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The Other Mother: How adopting my son inspired my PhD
No full textAuthor, Shanta Everington, describes her experiences as an adoptive parent and how adopting her son inspired a PhD
The in vitro differentiation of rat neural stem cells into an insulin-expressing phenotype
No full textMature beta-cells and nerve cells share many functional similarities despite originating from different embryonic germ layers. The aim of this study was to investigate the potential of neural stem cells (NSCs), isolated from foetal rat brain, as a starting material from which to generate functionally responsive, insulin-containing cells. Our results demonstrated that NSCs can be significantly expanded in vitro and can be induced to express increased preproinsulin mRNA levels. In addition, these NSC-derived cells expressed transcriptional and functional elements associated with a mature beta-cell phenotype. The differentiated cells showed functional responses typical of pancreatic beta-cells, including glucose-dependent increases in metabolism and rapid elevations in intracellular Ca(2+) in response to the sulphonylurea tolbutamide or to increased glucose concentration. These results suggest that NSCs may have potential as a starting material from which to generate beta-cell surrogates for the treatment of patients with Type 1 diabetes mellitus
Islet G-protein coupled receptors: therapeutic potential for diabetes
Get PDFThe incidence of type 2 diabetes (T2D) is increasing at an alarming rate, which is imposing substantial healthcare and economic burdens worldwide. T2D can be treated by a range of drugs, but there is a need to identify additional therapeutic options. Human islets express nearly three hundred G-protein-coupled receptors (GPCRs), which could be targeted for the treatment of T2D. However, to date, the GLP-1 receptor is the only islet GPCR for which agonists are in current clinical use. This review explores pharmaceutical development of drugs that activate individual or multiple β-cell GPCRs and explains how our knowledge of GPCR expression by human islets may inform direction on novel GPCR targets.</p
A role for the extracellular calcium-sensing receptor in cell-cell communication in pancreatic islets of Langerhans
Get PDFBackground: The extracellular calcium-sensing receptor (CaR) is expressed in many tissues that are not associated with Ca2+ homeostasis, including the endocrine cells in pancreatic islets of Langerhans. We have demonstrated previously that pharmacological activation of the CaR stimulates insulin secretion from islet -cells and insulin-secreting MIN6 cells. Methods: In the present study we have investigated the effects of CaR activation on MIN6 cell proliferation and have used shRNA-mediated CaR knockdown to determine whether the CaR is involved in the regulation of insulin secretion via cell-cell communication. Results: CaR activation caused the phosphorylation and activation of the p42/44 MAPK signalling cascade, and this activation was prevented by the shRNA-induced down-regulation of CaR mRNA expression. CaR activation also resulted in increased proliferation of MIN6 cells, consistent with the known role of the p42/44 MAPK system in the regulation of -cell proliferation. Down-regulation of CaR expression had no detectable effects on glucose-induced insulin secretion from MIN6 cells maintained as monolayers, but blocked the increases in insulin secretion that were observed when the cells were configured as three-dimensional islet-like structures (pseudoislets), consistent with a role for the CaR in cell-cell communication in pseudoislets. Conclusion: It is well established that islet function is dependent on communication between islet cells and the results of this study suggest that the CaR is required for -cell to -cell interactions within islet-like structures
Requirement of NF-kappaB signalling pathway for modulation of the cholinergic muscarinic M3 receptor expression by INGAP-PP in insulin-producing cells
Get PDFThe pentadecapeptide comprising the 104–118 amino acid sequence of the ilotropin-derived Reg3-related islet neogenesis-associated protein (INGAP-PP) has been implicated in beta cell neogenesis and enhancement of insulin secretion in pancreatic islets. The aim of this study was to investigate intracellular pathways by which INGAP-PP signals in insulin-producing cells. Treatment with INGAP-PP increased insulin secretion and intracellular calcium levels in MIN6 cells. INGAP-PP exposure activated c-Myc, serum and particularly nuclear factor-kappaB (NF-κB) response elements in insulin-producing cells (1.7 ± 0.1, 1.8 ± 0.1, 2.4 ± 0.3 for RINm5F, and 1.3 ± 0.1, 1.3 ± 0.1 and 1.6 ± 0.1 fold for MIN6 cells compared to controls, respectively). There was an increase in the proliferation rate of viable cells (162 ± 17% for RINm5F and 155 ± 13% for MIN6) that was accompanied by an increase in proliferating cell nuclear antigen (PCNA) protein expression (187 ± 19% and 170 ± 8% for RINm5F and MIN6 cells respectively) following INGAP-PP treatment. INGAP-PP increased the expression of the muscarinic M3 receptor subtype (169 ± 4% for RINm5F and 222 ± 20% for MIN6 cells). Activation of multiple serum response elements by foetal calf serum also increased muscarinic M3 receptor expression (173 ± 9% for RINm5F and 140 ± 7% for MIN6 cells). The blockade of NF-κB signalling pathway strongly decreased muscarinic M3 receptor expression in response to both stimuli. In summary, a network of intracellular signals that includes activation of c-Myc signalling pathway and increased PCNA expression might be related to the increased proliferation rate of insulin-producing cells following incubation with INGAP-PP. NF-κB signalling plays an essential role in controlling the expression of the muscarinic M3 receptor.Fil: Paula, Flavia M.M.. Universidade Estadual de Campinas; BrasilFil: Barbosa, Helena C.L.. Universidade Estadual de Campinas; BrasilFil: Carneiro, Everardo M.. Universidade Estadual de Campinas; BrasilFil: Persaud, Shanta J.. King's College London; Reino UnidoFil: Gagliardino, Juan Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Endocrinología Experimental y Aplicada (i); ArgentinaFil: Boschero, Antonio C.. Universidade Estadual de Campinas; BrasilFil: Souza, Kleber L.A.. Universidade Estadual de Campinas; Brasi
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