The human α cell in health and disease

Abstract

In commemoration of 100 years since the discovery of glucagon, we review current knowledge about the human α cell. Alpha cells make up 30-40% of human islet endocrine cells and play a major role in regulating whole-body glucose homeostasis, largely through the direct actions of their main secretory product – glucagon – on peripheral organs. Additionally, glucagon and other secretory products of α cells, namely acetylcholine, glutamate, and GLP-1, have been shown to play an indirect role in the modulation of glucose homeostasis through autocrine and paracrine interactions within the islet. Studies of glucagon’s role as a counterregulatory hormone have revealed additional important functions of the α cell, including the regulation of multiple aspects of energy metabolism outside that of glucose. At the molecular level, human α cells are defined by expression of conserved islet-enriched transcription factors and various enriched signature genes, many of which have currently unknown cellular functions. Despite these common threads, notable heterogeneity exists amongst human α cell gene expression and function. Even greater differences are noted at the interspecies level, underscoring the importance of further study of α cell physiology in the human context. Finally, studies on α cell morphology and function in type 1 and type 2 diabetes, as well as other forms of metabolic stress, reveal a key contribution of α cell dysfunction to dysregulated glucose homeostasis in disease pathogenesis, making targeting the α cell an important focus for improving treatment.

Subcellular Feature-Based Classification of α and β Cells Using Soft X-ray Tomography

“…However, EM techniques require fixation, staining, dehydration, and sectioning of the cell, which makes the technique labor-intensive. Additionally, previous studies have been limited to qualitative morphological features to differentiate cell types [11][12][13]. While cell and vesicle appearance are useful cues, their qualitative description lacks rigor and reproducibility.…”

100 years of glucagon anniversary

“…Aspects of α cell development, differentiation and identity including inter-species differences, along with the physiological regulation of glucagon secretion during health, and how this becomes dysregulated in diabetes, all remain relatively poorly understood. Encouragingly, a recent resurgence of interest in the islet α cell and glucagon has led to an acceleration in research on this topic (as illustrated in Figure 1 from Pettway et al (2023)). Based, in part on this resurgence in research interest, glucagon is considered to be a promising target for diabetes therapy.…”

“…Pettway, Saunders and Brissova (Pettway et al (2023)) delve more deeply into our current understanding of the human α cell, both in terms of morphology and function. This article highlights how the α cell is positioned to produce and receive paracrine/juxtacrine signals, the contribution of transcriptomics to better understand regulation of α cell identity and how the α cell responds to physiological (ageing and pregnancy) and pathological (obesity and diabetes) challenges.…”