β-cell dedifferentiation in diabetes is important, but what is it?

Abstract

This commentary discusses the concept of β-cell dedifferentiation in diabetes, which is important but not well defined. A broad interpretation is that a state of differentiation has been lost, which means changes in gene expression as well as in structural and functional elements. Thus, a fully mature healthy β cell will have its unique differentiation characteristics, but maturing cells and old β cells will have different patterns of gene expression and might therefore be considered as dedifferentiated. The meaning of dedifferentiation is now being debated because β cells in the diabetic state lose components of their differentiated state, which results in severe dysfunction of insulin secretion. The major cause of this change is thought to be glucose toxicity (glucotoxicity) and that lowering glucose levels with treatment results in some restoration of function. An issue to be discussed is whether dedifferentiated β cells return to a multipotent precursor cell phenotype or whether they follow a different pathway of dedifferentiation.

Keywords: dedifferentiation; diabetes; differentiation; insulin secretion; islets; β cell.

Figure 1. The differentiation state of a fully mature β cell can change with natural reversible events and during progression to death. The hyperglycemia of diabetes is thought to be the major determinant causing β cells to lose their differentiation (also termed dedifferentiation), which leads to dysfunctional insulin secretion. This process is also called glucose toxicity, which can be at least partially reversed by treatment of hyperglycemia. An unanswered question is whether the β cells in the diabetes revert toward a multipotent precursor phenotype or a separate reversible dedifferentiated state.

Figure 2. Baboons with chronic diabetes induced by streptozotocin were assessed for in vivo β-cell function, β-cell mass and insulin content after 5- 46 mo of diabetes. When pancreatic β-cell mass was 40–50% of that of the control animals, fasting hyperglycemia was present and accompanied by dysfunctional insulin secretion. Pancreatic sections from 3 separate tissue blocks/ animal (5 diabetic and 2 control animals; average of 60 ± 14 islets per section) were immunofluorescently stained for insulin (red) and a cocktail of antibodies against non-β-cell hormones (glucagon, somatostatin, and pancreatic polypeptide) (green). The pancreatic cross sections were examined by 2 blinded observers. This islet was from baboon after 34 mo of diabetes. All islet cells in all animals (control and with chronic diabetes) were immunostained for insulin, non-β-cell hormones or both. No “empty” cells could be identified.