Biology subjects

Brownrigg, G. P.

Publications and source records attributed to Brownrigg, G. P..

7 recordsLinked to original sources

bioRxiv2026

Female biases in islet cell gene expression, alpha cell number, and glucagon are present early in postnatal life

Biological sex significantly affects glucose homeostasis. Sex differences in insulin sensitivity in peripheral tissues play a role in this difference; however, a growing body of evidence suggests sex differences in islet cells also contribute to differential glucose homeostasis. Studies in rodent and human models have identified sex differences in alpha- and beta-cell gene expression, in islet cell composition, metabolism, and stress responses, and in circulating levels of glucoregulatory hormones. However, most of these studies used adult humans or mice, leaving the age at which these differences emerge less clear. We performed a detailed characterization of glucose homeostasis and islet biology in young male and female mice from two mouse strains widely used in diabetes research to model both Type 1 (non-obese diabetic, NOD) and Type 2 diabetes (C57BL/6J). We uncovered male-female differences in islet cell gene expression and composition, and in circulating levels of glucagon. Importantly, these differences were reproducible across both models and were present prior to diabetes-like phenotypes. Together, our data suggest sex differences in aspects of islet biology begin early in postnatal life.

physiology↗

bioRxiv2024

Signal transduction pathways controlling Ins2 gene activity and β cell state transitions

Pancreatic {beta} cells exist in low and high insulin gene activity states that are dynamic on a scale of hours to days. Here, we used live 3D imaging, mass spectrometry proteomics, and targeted perturbations of {beta} cell signaling to comprehensively investigate Ins2(GFP)HIGH and Ins2(GFP)LOW {beta} cell states. We identified the two Ins2 gene activity states in intact isolated islets and showed that cells in the same state were more likely to be nearer to each other. We report the proteomes of pure {beta} cells to a depth of 5555 proteins and show that {beta} cells with high Ins2 gene activity had reduced {beta} cell immaturity factors, as well as increased translation. We identified activators of cAMP signaling (GLP1, IBMX) as powerful drivers of transitions from Ins2(GFP)LOW to the Ins2(GFP)HIGH states. Okadaic acid and cyclosporine A had the opposite effects. This study provides new insight into the proteomic profiles and regulation of {beta} cell states.

cell biology↗

bioRxiv2024

β-Hydroxybutyrate promotes basal insulin secretion while decreasing glucagon secretion in mouse and human islets.

Dietary carbohydrates raise blood glucose and limiting carbohydrate intake improves glycemia in patients with type 2 diabetes. Low carbohydrate intake (< 25 g) allows the body to utilize fat as its primary fuel. As a consequence of increased fatty acid oxidation, the liver produces ketones to serve as an alternative energy source. {beta}-Hydroxybutyrate ({beta}HB) is the most abundant ketone. While {beta}HB has a wide range of functions outside of the pancreas, its direct effects on islet cell function remain understudied. We examined human islet secretory response to acute racemic {beta}HB treatment and observed increased insulin secretion at low glucose concentrations (3 mM glucose). Because {beta}HB is a chiral molecule, existing as both R and S forms, we further studied insulin and glucagon secretion following acute treatment with individual {beta}HB enantiomers in human and C57BL6/J mouse islets. We found that acute treatment with R-{beta}HB increased insulin secretion and decreased glucagon secretion at physiological glucose concentrations in both human and mouse islets. Proteomic analysis of human islets treated with R-{beta}HB over 72 h showed altered abundance of proteins that may promote islet cell health and survival. Collectively, our data show that physiological concentrations of {beta}HB influence hormone secretion and signaling within pancreatic islets.

cell biology↗

bioRxiv2022

Sex differences in islet stress responses support female beta cell resilience

ObjectivePancreatic {beta} cells play a key role in glucose homeostasis; dysfunction of this critical cell type causes type 2 diabetes (T2D). Emerging evidence points to sex differences in {beta} cells, but few studies have examined male-female differences in {beta} cell stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on sex differences in {beta} cell/islet gene expression and function using both human and rodent samples. MethodsWe compared {beta} cell gene expression and insulin secretion in donors living with T2D to non-diabetic donors in both males and females. In mice, we generated a well-powered islet RNAseq dataset from 20-week-old male and female siblings with equivalent insulin sensitivity. Because on our unbiased analysis of gene expression pointed to sex differences in endoplasmic reticulum (ER) stress response, we subjected islets isolated from age-matched male and female mice to thapsigargin treatment and monitored protein synthesis, cell death, and {beta} cell insulin production and secretion. Transcriptomic and proteomic analyses were used to characterize sex differences in islet responses to ER stress. ResultsOur single-cell analysis of human {beta} cells revealed sex-specific changes to gene expression and function in T2D, correlating with more robust insulin secretion in islets isolated from female donors living with T2D compared to male T2D donors. In mice, RNA sequencing 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 ER stress induction with thapsigargin. Specifically, female islets maintained better insulin secretion and showed a distinct transcriptional response under ER stress compared with males. ConclusionsOur data demonstrate that physiologically significant sex differences in {beta} cell gene expression exist in both humans and mice, and that female {beta} cells maintain better insulin production and secretion across multiple physiological and pathological contexts.

cell biology↗

bioRxiv2021

A low sugar diet enhances Drosophila body size in males and females via sex-specific mechanisms

In Drosophila, changes to dietary protein elicit different body size responses between the sexes. Whether this sex difference in nutrient-dependent body size regulation extends to other nutrients, such as dietary sugar, remains unclear. Here, we show that reducing dietary sugar enhanced body size in Drosophila male and female larvae. Indeed, the largest body size was found in larvae reared in a diet without added sugar. Despite the equivalent body size effects of a low sugar diet between males and females, we detected sex-specific changes to the insulin/insulin-like growth factor (IIS) and target of rapamycin (TOR) signaling pathways. Further, we show that the metabolic changes observed in larvae reared on a low sugar diet differ between the sexes. Thus, despite identical phenotypic responses to dietary sugar in males and females, distinct changes to cell signaling pathways and whole-body metabolism were associated with the increased body size in each sex. This highlights the importance of including both sexes in all mechanistic studies on larval growth, as males and females may use different molecular and metabolic mechanisms to achieve similar phenotypic outcomes.

physiology↗

bioRxiv2020

Genetic manipulation of insulin/insulin-like growth factor signaling pathway activity has sex-biased effects on Drosophila body size

In Drosophila, female body size is approximately 30% larger than male body size due to an increased rate of larval growth. While the mechanisms that control this sex difference in body size remain incompletely understood, recent studies suggest that the insulin/insulin-like growth factor signaling pathway (IIS) plays a role in the sex-specific regulation of growth during development. In larvae, IIS activity differs between the sexes, and there is evidence of sex-specific regulation of IIS ligands. Yet, we lack knowledge of how changes to IIS activity impact growth in each sex, as the majority of studies on IIS and body size use single- or mixed-sex groups of larvae and/or adult flies. The goal of our current study was to clarify the requirement for IIS activity in each sex during the larval growth period. To achieve this goal we used established genetic approaches to enhance, or inhibit, IIS activity, and quantified body size in male and female larvae. Overall, genotypes that inhibited IIS activity caused a female-biased decrease in body size, whereas genotypes that augmented IIS activity caused a male-specific increase in body size. This data extends our current understanding of larval growth by showing that most changes to IIS pathway activity have sex-biased effects on body size, and highlights the importance of analyzing data by sex in larval growth studies.

physiology↗

bioRxiv2020

Female-specific upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity

Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work in Drosophila showed that body size plasticity was higher in females, yet the mechanisms underlying the sex difference in body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-specific increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This increased IIS activity was triggered by a diet-induced increase in stunted, and required Drosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination gene transformer regulates the diet-induced increase in stunted and IIS activity, and mediates the sex difference in body size plasticity. This identifies one sex-specific mechanism underlying the nutrient-dependent regulation of IIS activity and body size plasticity, providing vital insight into conserved mechanisms that mediate sex differences in phenotypic plasticity.

physiology↗