Beta cells in type 2 diabetes

Abstract

Diabetes is a multifactorial disease with chronic hyperglycemia and systemic metabolic complications that appear as a consequence of the progressive loss or dysfunction of insulin-producing β cells. In Type 2 diabetes (T2D), the most prevalent form of this disease, insulin resistance promotes metabolic stress and β cell failure through mechanisms such as mitochondrial dysfunction, endoplasmic reticulum stress, glycolipotoxicity, and cell dedifferentiation and death¹. Although during their development and early postnatal stages, these cells are highly proliferative, in adult life, they are specialized and stable cells. That is why they depend on specific epigenetic systems that allow them to maintain cell functionality and identity.

Previously, it has been assumed that adult β cells constituted a homogeneous population within the islet, however, there is a remarkable heterogeneity that determines the existence of subpopulations exhibiting genetic and functional variations that affect both, their proliferative state, and susceptibility to metabolic stress, suggesting that not all of them will respond uniformly to glycemic stimuli and metabolic demands. The use of optogenetic techniques² and proteomic, epigenomic³, and transcriptomic⁴ studies by single-cell RNA sequencing made it possible to accurately map functional, epigenetic, and transcriptional differences between subpopulations, revealing specific markers and signaling pathways associated with survival and β cell function.

Thus, different subpopulations of β-cells were described in individuals with or without T2D⁴: a) Hub cells, acting as pacemakers for follower ones^2,4, b) Cells with different epigenetic marks at the methylation level of both, DNA at CpGs sites, and histone H3 (H3K27me3)^3,4, c) Cells with the presence or absence of CD9 and ST8SIA14 surface markers⁴, d) Cells with differences in their maturity degree, determined by their proliferative capacity, or by their level of insulin and Pdx-1 expression4, e) Cells with variable capacity to respond to stress (insulin and UPR expression)⁴. Understanding β cell heterogeneity provides a more accurate view of the physiopathology of T2D. It also offers new and effective therapies targeting specific subpopulations of β cells to improve T2D treatment and reduce the risk of its complications.