Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 3 • March 2013

New Discovery of Cause of Pancreatic Beta Cell
Failure In Diabetes May Point the Way to a Cure

It has long been thought that the loss of insulin release by pancreatic beta cells in diabetes is the result of the death (apoptosis) of these cells. In a new paper,1 researchers have discovered that the reason the beta cells (in a FOXO1 knockout mouse model of diabetes) stopped producing insulin is not because the cells died but because they dedifferentiated to an earlier stage of development in which they cannot produce insulin. “Dedifferentiated beta cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc.”1 These markers indicate that these beta cells are endocrine pre-beta cells.1

The scientists studied FOXO1 immunoreactivity in beta cells of mice with insulin-resistance diabetes, including mice with mild fasting hyperglycemia and severe hyperglycemia. “As hyperglycemia increased, loss of FOXO1 immunoreactivity paralleled loss of insulin content. To determine whether the loss of FOXO1 was a cause or effect of the beta cell failure and what happened to the “missing” beta cells, e.g., did they die or what, the researchers then studied mice with the FOXO1 gene knocked out in their beta cells. They were surprised to find that the beta cells without FOXO1 stopped producing insulin but nearly all of the cells remained alive. “The findings indicate that ‘empty’ beta cells in IKO [knockout] mice are not degranulated beta cells, but represent a distinctive pre-beta cell differentiation stage.”1

The authors point out, however: “While the metabolic abnormalities in mice with beta cell-specific FOXO1 specific knockout are not as marked as those seen in the other diabetic models, this might be due to compensatory increases in other FOXOs. Nevertheless, the impairment of beta cell mass and function caused by lack of FOXO1 is consistently observed in other models of diabetes.” “Importantly, we show that beta cell dedifferentiation is a regression to an endocrine progenitor-like stage rather than a degenerative stage.” “The model arising from our observations can help explain why decreases in beta cell mass occur slowly as a function of diabetes duration. It is consistent with and provides an explanation for the slow progression and temporary reversibility of beta cell dysfunction, vindicating the concept of ‘beta cell rest’ as a diabetes treatment.”

This mechanism (if reproduced) suggests that beta cell function might be restored in diabetes during a “window of opportunity” by redifferentiating the dedifferentiated beta cells, providing for a potential cure for diabetes. We offer our congratulations to the researchers who performed this work.


  1. Talchai et al. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 150:1223-34 (2012).

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