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Results: 181 to 190 of 190

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Intracellular amyloid-like deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressing the gene for human IAPP and transplanted human islets.
Paulsson JF, Andersson A, Westermark P, Westermark GT
(2006) Diabetologia 49: 1237-46
MeSH Terms: Amyloid, Amyloidosis, Animals, Apoptosis, Guinea Pigs, Humans, Insulin-Secreting Cells, Islet Amyloid Polypeptide, Islets of Langerhans Transplantation, Mice, Mice, Nude, Mice, Transgenic, Microscopy, Immunoelectron, Protein Precursors, Protein Processing, Post-Translational, Rabbits, Transplantation, Heterologous
Show Abstract · Added June 6, 2017
AIMS/HYPOTHESIS - Islet amyloid is a frequent finding in the islets of Langerhans of individuals with type 2 diabetes. The main amyloid constituent is the beta cell-derived polypeptide hormone islet amyloid polypeptide (IAPP). In general, amyloid refers to an extracellular deposit of a congophilic material, but intracellular amyloid is seen in some beta cells of transgenic mice expressing the gene for human IAPP and in human islets transplanted into nude mice. The aim of this study was to immunohistochemically characterise the intracellular amyloid.
METHODS - Antisera against the N- and C-terminal processing sites of proIAPP (which were therefore specific for proIAPP), the C-terminal flanking peptide and mature IAPP were used for immunoelectron microscopy.
RESULTS - Fibrillar aggregates were seen in the halo region of the secretory granules in some beta cells in human IAPP transgenic mice. These aggregates were labelled with proIAPP-specific antisera. Also, proIAPP reactivity was more widespread in the intracellular amyloid-like aggregates in beta cells of transgenic mice than in human islet transplants, in which the intracellular amyloid-like deposits were larger, but the proIAPP labelling was restricted to small spots within the amyloid deposits.
CONCLUSIONS/INTERPRETATION - We suggest that proIAPP forms the first amyloid fibrils and that this can occur already in the secretory granules of the beta cells. The proIAPP-derived fibrils can act as seed for further amyloid formation, now made up by IAPP. The observed difference between human islet transplants and human IAPP transgenic animals may reflect differences in stages of amyloid development.
1 Communities
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17 MeSH Terms
Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration.
Chong AS, Shen J, Tao J, Yin D, Kuznetsov A, Hara M, Philipson LH
(2006) Science 311: 1774-5
MeSH Terms: Animals, Autoimmunity, Blood Glucose, Cell Differentiation, Cell Transplantation, Combined Modality Therapy, Diabetes Mellitus, Type 1, Female, Freund's Adjuvant, Green Fluorescent Proteins, Insulin-Secreting Cells, Islets of Langerhans Transplantation, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Regeneration, Spleen, Stem Cells
Show Abstract · Added December 10, 2013
Autoimmune destruction of beta cells is the predominant cause of type 1 diabetes mellitus (T1DM) in humans and is modeled in non-obese diabetic (NOD) mice. Many therapeutic interventions prevent the development of T1DM in NOD mice, but few can induce its reversal once established. Intervention with Freund's complete adjuvant, semi-allogeneic splenocytes, and temporary islet transplantation has been reported to cure NOD mice of established T1DM. Using the same approach, we report here that this treatment cured 32% of NOD mice of established diabetes (>340 milligrams per deciliter blood glucose), although beta cells in these mice were not derived from donor splenocytes.
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19 MeSH Terms
The FoxM1 transcription factor is required to maintain pancreatic beta-cell mass.
Zhang H, Ackermann AM, Gusarova GA, Lowe D, Feng X, Kopsombut UG, Costa RH, Gannon M
(2006) Mol Endocrinol 20: 1853-66
MeSH Terms: Animals, Cell Proliferation, Cell Size, Down-Regulation, Forkhead Box Protein M1, Forkhead Transcription Factors, Gene Deletion, Gene Expression, Glucose Tolerance Test, Insulin, Insulin-Secreting Cells, Integrases, Islets of Langerhans, Mice, Mice, Knockout, Organ Specificity, Pancreas, Time Factors, Transcription Factors
Show Abstract · Added January 6, 2014
The FoxM1 transcription factor is highly expressed in proliferating cells and activates several cell cycle genes, although its requirement appears to be limited to certain tissue types. Embryonic hepatoblast-specific inactivation of Foxm1 results in a dramatic reduction in liver outgrowth and subsequent late gestation lethality, whereas inactivation of Foxm1 in adult liver impairs regeneration after partial hepatectomy. These results prompted us to examine whether FoxM1 functions similarly in embryonic outgrowth of the pancreas and beta-cell proliferation in the adult. We found that FoxM1 is highly expressed in embryonic and neonatal endocrine cells, when many of these cells are proliferating. Using a Cre-lox strategy, we generated mice in which Foxm1 was inactivated throughout the developing pancreatic endoderm by embryonic d 15.5 (Foxm1(Deltapanc)). Mice lacking Foxm1 in their entire pancreas were born with normal pancreatic and beta-cell mass; however, they displayed a gradual decline in beta-cell mass with age. Failure of postnatal beta-cell mass expansion resulted in impaired islet function by 6 wk of age and overt diabetes by 9 wk. The decline in beta-cell mass in Foxm1(Deltapanc) animals is due to a dramatic decrease in postnatal beta-cell replication and a corresponding increase in nuclear localization of the cyclin-dependent kinase inhibitor, p27(Kip1), a known target of FoxM1 inhibition. We conclude that Foxm1 is essential to maintain normal beta-cell mass and regulate postnatal beta-cell turnover. These results suggest that mechanisms regulating embryonic beta-cell proliferation differ from those used postnatally to maintain the differentiated cell population.
2 Communities
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19 MeSH Terms
Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes.
Stiles BL, Kuralwalla-Martinez C, Guo W, Gregorian C, Wang Y, Tian J, Magnuson MA, Wu H
(2006) Mol Cell Biol 26: 2772-81
MeSH Terms: Animals, Cell Death, Cell Proliferation, Diabetes Mellitus, Experimental, Drug Resistance, Gene Deletion, Glucose, Homeostasis, Insulin-Secreting Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Organ Size, Oxidative Stress, PTEN Phosphohydrolase, Streptozocin
Show Abstract · Added February 23, 2011
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase. PTEN inhibits the action of phosphatidylinositol-3-kinase and reduces the levels of phosphatidylinositol triphosphate, a crucial second messenger for cell proliferation and survival, as well as insulin signaling. In this study, we deleted Pten specifically in the insulin producing beta cells during murine pancreatic development. Pten deletion leads to increased cell proliferation and decreased cell death, without significant alteration of beta-cell differentiation. Consequently, the mutant pancreas generates more and larger islets, with a significant increase in total beta-cell mass. PTEN loss also protects animals from developing streptozotocin-induced diabetes. Our data demonstrate that PTEN loss in beta cells is not tumorigenic but beneficial. This suggests that modulating the PTEN-controlled signaling pathway is a potential approach for beta-cell protection and regeneration therapies.
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17 MeSH Terms
The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation.
Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, Fässler R, Gu G, Gerber HP, Ferrara N, Melton DA, Lammert E
(2006) Dev Cell 10: 397-405
MeSH Terms: Animals, Basement Membrane, Blood Vessels, Cell Line, Cell Proliferation, Endothelial Cells, Gene Expression Regulation, Insulin, Insulin-Secreting Cells, Integrin beta1, Laminin, Mice, Pancreas, Signal Transduction, Vascular Endothelial Growth Factor A
Show Abstract · Added February 3, 2014
Endocrine pancreatic beta cells require endothelial signals for their differentiation and function. However, the molecular basis for such signals remains unknown. Here, we show that beta cells, in contrast to the exocrine pancreatic cells, do not form a basement membrane. Instead, by using VEGF-A, they attract endothelial cells, which form capillaries with a vascular basement membrane next to the beta cells. We have identified laminins, among other vascular basement membrane proteins, as endothelial signals, which promote insulin gene expression and proliferation in beta cells. We further demonstrate that beta1-integrin is required for the beta cell response to the laminins. The proposed mechanism explains why beta cells must interact with endothelial cells, and it may apply to other cellular processes in which endothelial signals are required.
1 Communities
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15 MeSH Terms
Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells.
Miura A, Yamagata K, Kakei M, Hatakeyama H, Takahashi N, Fukui K, Nammo T, Yoneda K, Inoue Y, Sladek FM, Magnuson MA, Kasai H, Miyagawa J, Gonzalez FJ, Shimomura I
(2006) J Biol Chem 281: 5246-57
MeSH Terms: ATP-Binding Cassette Transporters, Adenosine Triphosphate, Animals, Arginine, Blood Glucose, Blotting, Western, Calcium, Cytosol, Exons, Female, Genotype, Glucose, Hepatocyte Nuclear Factor 4, Heterozygote, Immunohistochemistry, Insulin, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, Models, Genetic, Multidrug Resistance-Associated Proteins, Patch-Clamp Techniques, Polymerase Chain Reaction, Potassium, Potassium Channels, Inwardly Rectifying, Potassium Chloride, RNA, Messenger, Receptors, Drug, Reverse Transcriptase Polymerase Chain Reaction, Sulfonylurea Compounds, Sulfonylurea Receptors, Tissue Distribution, Transgenes
Show Abstract · Added February 23, 2011
Mutations in the hepatocyte nuclear factor (HNF)-4alpha gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of glucose-stimulated insulin secretion by pancreatic beta-cells. HNF-4alpha, a transcription factor belonging to the nuclear receptor superfamily, is expressed in pancreatic islets as well as in the liver, kidney, and intestine. However, the role of HNF-4alpha in pancreatic beta-cell is unclear. To clarify the role of HNF-4alpha in beta-cells, we generated beta-cell-specific HNF-4alpha knock-out (betaHNF-4alphaKO) mice using the Cre-LoxP system. The betaHNF-4alphaKO mice exhibited impairment of glucose-stimulated insulin secretion, which is a characteristic of MODY1. Pancreatic islet morphology, beta-cell mass, and insulin content were normal in the HNF-4alpha mutant mice. Insulin secretion by betaHNF-4alphaKO islets and the intracellular calcium response were impaired after stimulation by glucose or sulfonylurea but were normal after stimulation with KCl or arginine. Both NAD(P)H generation and ATP content at high glucose concentrations were normal in the betaHNF-4alphaKO mice. Expression levels of Kir6.2 and SUR1 proteins in the betaHNF-4alphaKO mice were unchanged as compared with control mice. Patch clamp experiments revealed that the current density was significantly increased in betaHNF-4alphaKO mice compared with control mice. These results are suggestive of the dysfunction of K(ATP) channel activity in the pancreatic beta-cells of HNF-4alpha-deficient mice. Because the K(ATP) channel is important for proper insulin secretion in beta-cells, altered K(ATP) channel activity could be related to the impaired insulin secretion in the betaHNF-4alphaKO mice.
1 Communities
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38 MeSH Terms
RIP-Cre revisited, evidence for impairments of pancreatic beta-cell function.
Lee JY, Ristow M, Lin X, White MF, Magnuson MA, Hennighausen L
(2006) J Biol Chem 281: 2649-53
MeSH Terms: Animals, Female, Gene Targeting, Glucose Intolerance, Insulin, Insulin-Secreting Cells, Integrases, Male, Mice, Mice, Transgenic, Promoter Regions, Genetic, Rats
Show Abstract · Added February 23, 2011
The Cre/loxP recombinase system for performing conditional gene targeting experiments has been very useful in exploring genetic pathways that control both the development and function of pancreatic beta-cells. One particular line of transgenic mice (B6.Cg-Tg(Ins2-cre)25Mgn/J), commonly called RIP-Cre, in which expression of Cre recombinase is controlled by a short fragment of the rat insulin II gene promoter has been used in at least 21 studies on at least 17 genes. In most of these studies inactivation of the gene of interest was associated with either glucose intolerance or frank diabetes. Experimental evidence has been gradually emerging to suggest that RIP-Cre mice alone display glucose intolerance. In this study experiments from three laboratories demonstrate that RIP-Cre mice, in the absence of genes targeted by loxP sites, are glucose intolerant, possibly due to impaired insulin secretion. In addition, we review the use of RIP-Cre mice and discuss possible molecular underpinnings and ramifications of our findings.
1 Communities
1 Members
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12 MeSH Terms
Regulation of two insulin granule populations within the reserve pool by distinct calcium sources.
Hao M, Li X, Rizzo MA, Rocheleau JV, Dawant BM, Piston DW
(2005) J Cell Sci 118: 5873-84
MeSH Terms: Animals, Biological Transport, Calcium, Calcium Signaling, Cell Line, Cytoskeleton, Endoplasmic Reticulum, Glucose, Humans, Image Processing, Computer-Assisted, Insulin-Secreting Cells, Microscopy, Fluorescence, Models, Biological, Proinsulin, Secretory Vesicles
Show Abstract · Added May 5, 2017
Insulin granule trafficking is a key step of glucose-stimulated insulin secretion from pancreatic beta cells. Using quantitative live cell imaging, we examined insulin granule movements within the reserve pool upon secretory stimulation in betaTC3 cells. For this study, we developed a custom image analysis program that permitted automatic tracking of the individual motions of over 20,000 granules. This analysis of a large sample size enabled us to study micro-populations of granules that were not quantifiable in previous studies. While over 90% of the granules depend on Ca2+ efflux from the endoplasmic reticulum for their mobilization, a small and fast-moving population of granules responds to extracellular Ca2+ influx after depolarization of the plasma membrane. We show that this differential regulation of the two granule populations is consistent with localized Ca2+ signals, and that the cytoskeletal network is involved in both types of granule movement. The fast-moving granules are correlated temporally and spatially to the replacement of the secreted insulin granules, which supports the hypothesis that these granules are responsible for replenishing the readily releasable pool. Our study provides a model by which glucose and other secretory stimuli can regulate the readily releasable pool through the same mechanisms that regulate insulin secretion.
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15 MeSH Terms
Islet auto-transplantation into an omental or splenic site results in a normal beta cell but abnormal alpha cell response to mild non-insulin-induced hypoglycemia.
Gustavson SM, Rajotte RV, Hunkeler D, Lakey JR, Edgerton DS, Neal DW, Snead WL, Penaloza AR, Cherrington AD
(2005) Am J Transplant 5: 2368-77
MeSH Terms: Animals, Area Under Curve, Arginine, Blood Glucose, Cell Survival, Cell Transplantation, Dogs, Female, Glucagon, Glucagon-Secreting Cells, Glycogen Phosphorylase, Graft Survival, Hypoglycemia, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Islets of Langerhans Transplantation, Male, Pancreas, Spleen, Time Factors, Transplantation, Autologous
Show Abstract · Added December 10, 2013
The present studies were designed to determine if totally pancreatectomized dogs that underwent islet auto-transplantation retained a functional pancreatic counterregulatory response to mild non-insulin-induced hypoglycemia. Six dogs underwent total pancreatectomy followed by islet auto-transplantation to spleen or omentum. The animals recovered and fasting plasma glucose and insulin levels were normal. Each study consisted of a 40-min control and 2-h test period. At the onset of the test period, a glycogen phosphorylase inhibitor was administered to create mild hypoglycemia. Plasma glucose in the transplanted dogs fell from 120 +/- 4 to 80 +/- 3 mg/dL, similar to the minimum in control dogs without islet auto-transplantation (108 +/- 2 to 84 +/- 5 mg/dL). The fall in plasma insulin was similar in both groups. Glucagon, however, rose in response to hypoglycemia in the control dogs (Delta24 +/- 7 pg/mL; p < 0.05), but failed to rise significantly in the transplanted dogs (Delta9 +/- 6 pg/mL). In fact, only 1 of 7 control dogs failed to increase plasma glucagon by at least 25%, whereas 4 of 6 transplanted dogs failed to do so. In conclusion, in conscious dogs with successfully auto-transplanted islets, the beta cell response to mild non-insulin-induced hypoglycemia was normal, whereas the alpha cell response was not.
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22 MeSH Terms
Optical imaging of pancreatic beta cells in living mice expressing a mouse insulin I promoter-firefly luciferase transgene.
Park SY, Wang X, Chen Z, Powers AC, Magnuson MA, Head WS, Piston DW, Bell GI
(2005) Genesis 43: 80-6
MeSH Terms: Animals, Cell Culture Techniques, Insulin-Secreting Cells, Luciferases, Firefly, Luminescent Agents, Mice, Mice, Transgenic, Proinsulin, Promoter Regions, Genetic, Transgenes
Show Abstract · Added February 23, 2011
We generated transgenic mice expressing firefly (Photinus pyralis) luciferase (luc) under the control of the mouse insulin I promoter (MIP). The mice have normal glucose tolerance and pancreatic islet architecture. The luciferase-expressing beta cells can be readily visualized in living mice using whole-body bioluminescent imaging. The MIP-luc transgenic mice may be useful for monitoring changes in beta cell function or mass in living animals with normal or altered metabolic states.
genesis 43:80-86, 2005. (c) 2005 Wiley-Liss, Inc.
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10 MeSH Terms