Alterations in Beta Cell Identity in Type 1 and Type 2 Diabetes

Abstract

Purpose of Review To discuss the current understanding of “β cell identity” and factors underlying altered identity of pancreatic β cells in diabetes, especially in humans. Recent Findings Altered identity of β cells due to dedifferentiation and/or transdifferentiation has been proposed as a mechanism of loss of β cells in diabetes. In dedifferentiation, β cells do not undergo apoptosis; rather, they lose their identity and function. Dedifferentiation is well characterized by the decrease in expression of key β cell markers such as genes encoding major transcription factors, e.g., MafA, NeuroD1, Nkx6.1, and Foxo1, and an increase in atypical or “disallowed” genes for β cells such as lactate dehydrogenase, monocarboxylate transporter MCT1, or progenitor cell genes (Neurog3, Pax4, or Sox9). Moreover, altered identity of mature β cells in diabetes also involves transdifferentiation of β cells into other islet hormone producing cells. For example, overexpression of α cell specific transcription factor Arx or ablation of Pdx1 resulted in an increase of α cell numbers and a decrease in β cell numbers in rodents. The frequency of α-β double-positive cells was also prominent in human subjects with T2D. These altered identities of β cells likely serve as a compensatory response to enhance function/expand cell numbers and may also camouflage/protect cells from ongoing stress. However, it is equally likely that this may be a reflection of new cell formation as a frank regenerative response to ongoing tissue injury. Physiologically, all these responses are complementary. Summary In diabetes, (1) endocrine identity recapitulates the less mature/less-differentiated fetal/neonatal cell type, possibly representing an adaptive mechanism; (2) residual β cells may be altered in their subtype proportions or other molecular features; (3) in humans, “altered identity” is a preferable term to dedifferentiation as their cellular fate (differentiated cells losing identity or progenitors becoming more differentiated) is unclear as yet.

β-Cell Maturation and Identity in Health and Disease

“…Ectopic expression of key TFs and hormones specific for other endocrine cell types [147] indicates the plasticity of β-cells to differentiate toward other endocrine cell types (Figure 3) [148]. Evidence of ectopic expression of other hormones in β-cells comes from a mouse model with impaired insulin secretion and glucose intolerance caused by the lack of Nkx2-2 (TF needed for maintaining mature β-cell identity).…”

The TFIID subunit Taf4 is required for pancreatic beta cell function and identity

“…Furthermore, the number of Taf4-expressing BCs did not increase between 34 and 55 weeks arguing against proliferation of non-recombined BCs. Alternatively, Taf4-expressing BCs may arise from trans-differentiation of alpha cells or other islet populations into BCs as has been previously described, for example under conditions of reduced BC-mass [30][31][32][33] , one of the consequences of Taf4 inactivation. Notwithstanding the mechanisms involved, these data showed that despite reduced BC mass through increased apoptosis and an ensuing elevated glycaemia, the BC population was only partially and slowly replaced by newly generated BCs.…”

“…Bulk RNA-seq and ATAC-seq showed that Taf4 inactivation had a potent impact on BC trans-differentiation into alpha cells and vice versa has been described in diabetes, in genetically modified mice and after various pathological or chemical treatments. The molecular mechanisms involved particularly at the transcriptional level are however not fully understood 30,32,[45][46][47] . In type 2 diabetes, hyperglycaemia seems to induce BC dedifferentiation with diminished expression BC function genes and key BC transcription factors, but expression of BC forbidden genes and it may involve reversion to a Ngn3-expressing precursor state as a prerequisite to trans-differentiation to alpha or delta cells 33,40,48 .…”

Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Targets

“…Several studies in experimental hypothyroidism support this concept. In diabetes, hypothyroidism induces the dedifferentiation and/or transdifferentiation of pancreatic β -cells, and these phenomena (instead of apoptosis) have been proposed as putative explanations for pancreatic β -cell loss ( Moin and Butler, 2019 ). Notably, the simultaneous overexpression of TRα1 and the administration of T3 enhanced cell cycle progression and proliferation, leading to the reprogramming of pancreatic cells into insulin-producing cells, in both the rat β -cell line and in an animal model of STZ-induced diabetes ( Furuya et al, 2010 ).…”