Genomics of Islet (Dys)function and Type 2 Diabetes

Abstract

Pancreatic islet dysfunction and beta cell failure are hallmarks of type 2 diabetes mellitus (T2DM) pathogenesis. In this review, we discuss how genome-wide association studies (GWASs) and recent developments in islet (epi)genome and transcriptome profiling (particularly single cell analyses) are providing novel insights into the genetic, environmental, and cellular contributions to islet (dys)function and T2DM pathogenesis. Moving forward, study designs that interrogate and model genetic variation [e.g., allelic profiling and (epi)genome editing] will be critical to dissect the molecular genetics of T2DM pathogenesis, to build next-generation cellular and animal models, and to develop precision medicine approaches to detect, treat, and prevent islet (dys)function and T2DM.

Keywords: Type 2 diabetes (T2D); epigenomics; genomics; pancreatic islets; single cell; transcriptomics.

Figure 1. Genomic Effects of Genetic and Environmental Perturbations Contributing to Pancreatic Islet Dysfunction and Type 2 Diabetes (T2D)

(Left) DNA single nucleotide variants (SNVs) may enhance (gain-of-function) or diminish (loss-of-function) transcription element (e.g., enhancer) activity and islet gene expression. The majority of T2D-associated SNVs reside in non-coding regions of the genome and overlap islet REs [2,3,12,14,15,32,47] implicating disruptions in gene regulatory network components as a central molecular feature in disease pathogenesis. A subset of SNVs have been linked to changes in basal islet gene expression [11,31]. (Right) Environmental factors such as inflammation, diet, aging, circadian rhythms, and stress may also influence RE activity, resulting in altered and/or novel transcription of genes essential for islet function [–,–50,57,58]. TF = transcription factor, TSS = transcription start site.

Figure 2 (Key Figure). Converging and Diverging Genetic, Environmental, and Cellular Aspects of Islet (Dys)function and T2D in Mice and Humans

Parallel analyses of human and mouse islets are revealing important similarities (center) and differences (left, right) between molecular features of islet identity and (dys)function in mice and humans. Text colored in black highlight significant findings regarding islet cellular composition and identity. Text colored in blue highlight longitudinal/comparative analyses of genome-wide molecular datasets and environmental effects on islet (dys)function. These features reaffirm the value of modeling T2D in mice to delineate important species-specific differences in islet biology that may reflect distinct T2D causative mechanisms. RE = regulatory element; TF = transcription factor; ↑ = increase; ↓ = decrease; T2D = type 2 diabetes; T1D = type 1 diabetes; GWAS = genome-wide association study.

Figure 3. Proposed Cellular Mechanisms Contributing to T2D Development

(Center) Cartoon representation of human islet cellular composition. Studies have described the following phenomena: (A) Islet single cell transcriptomic studies [75,80,83] suggest that cell type-specific changes in gene expression (depicted as half-shaded cells) contribute to T2D pathogenesis. These studies suggest that potential pathogenic expression changes may occur in each islet cell type, not just beta cells. (B) Decreases in beta cell (depicted in yellow) numbers [25,92,100,101], thought to precede islet dysfunction and development of insulin resistance. (C) Alterations in islet cellular identity may also account for islet failure. De-differentiation of islet cell types to precursor cell types/states (depicted via hexagons) has been proposed to underlie loss of beta cell mass and function in T2D [,–92]. (D) Similarly, trans-differentiation of islet cell types may lead to imbalances in islet cell proportions and improper function [72,88,89].