The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

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Abstract

Aims/hypothesis

Transmembrane protein 27 (TMEM27) is a membrane protein cleaved and shed by pancreatic beta cells that has been proposed as a beta cell mass biomarker. Despite reports of its possible role in insulin exocytosis and cell proliferation, its function in beta cells remains controversial. We aimed to characterise the function of TMEM27 in islets and its potential use as a beta cell mass biomarker.

Methods

To determine TMEM27 function, we studied TMEM27 gene expression and localisation in human healthy and diabetic islets, the correlation of its expression with cell cycle and insulin secretion genes in human islets, its expression in tungstate-treated rats, and the effects of its overproduction on insulin secretion and proliferation in a beta cell line and islets. To elucidate its utility as a beta cell mass biomarker, we studied TMEM27 cleavage in a beta cell line, islets and primary proximal tubular cells.

Results

TMEM27 mRNA levels in islets are lower in diabetic donors than in controls. Its gene expression correlates with that of insulin and SNAPIN in human islets. TMEM27 expression is downregulated in islets of tungstate-treated rats, which exhibit decreased insulin secretion and increased proliferation. TMEM27 overproduction in a beta cell line and islets significantly enhanced glucose-induced insulin secretion, with modest or no effects on proliferation. Finally, TMEM27 is cleaved and shed by renal proximal tubular cells and pancreatic islets.

Conclusions/interpretation

Our data support a role for TMEM27 in glucose-induced insulin secretion but not in cell proliferation. The finding that its cleavage is not specific to beta cells challenges the current support for its use as a potential beta cell mass biomarker.

Electronic supplementary material

The online version of this article (doi:10.1007/s00125-010-1728-6) contains supplementary material, which is available to authorised users.

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Most cited references 24

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Functional and molecular defects of pancreatic islets in human type 2 diabetes.

Scilla Torri, Piero Marchetti, Simone Sbrana … (2005)

To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy.

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Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes.

Jenny E. Gunton, S Yim, W Hawthorne … (2005)

beta cell dysfunction is a central component of the pathogenesis of type 2 diabetes. Using oligonucleotide microarrays and real-time PCR of pancreatic islets isolated from humans with type 2 diabetes versus normal glucose-tolerant controls, we identified multiple changes in expression of genes known to be important in beta cell function, including major decreases in expression of HNF4alpha, insulin receptor, IRS2, Akt2, and several glucose-metabolic-pathway genes. There was also a 90% decrease in expression of the transcription factor ARNT. Reducing ARNT levels in Min6 cells with small interfering RNA (siRNA) resulted in markedly impaired glucose-stimulated insulin release and changes in gene expression similar to those in human type 2 islets. Likewise, beta cell-specific ARNT knockout mice exhibited abnormal glucose tolerance, impaired insulin secretion, and changes in islet gene expression that mimicked those in human diabetic islets. Together, these data suggest an important role for decreased ARNT and altered gene expression in the impaired islet function of human type 2 diabetes.

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Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle.

Erich Nigg (1995)

Passage through the cell cycle requires the successive activation of different cyclin-dependent protein kinases (CDKs). These enzymes are controlled by transient associations with cyclin regulatory subunits, binding of inhibitory polypeptides and reversible phosphorylation reactions. To promote progression towards DNA replication, CDK/cyclin complexes phosphorylate proteins required for the activation of genes involved in DNA synthesis, as well as components of the DNA replication machinery. Subsequently, a different set of CDK/cyclin complexes triggers the phosphorylation of numerous proteins to promote the profound structural reorganizations that accompany the entry of cells into mitosis. At present, much research is focused on elucidating the links between CDK/cyclin complexes and signal transduction pathways controlling cell growth, differentiation and death. In future, a better understanding of the cell cycle machinery and its deregulation during oncogenesis may provide novel opportunities for the diagnostic and therapeutic management of cancer and other proliferation-related diseases.

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Author and article information

Contributors

R. Gomis: rgomis@clinic.ub.es

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer-Verlag (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 13 April 2010

Publication date (Print): 2010

Volume: 53

Issue: 7

Pages: 1406-1414

Affiliations

[1 ]GRID grid.5841.8, ISNI 0000000419370247, Laboratory of Diabetes and Obesity, Endocrinology and Nutrition Unit, , Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic de Barcelona, ; Villarroel 170, 08036 Barcelona, Spain

[2 ]GRID grid.430579.c, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Spain, ;

[3 ]GRID grid.410458.c, ISNI 0000000096359413, Department of Nephrology and Renal Transplantation, Laboratori Experimental de Nefrologia i Trasplantament, , Hospital Clínic i Provincial de Barcelona, ; Barcelona, Spain

[4 ]GRID grid.7722.0, ISNI 0000000118116966, Institute for Research in Biomedicine, ; Scientific Park, Barcelona, Spain

[5 ]GRID grid.411106.3, ISNI 0000000098542756, Department of Nephrology, , Hospital Universitario Miguel Servet, ; Zaragoza, Spain

[6 ]GRID grid.5841.8, ISNI 0000000419370247, Department of Statistics, , University of Barcelona, ; Barcelona, Spain

[7 ]GRID grid.5841.8, ISNI 0000000419370247, Department of Medicine, , University of Barcelona, ; Barcelona, Spain

Article

Publisher ID: 1728

DOI: 10.1007/s00125-010-1728-6

PMC ID: 7096040

PubMed ID: 20386877

SO-VID: 4c90dcf2-7066-4fa0-95fc-8759cad9fe38

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

History

Date received : 6 January 2010

Date accepted : 28 January 2010

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: beta cell,islet,biomarker,insulin secretion,proliferation,tmem27

Data availability:

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: beta cell, islet, biomarker, insulin secretion, proliferation, tmem27

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The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

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Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Electronic supplementary material

Related collections

GLUT4 biology

Most cited references 24

Functional and molecular defects of pancreatic islets in human type 2 diabetes.

Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes.

Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle.

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Cited by 8

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