Aging of human endocrine pancreatic cell types is heterogeneous and sex-specific

Drigo, Rafael Arrojo e; Erikson, Galina; Capitanio, Juliana S.; Lyon, James; Af, Spigelman; Bautista, Austin; Je, Manning Fox; Shokhirev, Maxim N.; Pe, MacDonald; Mw, Hetzer

doi:10.1101/729541

Cited by 11 publications

(22 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, the cycling of beta cells through states of high stress vs high insulin expression would be consistent with the recent observation of 'extreme' beta cells, postulated to disproportionately contribute to basal insulin secretion [17]. Our analysis suggests three beta cell states consistent with: high levels of beta cell identity and functional markers (state 1); high expression of p53, along with Wnt and insulin-IGF1 signalling (state 2); and ribosomal biogenesis and mRNA translation (state 3) [15].…”

Section: Linking Molecular and Functional Heterogeneity Of Human Betasupporting

confidence: 88%

“…Although questions persist about an apparently limited overlap of observed subpopulations and markers between single-cell RNA sequencing (scRNA-seq) studies [13], it remains that this may, in part, be addressed by ongoing efforts to improve the bioinformatic and systems biology approaches used in this context. Recent meta-analyses combining published datasets [14], including our own recent work [15], largely confirm the existence of these beta cell subpopulations across several studies and donors. It seems likely that some of these beta cell subpopulations, in fact, represent 'cellular states' through which the cells cycle at the transcriptional and functional levels [14,16].…”

Section: Linking Molecular and Functional Heterogeneity Of Human Betamentioning

confidence: 77%

See 1 more Smart Citation

Molecular and functional profiling of human islets: from heterogeneity to human phenotypes

2020

Self Cite

View full text Add to dashboard Cite

Efforts to phenotype pancreatic islets have contributed tremendously to our present understanding of endocrine function and diabetes. A continued evolution in approaches to study islet physiology is important given the need to establish reference points for mature islet functionality, understanding biological variation amongst individuals and cells, and the ongoing appreciation of the role for islets in diabetes susceptibility. Recent efforts in islet biology have focused on technological improvements in imaging, molecular profiling and data analysis, along with a push for enhanced transparency and reporting. The integration of these approaches within a classical islet physiology framework, and approaches to link these data with in vivo human phenotypes, will be critical as we move towards a better understanding of islet function in health and disease. Here we discuss what we feel are important issues and useful approaches to consider as we move forward as a field in islet and beta cell phenotyping.

show abstract

Section: Linking Molecular and Functional Heterogeneity Of Human Betasupporting

confidence: 88%

Section: Linking Molecular and Functional Heterogeneity Of Human Betamentioning

confidence: 77%

Molecular and functional profiling of human islets: from heterogeneity to human phenotypes

2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Beyond gene expression, studies on insulin production provide additional insight into sex differences in β cells. Human female islets show higher glucose-stimulated insulin secretion than males in some ( 41 ), but not all ( 40 ) studies, with similar findings in rodents ( 42 ). These differences are likely shaped by gonadal hormones, as 17β-estradiol (E2) treatment in rodents increased insulin content and secretion, improved insulin sensitivity, and conferred protective effects against β cell apoptosis ( 12, 43–48 ).…”

Section: Introductionmentioning

confidence: 58%

Sex differences in islet stress responses support female beta cell resilience

Brownrigg

Xia

Chu

et al. 2022

Preprint

View full text Add to dashboard Cite

Type 2 diabetes risk is ∼40% higher in men than in pre-menopausal women. Despite evidence that sex differences in pancreatic β cells play a role in this differential diabetes risk, few studies have examined diabetes-associated changes to β cell function in each sex. Our single-cell analysis of human β cells revealed profound sex-specific changes to gene expression and function in type 2 diabetes. To gain deeper insight into sex differences in β cells, we generated a well-powered islet RNAseq dataset from 20-week-old male and female mice with equivalent insulin sensitivity. This unbiased analysis revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was biologically significant, as female islets were more resilient to endoplasmic reticulum (ER) stress induction with thapsigargin. Specifically, female islets maintained better insulin secretion and showed a distinct transcriptional response under ER stress compared with males. Given the known links between ER stress and T2D pathogenesis, our findings suggest sex differences in β cells contribute to the differential T2D risk between men and women.

show abstract

“…Sex differences in homeostatic physiology are being recognized as the basis for differences in both pathology and treatment responses in specific brain regions and in stress-based pathophysiology, and this is true for insulin secretion in both rodent models and humans 40,41 . Significant reductions in insulin secretion are observed with aging in humans, but only in males 42 , an effect that may be attributed to sex-specific genomic methylation patterns 43 . Our data raise the possibility that b cells in males uniquely rely on SRC under normal conditions to fulfill an insulin secretory response.…”

Section: Discussionmentioning

confidence: 99%

ROMO1 and Mitochondrial Complex II/SDH are Required for Spare Respiratory Capacity and Glucose Homeostasis in Mice

Wells

Iorio

et al. 2021

Preprint

View full text Add to dashboard Cite

Reactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses ROS and regulates mitochondrial dynamics (1). ROMO1 is required for mitochondrial fusion in vitro, and silencing ROMO1 increases sensitivity to cell death stimuli. How ROMO1 promotes mitochondrial fusion and its physiological role remain unclear. Here we show that ROMO1 is essential for embryonic development, as ROMO1-null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 that catalyze mitochondrial membrane fusion. Knockout of ROMO1 in adult pancreatic beta cells results in impaired glucose homeostasis in male mice due to an insulin secretion defect resulting from impaired glucose sensing. Mitochondria in ROMO1 beta cell KO cells were swollen and fragmented, consistent with a role for ROMO1 in mitochondrial fusion in vivo. While basal respiration was normal in ROMO1 beta cell KO islets, spare respiratory capacity was lost. Taken together, our data indicate that ROMO1 is required for nutrient coupling in the beta cell and point to a critical role for spare respiratory capacity in the maintenance of euglycemia in males.

show abstract

Aging of human endocrine pancreatic cell types is heterogeneous and sex-specific

Cited by 11 publications

References 50 publications

Molecular and functional profiling of human islets: from heterogeneity to human phenotypes

Molecular and functional profiling of human islets: from heterogeneity to human phenotypes

Sex differences in islet stress responses support female beta cell resilience

ROMO1 and Mitochondrial Complex II/SDH are Required for Spare Respiratory Capacity and Glucose Homeostasis in Mice

Contact Info

Product

Resources

About