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Alterations in pancreatic β cell function and Trypanosoma cruzi infection: evidence from human and animal studies

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Abstract

The parasite Trypanosoma cruzi causes a persistent infection, Chagas disease, affecting millions of persons in endemic areas of Latin America. As a result of immigration, this disease has now been diagnosed in non-endemic areas worldwide. Although, the heart and gastrointestinal tract are the most studied, the insulin-secreting β cell of the endocrine pancreas is also a target of infection. In this review, we summarize available clinical and laboratory evidence to determine whether T. cruzi-infection-mediated changes of β cell function is likely to contribute to the development of hyperglycemia and diabetes. Our literature survey indicates that T. cruzi infection of humans and of experimental animals relates to altered secretory behavior of β cells. The mechanistic basis of these observations appears to be a change in stimulus-secretion pathway function rather than the loss of insulin-producing β cells. Whether this attenuated insulin release ultimately contributes to the pathogenesis of diabetes in human Chagas disease, however, remains to be determined. Since the etiologies of diabetes are multifactorial including genetic and lifestyle factors, the use of cell- and animal-based investigations, allowing direct manipulation of these factors, are important tools in testing if reduced insulin secretion has a causal influence on diabetes in the setting of Chagas disease. Long-term clinical investigations will be required to investigate this link in humans.

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References

  • Albuquerque RH, Ribeiro RD, Lopes RA, Lamano Carvalho TL, Paula-Lopes OV (1990) Tissue tropism of different Trypanosoma cruzi strains. IX. Alterations in A and B Langerhans islet cells produced by the slender and broad forms of the Bolivian strain. Mem Inst Oswaldo Cruz. 85:8

  • Bergman M, Chetrit A, Roth J, Jagannathan R, Sevick M, Dankner R (2016) One-hour post-load plasma glucose level during the OGTT predicts dysglycemia: observations from the 24 year follow-up of the Israel Study of Glucose Intolerance, Obesity and Hypertension. Diabetes Res Clin Pract 120:221–228

    Article  CAS  PubMed  Google Scholar 

  • Bern C (2015) Chagas’ Disease. N Engl J Med 373:1882

    Article  PubMed  Google Scholar 

  • Bern C, Kjos S, Yabsley MJ, Montgomery SP (2011) Trypanosoma cruzi and Chagas’ disease in the United States. Clin Microbiol Rev 24:655–681

    Article  PubMed  PubMed Central  Google Scholar 

  • Brasil PE, Castro R, Castro L (2016) Commercial enzyme-linked immunosorbent assay versuspolymerase chain reaction for the diagnosis of chronic Chagas disease: a systematic review and meta-analysis. Mem Inst Oswaldo Cruz 111:1–19

    Article  PubMed  PubMed Central  Google Scholar 

  • Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J, Schermerhorn T, Straub SG, Yajima H, Sharp GW (2002) Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion. Diabetes 51(Suppl 1):S83–S90

    Article  CAS  PubMed  Google Scholar 

  • Brima W, Eden DJ, Mehdi SF, Bravo M, Wiese MM, Stein J, Almonte V, Zhao D, Kurland I, Pessin JE, Zima T, Tanowitz HB, Weiss LM, Roth J, Nagajyothi F (2015) The brighter (and evolutionarily older) face of the metabolic syndrome: evidence from Trypanosoma cruzi infection in CD-1 mice. Diabetes Metab Res Rev 31:346–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cabalen ME, Cabral MF, Sanmarco LM, Andrada MC, Onofrio LI, Ponce NE, Aoki MP, Gea S, Cano RC (2016) Chronic Trypanosoma cruzi infection potentiates adipose tissue macrophage polarization toward an anti-inflammatory M2 phenotype and contributes to diabetes progression in a diet-induced obesity model. Oncotarget 7:13400–13415

    PubMed  PubMed Central  Google Scholar 

  • Calabrese KS, Lagrange PH, da Costa SC (1994) Trypanosoma cruzi: histopathology of endocrine system in immunocompromised mice. Int J Exp Pathol 75:453–462

    CAS  PubMed  PubMed Central  Google Scholar 

  • Conners EE, Vinetz JM, Weeks JR, Brouwer KC (2016) A global systematic review of Chagas disease prevalence among migrants. Acta Trop 156:68–78

    Article  PubMed  Google Scholar 

  • Corbett CE, Scremin LH, Lombardi RA, Gama-Rodrigues JJ, Okumura M (2002) Pancreatic lesions in acute experimental Chagas’ disease. Rev Hosp Clin Fac Med Sao Paulo 57:63–66

    PubMed  Google Scholar 

  • Creutzfeldt W, Ebert R, Nauck M, Stockmann F (1983) Disturbances of the entero-insular axis. Scand J Gastroenterol Suppl 82:111–119

    CAS  PubMed  Google Scholar 

  • Dandona P, Aljada A, Dhindsa S, Garg R (2003) Insulin as an anti-inflammatory and antiatherosclerotic hormone. Clin Cornerstone Suppl 4:S13–S20

    Article  Google Scholar 

  • Dhar A, Castillo L (2011) Insulin resistance in critical illness. Curr Opin Pediatr 23:269–274

    Article  CAS  PubMed  Google Scholar 

  • Dobson L, Sheldon CD, Hattersley AT (2004) Conventional measures underestimate glycaemia in cystic fibrosis patients. Diabet Med 21:691–696

    Article  CAS  PubMed  Google Scholar 

  • Dooley KE, Chaisson RE (2009) Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis 9(12):737–746

    Article  PubMed  PubMed Central  Google Scholar 

  • dos Santos VM, da Cunha SF, Teixeira Vde P, Monteiro JP, dos Santos JA, dos Santos TA, dos Santos LA, da Cunha DF (1999a) Frequency of diabetes mellitus and hyperglycemia in chagasic and non-chagasic women. Rev Soc Bras Med Trop 32:489–496

    Article  PubMed  Google Scholar 

  • dos Santos VM, de Lima MA, Cabrine-Santos M, de Stefani MD, de Araújo PG, Lages-Silva E, Ramírez LE (2004) Functional and histopathological study of the pancreas in hamsters (Mesocricetus auratus) infected and reinfected with Trypanosoma cruzi. Parasitol Res 94:125–133

    PubMed  Google Scholar 

  • dos Santos VM, Teixeira Vde P, da Cunha DF, da Cunha SF, Monteiro JP, dos Santos JA, dos Santos TA, dos Santos LA (1999b) Pancreatic anatomopathologic changes in chronic chagasic women. Preliminary data. Arq Gastroenterol 36:127–132

    PubMed  Google Scholar 

  • Fiorentino TV, Andreozzi F, Mannino GC, Pedace E, Perticone M, Sciacqua A, Perticone F, Sesti G (2016) One-hour post-load hyperglycemia combined with HbA1c identifies pre-diabetic individuals with a higher cardio-metabolic risk burden. Atherosclerosis 253:61–69

    Article  CAS  PubMed  Google Scholar 

  • Fu Z, Gilbert ER, Liu D (2013) Regulation of insulin synthesis and secretion and pancreatic B-cell dysfunction in diabetes. Curr Diabetes Rev 9:25–53

    Article  PubMed  PubMed Central  Google Scholar 

  • Garcia MN, Aguilar D, Gorchakov R, Rossmann SN, Montgomery SP, Rivera H, Woc-Colburn L, Hotez PJ, Murray KO (2015) Evidence of autochthonous Chagas disease in southeastern Texas. Am J Trop Med Hyg 92:325–330

    Article  PubMed  PubMed Central  Google Scholar 

  • Garg N, Gerstner A, Bhatia V, DeFord J, Papaconstantinou J (2004) Gene expression analysis in mitochondria from chagasic mice: alterations in specific metabolic pathways. Biochem J 381(Pt 3):743–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodyear LJ, Kahn BB (1998) Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49:235–261

    Article  CAS  PubMed  Google Scholar 

  • Guariento ME, Olga E, Muscelli A, Gontijo JA (1994) Chronotropic and blood pressure response to oral glucose load in Chagas’ disease. Sao Paulo Med J 112:602–606

    Article  CAS  PubMed  Google Scholar 

  • Guariento ME, Saad MJ, Muscelli EO, Gontijo JA (1993) Heterogenous insulin response to an oral glucose load by patients with the indeterminate clinical form of Chagas’ disease. Braz J Med Biol Res 26:491–495

    CAS  PubMed  Google Scholar 

  • Hameed S, Jaffe A, Verge CF (2011) Cystic fibrosis related diabetes (CFRD)—the end stage of progressive insulin deficiency. Pediatr Pulmonol 46:747–760

    Article  PubMed  Google Scholar 

  • Handwerger S, Roth J, Gorden P, Di Sant’ Agnese P, Carpenter DF, Peter G (1969) Glucose intolerance in cystic fibrosis. N Engl J Med 281:451–461

    Article  CAS  PubMed  Google Scholar 

  • Henquin JC, Nenquin M, Ravier MA, Szollosi A (2009) Shortcomings of current models of glucose-induced insulin secretion. Diabetes Obes Metab 11(Suppl 4):168–179

    Article  CAS  PubMed  Google Scholar 

  • Hutton JC (1986) Calcium-binding proteins and secretion. Cell Calcium 7:339–352

    Article  CAS  PubMed  Google Scholar 

  • Hutton JC, Bailyes EM, Rhodes CJ, Rutherford NG, Arden SD, Guest PC (1990) Biosynthesis and storage of insulin. Biochem Soc Trans 18:122–124

    Article  CAS  PubMed  Google Scholar 

  • Igarashi M, Yamatani K, Fukase N, Daimon M, Ohnuma H, Takahashi H, Manaka H, Tominaga M, Sasaki H (1992) Sepsis inhibits insulin-stimulated glucose transport in isolated rat adipocytes. Diabetes Res Clin Pract 15:213–218

    Article  CAS  PubMed  Google Scholar 

  • Jackson Y, Castillo S, Hammond P, Besson M, Brawand-Bron A, Urzola D, Gaspoz JM, Chappuis F (2012) Metabolic, mental health, behavioural and socioeconomic characteristics of migrants with Chagas disease in a non-endemic country. Trop Med Int Health 17:595–603

    Article  PubMed  Google Scholar 

  • Juhl K, Hutton J (2004) Stimulus-secretion coupling in the pancreatic β-cell. Adv Exp Med Biol 552:66–90

    CAS  PubMed  Google Scholar 

  • Konrad K, Thon A, Fritsch M, Fröhlich-Reiterer E, Lilienthal E, Wudy SA, Holl RW (2013) Comparison of cystic fibrosis-related diabetes with type 1 diabetes based on a German/Austrian pediatric diabetes registry. Diabetes Care 36:879–886

    Article  PubMed  PubMed Central  Google Scholar 

  • Kumar AK, Chandrasekaran V, Kannan T, Murali AL, Lavanya J, Sudha V, Swaminathan S1, Ramachandran G (2016) Anti-tuberculosis drug concentrations in tuberculosis patients with and without diabetes mellitus. Eur J Clin Pharmacol. In Press

  • Lacy PE (1975) Endocrine secretory mechanisms. Am J Pathol 79:170–188

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lenzi HL, Oliveira DN, Lima MT, Gattass CR (1996) Trypanosoma cruzi: paninfectivity of CL strain during murine acute infection. Exp Parasitol 84:16–27

    Article  CAS  PubMed  Google Scholar 

  • Levy J, Herchuelz A, Sener A, Malaisse WJ (1976) The stimulus-secretion coupling of glucose-induced insulin release.XX fasting: a model for altered glucose recognition by the B-cell. Metabolism 25:583–591

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Shah-Simpson S, Okrah K, Belew AT, Choi J, Caradonna KL, Padmanabhan P, Ndegwa DM, Temanni MR, Corrada Bravo H, El-Sayed NM, Burleigh BA (2016) Transcriptome remodeling in Trypanosoma cruzi and human cells during intracellular infection. PLoS Pathog 12(4):e1005511

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE (2005) The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem 280:4617–4626

    Article  CAS  PubMed  Google Scholar 

  • Long RG, Albuquerque RH, Bishop AE, Polak JM, Bloom SR (1980a) The peptidergic system in Chagas’s disease [proceedings]. Trans R Soc Trop Med Hyg 74:273–274

    CAS  PubMed  Google Scholar 

  • Long RG, Albuquerque RH, Prata A, Barnes AJ, Adrian TE, Christofides ND, Bloom SR (1980b) Response of plasma pancreatic and gastrointestinal hormones and growth hormone to oral and intravenous glucose and insulin hypoglycaemia in Chagas’s disease. Gut 21:772–777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maechler P (2002) Mitochondria as the conductor of metabolic signals for insulin exocytosis in pancreatic β-cells. Cell Mol Life Sci 59:1803–1818

    Article  CAS  PubMed  Google Scholar 

  • Maechler P (2013) Mitochondrial function and insulin secretion. Mol Cell Endocrinol 379:12–18

    Article  CAS  PubMed  Google Scholar 

  • Mott Cde B, Guarita DR, Sipahi AM, Bettarello A (1988a) Functional evaluation of the exocrine pancreas in patients with chronic Chagas’ disease. Rev Hosp Clin Fac Med Sao Paulo 43:279–287

    PubMed  Google Scholar 

  • Mott Cde M, Guarita DR, Bettarello A (1988b) The exocrine pancreas and Chagas’ disease. Rev Hosp Clin Fac Med Sao Paulo 43:177–179

    PubMed  Google Scholar 

  • Nagajyothi F, Desruisseaux MS, Weiss LM, Chua S, Albanese C, Machado FS, Esper L, Lisanti MP, Teixeira MM, Scherer PE, Tanowitz HB (2009) Chagas disease, adipose tissue and the metabolic syndrome. Mem Inst Oswaldo Cruz 104(Suppl 1):219–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagajyothi F, Kuliawat R, Kusminski CM, Machado FS, Desruisseaux MS, Zhao D, Schwartz GJ, Huang H, Albanese C, Lisanti MP, Singh R, Li F, Weiss LM, Factor SM, Pessin JE, Scherer PE, Tanowitz HB (2013) Alterations in glucose homeostasis in a murine model of Chagas disease. Am J Pathol 182:886–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nedrebo T, Karlsen TV, Salvesen GS, Reed RK (2004) A novel function of insulin in rat dermis. J Physiol 559(Pt 2):583–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790

    Article  CAS  PubMed  Google Scholar 

  • Novaes RD, Gonçalves RV, Penitente AR, Talvani A, Neves CA, Natali AJ, Maldonado IR (2012) Trypanosoma cruzi infection alters glucose metabolism at rest and during exercise without modifying the morphology of pancreatic islets in rats. Pathol Res Pract 208:480–488

    Article  CAS  PubMed  Google Scholar 

  • Oliveira LC, Juliano Y, Novo NF, Neves MM (1993) Blood glucose and insulin response to intravenous glucose by patients with chronic Chagas’ disease and alcoholism. Braz J Med Biol Res 26:1187–1190

    CAS  PubMed  Google Scholar 

  • Pisania A, Weir GC, O’Neil JJ, Omer A, Tchipashvili V, Lei J, Colton CK, Bonner-Weir S (2010) Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab Invest 90:1661–1675

    Article  PubMed  PubMed Central  Google Scholar 

  • Rocha A, de Oliveira LC, Alves RS, Lopes ER (1998) Pancreatic neuronal loss in chronic Chagas’ disease patients. Rev Soc Bras Med Trop 31:43–49

    Article  CAS  PubMed  Google Scholar 

  • Rosan RC, Shwachman H, Kulczvcki LI (1962) Diabetes mellitus and cystic fibrosis of the pancreas. Laboratory and clinical observations. Am J Dis Child 104:625–634

    Article  CAS  PubMed  Google Scholar 

  • Saldanha JC (1997) Avaliação morfológica e morfométrica das ilhotas pancreáticas na fase crônica da doença de Chagas. Rev Soc Bras Med Trop 30:165–166

    Article  Google Scholar 

  • Saldanha JC, dos Santos VM, dos Reis MA, da Cunha DF, Antunes Teixeira VP (2001) Morphologic and morphometric evaluation of pancreatic islets in chronic Chagas’ disease. Rev Hosp Clin Fac Med Sao Paulo 56:131–138

    CAS  PubMed  Google Scholar 

  • Schebeleski-Soares C, Occhi-Soares RC, Franzói-de-Moraes SM, de Oliveira Dalálio MM, Almeida FN, de Ornelas Toledo MJ, de Araújo SM (2009) Preinfection aerobic treadmill training improves resistance against Trypanosoma cruzi infection in mice. Appl Physiol Nutr Metab 34:659–665

    Article  PubMed  Google Scholar 

  • Shwachman H, Leubner H, Catzel P (1955) Mucoviscidosis. Adv Ped 7:249–323

    CAS  Google Scholar 

  • Siddiqui AN, Khayyam KU, Sharma M (2016) Effect of diabetes mellitus on tuberculosis treatment outcome and adverse reactions in patients receiving directly observed treatment strategy in India: a prospective study. Biomed Res Int 2016:7273935. doi:10.1155/2016/7273935

  • Sosnicki S, Kapral M, Weglarz L (2016) Molecular targets of metformin antitumor action. Pharmacol Rep 68:918–925

    Article  CAS  PubMed  Google Scholar 

  • Steiner DF, James DE (1992) Cellular and molecular biology of the beta cell. Diabetologia 35(Suppl 2):S41–S48

    Article  PubMed  Google Scholar 

  • Steiner DF, Park SY, Stoy J, Philipson LH, Bell GI (2009) A brief perspective on insulin production. Diabetes Obes Met Suppl 4:189–196

    Article  Google Scholar 

  • Tanowitz HB, Amole B, Hewlett D, Wittner M (1988) Trypanosoma cruzi infection in diabetic mice. Trans R Soc Trop Med Hyg 82:90–93

    Article  CAS  PubMed  Google Scholar 

  • Tanowitz HB, Weiss LM, Montgomery SP (2011) Chagas disease has now gone global. PLoS Negl Trop Dis 5(4):e1136

    Article  PubMed  PubMed Central  Google Scholar 

  • Tuomi T, Santoro N, Caprio S, Cai M, Weng J, Groop L (2014) The many faces of diabetes: a disease with increasing heterogeneity. Lancet 383:1084–1094

    Article  PubMed  Google Scholar 

  • van Crevel R, van de Vijver S, Moore DA (2016) The global diabetes epidemic: what does it mean for infectious diseases in tropical countries?. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(16)30081-X

  • van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359–1367

    Article  PubMed  Google Scholar 

  • Vieira CB, Soubihe NV, Ferriolli Filho F (1970) Peculiarities of insulin hypoglycemia in the chronic stage of Chagas’ disease. II. Experimental study in dogs and mice infected with Trypanosoma cruzi. Rev Inst Med Trop Sao Paulo 12:179–184

    CAS  PubMed  Google Scholar 

  • Wang Z, Thurmond DC (2009) Mechanisms of biphasic insulin-granule exocytosis - roles of the cytoskeleton, small GTPases and SNARE proteins. J Cell Sci 122(Pt 7):893–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by NIH Grants R01-DK55758, R01-DK099110, and P01-DK088761 as well as a grant from the Cancer Prevention and Research Institute of Texas (CPRIT RP140412) to P.E.S., NIH Grants R21-AI-124000 to H.B.T.and HL122866 and HL-112099 to J.N. Einstein Research Fellowship, from Office of Medical Student Research Albert Einstein College of Medicine and the Medical Scholars Award from IDSA Education and Research Foundation, were both to Q.D. Figure 1 (c) represents a modified version of a diagram by Jean-Philippe Cartailler (Vanderbilt University/β Cell Biology Consortium) and his permission for its use is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Quinn Dufurrena, Farhad M. Amjad, Louis M. Weiss & Herbert B. Tanowitz

  2. Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Philipp E. Scherer

  3. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    Louis M. Weiss & Herbert B. Tanowitz

  4. Public Health Research Institute Center at the International Center for Public Health (ICPH), Department of Microbiology and Molecular Genetics, Rutgers Medical School Rutgers University, The State University of New Jersey, Newark, NJ, USA

    Jyothi Nagajyothi

  5. The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA

    Jesse Roth

  6. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Quinn Dufurrena & Regina Kuliawat

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  1. Quinn Dufurrena
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Correspondence to Herbert B. Tanowitz or Regina Kuliawat.

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Dufurrena, Q., Amjad, F.M., Scherer, P.E. et al. Alterations in pancreatic β cell function and Trypanosoma cruzi infection: evidence from human and animal studies. Parasitol Res 116, 827–838 (2017). https://doi.org/10.1007/s00436-016-5350-5

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