131 research outputs found
Reduced pancreatic β-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats
A low-protein diet leads to functional and structural pancreatic islet alterations, including islet hypotrophy. Insulin-signaling pathways are involved in several adaptive responses by pancreatic islets. We determined the levels of some insulin-signaling proteins related to pancreatic islet function and growth in malnourished rats. Adult male Wistar rats (N = 20 per group) were fed a 17% protein (normal-protein diet; NP) or 6% protein (low-protein diet; LP), for 8 weeks. At the end of this period, blood glucose and serum insulin and albumin levels were measured. The morphometric parameters of the endocrine pancreas and the content of some proteins in islet lysates were determined. The β-cell mass was significantly reduced (≅65%) in normoglycemic but hypoinsulinemic LP rats compared to NP rats. Associated with these alterations, a significant 30% reduction in insulin receptor substrate-1 and a 70% increase in insulin receptor substrate-2 protein content were observed in LP islets compared to NP islets. The phosphorylated serine-threonine protein kinase (pAkt)/Akt protein ratio was similar in LP and NP islets. The phosphorylated forkhead-O1 (pFoxO1)/FoxO1 protein ratio was decreased by 43% in LP islets compared to NP islets (P < 0.05). Finally, the ratio of phosphorylated-extracellular signal-related kinase 1/2 (pErk1/2) to total Erk1/2 protein levels was decreased by 71% in LP islets compared to NP islets (P < 0.05). Therefore, the reduced β-cell mass observed in LP rats is associated with the reduction of phosphorylation in mitogenic-related signals, FoxO1 and Erk proteins. The cause/effect basis of this association remains to be determined.FAPES
Reduced pancreatic β-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats
A low-protein diet leads to functional and structural pancreatic islet alterations, including islet hypotrophy. Insulin-signaling pathways are involved in several adaptive responses by pancreatic islets. We determined the levels of some insulin-signaling proteins related to pancreatic islet function and growth in malnourished rats. Adult male Wistar rats (N = 20 per group) were fed a 17% protein (normal-protein diet; NP) or 6% protein (low-protein diet; LP), for 8 weeks. At the end of this period, blood glucose and serum insulin and albumin levels were measured. The morphometric parameters of the endocrine pancreas and the content of some proteins in islet lysates were determined. The β-cell mass was significantly reduced (≅65%) in normoglycemic but hypoinsulinemic LP rats compared to NP rats. Associated with these alterations, a significant 30% reduction in insulin receptor substrate-1 and a 70% increase in insulin receptor substrate-2 protein content were observed in LP islets compared to NP islets. The phosphorylated serine-threonine protein kinase (pAkt)/Akt protein ratio was similar in LP and NP islets. The phosphorylated forkhead-O1 (pFoxO1)/FoxO1 protein ratio was decreased by 43% in LP islets compared to NP islets (P < 0.05). Finally, the ratio of phosphorylated-extracellular signal-related kinase 1/2 (pErk1/2) to total Erk1/2 protein levels was decreased by 71% in LP islets compared to NP islets (P < 0.05). Therefore, the reduced β-cell mass observed in LP rats is associated with the reduction of phosphorylation in mitogenic-related signals, FoxO1 and Erk proteins. The cause/effect basis of this association remains to be determined4210935941FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2/04310-4; 04/11684-9; 03/10829-
Reduced Pancreatic β-cell Mass Is Associated With Decreased Foxo1 And Erk1/2 Protein Phosphorylation In Low-protein Malnourished Rats
A low-protein diet leads to functional and structural pancreatic islet alterations, including islet hypotrophy. Insulin-signaling pathways are involved in several adaptive responses by pancreatic islets. We determined the levels of some insulin-signaling proteins related to pancreatic islet function and growth in malnourished rats. Adult male Wistar rats (N = 20 per group) were fed a 17% protein (normal-protein diet; NP) or 6% protein (low-protein diet; LP), for 8 weeks. At the end of this period, blood glucose and serum insulin and albumin levels were measured. The morphometric parameters of the endocrine pancreas and the content of some proteins in islet lysates were determined. The β-cell mass was significantly reduced (≅65%) in normoglycemic but hypoinsulinemic LP rats compared to NP rats. Associated with these alterations, a significant 30% reduction in insulin receptor substrate-1 and a 70% increase in insulin receptor substrate-2 protein content were observed in LP islets compared to NP islets. The phosphorylated serine-threonine protein kinase (pAkt)/Akt protein ratio was similar in LP and NP islets. The phosphorylated forkhead-O1 (pFoxO1)/FoxO1 protein ratio was decreased by 43% in LP islets compared to NP islets (P < 0.05). Finally, the ratio of phosphorylated-extracellular signal-related kinase 1/2 (pErk1/2) to total Erk1/2 protein levels was decreased by 71% in LP islets compared to NP islets (P < 0.05). Therefore, the reduced β-cell mass observed in LP rats is associated with the reduction of phosphorylation in mitogenic-related signals, FoxO1 and Erk proteins. The cause/effect basis of this association remains to be determined.4210935941Snoeck, A., Remacle, C., Reusens, B., Hoet, J.J., Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas (1990) Biology of the Neonate, 57 (2), pp. 107-118Dahri, S., Snoeck, A., Reusens-Billen, B., Remacle, C., Hoet, J.J., Islet function in offspring of mothers on low-protein diet during gestation (1991) Diabetes, 40 (SUPPL. 2), pp. 115-120Petrik, J., Reusens, B., Arany, E., Remacle, C., Coelho, C., Hoet, J.J., Hill, D.J., A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor-II (1999) Endocrinology, 140 (10), pp. 4861-4873Dumortier, O., Blondeau, B., Duvillie, B., Reusens, B., Breant, B., Remacle, C., Different mechanisms operating during different critical time-windows reduce rat fetal beta cell mass due to a maternal low-protein or low-energy diet (2007) Diabetologia, 50 (12), pp. 2495-2503. , DOI 10.1007/s00125-007-0811-0Ferreira, F., Filiputti, E., Arantes, V.C., Stoppiglia, L.F., Araujo, E.P., Delghingaro-Augusto, V., Latorraca, M.Q., Carneiro, E.M., Decreased cholinergic stimulation of insulin secretion by islets from rats fed a low protein diet is associated with reduced protein kinase C alpha expression (2003) Journal of Nutrition, 133 (3), pp. 695-699Giozzet, V.A.G., Rafacho, A., Boschero, A.C., Carneiro, E.M., Bosqueiro, J.R., Dexamethasone treatment in vivo counteracts the functional pancreatic islet alterations caused by malnourishment in rats (2008) Metabolism: Clinical and Experimental, 57 (5), pp. 617-624. , DOI 10.1016/j.metabol.2007.12.004, PII S0026049508000139Reis, M.A., Carneiro, E.M., Mello, M.A., Boschero, A.C., Saad, M.J., Velloso, L.A., Glucose-induced insulin secretion is impaired and insulin-induced phosphorylation of the insulin receptor and insulin receptor substrate-1 are increased in protein-deficient rats (1997) J Nutr, 127, pp. 403-410Swenne, I., Borg, L.A., Crace, C.J., Schnell, L.A., Persistent reduction of pancreatic beta-cell mass after a limited period of protein-energy malnutrition in the young rat (1992) Diabetologia, 35, pp. 939-945Tse, E.O., Gregoire, F.M., Reusens, B., Remacle, C., Hoet, J.J., Johnson, P.R., Changes of islet size and islet size distribution resulting from protein-malnutrition in lean (Fa/Fa) and obese (fa/fa) Zucker rats (1997) Obes Res, 5, pp. 563-571Liu, Y.Q., Jetton, T.L., Leahy, J.L., Beta-cell adaptation to insulin resistance. Increased pyruvate carboxylase and malate-pyruvate shuttle activity in islets of nondiabetic Zucker fatty rats (2002) J Biol Chem, 277, pp. 39163-39168Prentki, M., Nolan, C.J., Islet beta cell failure in type 2 diabetes (2006) Journal of Clinical Investigation, 116 (7), pp. 1802-1812. , http://www.jci.org/cgi/reprint/116/7/1802.pdf, DOI 10.1172/JCI29103Rafacho, A., Giozzet, V.A., Boschero, A.C., Bosqueiro, J.R., Functional alterations in endocrine pancreas of rats with different degrees of dexamethasone-induced insulin resistance (2008) Pancreas, 36, pp. 284-293Jetton, T.L., Everill, B., Lausier, J., Roskens, V., Habibovic, A., LaRock, K., Enhanced beta-cell mass without increased proliferation following chronic mild glucose infusion (2008) Am J Physiol Endocrinol Metab, 294, pp. E679-E687Kasuga, M., Karlsson, F.A., Kahn, C.R., Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor (1982) Science, 215 (4529), pp. 185-187Ullrich, A., Bell, J.R., Chen, E.Y., Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes (1985) Nature, 313 (6005), pp. 756-761. , DOI 10.1038/313756a0Backer, J.M., Myers Jr., M.G., Shoelson, S.E., Chin, D.J., Sun, X.J., Miralpeix, M., Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation (1992) EMBO J, 11, pp. 3469-3479Saad, M.J., Molecular mechanisms of insulin resistance (1994) Braz J Med Biol Res, 27, pp. 941-957Sesti, G., Federici, M., Hribal, M.L., Lauro, D., Sbraccia, P., Lauro, R., Defects of the insulin receptor substrate (IRS) system in human metabolic disorders (2001) FASEB Journal, 15 (12), pp. 2099-2111. , DOI 10.1096/fj.01-0009revRafacho, A., Roma, L.P., Taboga, S.R., Boschero, A.C., Bosqueiro, J.R., Dexamethasone-induced insulin resistance is associated with increased connexin 36 mRNA and protein expression in pancreatic rat islets (2007) Canadian Journal of Physiology and Pharmacology, 85 (5), pp. 536-545. , DOI 10.1139/Y07-037Rafacho, A., Ribeiro, D.L., Boschero, A.C., Taboga, S.R., Bosqueiro, J.R., Increased pancreatic islet mass is accompanied by activation of the insulin receptor substrate-2/serine-threonine kinase pathway and augmented cyclin D2 protein levels in insulin-resistant rats (2008) International Journal of Experimental Pathology, 89 (4), pp. 264-275. , DOI 10.1111/j.1365-2613.2008.00588.xRafacho, A., Cestari, T.M., Taboga, S.R., Boschero, A.C., Bosqueiro, J.R., High doses of dexamethasone induce increased beta-cell proliferation in pancreatic rat islets (2009) Am J Physiol Endocrinol Metab, 296, pp. E681-E689Saltiel, A.R., Kahn, C.R., Insulin signalling and the regulation of glucose and lipid metabolism (2001) Nature, 414 (6865), pp. 799-806. , DOI 10.1038/414799aKulkarni, R.N., Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function (2002) Biochem Soc Trans, 30, pp. 317-322Okada, T., Chong, W.L., Hu, J., Hinault, C., Michael, M.D., Krutzfeldt, J., Yin, C., Kulkarni, R.N., Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance (2007) Proceedings of the National Academy of Sciences of the United States of America, 104 (21), pp. 8977-8982. , DOI 10.1073/pnas.0608703104Porzio, O., Federici, M., Hribal, M.L., Lauro, D., Accili, D., Lauro, R., The Gly972→Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells (1999) J Clin Invest, 104, pp. 357-364Kulkarni, R.N., Winnay, J.N., Daniels, M., Bruning, J.C., Flier, S.N., Hanahan, D., Kahn, C.R., Altered function of insulin receptor substrate 1-deficient mouse islets and cultured beta-cell lines (1999) Journal of Clinical Investigation, 104 (12), pp. R69-R75Hennige, A.M., Ozcan, U., Okada, T., Jhala, U.S., Schubert, M., White, M.F., Kulkarni, R.N., Alterations in growth and apoptosis of insulin receptor substrate-1-deficient beta-cells (2005) American Journal of Physiology - Endocrinology and Metabolism, 289 (2), pp. E337-E346. , DOI 10.1152/ajpendo.00032.2004Withers, D.J., Gutierrez, J.S., Towery, H., Burks, D.J., Ren, J.-M., Previs, S., Zhang, Y., White, M.F., Disruption of IRS-2 causes type 2 diabetes in mice (1998) Nature, 391 (6670), pp. 900-904. , DOI 10.1038/36116Niessen, M., On the role of IRS2 in the regulation of functional beta-cell mass (2006) Archives of Physiology and Biochemistry, 112 (2), pp. 65-73. , DOI 10.1080/13813450600711409, PII N0HRTV1317M65040Downward, J., Mechanisms and consequences of activation of protein kinase B/Akt (1998) Current Opinion in Cell Biology, 10 (2), pp. 262-267. , DOI 10.1016/S0955-0674(98)80149-XCho, H., Thorvaldsen, J.L., Chu, Q., Feng, F., Birnbaum, M.J., Akt1/PKBalpha Is Required for Normal Growth but Dispensable for Maintenance of Glucose Homeostasis in Mice (2001) Journal of Biological Chemistry, 276 (42), pp. 38349-38352. , DOI 10.1074/jbc.C100462200Kitamura, T., Ido Kitamura, Y., Role of FoxO proteins in pancreatic beta cells (2007) Endocrine Journal, 54 (4), pp. 507-515. , http://www.jstage.jst.go.jp/article/endocrj/54/4/507/_pdf, DOI 10.1507/endocrj.KR-109Johnson, J.D., Ahmed, N.T., Luciani, D.S., Han, Z., Tran, H., Fujita, J., Misler, S., Polonsky, K.S., Increased islet apoptosis in Pdx1+/- mice (2003) Journal of Clinical Investigation, 111 (8), pp. 1147-1160. , DOI 10.1172/JCI200316537Okamoto, H., Nakae, J., Kitamura, T., Park, B.-C., Dragatsis, I., Accili, D., Transgenic rescue of insulin receptor-deficient mice (2004) Journal of Clinical Investigation, 114 (2), pp. 214-223. , DOI 10.1172/JCI200421645Kitamura, T., Nakae, J., Kitamura, Y., Kido, Y., Biggs III, W.H., Wright, C.V.E., White, M.F., Accili, D., The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth (2002) Journal of Clinical Investigation, 110 (12), pp. 1839-1847. , DOI 10.1172/JCI200216857Mordret, G., MAP kinase kinase: A node connecting multiple pathways (1993) Biology of the Cell, 79 (3), pp. 193-207. , DOI 10.1016/0248-4900(93)90138-5Marshall, C.J., MAP kinase kinase kinase, MAP kinase kinase and MAP kinase (1994) Curr Opin Genet Dev, 4, pp. 82-89Giorgetti, S., Pelicci, P.G., Pelicci, G., Von Obberghen, E., Involvement of Src-homology/collagen (SHC) proteins in signaling through the insulin receptor and the insulin-like-growth-factor-I-receptor (1994) European Journal of Biochemistry, 223 (1), pp. 195-202. , DOI 10.1111/j.1432-1033.1994.tb18983.xHolt, K.H., Kasson, B.G., Pessin, J.E., Insulin stimulation of a MEK-dependent but ERK-independent SOS protein kinase (1996) Molecular and Cellular Biology, 16 (2), pp. 577-583Lingohr, M.K., Dickson, L.M., McCuaig, J.F., Hugl, S.R., Twardzik, D.R., Rhodes, C.J., Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation (2002) Diabetes, 51, pp. 966-97
Morphofunctional Alterations in Endocrine Pancreas of Short- and Long-term Dexamethasone-treated Rats
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Long-term dexamethasone therapy may induce peripheral insulin resistance (IR), which in turn elicits increased beta-cell function and proliferation. However, whether such adaptive compensations occur during short-term treatment with dexamethasone is unclear. Here, we compared morphofunctional parameters in endocrine pancreas after short- and long-term dexamethasone administration. Groups of rats received daily i.p. injection of 1 mg/kg b.w. dexamethasone for 1 (DEX-1), 3 (DEX-3), or 5 consecutive days (DEX-5), whilst control rats were saline-treated (CTL). Despite the absence of apparent IR in DEX-1 rats, this group exhibited increased circulating insulin levels and glucose-stimulated insulin secretion (GSIS), compared to the CTL group (p < 0.05). Evident IR as well as marked hyperinsulinemia and GSIS, as judged by the static and dynamic insulin secretion values, were observed in DEX-3 and DEX-5 rats (p < 0.05). GSIS in islets cultured with 1 mu M dexamethasone was lower compared to the control (p < 0.05). Marked increases in beta-cell proliferation were observed in DEX-3 and DEX-5 rats, compared to CTL and DEX-1 rats (p < 0.05). The alterations observed in DEX-3 rats were more pronounced in DEX-5 rats, which also exhibited a higher content of islet Cdk4 and Cd2 proteins, compared to the CTL group (p < 0.05). We conclude that short-term dexamethasone treatment (DEX-1) induces an increase in beta-cell function that does not require the presence of discernible IR. As the treatment continues, the IR develops rapidly, and increased insulin secretion as well as beta-cell hyperplasia is demanded for the appropriate maintenance of glucose homeostasis.434275281Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)INOD (Instituto Nacional de Obesidade e Diabetes)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq
Reduced pancreatic beta-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)A low-protein diet leads to functional and structural pancreatic islet alterations, including islet hypotrophy. Insulin-signaling pathways are involved in several adaptive responses by pancreatic islets. We determined the levels of some insulin-signaling proteins related to pancreatic islet function and growth in malnourished rats. Adult male Wistar rats (N = 20 per group) were fed a 17% protein (normal-protein diet; NP) or 6% protein (low-protein diet; LP), for 8 weeks. At the end of this period, blood glucose and serum insulin and albumin levels were measured. The morphometric parameters of the endocrine pancreas and the content of some proteins in islet lysates were determined. The beta-cell mass was significantly reduced (congruent to 65%) in normoglycemic but hypoinsulinemic LP rats compared to NP rats. Associated with these alterations, a significant 30% reduction in insulin receptor substrate-1 and a 70% increase in insulin receptor substrate-2 protein content were observed in LP islets compared to NP islets. The phosphorylated serine-threonine protein kinase (pAkt)/Akt protein ratio was similar in LP and NP islets. The phosphorylated forkhead-O1 (pFoxO1)/FoxO1 protein ratio was decreased by 43% in LP islets compared to NP islets (P < 0.05). Finally, the ratio of phosphorylated-extracellular signal-related kinase 1/2 (pErk1/2) to total Erk1/2 protein levels was decreased by 71% in LP islets compared to NP islets (P < 0.05). Therefore, the reduced beta-cell mass observed in LP rats is associated with the reduction of phosphorylation in mitogenic-related signals, FoxO1 and Erk proteins. The cause/effect basis of this association remains to be determined.4210935941Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [02/04310-4, 04/11684-9, 03/10829-0
Association between different levels of dysglycemia and metabolic syndrome in pregnancy
<p>Abstract</p> <p>Background</p> <p>In this study, we sought to evaluate the prevalence of metabolic syndrome (MS) in a cohort of pregnant women with a wide range of glucose tolerance, prepregnancy risk factors for MS during pregnancy, and the effects of MS in the outcomes in the mother and in the newborn.</p> <p>Methods</p> <p>One hundred and thirty six women with positive screening for gestational diabetes mellitus (GDM) were classified by two diagnostic methods: glycemic profile and 100 g OGTT as normoglycemic, mild gestational hyperglycemic, GDM, and overt GDM. Markers of MS were measured between 2428<sup>th </sup>during the screening.</p> <p>Results</p> <p>The prevalence of MS was: 0%; 20.0%; 23.5% and 36.4% in normoglycemic, mild hyperglycemic, GDM, and overt GDM groups, respectively. Previous history of GDM with or without insulin use, BMI ≥ 25, hypertension, family history of diabetes in first degree relatives, non-Caucasian ethnicity, history of prematurity and polihydramnios were statistically significant prepregnancy predictors for MS in the index pregnancy, that by its turn increased the adverse outcomes in the mother and in the newborn.</p> <p>Conclusion</p> <p>The prevalence of MS increases with the worsening of glucose tolerance; impaired glycemic profile identifies pregnancies with important metabolic abnormalities even in the presence of a normal OGTT, in patients that are not classified as having GDM.</p
Short-term low-protein diet during pregnancy alters islet area and protein content of phosphatidylinositol 3-kinase pathway in rats
Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice
The −930A>G polymorphism of the CYBA gene is associated with premature coronary artery disease. A case–control study and gene–risk factors interactions
Involvement of the cholinergic pathway in glucocorticoid-induced hyperinsulinemia in rats
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Aims: We investigated the contribution of the cholinergic nervous system to dexamethasone-induced insulin resistance and hyperinsulinemia in rats. Methods: Seventy-day-old Wistar male rats were distributed in groups: control (CTL), vagotomized (VAG), and sham operated (SHAM). On the 90th day of life, half of the rats were treated daily with 1 mg/kg of dexamethasone for 5 days (CTL DEX, VAG DEX, and SHAM DEX). Results: In the presence of 8.3 mM glucose plus 100 mu M carbachol (Cch), isolated islets from CTL DEX secreted significantly more insulin than CTL. Cch-enhancement of secretion was further increased in islets from VAG CTL and VAG DEX than SHAM CTL and SHAM DEX, respectively. In CTL DEX islets, M3R and PLC beta 1 and phosphorylated PKC alpha, but not PKC alpha, protein content was significantly higher compared with each respective control. In islets from VAG DEX, the expression of M3R protein increased significantly compared to VAG CTL and SHAM DEX. Vagotomy per se did not affect insulin resistance, but attenuated fasted and fed insulinemia in VAG DEX, compared with SHAM DEX rats. Conclusion: These data indicate an important participation of the cholinergic nervous system through muscaric receptors in dexamethasone-induced hyperinsulinemia in rats. (C) 2009 Elsevier Ireland Ltd. All rights reserved.872184191Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq
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