Poster Q2 - Changes in extracellular matrix stiffness mediate pancreatic islet function: insights into glucose metabolism and mitochondrial dynamics

Introduction: In the pancreas, the islet is surrounded by a specialized extracellular matrix (ECM) which regulates cell survival and insulin secretion from islet β-cells. Little is known about how mechanical properties, like stiffness, of the ECM regulate islet function in health and disease. Previous research conducted on islets from a rat model of type 2 diabetes (T2D), characterized by increased ECM stiffness and reduced insulin secretion, revealed changes in mitochondrial morphology marked by increased mitochondrial fragmentation. Mitochondrial morphology is regulated by membrane potential (ΔΨ), with alterations in ΔΨ influencing fusion-fission dynamics crucial for maintaining mitochondrial function. Insulin secretion in the β-cell is tightly controlled by metabolism and mitochondrial function; however, the mechanisms underlying mechanotransduction regulation of glucose metabolism and mitochondrial dynamics have not been well studied in intact islets. We hypothesize that increasing matrix stiffness will yield a depolarized ΔΨ, an increase in mitochondrial fragmentation, and impaired insulin secretion.

Materials and

Methods: To test our hypothesis, mouse and human cadaveric islets were encapsulated in PEG-maleimide with an RGD-cysteine binding ligand crosslinked via Michael-type addition to PEG-dithiol. This 3D PEG hydrogel mimics the islet microenvironment, where 3wt% PEG gels (0.204±0.007 kPa) represent healthy pancreas stiffness and 7.5wt% (2.25±0.153 kPa) represents stiffness seen in T2D ECM.

Results, Conclusions, and Discussions: Our results indicate that increased scaffold stiffness causes a 57% reduction in insulin secretion stimulation index (p=0.029), a 220-240% decrease in TMRE fluorescence intensity (p=0.0043) indicating depolarization of the ΔΨ at 2mM and 20mM glucose respectively, and mitochondrial fragmentation. Overall, our results emphasize the role mechanical properties of the islet microenvironment plays in regulating insulin secretion and mitochondrial function. It also supports further investigation into the modulation of glucose metabolism and mitochondrial dynamics to restore islet function in diseases like T2D where fibrosis of the peri-islet ECM leads to increased tissue stiffness and islet dysfunction.

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