Shared signaling regulator may link liver and pancreas dysfunction in type 2 diabetes
Maintaining healthy blood glucose levels involves striking a balance between the glucose produced by the liver during fasting and the insulin released from pancreatic beta cells after meals. In type 2 diabetes, glucose production goes into overdrive while insulin secretion becomes insufficient, a multiorgan dysfunction that contributes to hyperglycemia, or high blood glucose levels.
Intracellular calcium signaling plays a pivotal role in both liver and pancreas function in type 2 diabetes, potentially linking the two disparate processes. Until now, a shared molecular regulator has evaded discovery. Protein carbonic anhydrase VIII—CA8—has been found to bind to IP3R1, a calcium-release channel in the endoplasmic reticulum, although it lacks usual enzyme activity.
Researchers at Kyoto University observed CA8 to be enriched in pancreatic islets and hepatocytes, sparking curiosity about its potential role in metabolic control. Utilizing metabolic testing and experiments on isolated pancreatic islets and liver hepatocytes, the team discovered that CA8 impacts insulin secretion, glucose production, calcium responses, and gene expression in these tissues.
Further assays revealed that chronic glucagon exposure elevates CA8 expression, which diminishes the response to additional glucagon stimulation, potentially explaining the function of emerging glucagon-based therapies for type 2 diabetes. The study also revealed that obese and diabetic mice displayed varying CA8 expression patterns in the pancreas and liver, correlating with impaired insulin secretion and excessive glucose production.
Restoring CA8 expression in the liver alleviated excessive hepatic glucose production and hyperglycemia during fasting. While the study's results suggest CA8 as a promising therapeutic target, further validation in human tissues and cells is required before considering it as a treatment option.
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