A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune function, metabolism, and glucose homeostasis through activation of chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled receptor 1 (GPR1) in mammals, binds chemerin with an affinity similar to CMKLR1; however, the function of GPR1 in mammals is essentially unknown. Herein, we report that expression of murineGpr1mRNA is high in brown adipose tissue and white adipose tissue (WAT) and skeletal muscle. In contrast to chemerin (Rarres2) andCmklr1,Gpr1expression predominates in the non-adipocyte stromal vascular fraction of WAT. Heterozygous and homozygousGpr1-knockout mice fed on a high-fat diet developed more severe glucose intolerance than WT mice despite having no difference in body weight, adiposity, or energy expenditure. Moreover, mice lackingGpr1exhibited reduced glucose-stimulated insulin levels and elevated glucose levels in a pyruvate tolerance test. This study is the first, to our knowledge, to report the effects ofGpr1deficiency on adiposity, energy balance, and glucose homeostasisin vivo. Moreover, these novel results demonstrate that GPR1 is an active chemerin receptor that contributes to the regulation of glucose homeostasis during obesity.

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Adrb2 controls glucose homeostasis by developmental regulation of pancreatic islet vasculature

eLife ◽

10.7554/elife.39689 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 2

Author(s):

Alexis M Ceasrine ◽

Eugene E Lin ◽

David N Lumelsky ◽

Radhika Iyer ◽

Rejji Kuruvilla

Keyword(s):

Glucose Homeostasis ◽

Developmental Regulation ◽

Vascular Endothelial ◽

Β Cells ◽

Functional Deficits ◽

Vascular Growth ◽

Impaired Insulin ◽

And Function ◽

Endothelial Growth Factor ◽

Specific Deletion

A better understanding of processes controlling the development and function of pancreatic islets is critical for diabetes prevention and treatment. Here, we reveal a previously unappreciated function for pancreatic β2-adrenergic receptors (Adrb2) in controlling glucose homeostasis by restricting islet vascular growth during development. Pancreas-specific deletion of Adrb2 results in glucose intolerance and impaired insulin secretion in mice, and unexpectedly, specifically in females. The metabolic phenotypes were recapitulated by Adrb2 deletion from neonatal, but not adult, β-cells. Mechanistically, Adrb2 loss increases production of Vascular Endothelial Growth Factor-A (VEGF-A) in female neonatal β-cells and results in hyper-vascularized islets during development, which in turn, disrupts insulin production and exocytosis. Neonatal correction of islet hyper-vascularization, via VEGF-A receptor blockade, fully rescues functional deficits in glucose homeostasis in adult mutant mice. These findings uncover a regulatory pathway that functions in a sex-specific manner to control glucose metabolism by restraining excessive vascular growth during islet development.

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Essential Role of Insulin and Insulin-Like Growth Factor 1 Receptor Signaling in Cardiac Development and Function

Molecular and Cellular Biology ◽

10.1128/mcb.01110-06 ◽

2006 ◽

Vol 27 (5) ◽

pp. 1649-1664 ◽

Cited By ~ 107

Author(s):

Palle G. Laustsen ◽

Steven J. Russell ◽

Lei Cui ◽

Amelia Entingh-Pearsall ◽

Martin Holzenberger ◽

...

Keyword(s):

Growth Factor ◽

Insulin Receptor ◽

Glucose Homeostasis ◽

Cardiac Metabolism ◽

Oligonucleotide Array ◽

Insulin Like Growth Factor ◽

Altered Expression ◽

Mitochondrial Fatty Acid ◽

And Function ◽

Combined Deficiency

ABSTRACT Cardiovascular disease is the leading cause of death in people with type 2 diabetes and is linked to insulin resistance even in the absence of diabetes. Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. By contrast, mice lacking the IGF-1 receptor or the IGF-1 receptor plus one Ir allele appear normal. Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function.

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Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter

Human Molecular Genetics ◽

10.1093/hmg/ddg263 ◽

2003 ◽

Vol 12 (19) ◽

pp. 2547-2558 ◽

Cited By ~ 66

Author(s):

L.-Y. Chen

Keyword(s):

Glucose Homeostasis ◽

Phosphate Transporter ◽

And Function

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The long non-coding RNA Pax6os1/PAX6-AS1 modulates pancreatic β-cell identity and function

10.1101/2020.07.17.209015 ◽

2020 ◽

Author(s):

Livia Lopez-Noriega ◽

Rebecca Callingham ◽

Aida Martinez-Sánchez ◽

Grazia Pizza ◽

Nejc Haberman ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Pancreatic Islets ◽

Glucose Homeostasis ◽

High Glucose ◽

High Fat Diet ◽

High Fat ◽

Β Cell ◽

And Function

AbstractLong non-coding RNAs (lncRNAs) are emerging as crucial regulators of β-cell development and function. Consequently, the mis-expression of members of this group may contribute to the risk of type 2 diabetes (T2D). Here, we investigate roles for an antisense lncRNA expressed from the Pax6 locus (annotated as Pax6os1 in mice and PAX6-AS1 in humans) in β-cell function. The transcription factor Pax6 is required for the development of pancreatic islets and maintenance of a fully differentiated β-cell phenotype. Pax6os1/PAX6-AS1 expression was increased in pancreatic islets and β-cell lines at high glucose concentrations, in islets from mice fed a high fat diet, and in those from patients with type 2 diabetes. Silencing or deletion of Pax6os1/PAX6-AS1 in MIN6 cells and EndoC-βH1cells, respectively, upregulated β-cell signature genes, including insulin. Moreover, shRNA-mediated silencing of PAX6-AS1 in human islets not only increased insulin mRNA, but also enhanced glucose-stimulated insulin secretion and calcium dynamics. In contrast, inactivation of Pax6os1 in mice was largely without effect on glucose homeostasis, though female Pax6os1 null mice on high fat diet (HFD) showed a tendency towards enhanced glucose clearance. Together, our results suggest that increased expression of PAX6-AS1 at high glucose levels may contribute to β-cell dedifferentiation and failure in some forms of type 2 diabetes. Thus, targeting PAX6-AS1 may provide a promising strategy to enhance insulin secretion and improve glucose homeostasis in type 2 diabetes.

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