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New research from the Joslin Diabetes Center helps illuminate the process of glucose toxicity in pancreatic beta cells.
By looking at the behavior of these cells in laboratory rats after a partial pancreatectomy, the researchers were able to see how consistent small increases in blood sugar levels typical of prediabetes caused changes in gene expression that impeded the cells’ ability. beta to make insulin.
In a recently published article in the magazine. Molecular metabolismGordon Weir and colleagues detailed changes in gene expression that may explain their loss of insulin-producing function, but also the progression of diabetic disease.
In healthy people with normal blood glucose levels, Weir explains, the body responds quickly to glucose with a large spike in insulin secretion. “If you then take people who have slightly higher glucose levels, greater than 100 mg / dl, which is not diabetes yet, this first-phase insulin release is affected,” he says. “And when the level exceeds 115 mg / dl, it goes away. So virtually all beta cells don’t respond to that acute stimulus.”
Weir and colleagues studied this same phenomenon in rats with partial pancreatectomy, and found that the remaining beta cells in the rats secreted less insulin. They then used RNA sequencing either four to ten weeks after surgery to control gene expression. “We found incredible changes in gene expression, and the higher the glucose, the worse the changes,” says Weir.
Weir’s team showed that many of the critical genes responsible for insulin secretion were down-regulated as expression of normally suppressed genes increased. Furthermore, there were marked changes in genes associated with replication, aging, senescence, stress, inflammation, and increased expression of genes that control MHC class I and II antigens, suggesting that mild glucose elevations in the early stages of diabetes they lead to phenotypic changes that impair the function, growth and vulnerability of beta cells.
For example, changes in the expression of the MCH gene could make beta cells a better target for autoimmune attack and thus accelerate disease progression. This finding may improve the understanding of rapid beta cell death that patients often experience just before being diagnosed with type 1 diabetes, Weir says. It may also shed light on the “honeymoon” period that some people experience after diagnosis, in which their blood glucose levels are relatively easy to control. During this period, if insulin treatments can reduce the remaining beta cells to only slightly elevated glucose levels, the cells can function much better, he says.
Glucose toxicity could also trigger the loss of insulin release in the first phase as type 2 diabetes develops, Weir says. Immunologists often attribute this loss to inflammation of beta cells, but other studies have shown that less than half of these cells appear to be inflamed. “So somehow these beta cells without evidence of inflammation end up not secreting properly,” says Weir. “We believe that these higher glucose levels are causing the problem.”
More evidence of the role of higher blood glucose levels in type 2 diabetes comes from the subset of people undergoing gastric bypass surgery who are “cured” of diabetes and return to healthy blood glucose levels. “His insulin release in the first phase also returns to normal, which fits perfectly with our hypothesis,” he says.
The full text of the article “Changes in beta cell identity with mild hyperglycemia: implications for function, growth and vulnerability” can be found here: http://dx.doi.org/10.1016/j.molmet. 2020.02.002
