Different Regulated Expression of the Tyrosine Phosphatase-Like Proteins IA-2 and Phogrin by Glucose and Insulin in Pancreatic Islets

Löbner, Kristian; Steinbrenner, Holger; Roberts, Graham; Ling, Zhidong; Huang, Guo-Cai; Piquer, Sandra; Pipeleers, Daniël; Seißler, Jochen; Christie, Michael R.

doi:10.2337/diabetes.51.10.2982

Cited by 28 publications

(21 citation statements)

References 40 publications

(41 reference statements)

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“…The IR-AB was used under conditions that have previously been shown to inhibit insulin action [31,32]; similarly, 10 μmol/l HNMPA(AM) 3 and 10 μmol/l LY 294002 were found to reverse the effect of insulin on noradrenaline-induced glucagon release in parallel secretion experiments.…”

Section: Resultsmentioning

confidence: 99%

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

et al. 2012

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Aims/hypothesis Somatostatin from islet delta cells inhibits insulin and glucagon secretion, but knowledge of the regulation of pancreatic somatostatin release is limited. Some insulin secretagogues stimulate somatostatin secretion, and here we investigated whether delta cell secretory responses are indirectly regulated in a paracrine manner by insulin released from beta cells. Methods Hormone release from static incubations of primary mouse islets or somatostatin-secreting TGP52 cells was measured by RIA. mRNA expression was assessed by RT-PCR. Results Glucose and a range of other physiological and pharmacological agents stimulated insulin and somatostatin release, and insulin receptor mRNA was expressed in islets, MIN6 beta cells and TGP52 cells. However, exogenous insulin did not modulate basal or glucose-induced somatostatin secretion from islets, nor did pre-incubation with an antibody against the insulin receptor or with the insulin receptor tyrosine kinase inhibitor, HNMPA(AM) 3 . Glucose and tolbutamide stimulated somatostatin release from TGP52 cells, whereas a range of receptor-operating agents had no effect, the latter being consistent with a lack of corresponding receptor mRNA expression in these cells. Parasympathetic activation stimulated insulin, but inhibited somatostatin release from mouse islets in accordance with differences in muscarinic receptor mRNA expression in islets, MIN6 and TGP52 cells. The inhibitory effect on somatostatin secretion was reversed by pertussis toxin or the muscarinic receptor 2 antagonist, methoctramine. Conclusions/interpretations A number of insulin secretagogues have analogous effects on insulin and somatostatin release, but this similarity of response is not mediated by an indirect, paracrine action of insulin on delta cells.

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Section: Resultsmentioning

confidence: 99%

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

et al. 2012

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“…To study glucose-stimulated insulin release, insulin in the culture medium was measured after a 4-h incubation period in basal medium containing 2.5 mmol/l glucose, followed by 4 h of incubation in 20 mmol/l glucose (serum-and glutamine-free HAM-10 medium; Gibco) [23].…”

Section: Methodsmentioning

confidence: 99%

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

Baeyens¹,

Breuck²,

Lardon³

et al. 2004

Diabetologia

291

224

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Aims/hypothesis: Transplantation of insulinproducing beta cells from donors can cure diabetes, but they are available in insufficient quantities. In this study, we investigated the possibility of generating insulinproducing cells from adult rat exocrine cells cultured in the presence of growth factors. Methods: Rat exocrine pancreatic cells were isolated and treated in vitro with epidermal growth factor (EGF) and leukaemia inhibitory factor (LIF). Analysis was performed by immunocytochemistry, DNA measurement and radioimmunoassay. Cells were transplanted to alloxan-treated (70 mg/kg) nude mice and glycaemia was monitored for 21 days. Nephrectomy was performed on day 15. Results: In a 3-day culture period, addition of LIF plus EGF to the medium resulted in an 11-fold increase of the beta cell mass. This could not be attributed to the very low mitotic activity of contaminating beta cells. Furthermore, when contaminating beta cells were initially destroyed with alloxan, this effect was even more pronounced. The newly formed cells secreted insulin in response to glucose and were immunoreactive for C-peptide-I, Pdx-1 and GLUT-2, which are characteristics of mature beta cells. Electron microscopy showed that they also contained insulinimmunoreactive secretory granules. Some insulin-positive cells were immunoreactive for amylase and cytokeratin-20, or were binucleated, which are characteristics of exocrine cells. The cells were able to restore normoglycaemia when transplanted to alloxan-diabetic mice, and hyperglycaemia recurred upon removal of the graft. Conclusions/interpretation: Our study shows that functional beta cells can be generated from exocrine tissue by transdifferentiation and thereby may offer a new perspective for beta cell therapy.

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“…IA-2 expression increases in accordance with development in rodent tissues (30 -32). IA-2 expression in ␤-cells is influenced by glucose, insulin, cAMP-generating agents, and proinflammatory cytokines (32)(33)(34). In contrast, phogrin expression is constant in the developmental stage of islets and is not significantly affected by glucose levels (32).…”

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confidence: 99%

Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth

et al. 2009

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1OBJECTIVE-Phogrin and IA-2, autoantigens in insulin-dependent diabetes, have been shown to be involved in insulin secretion in pancreatic ␤-cells; however, implications at a molecular level are confusing from experiment to experiment. We analyzed biological functions of phogrin in ␤-cells by an RNA interference technique. RESEARCH DESIGN AND METHODS-Adenovirus-mediated expression of short hairpin RNA specific for phogrin (shPhogrin) was conducted using cultured ␤-cell lines and mouse islets. Both glucose-stimulated insulin secretion and cell proliferation rate were determined in the phogrin-knockdown cells. Furthermore, protein expression was profiled in these cells. To see the binding partner of phogrin in ␤-cells, coimmunoprecipitation analysis was carried out. RESULTS-Adenoviral expression of shPhogrin efficiently decreased its endogenous expression in pancreatic ␤-cells. Silencing of phogrin in ␤-cells abrogated the glucose-mediated mitogenic effect, which was accompanied by a reduction in the level of insulin receptor substrate 2 (IRS2) protein, without any changes in insulin secretion. Phogrin formed a complex with insulin receptor at the plasma membrane, and their interaction was promoted by high-glucose stimulation that in turn led to stabilization of IRS2 protein. Corroboratively, phogrin knockdown had no additional effect on the proliferation of ␤-cell line derived from the insulin receptor-knockout mouse. CONCLUSIONS-Phogrin is involved in ␤-cell growth via regulating stability of IRS2 protein by the molecular interaction with insulin receptor. We propose that phogrin and IA-2 function as an essential regulator of autocrine insulin action in pancreatic ␤-cells. Diabetes 58:682-692, 2009 G lucose is a principle regulator of pancreatic ␤-cell survival and growth as well as insulin secretion (1). It is a potent mitogen on pancreatic ␤-cells and regulates islet ␤-cell mass through their replication (2). Recent studies have suggested that insulin secreted in response to elevated glucose exerts autocrine/paracrine effects, including promotion of insulin biosynthesis and proliferation of ␤-cells (3,4). The importance of insulin signaling in maintaining ␤-cell mass was demonstrated by targeted knockouts of the insulin receptor and insulin receptor substrate 2 (IRS2) (5-8). Although insulin receptor knockout had a restricted effect on ␤-cell mass (7), its mitogenic function on ␤-cells was clearly shown by short interfering RNA (siRNA)-based silencing of insulin receptor in ␤-cell-derived MIN6 cells (9,10). More recently, another pathway was demonstrated showing that glucose metabolism leads to increased ␤-cell mass through the transcriptional activation of IRS2 (11). Calcium/calmodulin-dependent protein kinases and increased cAMP levels were suggested to contribute to IRS2 expression, and this pathway has been shown to be modulated by the incretin hormone glucagonlike peptide 1 (GLP-1) (12,13). In both cases, IRS2 must be a key mediator for glucose-responsive ␤-cell growth (14).Phogrin (IA-2␤) and IA-2 (ICA51...

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Different Regulated Expression of the Tyrosine Phosphatase-Like Proteins IA-2 and Phogrin by Glucose and Insulin in Pancreatic Islets

Cited by 28 publications

References 40 publications

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth

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