Hitting two organs with one common signaling regulator

Researchers

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Kyoto, Japan -- 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 dwindles to insufficiency, a multiple-organ dysfunction that contributes to hyperglycemia, or high blood glucose levels.

Intracellular calcium signaling is essential to both processes and could represent a crucial link between them, yet a common molecular regulator has yet to be found. While the protein carbonic anhydrase VIII -- CA8 -- is known to bind IP3R1, a calcium-release channel in the endoplasmic reticulum, as well as restrain calcium signaling in other tissues, this protein lacks the usual enzyme activity. However, a team of researchers at Kyoto University found the protein to be enriched in pancreatic islets and hepatocytes, and wondered whether CA8 may play a role in controlling metabolic functions in the liver and pancreas.

The team combined metabolic testing of Car8^wdl mice -- lacking functional CA8 -- with experiments on the mice's isolated pancreatic islets and liver hepatocytes. They measured insulin secretion, glucose production, calcium responses, and gene expression, and then used pharmacological and genetic tests to assess whether the effects depended on IP3R1.

In further experiments, the researchers found that chronic exposure to glucagon, the very hormone that triggers glucose production, increased CA8 expression which in turn rendered further glucagon stimulation. This glucagon desensitizing effect mediated by CA8 may provide a mechanistic explanation for the emerging glucagon-based T2D therapy. The team also analyzed obese and diabetic mice along with public RNA-sequencing data of mice fed high-fat diets and found intensified CA8 expression in islets, hinting at the protein's roles in T2D pathogenesis.

The team's results reveal CA8 to be a promising therapeutic target. While the CA8-deficient mice showed an increase in the secretion of both glucose in the liver and glucose-induced insulin in the pancreas, in obese and diabetic mice, CA8 expression shifted in opposite directions, rising in the pancreas' islets while falling in the liver's hepatocytes in accordance with impaired insulin secretion and excessive glucose production. The team also observed that restoring CA8 expression in the liver reduced excessive hepatic glucose production and hyperglycemia during fasting.

"We were intrigued that a single intracellular regulator could act as a common 'brake' in two organs but produce very different physiological outcomes," says first author Muhammad Fauzi. "That organ-specific duality gives us a new way to think about the multi-organ nature of type 2 diabetes."

This study suggests that a multi-organ disease can arise from tissue-specific changes in a shared molecular mechanism, pointing toward treatment strategies for type 2 diabetes that consider the pancreas and liver as one coordinated glucose-control system rather than targeting either organ in isolation. However, as much of the physiology was established in mice, further studies in human tissues and cells are necessary before CA8 can be considered a therapeutic target.

"Our findings may help explain part of the complexity of this disease," says corresponding author Takaaki Murakami. "We hope to use this multi-organ perspective to develop treatments that act appropriately in each tissue."

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