Blood glucose levels are tightly controlled by the coordinated actions of hormone-producing endocrine cells that reside in pancreatic islets. Islet cell malfunction underlies diabetes development and progression. Due to the cellular heterogeneity within islets, it has been challenging to uncover how specific islet cells contribute to glucose homeostasis and diabetes pathogenesis. Recent advances in single-cell technologies and computational methods have opened up new avenues to resolve islet heterogeneity and study islet cell states in health and disease.
In the past year, a multitude of studies have been published that used single-cell approaches to interrogate the transcriptome and proteome of the different islet cell types. Here, UCSD researchers summarize the conclusions of these studies, and discuss the technologies used and the challenges faced with computational analysis of single-cell data from islet studies.
Single-cell approaches to interrogate the transcriptome and proteome
of islet cell types in health and disease
Transcriptomic and proteomic studies of single islet cells have provided novel insights into islet cell function, proliferation and aging, and type 2 diabetes (T2D) pathogenesis. For example, single-cell studies have identified receptors for neurotransmitters, growth factors, and hormones specifically expressed in epsilon, delta, and gamma cells (bottom, left panel), suggesting these rare islet cell types integrate systemic cues and metabolic signals. Identification of transcriptionally distinct subpopulations of beta cells (bottom, left panel) and alpha cells (bottom, left and middle panels) has provided insight into different functional states of endocrine cells as well as enabled profiling of rare proliferating cells. Proteomic profiling of single islet cells has shown that multiple endocrine cell types exhibit reduced proliferation with age (bottom, middle panel). Finally, single-cell profiling has uncovered differentially expressed genes in islet cells from healthy and diabetic individuals (bottom, right panel), showing contribution of multiple endocrine cell types to islet pathophysiology and revealing novel genes and pathways with potential for therapeutic targeting.
By analyzing single islet cells from rodents and humans at different ages and disease states, the studies reviewed here have provided new insight into endocrine cell function and facilitated a high resolution molecular characterization of poorly understood processes, including regeneration, maturation, and diabetes pathogenesis. Gene expression programs and pathways identified in these studies pave the way for the discovery of new targets and approaches to prevent, monitor, and treat diabetes.