Biology subjects

Tigue, M.

Publications and source records attributed to Tigue, M..

3 recordsLinked to original sources

bioRxiv2026

The ortholog of the Human T2D Risk Gene STEAP2 is Required for Glucose Stimulated Insulin Secretion in Mice

Type 2 diabetes is a complex metabolic disease with a strong genetic component, yet this genetic risk is driven by common variants in up to 600 loci with small effect sizes. Variants in the STEAP2 locus, encoding Six-transmembrane epithelial antigen of the prostate-2, are highly associated with altered glycemic traits and type 2 diabetes risk. To elucidate its function in pancreatic beta-cells, we utilized Crisp-Cas9 assisted homologous recombination to derive a conditional null allele for Steap2 (Steap2fl/fl) in mice and crossed this to the rat insulin promoter (Rip)-Cre transgene. Ablation of Steap2 induced glucose intolerance, blunted glucose-stimulated Ca2+ mobilization and stunted first phase glucose-simulated insulin secretion. In contrast, the incretin effect and second phase insulin secretion were not affected. Islet respirometry and transmission electron microscopy (TEM) identified disrupted cristate morphology and impaired glucose-stimulated oxygen consumption as causally responsible for the observed, impaired triggering pathway of insulin secretion. These findings suggest that at least part of the genetic risk for T2D conferred by Steap2 variants is likely due to its function in maintaining optimal mitochondrial respiration in pancreatic beta-cells.

genetics↗

bioRxiv2023

G6PC2 controls glucagon secretion by defining the setpoint for glucose in pancreatic α-cells

Impaired glucose suppression of glucagon secretion (GSGS) is a hallmark of type 2 diabetes. A critical role for -cell intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the G6PC2 locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c levels. Here, we find that trait-associated variants in the G6PC2 promoter are located in open chromatin not just in {beta}- but also in -cells, and document allele-specific G6PC2 expression of linked variants in human - cells. Using -cell specific gene ablation of G6pc2 in mice, we show that this gene plays a critical role in controlling glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology; findings we confirmed in primary human -cells. Collectively, our data demonstrate that G6PC2 impacts glycemic control via its action in -cells and suggest that G6PC2 inhibitors could help control blood glucose through a novel, bi-hormonal mechanism.

genetics↗

bioRxiv2017

HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

biochemistry↗