There is no cure for diabetes—yet. But work toward a cure continues to progress. In the Pathway to Stop Diabetes symposium on Friday, five up-and-coming researchers outlined new approaches to this goal being funded by the American Diabetes Association® (ADA). These investigators are looking at the gut microbiome, cloaked beta-cells, branched-chain amino acid, dysregulation of the gut-brain axis by sugar, and diabetes distress with new perspectives.
The session can be viewed on-demand 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.
The ADA Pathway to Stop Diabetes program aims to cultivate a new generation of scientists by providing freedom, autonomy, and resources to facilitate groundbreaking discoveries in translational science that ultimately lead to breakthroughs in diabetes.
The Gut Microbiome
The gut has long been recognized as a key player in diabetes. However, the real player may be the gut microbiome, said Aleksandar D. Kostic, PhD, Assistant Professor of Microbiology, Harvard Medical School, and Assistant Investigator, Joslin Diabetes Center.
“The gut has an entire microbiome of 150 trillion organisms,” he said. “Many of these microbes can help us treat diabetes.”
The gut microbiome can modulate immune tolerance by inducing T regulatory cells to block the autoimmune activity of killer T-cells to protect beta-cells and insulin secretion.
The effects of a healthy gut microbiome on type 1 diabetes can be seen most vividly in Finland, Dr. Kostic said. Type 1 diabetes incidence is six times higher in urbanized populations compared to individuals living in rural areas with a traditional lifestyle. Similar distinctions can be seen in microbiomes and type 1 diabetes in hunter-gatherer populations and in elite athletes.
Working with 10,000 parabacteroides goldsteinii ASF519 mutants, Dr. Kostic’s lab showed that adenosine fosters immune tolerance to promote gut colonization and immune homeostasis. Work with germ-free non-obese diabetic (NOD) mice suggests that inoculation with the appropriate microbial species can enhance adenosinergic signaling to increase beta-cell mass and insulin secretion, improve thermogenesis, and enhance other metabolic processes impaired in type 1 diabetes.
Cloaking Beta-Cells Against Immune Attack
Autoimmunity against beta-cells gives rise to type 1 diabetes. Replacing lost beta-cells, either through direct implantation or implanting stem cells that give rise to beta-cells, can help, but the new cells are subject to recurrent attack by the immune system.
“We know that some beta-cells escape immune attack in patients even after years of living with type 1 diabetes,” said Judith Agudo, PhD, Principal Investigator in Cancer Immunology and Virology, Dana-Farber Cancer Institute and Assistant Professor of Immunology, Harvard Medical School. “We used JEDI (just EGFP death-inducing) T-cells to model type 1 diabetes.”
What Dr. Agudo found was “Goldilocks” levels of major histocompatibility complex (MHC) class I that allow escape from T-cells and NK-cells. The goal, she said, is to engineer islets so they are cloaked from immune cells and escape autoimmune attack.
Branched-Chain Amino Acids
Branched-chain amino acid (BCAA) levels have been associated with diabetes since at least the late 1960s and contribute to diabetes risk. Modulating BCAA oxidation by manipulating the branched-chain alpha-keto acid (BCKA) regulatory network can have robust effects on systemic BCAA homeostasis.
“Activation of BCKA oxidation lowers liver fat and improves glucose control,” said Phillip J. White, PhD, Assistant Professor of Endocrinology, Metabolism and Nutrition, Duke University School of Medicine. “The BDK/PPM1K (branched-chain alpha-keto acid dehydrogenase kinase/protein phosphatase 1K) axis integrates BCAA and lipid metabolism in the liver in mice. In humans, BDK/PPM1K disequilibrium is associated with fatty liver disease.”
BCKA also links metabolic disease to cardiac dysfunction. The goal is to identify the factors that are regulated by BDK and PPM1K and to explore the therapeutic potential of BDK/PPM1K modulators, Dr. White explained.
Your Brain on Sugar
Food rapidly changes the neural activities that control hunger. But all foods are not equal. Too much sugar can dysregulate the gut-brain axis, resulting in excessive food intake, obesity, type 2 diabetes, and other metabolic diseases.
High-fat diets selectively blunt the inhibition of lipid-mediated hunger neurons, said Lisa Beutler, MD, PhD, Assistant Professor of Endocrinology, Northwestern University, while high-sugar diets selectively blunt glucose-mediated neuron inhibition, at least in mice. That means nutrient intake does not alleviate hunger as effectively in obese mice as it does in normoweight mice.
“Weight regain is a major limitation of current medical therapies for diabetes,” Dr. Beutler said. “Plasticity of gut-brain circuits induced by obesity may drive this pattern. We want to manipulate the gut-brain axis to prevent or reverse obesity. At the end of the day, I want to move the needle for my patients with diabetes and obesity.”
Routine Treatment of Diabetes Distress
Current type 1 diabetes guidelines recommend screening and prompt treatment of diabetes distress but lack specific steps clinicians can and should take.
“Diabetes distress is prevalent, quantifiable, clinically relevant, does not self-resolve, and is very responsive to treatment,” said Anna Kahkoska, MD, PhD, Assistant Professor of Nutrition, University of North Carolina (UNC) Gillings School of Global Public Health and Adjunct Assistant Professor of Endocrinology and Metabolism, UNC School of Medicine. “It is also time- and resource-intensive to treat and heterogeneous. The same treatments do not work for everyone. We need a new approach.”
Diabetes clinicians recognize diabetes distress and the burdens, fears, and threats that arise from the challenges of living with diabetes, Dr. Kahkoska continued. But they don’t know how best to incorporate diabetes distress assessments into routine care or how to treat it more effectively in more of their patients.
“We are working on new strategies to identify diabetes distress in the clinic, to improve access to evidence-based treatments, and to reduce barriers at the provider and clinic levels,” Dr. Kahkoska said. “We need robust data for individualized diabetes distress treatments.”