A potential new therapy for diabetics has been discovered that could prove to be a major breakthrough in the management of type 2 diabetes.
The latest research centers on a specific gene, SMOC1. In healthy individuals, this gene is typically active only in alpha cells, which produce glucagon, a hormone that regulates blood sugar levels, to raise blood sugar.
However, in people with type 2 diabetes (T2D), the SMOC1 gene is active in beta cells. This is a critical problem because beta cells produce insulin, another hormone that regulates blood sugar levels, to lower blood sugar.
In people with T2D, beta cells are reprogrammed into dysfunctional alpha-like cells, and the SMOC1 gene is the primary driver of this damaging transformation.
Additionally, introducing the SMOC1 protein to healthy beta cells impaired their ability to produce and release insulin. The inability to make or use insulin effectively is the defining characteristic of diabetes.
Discovering SMOC1 as the key culprit driving the harmful transformation could lead to the development of a drug to block SMOC1’s action and halt the progression of T2D.
Dr Geming Lur, co-corresponding author and researcher at City of Hope, one of the country’s most advanced cancer treatment organizations, said: ‘Normally, SMOC1 is active in healthy people’s alpha cells.
‘But we saw it start showing up in the diabetic beta cells, too. It should not have been there.’
The study identifies SMOC1 as the key driver of beta cell failure, making it a promising drug target. Blocking it could protect insulin-producing cells and halt T2D progression (stock)
Using advanced single-cell RNA sequencing, City of Hope scientists analyzed pancreatic tissue from 26 donors: 13 with T2D, which affects more than 37 million Americans, and 13 without.
This approach allowed the researchers not only to identify cell types but also to categorize the cells into precise groups and map the dysfunctional pathways that cause insulin-producing cells to transform and fail in people with T2D.
After gathering a massive genetic dataset, the team used sophisticated computational analyses to identify the five alpha cell subtypes, including AB cells, immature cells that can develop into either alpha or beta cells.
To confirm that the gene SMOC1 was a key driver of beta cell dysfunction, the researchers increased SMOC1 levels in human beta cells in the lab and observed a direct, detrimental effect.
Insulin production dropped and the cells began to lose their identity, transforming into a different, dysfunctional cell type.
Further tests revealed that SMOC1 crippled beta cell function by simultaneously halting insulin secretion and disrupting the cell’s ability to produce new, functional insulin.
This is critical because insulin is the hormone that signals to the body’s cells to allow sugar from the blood to enter and be used for energy.
Without enough properly functioning insulin, sugar builds up in the bloodstream, which is the root cause of the high blood sugar levels that define diabetes.
The researchers’ final round of validation showed that SMOC1 protein levels were significantly higher in diabetic patients and, critically, that this protein was present within the insulin-producing beta cells themselves, confirming its role in the human disease.
Randy Kang, senior research associate at City of Hope and a co-author, said: ‘The SMOC1 gene has barely been studied in diabetes.
‘Based on these properties, we suspect SMOC1 strongly influences the differentiation and function of beta cells.’
This discovery opens a new front in diabetes treatment.
While current medications like GLP-1 receptor agonists, such as Ozempic, manage blood sugar, a therapy that directly targets and inhibits SMOC1 could be the first to address the root cause of beta cell failure by protecting their identity and function, potentially halting or reversing disease progression.
Currently, there are no approved gene therapies targeting the SMOC1 gene for T2D. The discovery of SMOC1’s role is very recent, placing it at the earliest stages of therapeutic development.
The research was published in the journal Nature Communications.
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