“Our work has led to a new concept of how β-cells sense nutrients that we hope will allow the development of more effective therapies to treat diabetes.”
– Dr. Matthew Merrins
At a Glance
Diabetes affects almost 600,000 people in Wisconsin and costs state residents $6.15 billion per year, numbers which are expected to triple in the next 15 years. Type 2 diabetes (T2D) accounts for the majority of these cases and is linked to the failure of insulin secretion from pancreatic β-cells (beta cells) that keep blood sugar in check. These rapidly climbing number pose a significant burden on the healthcare system.
The researchers identified a new potential target for diabetes therapy, the metabolic enzyme pyruvate kinase (PK), which has been found to be sufficient in initiating and amplifying insulin secretion. Their work suggests that PK activation could be utilized to promote the healthy metabolic function of β-cells in order to prevent or reduce T2D.
The Challenge
Two-thirds of adults in Wisconsin are either overweight or obese, both being recognized as health risks associated with T2D. When an individual develops diabetes, diabetic β-cells stop secreting insulin, which is linked to metabolic failure in the pancreatic islet β-cell. Thus, additional studies are needed to provide a strong scientific basis for a clinical intervention that preserves β-cell metabolic health in people.
Project Goals
The overarching goal of this project was to test the hypothesis that PK-activating drugs enhance insulin secretion and protect endoplasmic reticulum calcium in human islets. The researchers also aimed to publish their novel imaging methods for assessing mitochondrial anaplerosis-cataplerosis, a signal of fuel abundance that contributes to activation of insulin secretion from β-cells.
Results
The researchers have identified PK as a new potential target for diabetes therapy. PK-activating drugs are currently in clinical trials for rare genetic disorders of PK deficiency that cause anemia. Although the current theory of how β-cells sense glucose suggests that these drugs should have no impact on insulin secretion, the researchers have found that PK-activating drugs can stimulate β-cells to more efficiently release insulin without risking hypoglycemia. This work has made way for the development of more effective therapies to treat diabetes.
The techniques developed during the award period contributed to multiple NIH and VA grants (R01DK113013, R01DK127637, and I01BX004921), and three collaborative awards with investigators at Duke (Dr. Jon Campbell, R01DK123075), UCSF (Dr. Gregory Ku, R01DK118337), and UW–Madison (Dr. Jon Odorico, DOD/PRMRP).
This study of pyruvate kinase resulted directly in two companion papers published in Cell Metabolism: Lewandowski et al., Cell Metabolism 2020 and Abulizi et al., Cell Metabolism 2020. Many of the optical techniques for monitoring cellular metabolism developed during the award were also published, including Sdao et al., Cell Reports 2021.
This study also resulted in new partnerships which led to five collaborative manuscripts being published with Dr. Melissa Skala at the University of Wisconsin (Sharick et al., Scientific Reports 2018), Dr. Gregory Ku at UCSF (Hennings et al, Endocrinology 2018), Dr. Jon Campbell at Duke (Capozzi et al., JCI Insight 2019) and Dr. Dave D’Alessio at Duke (Douros et al., JCI Insight 2019; Molecular Metabolism 2019).
Looking to the Future
This awarded grant has led to a significant expansion of the researchers’ NIH funded work, which allows for further exploration into the effects of the PK activation on electrical activity in human islets.
Lasting Impact
As the numbers related to diabetes grow in the coming years, the results of this project may contribute to additional effective treatments to combat the increasing burden Type 2 diabetes has on the residents of Wisconsin.
