The intertwining roles of mechanosensitive channels, cellular stress, and the proteasome in β cell function
Open Access DepositedThe pancreas is a retroperitoneal organ comprised of heterogeneous exocrine and endocrine tissues that broadly function in digestion, appetite regulation, and blood glucose homeostasis. The endocrine pancreas is comprised of clusters of neuroendocrine cells that each have a highly specialized role in blood glucose homeostasis. Endocrine pancreatic beta cells secrete insulin and islet amyloid polypeptide (IAPP) in response to increases in blood glucose. Insulin promotes skeletal muscle and adipose tissue to take up excess blood glucose. IAPP binds to multiple tissues including skeletal muscle and the hindbrain to elicit various responses.The most common disease caused by pancreatic dysfunction is type two diabetes. Although chronic hyperglycemia and insufficient insulin secretion are hallmarks of this disease, heterogenous processes drive its development. Metabolic stress contributes to beta cell failure as constant glucose inundation creates oxidative stress and impairs beta cell blood glucose sensing, lowering insulin secretion. Cells damaged by oxidative stress release danger-associated molecular patterns that recruit innate immune cells into the tissue. As insulitis progresses, interleukin 1-beta production increases, reducing insulin secretion and inducing apoptosis mediated by TXNIP interactions with various binding partners. Despite the major roles metabolic and proinflammatory stress play in the development of type two diabetes, the potential signaling cross talk between stressors remains poorly understood. Here, we observed concurrent high glucose and proinflammatory cytokines is required for changes in gene expression. Immunoprecipitation studies refuted direct binding between TXNIP and NF-kB in this process, suggesting two pro-inflammatory pathways operate in parallel in stressed beta cells. As type two diabetes progresses, there is a further loss of insulin secretion due to beta cell apoptosis and de-differentiation. Beta cell amyloidosis contributes heavily to apoptosis as IAPP oligomers are found in most individuals with type two diabetes. The exact cause of IAPP oligomerization is unknown but is linked to impaired proteasome function seen in type two diabetes. These IAPP aggregates cause protein stress leading to reactive oxygen species formation, reduced mitochondrial membrane potential, and decreased proteolytic functions. To assess additional effects of protein stress, we compared changes in gene expression in human islet under acutely induced proteasome inhibition and type two diabetes induced proteasome inhibition. We observed downregulation of beta cell identity marker genes and genes required for glucose sensing and glucose induced insulin secretion in proteasome-inhibited samples. We also found impaired pyruvate production and decreased mitochondrial membrane potential under proteasome inhibition suggesting proteasome function and/or associated protein stress reduces beta cell ATP production to reduce ATP-dependent peptide hormone secretion from these cells. Despite improving treatments, approximately half of people with type two diabetes will fail to achieve glycemic control leading to complications like nephropathy. Current pharmacological treatments reduce blood glucose by reducing appetite and gastric glucose absorption
however, they carry side effects like gastric disturbances while also having high financial costs and supply shortages. Given the need for improved type two diabetes treatments, non-pharmacological treatments have been developed including therapeutic ultrasound-induced insulin secretion. The broader effects of ultrasound treatment on beta cell physiology remain unknown as well as how these cells detect ultrasound stimulation. Here, we identified expression of mechanosensitive channels in human and rodent pancreatic beta cells that are implicated in both ultrasound-mediated reactive oxygen species formation and downregulation of essential beta cell genes.
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