exposure, Dr. Bruin noted that exposed offspring and dams showed similar levels at the birth of the offspring, indicating there was transfer of TCDD to the baby. Also, the dam and pups were both hypoglycemic.
TCDD-exposed offspring didn’t show major glucose abnormalities, Dr. Bruin said, but dams who were switched to a high-fat diet gained more weight than those not exposed to TCDD and developed severe hyperglycemia.
Research indicates that chronic low-dose TCDD in adult mice has a minimal effect without a secondary metabolic stressor, Dr. Bruin said, and that TCDD-exposed females have more difficulty adapting to metabolic stressors than males. More work is being done to determine if chronic low-dose TCDD has any effect on pancreas development.