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

Altirriba, Jordi; Gasa, Rosa; Casas, Sandra; Ramírez-Bajo, María José; Ros, Susana; Gutiérrez-Dalmau, Álex; Villa, M. C. Ruiz de; Barberà, Albert; Gomis, Ramón

doi:10.1007/s00125-010-1728-6

Cited by 29 publications

(29 citation statements)

References 30 publications

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“…Islet isolation and culture Mouse and rat pancreatic islets were isolated as described previously [21,22]. Islets were used either fresh or after culture in RPMI medium (Sigma, St Louis, MO, USA) at 5 or 25 mmol/l glucose.…”

Section: Methodsmentioning

confidence: 99%

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Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

et al. 2016

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Aims/hypothesis Glycogen accumulation occurs in beta cells of diabetic patients and has been proposed to partly mediate glucotoxicity-induced beta cell dysfunction. However, the role of glycogen metabolism in beta cell function and its contribution to diabetes pathophysiology remain poorly understood. We investigated the function of beta cell glycogen by studying glucose homeostasis in mice with (1) defective glycogen synthesis in the pancreas; and (2) excessive glycogen accumulation in beta cells. Methods Conditional deletion of the Gys1 gene and overexpression of protein targeting to glycogen (PTG) was accomplished by Cre-lox recombination using pancreasspecific Cre lines. Glucose homeostasis was assessed by determining fasting glycaemia, insulinaemia and glucose tolerance. Beta cell mass was determined by morphometry. Glycogen was detected histologically by periodic acidSchiff's reagent staining. Isolated islets were used for the determination of glycogen and insulin content, insulin secretion, immunoblots and gene expression assays. Results Gys1 knockout (Gys1 KO ) mice did not exhibit differences in glucose tolerance or basal glycaemia and insulinaemia relative to controls. Insulin secretion and gene expression in isolated islets was also indistinguishable between Gys1 KO and controls. Conversely, despite effective glycogen overaccumulation in islets, mice with PTG overexpression (PTG OE ) presented similar glucose tolerance to controls. However, under fasting conditions they exhibited lower glycaemia and higher insulinaemia. Importantly, neither young nor aged PTG OE mice showed differences in beta cell mass relative to age-matched controls. Finally, a high-fat diet did not reveal a beta cell-autonomous phenotype in either model. Conclusions/interpretation Glycogen metabolism is not required for the maintenance of beta cell function. Glycogen accumulation in beta cells alone is not sufficient to trigger the dysfunction or loss of these cells, or progression to diabetes.

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Section: Methodsmentioning

confidence: 99%

“…In vitro insulin secretion Islets were incubated for 30 min in Hepes-buffer Krebs-Ringer solution [21] with glucose at 2.8 mmol/l. Groups of six islets were incubated in a shaker at 37°C for 90 min in the solution described containing 2.8 or 16.7 mmol/l glucose.…”

Section: Methodsmentioning

confidence: 99%

Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

et al. 2016

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“…Biological samples and experimental design Mouse pancreatic islets were isolated from wild-type and Cdkn2a −/− [34] C57Bl/6J male mice by collagenase digestion and a Histopaque gradient (Sigma-Aldrich, St Louis, MO, USA) [35]. Islets were allowed to recover overnight at 37°C and 5% CO 2 in RPMI containing 11 mmol/l glucose, supplemented with 10% FCS (vol./vol.)…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescence and morphometric analysis Immunofluorescence in paraffin-embedded pancreases from at least three different mice was performed as described elsewhere [35], using guinea pig anti-insulin (1:2,500) and mouse anti-glucagon (1:1,000) (Dako, Glostrup, Denmark), and Cy2-and Cy3-labelled secondary antibodies (1:200; Jackson ImmunoResearch, Newmarket, UK). Hoechst 33258 (Sigma-Aldrich) was used as a nuclear marker.…”

Section: Methodsmentioning

confidence: 99%

Glucose regulation of a cell cycle gene module is selectively lost in mouse pancreatic islets during ageing

et al. 2013

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Aims/hypothesis Transcriptional networks in beta cells are modulated by extracellular signals such as glucose, thereby ensuring beta cell adaptation to systemic insulin demands. Ageing is a main risk factor for type 2 diabetes and has been associated with perturbed expression of genes essential for beta cell function. We aimed to uncover glucose-dependent gene modules in mouse pancreatic islets and investigate how this regulation is affected by ageing. Methods Global gene expression was assessed in pancreatic islets from young and aged wild-type and Cdkn2a (Ink4a/Arf)-deficient mice exposed to different glucose concentrations. Gene modules were identified by gene ontology and gene set enrichment analysis. Results Gene expression profiling revealed that variations in glucose levels have a widespread and highly dynamic impact on the islet transcriptome. Stimulatory glucose levels induced the expression of highly beta cell-selective genes and repressed the expression of ubiquitous genes involved in stress and antiproliferative responses, and in organelle biogenesis. Interestingly, a module comprising cell cycle genes was significantly induced between non-stimulatory and stimulatory glucose concentrations. Unexpectedly, glucose regulation of gene expression was broadly maintained in islets from old mice. However, glucose induction of mitotic genes was selectively lost in aged islets and was not even restored in the absence of the cell cycle inhibitors p16INK4a and p19 ARF , which have been implicated in the restricted proliferative capacity of beta cells with advanced age. Conclusions/interpretation Glucose-dependent transcriptional networks in islets are globally conserved during ageing, with the exception of the ability of stimulatory glucose levels to induce a cell cycle gene module.

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“…P28 islets were individually handpicked under a stereomicroscope after undergoing collagenase digestion, whereas adult islets were purified using a Histopaque gradient (Sigma-Aldrich) [18]. Insulin secretion was evaluated using freshly isolated islets in static incubation assays [19]. Insulin was measured by ELISA (Mercodia, Uppsala, Sweden).…”

Section: Methodsmentioning

confidence: 99%

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

et al. 2012

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Aims/hypothesis Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. Methods Rkip1 (also known as Pebp1) knockout (Rkip1 −/− ) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 −/− mice after streptozotocin treatment. Results Rkip1 −/− mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 −/− mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice.Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2696-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.

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

Cited by 29 publications

References 30 publications

Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis

Glucose regulation of a cell cycle gene module is selectively lost in mouse pancreatic islets during ageing

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

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