Type 2 Diabetes-a Matter of ß-Cell Life and Death?

Rhodes, Christopher J.

doi:10.1126/science.1104345

Cited by 856 publications

(724 citation statements)

References 50 publications

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“…FCCM contains a variety of metabolites and signalling molecules, including known adipocytokines such as leptin, adiponectin, IL-6, TNF-α and resistin. However, these adipocytokines are not thought to mediate beta cell proliferation [5,38,39]. In addition to these known adipocytokines, Wnt signalling molecules are secreted by adipocytes [9,12].…”

Section: Discussionmentioning

confidence: 99%

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Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

et al. 2007

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Aims/hypothesis Adipocytes secrete signalling molecules that elicit responses from target cells, including pancreatic beta cells. Wnt signalling molecules have recently been identified as novel adipocyte-derived factors. They also regulate insulin secretion in pancreatic beta cells and the cell cycle. The aim of this study was to investigate the effect of adipocyte-derived Wnt signalling molecules on insulin secretion and beta cell proliferation. Methods Human adipocytes were isolated to generate fat cell-conditioned medium (FCCM). Ins-1 cells were stimulated with FCCM and transiently transfected with reporter genes. Proliferation assays using [ 3 H]thymidine incorporation were carried out in Ins-1 cells and primary islet cells. Insulin secretion from primary islets was assessed by radioimmunoassay. Gene expression in primary islets was assessed by Taqman PCR. Results Treatment with human FCCM increased the transcription of a T cell-specific transcription factor reporter gene (TOPFLASH) in Ins-1 cells (241%, p<0.05). FCCM induced the proliferation of Ins-1 cells (1.8 fold, p<0.05) and primary mouse islet cells (1.6 fold, p<0.05). Antagonizing Wnt signalling with secreted Frizzled-related protein 1 (FRP-1) inhibited the proliferative effect induced by Wnt3a and FCCM on Ins-1 cells by 49 and 41%, respectively. In addition, FCCM led to a twofold (p<0.05) induction of cyclin D1 promoter activity in Ins-1 cells. Furthermore, FCCM stimulated insulin secretion (204% of controls, p>0.05) in primary mouse islets, and this stimulation was inhibited by sFRP-1. At a molecular level, canonical Wnt signalling induced glucokinase gene transcription in a peroxisome proliferator-activated receptor γ-dependent fashion, thereby defining the glucokinase gene as a novel Wnt target gene. Conclusions/interpretation Taken together, these data show that adipocyte-derived Wnt signalling molecules induce beta cell proliferation and insulin secretion in vitro, suggesting a novel mechanism linking obesity to hyperinsulinaemia.

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Section: Discussionmentioning

confidence: 99%

“…The mechanisms linking obesity and insulin resistance to hyperinsulinaemia and beta cell hyperplasia are incompletely understood [3]. Adipocytes are hormonally active and adipocytokines are able to elicit a response from beta cells [5]. Studies have shown that adipocytes secrete Wnt signalling molecules to regulate adipocyte differentiation [9][10][11].…”

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confidence: 99%

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

et al. 2007

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“…This finding suggests that subtle increases in HH signalling might induce a decrease in beta cell mass. A decrease in beta cell mass is a typical feature of the onset of type 2 diabetes [35,36]. Thus, we investigated the glucose tolerance and beta cell mass in our Ptch1 +/mes and Ptch1 +/− mice after adjusting for genetic background.…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

et al. 2008

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Aims/hypothesis Ectopic activation of hedgehog (HH) signalling in pancreas induces various abnormal morphogenetic events in the pancreas. This study analysed the dose-dependent requirement of patched homologue 1 (PTCH1), a negative regulator of HH signalling on pancreatic development. Methods We used a recessive spontaneous mutant mouse denoted as mes which carries a mutated Ptch1 resulting in deletion of the most carboxy-terminal cytoplasmic domain of the PTCH1 protein. In this study, we analysed pancreatic morphology in Ptch1 +/+ , Ptch1 +/mes , Ptch1 +/− , Ptch1 mes/mes and Ptch1 −/mes mouse embryos, as well as the islet mass in adult Ptch1 +/+ , Ptch1 +/mes and Ptch1 +/− mice. Results Until embryonic day (E) 12.5, no obvious abnormality of pancreas was observed in any of the Ptch1 mutants. The levels of PDX1 and glucagon were also not evidently different among the mice genotypes studied. Thereafter, morphological abnormalities appeared in the Ptch1 mutant mice. The beta, alpha and exocrine cell masses decreased at E18.5 in parallel with increased HH signalling, with beta cell mass showing the highest sensitivity to HH signalling with a significant decrease even in Ptch1 +/mes mice. Adult Ptch1 +/− mice also showed a significant decrease in beta cell mass compared with wild-type mice. Conclusions/interpretation Our findings indicate that the carboxy-terminal domain of Ptch1 is essential for pancreatic development. In addition, the loss of Ptch1 function decreases both the endocrine and exocrine cell mass in a dose-dependent manner, with beta cells particularly sensitive to changes in HH signalling.

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“…However, in individuals destined to develop type 2 diabetes, pancreatic beta cells fail to produce enough insulin to meet systemic demand. This beta cell failure is caused by insufficient beta cell response to glucose and inadequate beta cell mass expansion [1]. Recently, several reports have convincingly confirmed the contribution of beta cell mass reduction to type 2 diabetes [2,3], at least in its advanced stages.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several reports have convincingly confirmed the contribution of beta cell mass reduction to type 2 diabetes [2,3], at least in its advanced stages. Although the cause of this decrease is unknown, increased apoptosis may play an important role [1,2]. In addition to genetic factors, processes involving glucotoxicity and/or lipotoxicity are likely to be contributory [4].…”

Section: Introductionmentioning

confidence: 99%

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

et al. 2009

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Aims/hypothesis The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death. Methods We studied the effect of breeding Wfs1 −/− mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A y /a). We also treated the mice with pioglitazone.

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Type 2 Diabetes-a Matter of ß-Cell Life and Death?

Cited by 856 publications

References 50 publications

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

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