This direction was fascinating to me because it is the first time I see it applied to diabetes—I also see some great potential!
This brand new study, also out of UCSF (the third in a week!), looks at a radically different approach. Rather than assuming that the immune system is at fault, it looked for (in mice bred for diabetes), and found, signs that beta cells get early DNA damage that, in turn, triggers cell senescence. This, in turn, they hypothesize, provokes an immune system reaction. So they administered a drug that destroys senescent cells, and were able to lower the rate of diabetes in these mice from 75% to 30%. To verify that what they saw with mice also applies to humans, they examined tissue from 6 diabetics and 6 patients testing positive to diabetes autoantibodies, and found the same senescence markers in beta cells. Here is the UCSF press release:
The new findings contrast sharply with the prevalent belief that T1 diabetes is caused by an overly aggressive immune system attacking healthy beta cells. The new data suggest instead that inherent problems with DNA repair in some beta cells triggers senescence, which patrolling immune cells first fail to recognize and clear out. As a result, these cells accumulate and spread so widely within the pancreas that by the time the immune system eventually recognizes the problem, it essentially has to raze the whole insulin-producing system, leading to the onset of diabetes. […]
The researchers found that well before immune cells began to attack the pancreatic islets where beta cells reside, the beta cells began exhibiting signs of “secretory senescence,” a type of cellular decline caused by DNA damage in which cells stop functioning properly and begin producing molecules that harm nearby cells and attract the attention of the immune system.
To test whether eliminating senescent beta cells could help prevent T1 diabetes, Bhushan’s group tested a drug called ABT-199 (Venetoclax) […]— a drug that selectively eradicates senescent cells. Remarkably, the researchers found that while 75 percent of control mice developed diabetes by 28 weeks of age, only 30 percent of mice who were given ABT-199 for two weeks prior to the onset of symptoms went on to develop the disease. The researchers showed that the drug had rapidly eliminated senescent beta cells in these mice, after which their immune systems (which were not directly affected by the treatment) left the remaining, healthy beta cells alone, avoiding the loss of insulin production that causes diabetes.
“These findings support the idea that senescent beta cells are like the bad apples that spoil the whole basket,” Shah said. “Here we show that eliminating the bad apples can save the rest, which brings a new therapeutic avenue for treating patients with T1 diabetes.” […]
In line with their animal findings, the authors identified clear signs of DNA damage and secretory senescence in the beta cells of six donors with early-stage T1 diabetes, compared to six non-diabetic donors. The researchers also found signs of beta cell senescence in six donors without a diabetes diagnosis, but whose blood showed early signs of an immune reaction against beta cells, corroborating the idea that senescence is an early part of the chain of events leading to the disease.
“Seeing this data was an incredible moment,” said Thompson. “Many results from these diabetic mouse lines have not panned out in humans, but the fact that we were seeing the very same markers of senescence in human pancreas tissue indicated that the same process is occurring in the human disease as well.” […]
Bhushan’s group hopes these findings will lead to a therapy that could forestall the onset of T1 diabetes in young people at risk of developing the disease – which can currently be assessed via blood tests – and preserve remaining beta cell function in people with a recent T1 diabetes diagnoses. The animal experiments suggest that patients might be able to take such a drug periodically to clear out any senescent beta cells, and then perhaps be healthy for years.
I am so interested in this new direction that I quoted much more than I normally quote in an article. This is truly new!
LInk to the article abstract: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30021-X
More discussion is FierceBiotech: https://www.fiercebiotech.com/biotech/abbvie-s-cancer-drug-venclexta-blocks-diabetes-mice-by-targeting-beta-cell-senescence (but I like the press release better)