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Kenneth S Polonsky - One of the best experts on this subject based on the ideXlab platform.
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autophagy regulates pancreatic Beta Cell death in response to pdx1 deficiency and nutrient deprivation
Journal of Biological Chemistry, 2009Co-Authors: Kei Fujimoto, Eric L Ford, Burton M Wice, Hung Tran, James D Johnson, Piia T Hanson, Robert E Schmidt, Karen G Green, Kenneth S PolonskyAbstract:There are three types of Cell death; apoptosis, necrosis, and autophagy. The possibility that activation of the macroautophagy (autophagy) pathway may increase Beta Cell death is addressed in this study. Increased autophagy was present in pancreatic islets from Pdx1(+/-) mice with reduced insulin secretion and Beta Cell mass. Pdx1 expression was reduced in mouse insulinoma 6 (MIN6) Cells by delivering small hairpin RNAs using a lentiviral vector. The MIN6 Cells died after 7 days of Pdx1 deficiency, and autophagy was evident prior to the onset of Cell death. Inhibition of autophagy prolonged Cell survival and delayed Cell death. Nutrient deprivation increased autophagy in MIN6 Cells and mouse and human islets after starvation. Autophagy inhibition partly prevented amino acid starvation-induced MIN6 Cell death. The in vivo effects of reduced autophagy were studied by crossing Pdx1(+/-) mice to Becn1(+/-) mice. After 1 week on a high fat diet, 4-week-old Pdx1(+/-) Becn1(+/-) mice showed normal glucose tolerance, preserved Beta Cell function, and increased Beta Cell mass compared with Pdx1(+/-) mice. This protective effect of reduced autophagy had worn off after 7 weeks on a high fat diet. Increased autophagy contributes to pancreatic Beta Cell death in Pdx1 deficiency and following nutrient deprivation. The role of autophagy should be considered in studies of pancreatic Beta Cell death and diabetes and as a target for novel therapeutic intervention.
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diabetes mellitus and genetically programmed defects in Beta Cell function
Nature, 2001Co-Authors: Graeme I. Bell, Kenneth S PolonskyAbstract:The pathways that control insulin secretion and regulate pancreatic Beta-Cell mass are crucial in the development of diabetes mellitus. Maturity-onset diabetes of the young comprises a number of single-gene disorders affecting pancreatic Beta-Cell function, and the consequences of mutations in these genes are so serious that diabetes develops in childhood or adolescence. A genetic basis for the more common form of type 2 diabetes, which affects 10-20% of adults in many developed countries, is less clear cut. It is also characterized by abnormal Beta-Cell function, but other tissues are involved as well. However, in both forms identification of causative and susceptibility genes are providing new insight into the control of insulin action and secretion, as well as suggesting new treatments for diabetes.
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increased Beta Cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse
Diabetes, 1999Co-Authors: Seamus Sreenan, A J Pick, Matteo G Levisetti, W Pugh, Aaron C Baldwin, Kenneth S PolonskyAbstract:To determine whether loss of Beta-Cell mass and function in the NOD mouse occurs gradually, beginning after the onset of insulitis, or abruptly, just before the onset of overt diabetes, Beta-Cell mass and rates of Beta-Cell proliferation and insulin secretory responses from the perfused pancreas were measured in NOD and control NOD/Scid mice at 8-9, 13, and 18 weeks of age. Of the NOD mice, 11 and 70% had diabetes (fasting blood glucose >8.3 mmol/l) at 13 and 18 weeks of age, respectively. Beta-Cell mass in 8-week-old NOD mice was 69% of control mice (P>0.05), but the rate of 5-bromo-2-deoxyuridine uptake was greater, suggesting a compensatory proliferative response to ongoing autoimmune Beta-Cell destruction. Despite an increase in the rate of Beta-Cell proliferation, Beta-Cell mass was significantly reduced by 42% in 13-week-old nondiabetic NOD mice and by 73% in 18-week-old diabetic NOD mice. Insulin secretory responses to glucose and arginine demonstrated reductions of similar magnitude. In 18-week-old diabetic NOD mice, insulin secretion was reduced to a greater degree than Beta-Cell mass, suggesting the presence of Beta-Cell dysfunction in addition to reduced mass. These results suggest that in the NOD mouse, Beta-Cell destruction begins soon after the onset of insulitis. Despite a compensatory Beta-Cell proliferative response, Beta-Cell mass progressively falls and is significantly reduced by 13 weeks despite normal blood glucose concentrations. Diabetes may be present when residual Beta-Cell mass represents 30% of control levels.
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role of apoptosis in failure of Beta Cell mass compensation for insulin resistance and Beta Cell defects in the male zucker diabetic fatty rat
Diabetes, 1998Co-Authors: A J Pick, Susan Bonnerweir, J Clark, C Kubstrup, Matteo G Levisetti, W Pugh, Kenneth S PolonskyAbstract:To define the mechanisms involved in the evolution of diabetes in the Zucker diabetic fatty (ZDF) rat, Beta-Cell mass and replication rates were determined by immunochemistry, point-counting morphometry, and 6-h 5-bromo-29-deoxyuridine (BrdU) incorporation. The Beta-Cell mass in 5- to 7-week-old prediabetic ZDF rats (4.3 +/- 0.06 mg) was similar to age-matched insulin-resistant Zucker fatty (ZF) rats (3.7 +/- 0.05 mg) and greater than that in Zucker lean control (ZLC) rats (1.9 +/- 0.3, P
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role of apoptosis in failure of Beta Cell mass compensation for insulin resistance and Beta Cell defects in the male zucker diabetic fatty rat
Diabetes, 1998Co-Authors: A J Pick, Susan Bonnerweir, J Clark, C Kubstrup, Matteo G Levisetti, W Pugh, Kenneth S PolonskyAbstract:To define the mechanisms involved in the evolution of diabetes in the Zucker diabetic fatty (ZDF) rat, Beta-Cell mass and replication rates were determined by immunochemistry, point-counting morphometry, and 6-h 5-bromo-2'-deoxyuridine (BrdU) incorporation. The Beta-Cell mass in 5- to 7-week-old prediabetic ZDF rats (4.3 +/- 0.06 mg) was similar to age-matched insulin-resistant Zucker fatty (ZF) rats (3.7 +/- 0.05 mg) and greater than that in Zucker lean control (ZLC) rats (1.9 +/- 0.3, P < 0.05). At 12 weeks (after diabetes onset), Beta-Cell mass in the ZDF rats (8.1 +/- 1.7 mg) was significantly lower than the ZF rats (15.7 +/- 1.8 mg). The mass in the ZF rats was significantly greater than in the ZLC rats (4.3 +/- 0.8 mg, P < 0.05). The Beta-Cell proliferation rate (mean of both time points) was significantly greater in the ZDF rats (0.88 +/- 0.1%) compared with the ZF and ZLC rats (0.53 +/- 0.07%, 0.62 +/- 0.07%, respectively, P < 0.05), yet ZDF rats have a lower Beta-Cell mass than the ZF rats despite a higher proliferative rate. Morphological evidence of neogenesis and apoptosis is evident in the ZF and ZDF rats. In addition, even at 5-7 weeks a modest defect in insulin secretion per Beta-Cell unit was found by pancreas perfusion. These studies provide evidence that the expansion of Beta-Cell mass in response to insulin resistance and insulin secretory defects in diabetic ZDF rats is inadequate. This failure of Beta-Cell mass expansion in the ZDF rat does not appear to be from a reduction in the rate of Beta-Cell proliferation or neogenesis, suggesting an increased rate of Cell death by apoptosis.
Susan Bonnerweir - One of the best experts on this subject based on the ideXlab platform.
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angptl8 Betatrophin does not control pancreatic Beta Cell expansion
Cell, 2014Co-Authors: Viktoria Gusarova, Corey A Alexa, Erqian Na, Panayiotis Stevis, Susan Bonnerweir, Jonathan C Cohen, Helen H Hobbs, Andrew J Murphy, George D Yancopoulos, Jesper GromadaAbstract:Summary Recently, it was reported that angiopoietin-like protein 8 (ANGPTL8) was the long-sought "Betatrophin" that could control pancreatic Beta Cell proliferation. However, studies of Angptl8 −/− mice revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis. We now report that Angptl8 −/− mice undergo entirely normal Beta Cell expansion in response to insulin resistance resulting from either a high-fat diet or from the administration of the insulin receptor antagonist S961. Furthermore, overexpression of ANGPTL8 in livers of mice doubles plasma triglyceride levels, but does not alter Beta Cell expansion nor glucose metabolism. These data indicate that ANGPTL8 does not play a role in controlling Beta Cell growth, nor can it be given to induce such expansion. The findings that plasma triglyceride levels are reduced by Angptl8 deletion and increased following ANGPTL8 overexpression support the possibility that inhibition of ANGPTL8 represents a therapeutic strategy for hypertriglyceridemia.
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exendin 4 stimulates both Beta Cell replication and neogenesis resulting in increased Beta Cell mass and improved glucose tolerance in diabetic rats
Diabetes, 1999Co-Authors: Doris A Stoffers, Joel F Habener, Susan BonnerweirAbstract:Diabetes is a disease of increasing prevalence in the general population and of unknown cause. Diabetes is manifested as hyperglycemia due to a relative deficiency of the production of insulin by the pancreatic Beta-Cells. One determinant in the development of diabetes is an inadequate mass of Beta-Cells, either absolute (type 1, juvenile diabetes) or relative (type 2, maturity-onset diabetes). Earlier, we reported that the intestinal hormone glucagon-like peptide I (GLP-I) effectively augments glucose-stimulated insulin secretion. Here we report that exendin-4, a long-acting GLP-I agonist, stimulates both the differentiation of Beta-Cells from ductal progenitor Cells (neogenesis) and proliferation of Beta-Cells when administered to rats. In a partial pancreatectomy rat model of type 2 diabetes, the daily administration of exendin-4 for 10 days post-pancreatectomy attenuates the development of diabetes. We show that exendin-4 stimulates the regeneration of the pancreas and expansion of Beta-Cell mass by processes of both neogenesis and proliferation of Beta-Cells. Thus, GLP-I and analogs thereof hold promise as a novel therapy to stimulate Beta-Cell growth and differentiation when administered to diabetic individuals with reduced Beta-Cell mass.
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role of apoptosis in failure of Beta Cell mass compensation for insulin resistance and Beta Cell defects in the male zucker diabetic fatty rat
Diabetes, 1998Co-Authors: A J Pick, Susan Bonnerweir, J Clark, C Kubstrup, Matteo G Levisetti, W Pugh, Kenneth S PolonskyAbstract:To define the mechanisms involved in the evolution of diabetes in the Zucker diabetic fatty (ZDF) rat, Beta-Cell mass and replication rates were determined by immunochemistry, point-counting morphometry, and 6-h 5-bromo-29-deoxyuridine (BrdU) incorporation. The Beta-Cell mass in 5- to 7-week-old prediabetic ZDF rats (4.3 +/- 0.06 mg) was similar to age-matched insulin-resistant Zucker fatty (ZF) rats (3.7 +/- 0.05 mg) and greater than that in Zucker lean control (ZLC) rats (1.9 +/- 0.3, P
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role of apoptosis in failure of Beta Cell mass compensation for insulin resistance and Beta Cell defects in the male zucker diabetic fatty rat
Diabetes, 1998Co-Authors: A J Pick, Susan Bonnerweir, J Clark, C Kubstrup, Matteo G Levisetti, W Pugh, Kenneth S PolonskyAbstract:To define the mechanisms involved in the evolution of diabetes in the Zucker diabetic fatty (ZDF) rat, Beta-Cell mass and replication rates were determined by immunochemistry, point-counting morphometry, and 6-h 5-bromo-2'-deoxyuridine (BrdU) incorporation. The Beta-Cell mass in 5- to 7-week-old prediabetic ZDF rats (4.3 +/- 0.06 mg) was similar to age-matched insulin-resistant Zucker fatty (ZF) rats (3.7 +/- 0.05 mg) and greater than that in Zucker lean control (ZLC) rats (1.9 +/- 0.3, P < 0.05). At 12 weeks (after diabetes onset), Beta-Cell mass in the ZDF rats (8.1 +/- 1.7 mg) was significantly lower than the ZF rats (15.7 +/- 1.8 mg). The mass in the ZF rats was significantly greater than in the ZLC rats (4.3 +/- 0.8 mg, P < 0.05). The Beta-Cell proliferation rate (mean of both time points) was significantly greater in the ZDF rats (0.88 +/- 0.1%) compared with the ZF and ZLC rats (0.53 +/- 0.07%, 0.62 +/- 0.07%, respectively, P < 0.05), yet ZDF rats have a lower Beta-Cell mass than the ZF rats despite a higher proliferative rate. Morphological evidence of neogenesis and apoptosis is evident in the ZF and ZDF rats. In addition, even at 5-7 weeks a modest defect in insulin secretion per Beta-Cell unit was found by pancreas perfusion. These studies provide evidence that the expansion of Beta-Cell mass in response to insulin resistance and insulin secretory defects in diabetic ZDF rats is inadequate. This failure of Beta-Cell mass expansion in the ZDF rat does not appear to be from a reduction in the rate of Beta-Cell proliferation or neogenesis, suggesting an increased rate of Cell death by apoptosis.
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Beta Cell mass and growth after syngeneic islet Cell transplantation in normal and streptozocin diabetic c57bl 6 mice
Journal of Clinical Investigation, 1993Co-Authors: E Montana, Susan Bonnerweir, Gordon C WeirAbstract:In islet transplantation, nonimmunological factors such as limited growth capacity or increased death rate could reduce the Beta Cell mass in the graft and lead to failure of the transplant. We studied the evolution of Beta Cell replication and mass after transplantation of insufficient, minimally sufficient, or excessive islet tissue. Streptozocin diabetic C57BL/6 mice received 150 or 300 syngeneic islets under the kidney capsule and normal mice received 300 islets. In streptozocin diabetic mice 300 islets restored normoglycemia; Beta Cell replication in transplanted islets was similar to replication in normal pancreas and Beta Cell mass in the graft remained constant. In contrast, 150 islets were insufficient to achieve normoglycemia; Beta Cell replication was increased initially but not by 18 or 30 d despite persistent hyperglycemia, and Beta Cell mass fell progressively. When islets were transplanted into normal recipients, Beta Cell replication remained normal but Beta Cells underwent atrophy and mass in the graft was substantially reduced. Therefore, with a successful islet transplant, in diabetic mice Beta Cell replication and mass remain constant. In contrast, when insufficient islet tissue is transplanted an initial increase in Beta Cell replication can not compensate for a decline in Beta Cell mass. When excessive islet tissue is transplanted, Beta Cell mass is reduced despite normal Beta Cell replication.
A J Pick - One of the best experts on this subject based on the ideXlab platform.
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increased Beta Cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse
Diabetes, 1999Co-Authors: Seamus Sreenan, A J Pick, Matteo G Levisetti, W Pugh, Aaron C Baldwin, Kenneth S PolonskyAbstract:To determine whether loss of Beta-Cell mass and function in the NOD mouse occurs gradually, beginning after the onset of insulitis, or abruptly, just before the onset of overt diabetes, Beta-Cell mass and rates of Beta-Cell proliferation and insulin secretory responses from the perfused pancreas were measured in NOD and control NOD/Scid mice at 8-9, 13, and 18 weeks of age. Of the NOD mice, 11 and 70% had diabetes (fasting blood glucose >8.3 mmol/l) at 13 and 18 weeks of age, respectively. Beta-Cell mass in 8-week-old NOD mice was 69% of control mice (P>0.05), but the rate of 5-bromo-2-deoxyuridine uptake was greater, suggesting a compensatory proliferative response to ongoing autoimmune Beta-Cell destruction. Despite an increase in the rate of Beta-Cell proliferation, Beta-Cell mass was significantly reduced by 42% in 13-week-old nondiabetic NOD mice and by 73% in 18-week-old diabetic NOD mice. Insulin secretory responses to glucose and arginine demonstrated reductions of similar magnitude. In 18-week-old diabetic NOD mice, insulin secretion was reduced to a greater degree than Beta-Cell mass, suggesting the presence of Beta-Cell dysfunction in addition to reduced mass. These results suggest that in the NOD mouse, Beta-Cell destruction begins soon after the onset of insulitis. Despite a compensatory Beta-Cell proliferative response, Beta-Cell mass progressively falls and is significantly reduced by 13 weeks despite normal blood glucose concentrations. Diabetes may be present when residual Beta-Cell mass represents 30% of control levels.
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role of apoptosis in failure of Beta Cell mass compensation for insulin resistance and Beta Cell defects in the male zucker diabetic fatty rat
Diabetes, 1998Co-Authors: A J Pick, Susan Bonnerweir, J Clark, C Kubstrup, Matteo G Levisetti, W Pugh, Kenneth S PolonskyAbstract:To define the mechanisms involved in the evolution of diabetes in the Zucker diabetic fatty (ZDF) rat, Beta-Cell mass and replication rates were determined by immunochemistry, point-counting morphometry, and 6-h 5-bromo-29-deoxyuridine (BrdU) incorporation. The Beta-Cell mass in 5- to 7-week-old prediabetic ZDF rats (4.3 +/- 0.06 mg) was similar to age-matched insulin-resistant Zucker fatty (ZF) rats (3.7 +/- 0.05 mg) and greater than that in Zucker lean control (ZLC) rats (1.9 +/- 0.3, P
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role of apoptosis in failure of Beta Cell mass compensation for insulin resistance and Beta Cell defects in the male zucker diabetic fatty rat
Diabetes, 1998Co-Authors: A J Pick, Susan Bonnerweir, J Clark, C Kubstrup, Matteo G Levisetti, W Pugh, Kenneth S PolonskyAbstract:To define the mechanisms involved in the evolution of diabetes in the Zucker diabetic fatty (ZDF) rat, Beta-Cell mass and replication rates were determined by immunochemistry, point-counting morphometry, and 6-h 5-bromo-2'-deoxyuridine (BrdU) incorporation. The Beta-Cell mass in 5- to 7-week-old prediabetic ZDF rats (4.3 +/- 0.06 mg) was similar to age-matched insulin-resistant Zucker fatty (ZF) rats (3.7 +/- 0.05 mg) and greater than that in Zucker lean control (ZLC) rats (1.9 +/- 0.3, P < 0.05). At 12 weeks (after diabetes onset), Beta-Cell mass in the ZDF rats (8.1 +/- 1.7 mg) was significantly lower than the ZF rats (15.7 +/- 1.8 mg). The mass in the ZF rats was significantly greater than in the ZLC rats (4.3 +/- 0.8 mg, P < 0.05). The Beta-Cell proliferation rate (mean of both time points) was significantly greater in the ZDF rats (0.88 +/- 0.1%) compared with the ZF and ZLC rats (0.53 +/- 0.07%, 0.62 +/- 0.07%, respectively, P < 0.05), yet ZDF rats have a lower Beta-Cell mass than the ZF rats despite a higher proliferative rate. Morphological evidence of neogenesis and apoptosis is evident in the ZF and ZDF rats. In addition, even at 5-7 weeks a modest defect in insulin secretion per Beta-Cell unit was found by pancreas perfusion. These studies provide evidence that the expansion of Beta-Cell mass in response to insulin resistance and insulin secretory defects in diabetic ZDF rats is inadequate. This failure of Beta-Cell mass expansion in the ZDF rat does not appear to be from a reduction in the rate of Beta-Cell proliferation or neogenesis, suggesting an increased rate of Cell death by apoptosis.
Luc Bouwens - One of the best experts on this subject based on the ideXlab platform.
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circulating microrna 375 as biomarker of pancreatic Beta Cell death and protection of Beta Cell mass by cytoprotective compounds
PLOS ONE, 2017Co-Authors: Imane Song, Sarah Roels, Geert A. Martens, Luc BouwensAbstract:Objective Previous studies demonstrated that circulating microRNA-375 (miR-375) is a suitable plasma biomarker for real-time detection of Beta Cell death. The present study evaluated the use of this biomarker to assess the Beta cytoprotective effect of phenylpropenoic acid glucoside (PPAG), which was previously demonstrated to protect Beta Cells against various types of injury, and of exendin-4, which is an established antidiabetic drug. Methods PPAG or exendin-4 were administered in mice treated with streptozotocin (STZ) to acutely induce Beta Cell death. Beta Cell mass and apoptotic death were measured in pancreatic tissue sections. Circulating miR-375 was measured in blood plasma by RT-qPCR. The release of miR-375 was also measured in vitro by MIN-6 Beta Cells. Results Administration of STZ resulted in measurable circulating levels of miR-375, a decrease in Beta Cell mass and increase in frequency of apoptotic Beta Cells. In vitro, there was a good correlation between miR-375 release and the extent of Beta Cell death. Treatment of mice with PPAG or exendin-4 significantly attenuated STZ-induced loss of Beta Cell mass and Beta Cell apoptosis, and normalized the blood level of miR-375. Conclusions These findings show the potential use of serological miR-375 measurements to evaluate the Beta cytoprotective effect of (potential) antidiabetic drugs in vivo.
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Beta Cell mass restoration in alloxan diabetic mice treated with egf and gastrin
PLOS ONE, 2015Co-Authors: Imane Song, Oelfah Patel, Eddy Himpe, Christo J F Muller, Luc BouwensAbstract:One week of treatment with EGF and gastrin (EGF/G) was shown to restore normoglycemia and to induce islet regeneration in mice treated with the diabetogenic agent alloxan. The mechanisms underlying this regeneration are not fully understood. We performed genetic lineage tracing experiments to evaluate the contribution of Beta Cell neogenesis in this model. One day after alloxan administration, mice received EGF/G treatment for one week. The treatment could not prevent the initial alloxan-induced Beta Cell mass destruction, however it did reverse glycemia to control levels within one day, suggesting improved peripheral glucose uptake. In vitro experiments with C2C12 Cell line showed that EGF could stimulate glucose uptake with an efficacy comparable to that of insulin. Subsequently, EGF/G treatment stimulated a 3-fold increase in Beta Cell mass, which was partially driven by neogenesis and Beta Cell proliferation as assessed by Beta Cell lineage tracing and BrdU-labeling experiments, respectively. Acinar Cell lineage tracing failed to show an important contribution of acinar Cells to the newly formed Beta Cells. No appearance of transitional Cells co-expressing insulin and glucagon, a hallmark for alpha-to-Beta Cell conversion, was found, suggesting that alpha Cells did not significantly contribute to the regeneration. An important fraction of the Beta Cells significantly lost insulin positivity after alloxan administration, which was restored to normal after one week of EGF/G treatment. Alloxan-only mice showed more pronounced Beta Cell neogenesis and proliferation, even though Beta Cell mass remained significantly depleted, suggesting ongoing Beta Cell death in that group. After one week, macrophage infiltration was significantly reduced in EGF/G-treated group compared to the alloxan-only group. Our results suggest that EGF/G-induced Beta Cell regeneration in alloxan-diabetic mice is driven by Beta Cell neogenesis, proliferation and recovery of insulin. The glucose-lowering effect of the treatment might play an important role in the regeneration process.
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regulation of pancreatic Beta Cell mass
Physical Review, 2005Co-Authors: Luc Bouwens, Ilse RoomanAbstract:Beta-Cell mass regulation represents a critical issue for understanding diabetes, a disease characterized by a near-absolute (type 1) or relative (type 2) deficiency in the number of pancreatic Beta Cells. The number of islet Beta Cells present at birth is mainly generated by the proliferation and differentiation of pancreatic progenitor Cells, a process called neogenesis. Shortly after birth, Beta-Cell neogenesis stops and a small proportion of cycling Beta Cells can still expand the Cell number to compensate for increased insulin demands, albeit at a slow rate. The low capacity for self-replication in the adult is too limited to result in a significant regeneration following extensive tissue injury. Likewise, chronically increased metabolic demands can lead to Beta-Cell failure to compensate. Neogenesis from progenitor Cells inside or outside islets represents a more potent mechanism leading to robust expansion of the Beta-Cell mass, but it may require external stimuli. For therapeutic purposes, advantage could be taken from the surprising differentiation plasticity of adult pancreatic Cells and possibly also from stem Cells. Recent studies have demonstrated that it is feasible to regenerate and expand the Beta-Cell mass by the application of hormones and growth factors like glucagon-like peptide-1, gastrin, epidermal growth factor, and others. Treatment with these external stimuli can restore a functional Beta-Cell mass in diabetic animals, but further studies are required before it can be applied to humans.
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Beta Cell proliferation in normal and streptozotocin treated newborn rats site dynamics and capacity
Diabetologia, 1994Co-Authors: Rennian Wang, Luc Bouwens, Gunter KloppelAbstract:Regeneration of neonatal Beta Cells after streptozotocin (STZ)-induced destruction may be due to either replication from pre-existing intra-islet Beta Cells or extra-islet precursor Cells. To further investigate this issue, Beta-Cell growth was analysed in normal and streptozotocin-treated newborn rats (100 μg/g body weight) at several time points during the first 20 days of life. Beta Cells were identified by insulin immunostaining, non-isotopic in situ hybridization for rat preproinsulin mRNA, and electron microscopy. Their proliferative activity was recorded by bromodeoxyuridine-pulse labelling. Beta-Cell size and total volume were determined by computerized morphometry. In normal rats, there was a threefold increase in total Beta-Cell volume during the first 5 days of life, with no further expansion till day 20. The bromodeoxyuridine labelling index of the intraislet Beta Cells was smaller than that of the extra-islet Beta Cells (2–3% vs 15–20%). Comparison of the Cell birth rate, calculated from the Beta-Cell labelling index, with the observed increase in Beta-Cell volume suggested that in normal neonatal rats proliferation of the intra-islet Beta-Cell population could account for only 10% of the observed expansion. Administration of streptozotocin at birth resulted in more than 90% reduction of the total Beta-Cell volume at day 2, which then increased to 39% of the normal value by day 20. During this period of partial regeneration, which restored normoglycaemia, the labelling index of intra-islet Beta Cells was higher than in normal rats (9% vs 2%, p<0.001), whereas no change was seen in the extra-islet Beta-Cell labelling index. Comparison of Cell birth rate with the increase in Beta-Cell volume indicated that 50–60% of the observed Beta-Cell growth could result from the intra-islet Beta-Cell proliferation. These results suggest that replication from pre-existing, surviving Beta Cells plays an important role in regeneration of neonatal Beta Cells after destruction by streptozotocin.
Daniel Pipeleers - One of the best experts on this subject based on the ideXlab platform.
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Beta Cell count instead of Beta Cell mass to assess and localize growth in Beta Cell population following pancreatic duct ligation in mice
PLOS ONE, 2012Co-Authors: Marie Chintinne, Geert Stange, Bart Denys, Zhidong Ling, Peter Int Veld, Daniel PipeleersAbstract:BACKGROUND: Pancreatic-tail duct ligation (PDL) in adult rodents has been reported to induce Beta Cell generation and increase Beta Cell mass but increases in Beta Cell number have not been demonstrated. This study examines whether PDL increases Beta Cell number and whether this is caused by neogenesis of small clusters and/or their growth to larger aggregates. METHODOLOGY: Total Beta Cell number and its distribution over small ( 100 µm) clusters was determined in pancreatic tails of 10-week-old mice, 2 weeks after PDL or sham. PRINCIPAL FINDINGS: PDL increased total Beta Cell mass but not total Beta Cell number. It induced neogenesis of small Beta Cell clusters (2.2-fold higher number) which contained a higher percent proliferating Beta Cells (1.9% Ki67+Cells) than sham tails (<0.2%); their higher Beta Cell number represented <5% of total Beta Cell number and was associated with a similar increase in alpha Cell number. It is unknown whether the regenerative process is causally related to the inflammatory infiltration in PDL-tails. Human pancreases with inflammatory infiltration also exhibited activation of proliferation in small Beta Cell clusters. CONCLUSIONS/SIGNIFICANCE: The PDL model illustrates the advantage of direct Beta Cell counts over Beta Cell mass measurements when assessing and localizing Beta Cell regeneration in the pancreas. It demonstrates the ability of the adult mouse pancreas for neogenesis of small Beta Cell clusters with activated Beta Cell proliferation. Further studies should investigate conditions under which neoformed small Beta Cell clusters grow to larger aggregates and hence to higher total Beta Cell numbers.
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Beta Cell count instead of Beta Cell mass to assess and localize growth in Beta Cell population following pancreatic duct ligation in mice
PLOS ONE, 2012Co-Authors: Marie Chintinne, Geert Stange, Bart Denys, Zhidong Ling, Peter Int Veld, Daniel PipeleersAbstract:Background Pancreatic-tail duct ligation (PDL) in adult rodents has been reported to induce Beta Cell generation and increase Beta Cell mass but increases in Beta Cell number have not been demonstrated. This study examines whether PDL increases Beta Cell number and whether this is caused by neogenesis of small clusters and/or their growth to larger aggregates. Methodology Total Beta Cell number and its distribution over small ( 100 µm) clusters was determined in pancreatic tails of 10-week-old mice, 2 weeks after PDL or sham. Principal findings PDL increased total Beta Cell mass but not total Beta Cell number. It induced neogenesis of small Beta Cell clusters (2.2-fold higher number) which contained a higher percent proliferating Beta Cells (1.9% Ki67+Cells) than sham tails (<0.2%); their higher Beta Cell number represented <5% of total Beta Cell number and was associated with a similar increase in alpha Cell number. It is unknown whether the regenerative process is causally related to the inflammatory infiltration in PDL-tails. Human pancreases with inflammatory infiltration also exhibited activation of proliferation in small Beta Cell clusters. Conclusions/significance The PDL model illustrates the advantage of direct Beta Cell counts over Beta Cell mass measurements when assessing and localizing Beta Cell regeneration in the pancreas. It demonstrates the ability of the adult mouse pancreas for neogenesis of small Beta Cell clusters with activated Beta Cell proliferation. Further studies should investigate conditions under which neoformed small Beta Cell clusters grow to larger aggregates and hence to higher total Beta Cell numbers.
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contribution of postnatally formed small Beta Cell aggregates to functional Beta Cell mass in adult rat pancreas
Diabetologia, 2010Co-Authors: Marie Chintinne, Bart Denys, Zhidong Ling, Geert M Stange, In P T Veld, Karine Hellemans, M Pipeleersmarichal, Daniel PipeleersAbstract:Aims/hypothesis Neogenesis of Beta Cells and their clustering to small aggregates is a key process in prenatal development of Beta Cell mass. We investigated the contribution of postnatally formed small aggregates to functional Beta Cell mass in adult rats. Methods Conditions were defined for (1) counting total Beta Cell number in pancreases with relative error of 90% was generated postnatally, involving: (1) neo-formation of 30,000 aggregates with diameter 200 μm, their Beta Cells exhibited a higher basal insulin content that was also resistant to glibenclamide-induced degranulation. The pool of Ki67-positive Beta Cells was sixfold larger than at birth and distributed over all aggregate sizes. Conclusions/interpretation We describe a method for in situ counting of Beta Cell numbers and subpopulations with low relative error. In adult rats, >90% of Beta Cells and Beta Cell aggregates are formed after birth. Aggregates 200 μm, which are selected for isolated islet studies. Their topographic and functional properties contribute to the functional heterogeneity of the Beta Cell population; their growth to larger aggregates with characteristic Beta Cell functions may serve future metabolic needs.