Molecular mechanisms involved in pancreatic beta cell disfunction and dead in diabetes mellitus: strategies for the inhibition of these processes and restoration of the insular mass

• Grant number: 15/12611-0
• Support Opportunities: Research Projects - Thematic Grants
• Duration: January 01, 2016 - December 31, 2020
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Antonio Carlos Boschiero
• Grantee: Antonio Carlos Boschiero
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Claudio Cesar Zoppi ; Emerielle Cristine Vanzela ; Everardo Magalhães Carneiro ; Helena Coutinho Franco de Oliveira ; Helena Cristina de Lima Barbosa ; Leonardo dos Reis Silveira
• Associated grant(s): 17/04551-2 - 2nd Joint Meeting of the EASD - Islet Study Group and the Beta Cell Workshop, AR.EXT; 16/04791-0 - Effect of miR-696 e miR-let7b on the mitochondrial function in insulin resistant muscle cells, AV.EXT
• Associated scholarship(s): 18/15032-9 - Effect of resistance exercise training upon pancreatic beta-cell mass and function in healthy and diabetic mice, BP.DR; 18/24368-0 - Action of PPAR gamma (Peroxisome Proliferator Activated Receptor gamma) and AMPK (AMP-activated protein kinase) on the expression of IDE (Insulin Degrading Enzyme) in pancreatic beta cells, BP.DR; 17/25771-0 - Resistance exercise training effect upon pancreatic beta cell in in-vitro and in-vivo type-1 diabetic models, BP.IC; + associated scholarships 17/09890-0 - The possible effect of dipeptidyl peptidase-IV upon hypoglycemia prevention during exercise, in type 1 diabetic mice, BP.IC; 17/06475-1 - Effect of physical exercise on modulation of peroxisome proliferator-activated receptor ³ (PPAR³) and insulin-degrading enzyme (IDE) in the pancreatic islet of mice, BP.PD; 16/23140-0 - Endocrine pancreas plasticity of mice offspring after maternal treatment with glucocorticoid during late gestation, BP.DR; 15/23729-1 - Molecular mechanisms of the ARHGAP21 RhoGAP in the VLDL vesicles formation in hepatocytes of ARHGAP21-heterozygous C57BL/6 mice, BP.IC; 15/10705-7 - The role of insulin and hyperglycemia in the delta cell transdifferentiation to beta cell in streptozotocin diabetic mice, BP.PD; 15/03121-9 - Characterization of IL17 expression in the gastrointestinal tract in response to different nutrients: its potential role as an incretin, BP.PD; 13/24670-5 - The role of HNF4alfa in expansion of functional pancreatic beta cell in insulin resistant and, STZ-induced diabetic mice., BP.PD; 11/23370-2 - Cholesterol metabolism and insulin containing granule movement in islets from hypercholesterolemic mice: Possible participate of Endoplasmic Reticulum Stress, BP.PD - associated scholarships

Abstract

Diabetes mellitus (DM) is a syndrome that affects 380 million people in the world. This syndrome may cause chronic and severe health problems, increasing morbidity and mortality. Among these complications, visual defects and blindness, limb amputation, renal failure, neuropathies and cardiovascular diseases are the most frequent. The two most important forms of diabetes are DM1 (10 - 15%) and DM2 (80 - 85%). The development of the disease depends on the combination of genetic predisposition and environmental factors. Reduction of insulin production due to the loss of function, dedifferentiation, and increase in the apoptosis of beta cells, not compensated by regeneration, is a common characteristic for DM1 and DM2. In the DM1, the reduction of beta cell mass is due to their contact with immune cells and the release of proinflammatory mediators such as cytokines, leading to apoptosis. Inadequate formation of pancreatic islets, during perinatal life, as well as malnourishment, obesity, dyslipidemia, and aging contribute to the malfunctioning of the endocrine pancreas, provoking DM2. During the different periods of life, the adaptations of the endocrine pancreas are under the control of several hormones, chemical molecules, and neuronal signals, generated in the own pancreas or in other tissues. In this project, we will continue to study the molecular mechanisms that induce positive or negative modifications in beta cells, in association with the control of glucose homeostasis. We will focus our attention on substances coming from the own islets or from other tissues (cross talk), particularly during physical exercise and dyslipidemia. (AU)

Scientific publications

(31)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BORCK, PATRICIA CRISTINE; VETTORAZZI, JEAN FRANCIESCO; SOUTO BRANCO, RENATO CHAVES; BATISTA, THIAGO MARTINS; SANTOS-SILVA, JUNIA CAROLINA; NAKANISHI, VANESSA YUMI; BOSCHERO, ANTONIO CARLOS; RIBEIRO, ROSANE APARECIDA; CARNEIRO, EVERARDO MAGALHAES. Taurine supplementation induces long-term beneficial effects on glucose homeostasis in ob/ob mice. Amino Acids, v. 50, n. 6, p. 765-774, JUN 2018. (14/01717-9, 15/12611-0)

BARTH, ROBSON; RUOSO, CAROLINA; FERREIRA, SANDRA MARA; DE RAMOS, FRANCIELI CAROLINE; LIMA, FERNANDA BARBOSA; BOSCHERO, ANTONIO CARLOS; DOS SANTOS, GUSTAVO JORGE. Hepatocyte Nuclear Factor 4-alpha (HNF4 alpha) controls the insulin resistance-induced pancreatic beta-cell mass expansion. Life Sciences, v. 289, JAN 15 2022. (15/12611-0)

PAULA, FLAVIA M. M.; LEITE, NAYARA C.; BORCK, PATRICIA C.; FREITAS-DIAS, RICARDO; CNOP, MIRIAM; CHACON-MIKAHIL, MARA P. T.; CAVAGLIERI, CLAUDIA R.; MARCHETTI, PIERO; BOSCHERO, ANTONIO C.; ZOPPI, CLAUDIO C.; et al. Exercise training protects human and rodent beta cells against endoplasmic reticulum stress and apoptosis. FASEB JOURNAL, v. 32, n. 3, p. 1524-1536, MAR 2018. (15/12611-0)

ALVES, BRUNA LOURENCONI; ARAUJO, THIAGO DOS REIS; GUIMARAES, DIMITRIUS SANTIAGO PASSOS SIMOES FROES; ZOPPI, CLAUDIO CESAR; FIGUEIREDO, MARIANA SARTO; CARNEIRO, EVERARDO MAGALHAES. Amino acid restriction alters survival mechanisms in pancreatic beta cells: possible role of the PI3K/Akt pathway. EUROPEAN JOURNAL OF NUTRITION, v. 60, n. 7, p. 3947-3957, OCT 2021. (15/12611-0)

MARMENTINI, CARINE; BRANCO, RENATO C. S.; BOSCHERO, ANTONIO C.; KURAUTI, MIRIAN A.. slet amyloid toxicity: From genesis to counteracting mechanism. Journal of Cellular Physiology, v. 237, n. 2, OCT 2021. (18/24368-0, 15/12611-0)

FREITAS-DIAS, RICARDO; LIMA, TANES, I; COSTA-JUNIOR, JOSE MARIA; GONCALVES, LUCIANA M.; ARAUJO, HYGOR N.; PAULA, FLAVIA M. M.; SANTOS, GUSTAVO J.; SOUTO BRANCO, RENATO CHAVES; OU, KRISTY; KAESTNER, KLAUS H.; et al. Offspring from trained male mice inherit improved muscle mitochondrial function through PPAR co-repressor modulation. Life Sciences, v. 291, p. 8-pg., 2022-02-15. (15/12611-0, 14/01717-9)

RODRIGUES-DOS-SANTOS, KARINA; SOARES, GABRIELA M.; GUIMARAES, DIMITRIUS S. P. S. F.; ARAUJO, THIAGO R.; VETTORAZZI, JEAN F.; ZANGEROLAMO, LUCAS; MARCONATO-JUNIOR, EMILIO; CAI, RENZHI; SHA, WEI; SCHALLY, V, ANDREW; et al. Effects of growth hormone-releasing hormone agonistic analog MR-409 on insulin-secreting cells under cyclopiazonic acid-induced endoplasmic reticulum stress. Molecular and Cellular Endocrinology, v. 535, SEP 15 2021. (15/12611-0, 18/00665-6, 18/06363-1)

ZANGEROLAMO, LUCAS; SOARES, GABRIELA MOREIRA; VETTORAZZI, JEAN FRANCIESCO; DO AMARAL, MARIA ESMERIA; CARNEIRO, EVERARDO MAGALHAES; OLALLA-SAAD, SARA TERESINHA; BOSCHERO, ANTONIO CARLOS; BARBOSA-SAMPAIO, HELENA CRISTINA. ARHGAP21 deficiency impairs hepatic lipid metabolism and improves insulin signaling in lean and obese mice. Canadian Journal of Physiology and Pharmacology, v. 97, n. 11, p. 1018-1027, NOV 2019. (12/14993-9, 15/23729-1, 15/12611-0)

MARMENTINI, CARINE; SOARES, GABRIELA M.; BRONCZEK, GABRIELA A.; PIOVAN, SILVANO; MAREZE-COSTA, CECILIA E.; CARNEIRO, EVERARDO M.; BOSCHERO, ANTONIO C.; KURAUTI, MIRIAN A.. Aging Reduces Insulin Clearance in Mice. FRONTIERS IN ENDOCRINOLOGY, v. 12, MAY 12 2021. (15/12611-0, 18/24368-0, 13/07607-8, 17/06475-1)

BRONCZEK, GABRIELA ALVES; SOARES, GABRIELA MOREIRA; MARMENTINI, CARINE; BOSCHERO, ANTONIO CARLOS; COSTA-JUNIOR, JOSE MARIA. Resistance Training Improves Beta Cell Glucose Sensing and Survival in Diabetic Models. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 16, p. 17-pg., 2022-08-01. (13/07607-8, 21/04664-7, 18/15032-9, 15/12611-0, 16/17102-9)

BRONCZEK, GABRIELA ALVES; VETTORAZZI, JEAN FRANCIESCO; SOARES, GABRIELA MOREIRA; KURAUTI, MIRIAN AYUMI; SANTOS, CRISTIANE; BONFIM, MARESSA FERNANDES; CARNEIRO, EVERARDO MAGALHAES; BALBO, SANDRA LUCINEI; BOSCHERO, ANTONIO CARLOS; COSTA JONIOR, JOSE MARIA. The Bile Acid TUDCA Improves Beta-Cell Mass and Reduces Insulin Degradation in Mice With Early-Stage of Type-1 Diabetes. FRONTIERS IN PHYSIOLOGY, v. 10, MAY 15 2019. (17/13410-3, 15/12611-0)

BERTASSO, IALA MILENE; PIETROBON, CARLA BRUNA; RIBEIRO, ROSANE APARECIDA; SOARES, GABRIELA MOREIRA; DE OLIVEIRA, JANAINA CHAVES; PAIVA ALEGRE-MALLER, ANA CLAUDIA; BOSCHERO, ANTONIO CARLOS; FARIA ARAUJO, ALLAN CEZAR; BITTENCOURT GUIMARAES, ANA TEREZA; BONFLEUR, MARIA LUCIA; et al. Pregnancy and lactation after Roux-en-Y gastric bypass worsen nonalcoholic fatty liver disease in obese rats and lead to differential programming of hepatic de novo lipogenesis in offspring. JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE, v. 13, n. 2, p. 11-pg., 2021-05-17. (15/12611-0)

K.R. CANTELLI; G.M. SOARES; R.A. RIBEIRO; S.L. BALBO; C. LUBACZEUSKI; A.C. BOSCHERO; A.C.F. ARAÚJO; M.L. BONFLEUR. Duodenal-jejunal bypass normalizes pancreatic islet proliferation rate and function but not hepatic steatosis in hypothalamic obese rats. Brazilian Journal of Medical and Biological Research, v. 50, n. 5, 2017-03-30. (15/12611-0)

KURAUTI, MIRIAN A.; FERREIRA, SANDRA M.; SOARES, GABRIELA M.; VETTORAZZI, JEAN F.; CARNEIRO, EVERARDO M.; BOSCHERO, ANTONIO C.; COSTA-JUNIOR, JOSE M.. Hyperinsulinemia is associated with increasing insulin secretion but not with decreasing insulin clearance in an age-related metabolic dysfunction mice model. Journal of Cellular Physiology, v. 234, n. 6, p. 9802-9809, JUN 2019. (17/06475-1, 15/12611-0, 14/24719-7)

VETTORAZZI, JEAN FRANCIESCO; KURAUTI, MIRIAN AYUMI; SOARES, GABRIELA MOREIRA; BORCK, PATRICIA CRISTINE; FERREIRA, SANDRA MARA; SOUTO BRANCO, RENATO CHAVES; LIMA MICHELONE, LUCIANA DE SOUZA; BOSCHERO, ANTONIO CARLOS; COSTA JUNIOR, JOSE MARIA; CARNEIRO, EVERARDO MAGALHAES. Bile acid TUDCA improves insulin clearance by increasing the expression of insulin-degrading enzyme in the liver of obese mice. SCIENTIFIC REPORTS, v. 7, NOV 1 2017. (14/01717-9, 15/12611-0, 13/01318-4)

SOARES, GABRIELA MOREIRA; CANTELLI, KATHIA REGINA; BALBO, SANDRA LUCINEI; RIBEIRO, ROSANE APARECIDA; PAIVA ALEGRE-MALLER, ANA CLAUDIA; BARBOSA-SARNPAIO, HELENA CRISTINA; BOSCHERO, ANTONIO CARLOS; FARIA ARAUJO, ALLAN CEZAR; BONFLEUR, MARIA LUCIA. Liver steatosis in hypothalamic obese rats improves after duodeno-jejunal bypass by reduction in de novo lipogenesis pathway. Life Sciences, v. 188, p. 68-75, NOV 1 2017. (15/12611-0)

SOARES, GABRIELA M.; ZANGEROLAMO, LUCAS; AZEVEDO, ELIS G.; COSTA-JUNIOR, JOSE M.; CARNEIRO, EVERARDO M.; SAAD, SARA T.; BOSCHERO, ANTONIO C.; BARBOSA-SAMPAIO, HELENA C.. Whole body ARHGAP21 reduction improves glucose homeostasis in high-fat diet obese mice. Journal of Cellular Physiology, v. 233, n. 9, p. 7112-7119, SEP 2018. (15/12611-0, 12/14993-9)

BORCK, PATRICIA C.; BATISTA, THIAGO M.; VETTORAZZI, JEAN F.; SOARES, GABRIELA M.; LUBACZEUSKI, CAMILA; GUAN, DONGYIN; BOSCHERO, ANTONIO C.; VIEIRA, ELAINE; LAZAR, MITCHELL A.; CARNEIRO, EVERARDO M.. Nighttime light exposure enhances Rev-erb alpha-targeting microRNAs and contributes to hepatic steatosis. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 85, p. 250-258, AUG 2018. (13/26740-0, 14/01717-9, 15/12611-0)

KURAUTI, MIRIAN A.; COSTA-JUNIOR, JOSE M.; FERREIRA, SANDRA M.; SANTOS, GUSTAVO J.; SPONTON, CARLOS H. G.; CARNEIRO, EVERARDO M.; TELLES, GUILHERME D.; CHACON-MIKAHIL, MARA P. T.; CAVAGLIERI, CLAUDIA R.; REZENDE, LUIZ F.; et al. Interleukin-6 increases the expression and activity of insulin-degrading enzyme. SCIENTIFIC REPORTS, v. 7, APR 21 2017. (15/12611-0, 14/24719-7)

ZANGEROLAMO, LUCAS; VETTORAZZI, JEAN F.; ROSA, LUCAS R. O.; CARNEIRO, EVERARDO M.; BARBOSA, HELENA C. L.. The bile acid TUDCA and neurodegenerative disorders: An overview. Life Sciences, v. 272, MAY 1 2021. (13/07607-8, 18/06363-1, 15/23729-1, 18/20213-2, 15/12611-0)

ROSA, LUCAS RODOLFO DE OLIVEIRA; VETTORAZZI, JEAN FRANCIESCO; ZANGEROLAMO, LUCAS; CARNEIRO, EVERARDO MAGALHAES; BARBOSA, HELENA CRISTINA DE LIMA. UDCA receptors and their role on pancreatic beta cell. PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, v. 167, p. 26-31, DEC 2021. (19/23951-7, 12/14993-9, 15/12611-0, 13/07607-8, 18/06363-1)

COSTA-JUNIOR, JOSE MARIA; FERREIRA, SANDRA MARA; KURAUTI, MIRIAN AYUMI; BERNSTEIN, DIANA L.; RUANO, ELENA G.; KAMESWARAN, VASUMATHI; SCHUG, JONATHAN; FREITAS-DIAS, RICARDO; ZOPPI, CLAUDIO C.; BOSCHERO, ANTONIO C.; et al. aternal Exercise Improves the Metabolic Health of Offspring via Epigenetic Modulation of the Germlin. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 1, JAN 2022. (15/12611-0)

ZANGEROLAMO, LUCAS; VETTORAZZI, JEAN F.; SOLON, CARINA; BRONCZEK, GABRIELA A.; ENGEL, DAIANE F.; KURAUTI, MIRIAN A.; SOARES, GABRIELA M.; RODRIGUES, KARINA S.; VELLOSO, LICIO A.; BOSCHERO, ANTONIO C.; et al. The bile acid TUDCA improves glucose metabolism in streptozotocin-induced Alzheimer's disease mice model. Molecular and Cellular Endocrinology, v. 521, FEB 5 2021. (13/07607-8, 15/12611-0, 17/13410-3, 15/23729-1, 18/06363-1, 18/20213-2)

BRONCZEK, G. A.; SOARES, G. M.; CARNEIRO, E. M.; BOSCHERO, A. C.; COSTA-JUNIOR, J. M.. Resistance exercise training protects beta cell from apoptosis in an in vitro model of type 1 diabetes. Diabetologia, v. 64, n. SUPPL 1, p. 1-pg., 2021-09-01. (15/12611-0, 18/15032-9)

DOS SANTOS, CRISTIANE; RAFACHO, ALEX; FERREIRA, SANDRA MARA; VETTORAZZI, JEAN FRANCIESCO; DOS REIS ARAUJO, THIAGO; MATEUS GONCALVES, LUCIANA; RUHRMANN, SABRINA; BACOS, KARL; LING, CHARLOTTE; BOSCHERO, ANTONIO CARLOS; et al. Excess of glucocorticoids during late gestation impairs the recovery of offspring's beta-cell function after a postnatal injury. FASEB JOURNAL, v. 35, n. 8, AUG 2021. (19/10543-8, 16/23140-0, 15/12611-0)

PIETROBON, CARLA BRUNA; BERTASSO, IALA MILENE; RIBEIRO, ROSANE APARECIDA; PAIVA ALEGRE-MALLER, ANA CLAUDIA; LUBACZEUSKI, CAMILA; BOSCHERO, ANTONIO CARLOS; FARIA ARAUJO, ALLAN CEZAR; BALBO, SANDRA LUCINEI; BONFLEUR, MARIA LUCIA. Maternal Roux-en-Y gastric bypass impairs insulin action and endocrine pancreatic function in male F1 offspring. EUROPEAN JOURNAL OF NUTRITION, v. 59, n. 3, p. 1067-1079, APR 2020. (15/12611-0)

GARCIA-AREVALO, MARTA; LORZA-GIL, ESTELA; LEITE, NAYARA; BRUNETTO, SERGIO; BOSCHERO, ANTONIO CARLOS; CARNEIRO, EVERARDO MAGALHAES. The 17-Beta-Estradiol Improves Insulin Sensitivity in a Rapid Estrogen Receptor Alpha-Dependent Manner in an Animal Model of Malnourishment. JOURNAL OF ENDOCRINOLOGY AND METABOLISM, v. 9, n. 5, p. 133-146, OCT 2019. (14/09532-8, 15/12611-0, 14/01717-9)

SOARES, GABRIELA MOREIRA; ZANGEROLAMO, LUCAS; COSTA-JUNIOR, JOSE MARIA; VETTORAZZI, JEAN FRANCIESCO; CARNEIRO, EVERARDO MAGALHAES; SAAD, SARA TERESINHA; BOSCHERO, ANTONIO CARLOS; BARBOSA-SAMPAIO, HELENA CRISTINA. Whole-Body ARHGAP21-Deficiency Improves Energetic Homeostasis in Lean and Obese Mice. FRONTIERS IN ENDOCRINOLOGY, v. 10, MAY 29 2019. (12/14993-9, 15/12611-0)

BORCK, PATRICIA C.; LEITE, NAYARA DE C.; VALCANAIA, ANA C.; RICKLI, SARAH; ALIPIO, JESSICA C. DE L.; MACHADO, MICHAEL; VELLOSA, JOSE C.; MATHIAS, PAULO C. DE F.; BOSCHERO, ANTONIO C.; GRASSIOLLI, SABRINA. Swimming training reduces glucose-amplifying pathway and cholinergic responses in islets from lean- and MSG-obese rats. Clinical and Experimental Pharmacology and Physiology, v. 47, n. 2, NOV 2019. (15/12611-0)

ROSA, LUCAS R. O.; SOARES, GABRIELA M.; SILVEIRA, LEONARDO R.; BOSCHERO, ANTONIO C.; BARBOSA-SAMPAIO, HELENA C. L.. ARHGAP21 as a master regulator of multiple cellular processes. Journal of Cellular Physiology, v. 233, n. 11, p. 8477-8481, NOV 2018. (12/14993-9, 13/07607-8, 15/12611-0)

BRONCZEK, GABRIELA ALVES; SOARES, GABRIELA MOREIRA; DE BARROS, JAQUELINE FERNANDES; VETTORAZZI, JEAN FRANCIESCO; KURAUTI, MIRIAN AYUMI; MARCONATO-JUNIOR, EMILIO; ZANGEROLAMO, LUCAS; MARMENTINI, CARINE; BOSCHERO, ANTONIO CARLOS; COSTA-JUNIOR, JOSE MARIA. Resistance exercise training improves glucose homeostasis by enhancing insulin secretion in C57BL/6 mice. SCIENTIFIC REPORTS, v. 11, n. 1, APR 21 2021. (15/12611-0, 18/15032-9, 16/17102-9)