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A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes 总被引:1,自引:0,他引:1
Koeck T Olsson AH Nitert MD Sharoyko VV Ladenvall C Kotova O Reiling E Rönn T Parikh H Taneera J Eriksson JG Metodiev MD Larsson NG Balhuizen A Luthman H Stančáková A Kuusisto J Laakso M Poulsen P Vaag A Groop L Lyssenko V Mulder H Ling C 《Cell metabolism》2011,13(1):80-91
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Islets of Langerhans are a pancreatic endocrine compartment consisting of insulin-producing β cells together with several other hormone-producing cells. While some insulin-producing cells or immature pancreatic cells have been generated in vitro from ES and iPS cells, islets with proper functions and a three-dimensional (3D) structure have never been successfully produced. To test whether islets can be formed in vitro, we first examined the potential of mouse fetal pancreatic cells. We found that E16.5 pancreatic cells, just before forming islets, were able to develop cell aggregates consisting of β cells surrounded by glucagon-producing α cells, a structure similar to murine adult islets. Moreover, the transplantation of these cells improved blood glucose levels in hyperglycemic mice. These results indicate that functional islets are formed in vitro from fetal pancreatic cells at a specific developmental stage. By adopting these culture conditions to the differentiation of mouse iPS cells, we developed a two-step system to generate islets, i.e. immature pancreatic cells were first produced from iPS cells, and then transferred to culture conditions that allowed the formation of islets from fetal pancreatic cells. The islets exhibited distinct 3D structural features similar to adult pancreatic islets and secreted insulin in response to glucose concentrations. Transplantation of the islets improved blood glucose levels in hyperglycemic mice. In conclusion, the two-step culture system allows the generation of functional islets with a 3D structure from iPS cells. 相似文献
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Zhang B Yang L Yu L Lin B Hou Y Wu J Huang Q Han Y Guo L Ouyang Q Zhang B Lu L Zhang X 《Acta biochimica et biophysica Sinica》2012,44(3):207-216
Acetylcholinesterase (AChE) expression is pivotal during apoptosis. Indeed, AChE inhibitors partially protect cells from apoptosis. Insulin-dependent diabetes mellitus (IDDM) is characterized in part by pancreatic β-cell apoptosis. Here, we investigated the role of AChE in the development of IDDM and analyzed protective effects of AChE inhibitors. Multiple low-dose streptozotocin (MLD-STZ) administration resulted in IDDM in a mouse model. Western blot analysis, cytochemical staining, and immunofluorescence staining were used to detect AChE expression in MIN6 cells, primary β cells, and apoptotic pancreatic β cells of MLD-STZ-treated mice. AChE inhibitors were administered intraperitoneally to the MLD-STZ mice for 30 days. Blood glucose, plasma insulin, and creatine levels were measured, and glucose tolerance tests were performed. The effects of AChE inhibitors on MIN6 cells were also evaluated. AChE expression was induced in the apoptotic MIN6 cells and primary β cells in vitro and pancreatic islets in vivo when treated with STZ. Induction and progressive accumulation of AChE in the pancreatic islets were associated with apoptotic β cells during IDDM development. The administration of AChE inhibitors effectively decreased hyperglycemia and incidence of diabetes, and restored plasma insulin levels and plasma creatine clearance in the MLD-STZ mice. AChE inhibitors partially protected MIN6 cells from the damage caused by STZ treatment. Induction and accumulation of AChE in pancreatic islets and the protective effects of AChE inhibitors on the onset and development of IDDM indicate a close relationship between AChE and IDDM. 相似文献
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One of the characteristics of type 2 diabetes is that the insulin secretory response of β cells is selectively impaired to glucose. In the Goto-Kakizaki (GK) rat, a genetic model of type 2 diabetes mellitus, glucose-induced insulin secretion is selectively impaired due to deficient ATP production derived from impaired glucose metabolism. In addition, islets in GK rat and human type 2 diabetes are oxidatively stressed. In this issue, role of endogenous reactive oxygen species (ROS) production in impaired metabolism-secretion coupling of diabetic pancreatic β cells is reviewed. In β cells, ROS is endogenously produced by activation of Src, a non-receptor tyrosine kinase. Src inhibitors restore the impaired insulin release and impaired ATP elevation by reduction in ROS production in diabetic islets. Src is endogenously activated in diabetic islets, since the level of Src pY416 in GK islets is higher than that in control islets. In addition, exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, decreases Src pY416 and glucose-induced ROS production and ameliorates impaired ATP production dependently on Epac in GK islets. These results indicate that GLP-1 signaling regulates endogenous ROS production due to Src activation and that incretin has unique therapeutic effects on impaired glucose metabolism in diabetic β cells. 相似文献
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《Biochimica et Biophysica Acta (BBA)/General Subjects》2017,1861(8):2039-2047
BackgroundCompensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation.MethodsWe challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4 weeks and measured metabolic and pancreatic morphological parameters. We performed ex vivo experiments to analyse β cell insulin secretion and electrophysiology characteristics. Adenoviral-mediated overexpression and lentiviral-ShRNA-mediated knocking down proteins were applied in Min6 cells and cultured primary mouse islets.ResultsβRicKO mice showed a significant glucose intolerance and a reduced plasma insulin level and an unchanged level β cell mass versus the control mice under HFD. A HFD or palmitate treatment enhanced both glucose-induced insulin secretion (GIIS) and the PMA (phorbol 12-myristate 13-acetate)-induced insulin secretion in the control islets but not in the βRicKO islets. The KO β cells showed similar glucose-induced Ca2 + influx but lower membrane capacitance increments versus the control cells. The enhanced mTORC2/PKC proteins levels in the control HFD group were ablated by Rictor deletion. Replenishing PKCα by overexpression of PKCα-T638D restored the defective GIIS in βRicKO islets.ConclusionsThe mTORC2/Rictor pathway modulates β cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKCα.General significanceThis study suggests that the mTORC2/PKC pathway in β cells is involved in the pathogenesis of T2D. 相似文献
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Meur G Qian Q da Silva Xavier G Pullen TJ Tsuboi T McKinnon C Fletcher L Tavaré JM Hughes S Johnson P Rutter GA 《The Journal of biological chemistry》2011,286(15):13647-13656
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Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells
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Hanho Shin Ji Hye Han Juhwan Yoon Hyo Jung Sim Tae Joo Park Siyoung Yang Eun Kyung Lee Rohit N. Kulkarni Josephine M. Egan Wook Kim 《Journal of cellular and molecular medicine》2018,22(4):2337-2345
Cannabinoid 1 receptors (CB1Rs) are expressed in peripheral tissues, including islets of Langerhans, where their function(s) is under scrutiny. Using mouse β‐cell lines, human islets and CB1R‐null (CB1R?/?) mice, we have now investigated the role of CB1Rs in modulating β‐cell function and glucose responsiveness. Synthetic CB1R agonists diminished GLP‐1‐mediated cAMP accumulation and insulin secretion as well as glucose‐stimulated insulin secretion in mouse β‐cell lines and human islets. In addition, silencing CB1R in mouse β cells resulted in an increased expression of pro‐insulin, glucokinase (GCK) and glucose transporter 2 (GLUT2), but this increase was lost in β cells lacking insulin receptor. Furthermore, CB1R?/? mice had increased pro‐insulin, GCK and GLUT2 expression in β cells. Our results suggest that CB1R signalling in pancreatic islets may be harnessed to improve β‐cell glucose responsiveness and preserve their function. Thus, our findings further support that blocking peripheral CB1Rs would be beneficial to β‐cell function in type 2 diabetes. 相似文献
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Kaneko K Ueki K Takahashi N Hashimoto S Okamoto M Awazawa M Okazaki Y Ohsugi M Inabe K Umehara T Yoshida M Kakei M Kitamura T Luo J Kulkarni RN Kahn CR Kasai H Cantley LC Kadowaki T 《Cell metabolism》2010,12(6):619-632
Type 2 diabetes is characterized by insulin resistance and pancreatic β cell dysfunction, the latter possibly caused by a defect in insulin signaling in β cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in β cells and the pik3r2 gene systemically (βDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. β cells of βDKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca(2+) influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of βDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in β cells in?vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes. 相似文献
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Yoshikazu Hasegawa Yoko Daitoku Seiya Mizuno Yoko Tanimoto Saori Mizuno-Iijima Miki Matsuo Noriko Kajiwara Masatsugu Ema Hisashi Oishi Yoshihiro Miwa Kazuyuki Mekada Atsushi Yoshiki Satoru Takahashi Fumihiro Sugiyama Ken-ichi Yagami 《Experimental Animals》2014,63(2):183-191
Cre/loxP system-mediated site-specific recombination is utilized to study gene function
in vivo. Successful conditional knockout of genes of interest is
dependent on the availability of Cre-driver mice. We produced and characterized pancreatic
β cell-specific Cre-driver mice for use in diabetes mellitus research. The gene encoding
Cre was inserted into the second exon of mouse Ins1 in a bacterial
artificial chromosome (BAC). Five founder mice were produced by microinjection of
linearized BAC Ins1-cre. The transgene was integrated between
Mafa and the telomere on chromosome 15 in one of the founders, BAC
Ins1-cre25. To investigate Cre-loxP recombination, BAC Ins1-cre25 males were crossed with
two different Cre-reporters, R26R and R26GRR females. On gross observation, reporter
signal after Cre-loxP recombination was detected exclusively in the adult pancreatic
islets in both F1 mice. Immunohistological analysis indicated that Cre-loxP
recombination-mediated reporter signal was colocalized with insulin in pancreatic islet
cells of both F1 mice, but not with glucagon. Moreover, Cre-loxP recombination
signal was already observed in the pancreatic islets at E13.5 in both F1
fetuses. Finally, we investigated ectopic Cre-loxP recombination for
Ins1, because the ortholog Ins2 is also expressed in the
brain, in addition to the pancreas. However, there was no Cre-loxP recombination-mediated
reporter signal in the brain of both F1 mice. Our data suggest that BAC
Ins1-cre25 mice are a useful Cre-driver C57BL/6N for pancreatic β cell-specific Cre-loxP
recombination, except for crossing with knock-in mice carrying floxed gene on chromosome
15. 相似文献
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Dalgaard LT 《Biochemical and biophysical research communications》2012,417(1):495-500
Uncoupling Protein 2 (UCP2) is expressed in the pancreatic β-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/- islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2-/- and GK+/- islets compared with GK+/- islets and UCP2 deficiency improved glucose tolerance of GK+/- mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/- mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients. 相似文献
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Bao S Song H Wohltmann M Ramanadham S Jin W Bohrer A Turk J 《The Journal of biological chemistry》2006,281(30):20958-20973
Studies involving pharmacologic or molecular biologic manipulation of Group VIA phospholipase A(2) (iPLA(2)beta) activity in pancreatic islets and insulinoma cells suggest that iPLA(2)beta participates in insulin secretion. It has also been suggested that iPLA(2)beta is a housekeeping enzyme that regulates cell 2-lysophosphatidylcholine (LPC) levels and arachidonate incorporation into phosphatidylcholine (PC). We have generated iPLA(2)beta-null mice by homologous recombination and have reported that they exhibit reduced male fertility and defective motility of spermatozoa. Here we report that pancreatic islets from iPLA(2)beta-null mice have impaired insulin secretory responses to D-glucose and forskolin. Electrospray ionization mass spectrometric analyses indicate that the abundance of arachidonate-containing PC species of islets, brain, and other tissues from iPLA(2)beta-null mice is virtually identical to that of wild-type mice, and no iPLA(2)beta mRNA was observed in any tissue from iPLA(2)beta-null mice at any age. Despite the insulin secretory abnormalities of isolated islets, fasting and fed blood glucose concentrations of iPLA(2)beta-null and wild-type mice are essentially identical under normal circumstances, but iPLA(2)beta-null mice develop more severe hyperglycemia than wild-type mice after administration of multiple low doses of the beta-cell toxin streptozotocin, suggesting an impaired islet secretory reserve. A high fat diet also induces more severe glucose intolerance in iPLA(2)beta-null mice than in wild-type mice, but PLA(2)beta-null mice have greater responsiveness to exogenous insulin than do wild-type mice fed a high fat diet. These and previous findings thus indicate that iPLA(2)beta-null mice exhibit phenotypic abnormalities in pancreatic islets in addition to testes and macrophages. 相似文献
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Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells
Dominguez V Raimondi C Somanath S Bugliani M Loder MK Edling CE Divecha N da Silva-Xavier G Marselli L Persaud SJ Turner MD Rutter GA Marchetti P Falasca M Maffucci T 《The Journal of biological chemistry》2011,286(6):4216-4225
Phosphoinositide 3-kinases (PI3Ks) are critical regulators of pancreatic β cell mass and survival, whereas their involvement in insulin secretion is more controversial. Furthermore, of the different PI3Ks, the class II isoforms were detected in β cells, although their role is still not well understood. Here we show that down-regulation of the class II PI3K isoform PI3K-C2α specifically impairs insulin granule exocytosis in rat insulinoma cells without affecting insulin content, the number of insulin granules at the plasma membrane, or the expression levels of key proteins involved in insulin secretion. Proteolysis of synaptosomal-associated protein of 25 kDa, a process involved in insulin granule exocytosis, is impaired in cells lacking PI3K-C2α. Finally, our data suggest that the mRNA for PI3K-C2α may be down-regulated in islets of Langerhans from type 2 diabetic compared with non-diabetic individuals. Our results reveal a critical role for PI3K-C2α in β cells and suggest that down-regulation of PI3K-C2α may be a feature of type 2 diabetes. 相似文献
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Wicksteed B Alarcon C Briaud I Lingohr MK Rhodes CJ 《The Journal of biological chemistry》2003,278(43):42080-42090
Proinsulin biosynthesis is regulated in response to nutrients, most notably glucose. In the short term (=2h) this is due to increases in the translation of pre-existing mRNA. However, prolonging glucose stimulation (24 h) also increases preproinsulin mRNA levels. It has been proposed that secreted insulin from the pancreatic beta-cell regulates its own synthesis through a positive autocrine feedback mechanism. Here the comparative contributions of translation and mRNA levels on the levels of proinsulin biosynthesis were examined in isolated pancreatic islets. Also, the autocrine role of insulin upon four beta-cell functions (insulin secretion, proinsulin translation, preproinsulin mRNA levels, and total protein synthesis) was investigated in parallel. The results showed that proinsulin biosynthesis is regulated, in the short term (1 h), solely at the level of translation, through an approximately 6-fold increase in response to glucose (2.8 mm versus 16.7 mm glucose). In the longer term, when preproinsulin mRNA levels have increased approximately 2-fold, a corresponding increase was observed in the fold response of proinsulin translation to a stimulatory glucose concentration (>/=10-fold). Importantly, neither exogenously added nor secreted insulin were found to play any role in regulating insulin secretion, proinsulin translation, preproinsulin mRNA levels, or total protein synthesis. The results presented here indicate that long term nutritional state sets the preproinsulin mRNA level in the beta-cell at which translation control regulates short term changes in rates of proinsulin biosynthesis in response to glucose, but this is not mediated by any autocrine effect of insulin. 相似文献
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Aquaporin 7 is a beta-cell protein and regulator of intraislet glycerol content and glycerol kinase activity, beta-cell mass, and insulin production and secretion 总被引:1,自引:0,他引:1
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Matsumura K Chang BH Fujimiya M Chen W Kulkarni RN Eguchi Y Kimura H Kojima H Chan L 《Molecular and cellular biology》2007,27(17):6026-6037
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Shun-ichiro Asahara Tomokazu Matsuda Yoshiaki Kido Masato Kasuga 《Biochemical and biophysical research communications》2009,381(3):367-371
Aim
To study the changes in gene expression by pancreatic β cells under insulin resistance conditions.Method
An exhaustive gene expression analysis was performed, using isolated pancreatic islets of obese diabetic model Lepr−/− mice. Overexpression of cyclin D2 was induced in cells from the pancreatic β cell line, namely, INS-1.Results
Through a gene expression analysis using islets isolated from db/db mice, we found a significant increase in the expression of ribosome-related molecules. In addition, increased expression of cyclin D2 was found at certain protein levels. As INS-1 cells were induced to overexpress cyclin D2, we found an increase in the expression of ribosome-related molecules. Concurrently, an increase in the expression of endoplasmic reticulum stress (ER stress)-related molecules was also found.Conclusion
In cases of pancreatic β cell hyperplasia associated with insulin resistance, ribosomal biogenesis is increased, and ER stress is induced. 相似文献20.
Hong EG Jung DY Ko HJ Zhang Z Ma Z Jun JY Kim JH Sumner AD Vary TC Gardner TW Bronson SK Kim JK 《American journal of physiology. Endocrinology and metabolism》2007,293(6):E1687-E1696
Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in Ins2(Akita) mice leads to pancreatic beta-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2(Akita) and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2(Akita) mice developed insulin resistance, as indicated by an approximately 80% reduction in glucose infusion rate during clamps. Insulin resistance was due to approximately 50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKCepsilon levels in Ins2(Akita) mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCepsilon levels in Ins2(Akita) mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in Ins2(Akita) mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2(Akita) mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects. 相似文献