Advertisement

Structure and function of the exocrine pancreas in patients with type 1 diabetes

  • Laure Alexandre-Heymann
  • Roberto Mallone
  • Christian Boitard
  • Raphaël Scharfmann
  • Etienne LargerEmail author
Article

Abstract

In the last 10 years, several studies have shown that the pancreas of patients with type 1 diabetes (T1D), and even of subjects at risk for T1D, was smaller than the pancreas from healthy subjects. This arose the question of the relationships between the endocrine and exocrine parts of the pancreas in T1D pathogenesis. Our review underlines that histological anomalies of the exocrine pancreas are common in patients with T1D: intralobular and interacinar fibrosis, acinar atrophy, fatty infiltration, leucocytic infiltration, and pancreatic arteriosclerosis are all frequent observations. Moreover, 25% to 75% of adult patients with T1D present with pancreatic exocrine dysfunction. Our review summarizes the putative causal factors for these structural and functional anomalies, including: 1/ alterations of insulin, glucagon, somatostatin and pancreatic polypeptide secretion, 2/ global pancreatic inflammation 3/ autoimmunity targeting the exocrine pancreas, 4/ vascular and neural abnormalities, and 5/ the putative involvement of pancreatic stellate cells. These observations have also given rise to new theories on T1D: the primary event of T1D pathogenesis could be non-specific, e.g bacterial or viral or chemical, resulting in global pancreatic inflammation, which in turn could cause beta-cell predominant destruction by the immune system. Finally, this review emphasizes that it is advisable to evaluate pancreatic exocrine function in patients with T1D presenting with gastro-intestinal complaints, as a clinical trial has shown that pancreatic enzymes replacement therapy can reduce the frequency of hypoglycemia and thus might improve quality of life in subjects with T1D and exocrine failure.

Keywords

Pancreatic exocrine dysfunction Type 1 diabetes Fecal elastase Exocrine pancreas 

Notes

Acknowledgements

Images in this manuscript were provided by Network for Pancreatic Organ Donors with Diabetes (nPOD) online pathology site. nPOD is a collaborative type 1 diabetes research project sponsored by JDRF and the Helmsley Charitable Trust. Organ Procurement Organizations partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org//for-partners/npod-partners/.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hoppe-Seyler. Deutsches archiv fuer klinische medizin [Internet]. 1904 [cited 2018 May 31]. Available from: http://archive.org/details/deutschesarchiv68unkngoog. Accessed 31 May 2018.
  2. 2.
    Cecil RL. A study of the pathological anatomy of the pancreas in ninety cases of diabetes mellitus. J Exp Med. 1909;11:266–90.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Opie EL. Pathological changes affecting the islands of Langerhans of the pancreas. J Boston Soc Med Sci. 1900;4:251–60.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Katsarou A, Gudbjörnsdottir S, Rawshani A, Dabelea D, Bonifacio E, Anderson BJ, et al. Type 1 diabetes mellitus. Nat Rev Dis Primers. 2017;3:17016.CrossRefPubMedGoogle Scholar
  5. 5.
    Fonseca V, Berger LA, Beckett AG, Dandona P. Size of pancreas in diabetes mellitus: a study based on ultrasound. Br Med J (Clin Res Ed). 1985;291:1240–1.CrossRefGoogle Scholar
  6. 6.
    Chiarelli F, Verrotti A, Altobelli E, Blasetti A, Morgese G. Size of the pancreas in type I diabetic children and adolescents. Diabetes Care. 1995;18:1505–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Hardt PD, Krauss A, Bretz L, Porsch-Ozcürümez M, Schnell-Kretschmer H, Mäser E, et al. Pancreatic exocrine function in patients with type 1 and type 2 diabetes mellitus. Acta Diabetol. 2000;37:105–10.CrossRefPubMedGoogle Scholar
  8. 8.
    Icks A, Haastert B, Giani G, Rathmann W. Low fecal elastase-1 in type I diabetes mellitus. Z Gastroenterol. 2001;39:823–30.CrossRefPubMedGoogle Scholar
  9. 9.
    Korsgren S, Molin Y, Salmela K, Lundgren T, Melhus A, Korsgren O. On the etiology of type 1 diabetes: a new animal model signifying a decisive role for bacteria eliciting an adverse innate immunity response. Am J Pathol. 2012;181:1735–48.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Skog O, Korsgren S, Melhus A, Korsgren O. Revisiting the notion of type 1 diabetes being a T-cell-mediated autoimmune disease. Curr Opin Endocrinol Diabetes Obes. 2013;20:118–23.CrossRefPubMedGoogle Scholar
  11. 11.
    Campbell-Thompson M, Wasserfall C, Montgomery EL, Atkinson MA, Kaddis JS. Pancreas organ weight in individuals with disease-associated autoantibodies at risk for type 1 diabetes. JAMA. 2012;308:2337–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Rodriguez-Calvo T, Ekwall O, Amirian N, Zapardiel-Gonzalo J, von Herrath MG. Increased immune cell infiltration of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes. Diabetes. 2014;63:3880–90.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Longnecker DS. Anatomy and Histology of the Pancreas. Pancreapedia: The Exocrine Pancreas Knowledge Base [Internet]. 2014 [cited 2018 Aug 21]; Available from: /reviews/anatomy-and-histology-of-pancreas.Google Scholar
  14. 14.
    Maclean N, Ogilvie RF. Observations on the pancreatic islet tissue of young diabetic subjects. Diabetes. 1959;8:83–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Löhr M, Klöppel G. Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy. Diabetologia. 1987;30:757–62.CrossRefPubMedGoogle Scholar
  16. 16.
    Alzaid A, Aideyan O, Nawaz S. The size of the pancreas in diabetes mellitus. Diabet Med. 1993;10:759–63.CrossRefPubMedGoogle Scholar
  17. 17.
    Silva ME, Vezozzo DP, Ursich MJ, Rocha DM, Cerri GG, Wajchenberg BL. Ultrasonographic abnormalities of the pancreas in IDDM and NIDDM patients. Diabetes Care. 1993;16:1296–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Gilbeau JP, Poncelet V, Libon E, Derue G, Heller FR. The density, contour, and thickness of the pancreas in diabetics: CT findings in 57 patients. AJR Am J Roentgenol. 1992;159:527–31.CrossRefPubMedGoogle Scholar
  19. 19.
    Goda K, Sasaki E, Nagata K, Fukai M, Ohsawa N, Hahafusa T. Pancreatic volume in type 1 and type 2 diabetes mellitus. Acta Diabetol. 2001;38:145–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Philippe M-F, Benabadji S, Barbot-Trystram L, Vadrot D, Boitard C, Larger E. Pancreatic volume and endocrine and exocrine functions in patients with diabetes. Pancreas. 2011;40:359–63.CrossRefPubMedGoogle Scholar
  21. 21.
    Virostko J, Hilmes M, Eitel K, Moore DJ, Powers AC. Use of the electronic medical record to assess pancreas size in type 1 diabetes. PLoS One. 2016;11:e0158825.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lu J, Hou X, Pang C, Zhang L, Hu C, Zhao J, et al. Pancreatic volume is reduced in patients with latent autoimmune diabetes in adults. Diabetes Metab Res Rev. 2016;32:858–66.CrossRefPubMedGoogle Scholar
  23. 23.
    Sasamori H, Fukui T, Hayashi T, Yamamoto T, Ohara M, Yamamoto S, et al. Analysis of pancreatic volume in acute-onset, slowly-progressive and fulminant type 1 diabetes in a Japanese population. J Diabetes Investig. 2018.Google Scholar
  24. 24.
    Bilgin M, Balci NC, Momtahen AJ, Bilgin Y, Klör H-U, Rau WS. MRI and MRCP findings of the pancreas in patients with diabetes mellitus: compared analysis with pancreatic exocrine function determined by fecal elastase 1. J Clin Gastroenterol. 2009;43:165–70.CrossRefPubMedGoogle Scholar
  25. 25.
    Gaglia JL, Guimaraes AR, Harisinghani M, Turvey SE, Jackson R, Benoist C, et al. Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients. J Clin Invest. 2011;121:442–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Williams AJK, Thrower SL, Sequeiros IM, Ward A, Bickerton AS, Triay JM, et al. Pancreatic volume is reduced in adult patients with recently diagnosed type 1 diabetes. J Clin Endocrinol Metab. 2012;97:E2109–13.CrossRefPubMedGoogle Scholar
  27. 27.
    d’Annunzio G, Chiara A, Lorini R. Pancreatic gland size reduction and exocrine impairment in type 1 diabetic children. Diabetes Care. 1996;19:777–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Regnell SE, Peterson P, Trinh L, Broberg P, Leander P, Lernmark Å, et al. Pancreas volume and fat fraction in children with type 1 diabetes. Diabet Med. 2016;33:1374–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Saisho Y, Butler AE, Meier JJ, Monchamp T, Allen-Auerbach M, Rizza RA, et al. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes. Clin Anat. 2007;20:933–42.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kou K, Saisho Y, Jinzaki M, Itoh H. Relationship between body mass index and pancreas volume in Japanese people. JOP. 2014;15:626–7.PubMedGoogle Scholar
  31. 31.
    Bonnet-Serrano F, Diedisheim M, Mallone R, Larger E. Decreased α-cell mass and early structural alterations of the exocrine pancreas in patients with type 1 diabetes: an analysis based on the nPOD repository. PLoS One. 2018;13:e0191528.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    DeSouza SV, Singh RG, Yoon HD, Murphy R, Plank LD, Petrov MS. Pancreas volume in health and disease: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2018;12:757–66.CrossRefPubMedGoogle Scholar
  33. 33.
    Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965;14:619–33.CrossRefPubMedGoogle Scholar
  34. 34.
    Geraghty EM, Boone JM, McGahan JP, Jain K. Normal organ volume assessment from abdominal CT. Abdom Imaging. 2004;29:482–90.CrossRefPubMedGoogle Scholar
  35. 35.
    Raeder H, Haldorsen IS, Ersland L, Grüner R, Taxt T, Søvik O, et al. Pancreatic lipomatosis is a structural marker in nondiabetic children with mutations in carboxyl-ester lipase. Diabetes. 2007;56:444–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Van Dalem A, Demeester S, Balti EV, Keymeulen B, Gillard P, Lapauw B, et al. Prediction of impending type 1 diabetes through automated dual-label measurement of proinsulin:C-peptide ratio. PLoS One. 2016;11:e0166702.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Saisho Y. Pancreas volume and fat deposition in diabetes and Normal physiology: consideration of the interplay between endocrine and exocrine pancreas. Rev Diabet Stud. 2016;13:132–47.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hardt PD, Killinger A, Nalop J, Schnell-Kretschmer H, Zekorn T, Klör HU. Chronic pancreatitis and diabetes mellitus. A retrospective analysis of 156 ERCP investigations in patients with insulin-dependent and non-insulin-dependent diabetes mellitus. Pancreatology. 2002;2:30–3.CrossRefPubMedGoogle Scholar
  39. 39.
    Olsen TS. The incidence and clinical relevance of chronic inflammation in the pancreas in autopsy material. Acta Pathol Microbiol Scand A. 1978;86A:361–5.PubMedGoogle Scholar
  40. 40.
    Waguri M, Hanafusa T, Itoh N, Miyagawa J, Imagawa A, Kuwajima M, et al. Histopathologic study of the pancreas shows a characteristic lymphocytic infiltration in Japanese patients with IDDM. Endocr J. 1997;44:23–33.CrossRefPubMedGoogle Scholar
  41. 41.
    Foulis AK, Stewart JA. The pancreas in recent-onset type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue. Diabetologia. 1984;26:456–61.CrossRefPubMedGoogle Scholar
  42. 42.
    Diedisheim M, Mallone R, Boitard C, Larger E. β-Cell mass in nondiabetic autoantibody-positive subjects: an analysis based on the network for pancreatic organ donors database. J Clin Endocrinol Metab. 2016;101:1390–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Kopito LE, Shwachman H. The pancreas in cystic fibrosis: chemical composition and comparative morphology. Pediatr Res. 1976;10:742–9.PubMedGoogle Scholar
  44. 44.
    Mohapatra S, Majumder S, Smyrk TC, Zhang L, Matveyenko A, Kudva YC, et al. Diabetes mellitus is associated with an exocrine Pancreatopathy: conclusions from a review of literature. Pancreas. 2016;45:1104–10.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Majumder S, Zhang L, Philip N, Sah R, Mohapatra S, Zamboni G, et al. 959 exocrine Pancreatopathy (EP) associated with diabetes mellitus (DM) is histologically distinct from chronic pancreatitis (CP): an international multi-reader blinded study. Gastroenterology. 2016;150:S191.CrossRefGoogle Scholar
  46. 46.
    Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med. 2001;161:1989–96.CrossRefPubMedGoogle Scholar
  47. 47.
    Jones CM, Castle WB, Mulholland HB, Bailey F. Pancreatic and hepatic activity in diabetes mellitus: the alterations with some observations on the etiology of the disease. Arch Intern Med (Chic). 1925;35:315–36.CrossRefGoogle Scholar
  48. 48.
    Löser C, Möllgaard A, Fölsch UR. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut. 1996;39:580–6.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Vanga RR, Tansel A, Sidiq S, El-Serag HB, Othman MO. Diagnostic performance of measurement of fecal Elastase-1 in detection of exocrine pancreatic insufficiency: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16:1220–1228.e4.CrossRefPubMedGoogle Scholar
  50. 50.
    Lankisch PG, Schmidt I, König H, Lehnick D, Knollmann R, Löhr M, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mild to moderate exocrine pancreatic insufficiency. Gut. 1998;42:551–4.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Domínguez-Muñoz JE, Hieronymus C, Sauerbruch T, Malfertheiner P. Fecal elastase test: evaluation of a new noninvasive pancreatic function test. Am J Gastroenterol. 1995;90:1834–7.PubMedGoogle Scholar
  52. 52.
    Leeds JS, Oppong K, Sanders DS. The role of fecal elastase-1 in detecting exocrine pancreatic disease. Nat Rev Gastroenterol Hepatol. 2011;8:405–15.CrossRefPubMedGoogle Scholar
  53. 53.
    Conwell DL, Lee LS, Yadav D, Longnecker DS, Miller FH, Mortele KJ, et al. American pancreatic association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43:1143–62.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 2013;19:7258–66.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Agren G, Lagerlög H, Berglund H. The Secretin Test of Pancreatic Function in the Diagnosis of Pancreatic Disease1 - ÅGREN - 1936 - Acta Medica Scandinavica - Wiley Online Library [Internet]. 1936 [cited 2018 Jun 8]. Available from: https://onlinelibrary-wiley-com.gate2.inist.fr/doi/abs/10.1111/j.0954-6820.1936.tb14607.x. Accessed 8 June 2018.
  56. 56.
    Diamond JS, Siegel SA, Kantor JL. The secretin test in the diagnosis of pancreatic diseases with a report of one hundred thirty tests. Am J Dig Dis. 1940;7:435–42.CrossRefGoogle Scholar
  57. 57.
    Pollard HM, Miller L, Brewer WA. The external secretion of the pancreas and diabetes mellitus. Am J Dig Dis. 1943;10:20–3.CrossRefGoogle Scholar
  58. 58.
    Lankisch PG, Manthey G, Otto J, Koop H, Talaulicar M, Willms B, et al. Exocrine pancreatic function in insulin-dependent diabetes mellitus. Digestion. 1982;25:211–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Frier BM, Adrian TE, Saunders JH, Bloom SR. Serum trypsin concentration and pancreatic trypsin secretion in insulin-dependent diabetes mellitus. Clin Chim Acta. 1980;105:297–300.CrossRefPubMedGoogle Scholar
  60. 60.
    Frier BM, Saunders JH, Wormsley KG, Bouchier IA. Exocrine pancreatic function in juvenile-onset diabetes mellitus. Gut. 1976;17:685–91.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Creutzfeldt W, Gleichmann D, Otto J, Stöckmann F, Maisonneuve P, Lankisch PG. Follow-up of exocrine pancreatic function in type-1 diabetes mellitus. Digestion. 2005;72:71–5.CrossRefPubMedGoogle Scholar
  62. 62.
    Frier BM, Faber OK, Binder C, Elliot HL. The effect of residual insulin secretion on exocrine pancreatic function in juvenile-onset diabetes mellitus. Diabetologia. 1978;14:301–4.CrossRefPubMedGoogle Scholar
  63. 63.
    Chey WY, Shay H, Shuman CR. External pancreatic secretion in diabetes mellitus. Ann Intern Med. 1963;59:812–21.CrossRefPubMedGoogle Scholar
  64. 64.
    Dandona P, Freedman DB, Foo Y, Perkins J, Katrak A, Mikhailidis DP, et al. Exocrine pancreatic function in diabetes mellitus. J Clin Pathol. 1984;37:302–6.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Skrha J, Stĕpán J, Pacovský V. Serum lipase, isoamylase and pancreatic function test (PFT) in juvenile-onset insulin-dependent diabetes mellitus. Acta Diabetol Lat. 1983;20:357–61.CrossRefPubMedGoogle Scholar
  66. 66.
    Li X, Campbell-Thompson M, Wasserfall CH, McGrail K, Posgai A, Schultz AR, et al. Serum Trypsinogen Levels in Type 1 Diabetes. Diabetes Care. 2017;40:577–82.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Mohan V, Snehalatha C, Ahmed MR, Madanagopalan N, Chari S, Jayanthi V, et al. Exocrine pancreatic function in tropical fibrocalculous pancreatic diabetes. Diabetes Care. 1989;12:145–7.CrossRefPubMedGoogle Scholar
  68. 68.
    Adrian TE, Barnes AJ, Bloom SR. Hypotrypsinaemia in diabetes mellitus. Clin Chim Acta. 1979;97:213–6.CrossRefPubMedGoogle Scholar
  69. 69.
    Kamarýt J, Stejskal J, Osicková L. Urinary isoamylases in juvenile diabetics. J Clin Chem Clin Biochem. 1978;16:539–41.PubMedGoogle Scholar
  70. 70.
    Keller J, Layer P, Brückel S, Jahr C, Rosien U. 13C-mixed triglyceride breath test for evaluation of pancreatic exocrine function in diabetes mellitus. Pancreas. 2014;43:842–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Hardt PD, Hauenschild A, Nalop J, Marzeion AM, Jaeger C, Teichmann J, et al. High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase 1 concentrations in 1,021 diabetic patients. Pancreatology. 2003;3:395–402.CrossRefPubMedGoogle Scholar
  72. 72.
    Shivaprasad C, Pulikkal AA, Kumar KMP. Pancreatic exocrine insufficiency in type 1 and type 2 diabetics of Indian origin. Pancreatology. 2015;15:616–9.CrossRefPubMedGoogle Scholar
  73. 73.
    Cavalot F, Bonomo K, Perna P, Bacillo E, Salacone P, Gallo M, et al. Pancreatic elastase-1 in stools, a marker of exocrine pancreas function, correlates with both residual beta-cell secretion and metabolic control in type 1 diabetic subjects. Diabetes Care. 2004;27:2052–4.CrossRefPubMedGoogle Scholar
  74. 74.
    Bolado F, Prieto-Martínez C, Ruiz-Clavijo D, Urman J, Casi MA, Vila JJ. 918 low levels of pancreatic Elastase-1 may not reflect exocrine pancreatic insufficiency in type 1 diabetes mellitus. Gastroenterology. 2015;148:S-174.CrossRefGoogle Scholar
  75. 75.
    Larger E, Philippe MF, Barbot-Trystram L, Radu A, Rotariu M, Nobécourt E, et al. Pancreatic exocrine function in patients with diabetes: pancreatic function in patients with diabetes. Diabet Med. 2012;29:1047–54.CrossRefPubMedGoogle Scholar
  76. 76.
    Canaway S, Phillips I, Betts P. Pancreatic exocrine insufficiency and type 1 diabetes mellitus. Br J Nurs. 2000;9:2030–2.CrossRefPubMedGoogle Scholar
  77. 77.
    Laass MW, Henker J, Thamm K, Neumeister V, Kuhlisch E. Exocrine pancreatic insufficiency and its consequences on physical development and metabolism in children and adolescents with type 1 diabetes mellitus. Eur J Pediatr. 2004;163:681–2.PubMedGoogle Scholar
  78. 78.
    Hahn J-U, Kerner W, Maisonneuve P, Lowenfels AB, Lankisch PG. Low fecal elastase 1 levels do not indicate exocrine pancreatic insufficiency in type-1 diabetes mellitus. Pancreas. 2008;36:274–8.CrossRefPubMedGoogle Scholar
  79. 79.
    Rodieux F, Dirlewanger M, Hanquinet S, Tempia-Caliera MG, Schwitzgebel V. P135 - L’insuffisance pancréatique exocrine est rare chez les enfants avec un diabète de type 1. /data/revues/12623636/v37i1sS1/S1262363611707613/ [Internet]. 2011 [cited 2018 Jun 11]; Available from: http://www.em-consulte.com/en/article/291510. Accessed 11 June 2018.
  80. 80.
    Vujasinovic M, Zaletel J, Tepes B, Popic B, Makuc J, Epsek Lenart M, et al. Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus. Pancreatology. 2013;13:343–6.CrossRefPubMedGoogle Scholar
  81. 81.
    Landin-Olsson M, Borgström A, Blom L, Sundkvist G, Lernmark A. Immunoreactive trypsin(ogen) in the sera of children with recent-onset insulin-dependent diabetes and matched controls. The Swedish childhood diabetes group. Pancreas. 1990;5:241–7.CrossRefPubMedGoogle Scholar
  82. 82.
    Sato M, Yamamoto K, Mayama H, Yamashiro Y. Exocrine pancreatic function in diabetic children. J Pediatr Gastroenterol Nutr. 1984;3:415–20.CrossRefPubMedGoogle Scholar
  83. 83.
    Ewald N, Raspe A, Kaufmann C, Bretzel RG, Kloer HU, Hardt PD. Determinants of exocrine pancreatic function as measured by fecal Elastase-1 concentrations (FEC) in patients with diabetes mellitus. Eur J Med Res. 2009;14:118–22.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Domschke W, Tympner F, Domschke S, Demling L. Exocrine pancreatic function in juvenile diabetics. Am J Dig Dis. 1975;20:309–12.CrossRefPubMedGoogle Scholar
  85. 85.
    Vacca JB. The exocrine pancreas in diabetes mellitus. Ann Intern Med. 1964;61:242.CrossRefPubMedGoogle Scholar
  86. 86.
    Kondrashova A, Nurminen N, Lehtonen J, Hyöty M, Toppari J, Ilonen J, et al. Exocrine pancreas function decreases during the progression of the beta-cell damaging process in young prediabetic children. Pediatr Diabetes. 2017.Google Scholar
  87. 87.
    Fraser PA, Henderson JR. The arrangement of endocrine and exocrine pancreatic microcirculation observed in the living rabbit. Exp Physiol. 1980;65:151–8.CrossRefGoogle Scholar
  88. 88.
    Henderson JR, Moss MC. A morphometric study of the endocrine and exocrine capillaries of the pancreas. Q J Exp Physiol. 1985;70:347–56.CrossRefPubMedGoogle Scholar
  89. 89.
    Cohrs CM, Chen C, Jahn SR, Stertmann J, Chmelova H, Weitz J, et al. Vessel network architecture of adult human islets promotes distinct cell-cell interactions in situ and is altered after transplantation. Endocrinology. 2017;158:1373–85.CrossRefPubMedGoogle Scholar
  90. 90.
    Unger RH, Aguilar-Parada E, Müller WA, Eisentraut AM. Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest. 1970;49:837–48.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Walczak M, Mrozikiewicz D, Dmochowski K, Rewers M, Cichy W. Serum pancreatic polypeptide and glucagon immunoreactivity in fasting healthy and diabetic children. Mater Med Pol. 1989;21:38–42.PubMedGoogle Scholar
  92. 92.
    Ertan A, Arimura A, Akdamar K, Shibata T, Groot K, Luciano M, et al. Pancreatic immunoreactive somatostatin and diabetes mellitus. Dig Dis Sci. 1984;29:625–30.CrossRefPubMedGoogle Scholar
  93. 93.
    Hellman B, Wallgren A, Petersson B. Cytological characteristics of the exocrine pancreatic cells with regard to their position in relation to the islets of Langerhans. A study in normal and obese-hyperglycaemic mice. Acta Endocrinol. 1962;39:465–73.CrossRefPubMedGoogle Scholar
  94. 94.
    Henderson JR, Daniel PM, Fraser PA. The pancreas as a single organ: the influence of the endocrine upon the exocrine part of the gland. Gut. 1981;22:158–67.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Wallgren A, Hellman B. Influence of the islet a and B cells on the exocrine pancreatic tissue in the duck. Acta Anat (Basel). 1962;48:137–41.CrossRefGoogle Scholar
  96. 96.
    Kramer MF, Tan HT. The peri-insular acini of the pancreas of the rat. Z Zellforsch Mikrosk Anat. 1968;86:163–70.CrossRefPubMedGoogle Scholar
  97. 97.
    Hegyi P, Takács T, Jármay K, Nagy I, Czakó L, Lonovics J. Spontaneous and cholecystokinin-octapeptide-promoted regeneration of the pancreas following L-arginine-induced pancreatitis in rat. Int J Pancreatol. 1997;22:193–200.PubMedGoogle Scholar
  98. 98.
    Mössner J, Logsdon CD, Williams JA, Goldfine ID. Insulin, via its own receptor, regulates growth and amylase synthesis in pancreatic acinar AR42J cells. Diabetes. 1985;34:891–7.CrossRefPubMedGoogle Scholar
  99. 99.
    Williams JA, Goldfine ID. The insulin-pancreatic acinar axis. Diabetes. 1985;34:980–6.CrossRefPubMedGoogle Scholar
  100. 100.
    Korc M, Owerbach D, Quinto C, Rutter WJ. Pancreatic islet-acinar cell interaction: amylase messenger RNA levels ar determined by insulin. Science. 1981;213:351–3.CrossRefPubMedGoogle Scholar
  101. 101.
    Söling HD, Unger KO. The role of insulin in the regulation of -amylase synthesis in the rat pancreas. Eur J Clin Investig. 1972;2:199–212.CrossRefGoogle Scholar
  102. 102.
    Lee KY, Zhou L, Ren XS, Chang TM, Chey WY. An important role of endogenous insulin on exocrine pancreatic secretion in rats. Am J Phys. 1990;258:G268–74.Google Scholar
  103. 103.
    Otsuki M, Williams JA. Effect of diabetes mellitus on the regulation of enzyme secretion by isolated rat pancreatic acini. J Clin Invest. 1982;70:148–56.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Adler G, Kern HF. Regulation of exocrine pancreatic secretory process by insulin in vivo. Horm Metab Res. 1975;7:290–6.CrossRefPubMedGoogle Scholar
  105. 105.
    Saito A, Williams JA, Kanno T. Potentiation of cholecystokinin-induced exocrine secretion by both exogenous and endogenous insulin in isolated and perfused rat pancreata. J Clin Invest. 1980;65:777–82.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Benabdeljlil A, Palla JC, Desnuelle P. Effect of insulin on pancreatic amylase and chymotrypsinogen. Biochem Biophys Res Commun. 1965;18:71–5.CrossRefPubMedGoogle Scholar
  107. 107.
    Lam WF, Gielkens HA, Coenraad M, Souverijn JH, Lamers CB, Masclee AA. Effect of insulin and glucose on basal and cholecystokinin-stimulated exocrine pancreatic secretion in humans. Pancreas. 1999;18:252–8.CrossRefPubMedGoogle Scholar
  108. 108.
    Patel R, Singh J, Yago MD, Vilchez JR, Martínez-Victoria E, Mañas M. Effect of insulin on exocrine pancreatic secretion in healthy and diabetic anaesthetised rats. Mol Cell Biochem. 2004;261:105–10.CrossRefPubMedGoogle Scholar
  109. 109.
    Couture Y, Dunnigan J, null M. Stimulation of pancreatic amylase secretion and protein synthesis by insulin. Scand J Gastroenterol. 1972;7:257–63.CrossRefPubMedGoogle Scholar
  110. 110.
    Sherr J, Tsalikian E, Fox L, Buckingham B, Weinzimer S, Tamborlane WV, et al. Evolution of abnormal plasma glucagon responses to mixed-meal feedings in youth with type 1 diabetes during the first 2 years after diagnosis. Diabetes Care. 2014;37:1741–4.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Salter JM, Davidson IW, Best CH. The pathologic effects of large amounts of glucagon. Diabetes. 1957;6:248–52; discussion, 252–5.CrossRefPubMedGoogle Scholar
  112. 112.
    Cameron JM, Melrose AG. Changes in liver, pancreatic and stomach morphology following chronic glucagon administration in Guinea-pigs. Br J Exp Pathol. 1962;43:384–6.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Lazarus SS, Volk BW, Lofaro P. The effect of protracted glucagon administration on blood glucose and on pancreatic morphology. Endocrinology. 1958;63:359–71.CrossRefPubMedGoogle Scholar
  114. 114.
    Necheles H. Effects of glucagon on external secretion of the pancreas. Am J Phys. 1957;191:595–7.CrossRefGoogle Scholar
  115. 115.
    Nakajima S, Magee DF. Inhibition of exocrine pancreatic secretion by glucagon and D-glucose given intravenously. Can J Physiol Pharmacol. 1970;48:299–305.CrossRefPubMedGoogle Scholar
  116. 116.
    Dyck WP, Rudick J, Hoexter B, Janowitz HD. Influence of glucagon on pancreatic exocrine secretion. Gastroenterology. 1969;56:531–7.CrossRefPubMedGoogle Scholar
  117. 117.
    Shaw HM, Heath TJ. The effect of glucagon on the formation of pancreatic juice and bile in the rat. Can J Physiol Pharmacol. 1973;51:1–5.CrossRefPubMedGoogle Scholar
  118. 118.
    Liddle RC and RA. Regulation of Pancreatic Secretion. Pancreapedia: The Exocrine Pancreas Knowledge Base [Internet]. 2015 [cited 2018 Aug 22]; Available from: /reviews/regulation-of-pancreatic-secretion.Google Scholar
  119. 119.
    Gyr K, Beglinger C, Köhler E, Trautzl U, Keller U, Bloom SR. Circulating somatostatin. Physiological regulator of pancreatic function? J Clin Invest. 1987;79:1595–600.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Boden G, Sivitz MC, Owen OE, Essa-Koumar N, Landor JH. Somatostatin suppresses secretin and pancreatic exocrine secretion. Science. 1975;190:163–5.CrossRefPubMedGoogle Scholar
  121. 121.
    Heintges T, Lüthen R, Niederau C. Inhibition of exocrine pancreatic secretion by somatostatin and its analogues. Digestion. 1994;55:1–9.CrossRefPubMedGoogle Scholar
  122. 122.
    Adrian TE. Pancreatic polypeptide. J Clin Pathol. 1978;43–50:s1–8.Google Scholar
  123. 123.
    Greenberg GR, Mitznegg P, Bloom SR. Effect of pancreatic polypeptide on DNA-synthesis in the pancreas. Experientia. 1977;33:1332–3.CrossRefPubMedGoogle Scholar
  124. 124.
    Rahier J, Wallon J, Loozen S, Lefevre A, Gepts W, Haot J. The pancreatic polypeptide cells in the human pancreas: the effects of age and diabetes. J Clin Endocrinol Metab. 1983;56:441–4.CrossRefPubMedGoogle Scholar
  125. 125.
    Luce S, Briet C, Bécourt C, Lemonnier F, Boitard C. The targeting of β-cells by T lymphocytes in human type 1 diabetes: clinical perspectives. Diabetes Obes Metab. 2013;15(Suppl 3):89–97.CrossRefPubMedGoogle Scholar
  126. 126.
    Martin S, Kardorf J, Schulte B, Lampeter EF, Gries FA, Melchers I, et al. Autoantibodies to the islet antigen ICA69 occur in IDDM and in rheumatoid arthritis. Diabetologia. 1995;38:351–5.CrossRefPubMedGoogle Scholar
  127. 127.
    Mally MI, Cirulli V, Hayek A, Otonkoski T. ICA69 is expressed equally in the human endocrine and exocrine pancreas. Diabetologia. 1996;39:474–80.CrossRefPubMedGoogle Scholar
  128. 128.
    Wiberg A, Granstam A, Ingvast S, Härkönen T, Knip M, Korsgren O, et al. Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies. Clin Exp Immunol. 2015;182:278–88.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Endo T, Takizawa S, Tanaka S, Takahashi M, Fujii H, Kamisawa T, et al. Amylase alpha-2A autoantibodies: novel marker of autoimmune pancreatitis and fulminant type 1 diabetes. Diabetes. 2009;58:732–7.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Taniguchi T, Okazaki K, Okamoto M, Seko S, Tanaka J, Uchida K, et al. High prevalence of autoantibodies against carbonic anhydrase II and lactoferrin in type 1 diabetes: concept of autoimmune exocrinopathy and endocrinopathy of the pancreas. Pancreas. 2003;27:26–30.CrossRefPubMedGoogle Scholar
  131. 131.
    Hardt PD, Ewald N, Bröckling K, Tanaka S, Endo T, Kloer HU, et al. Distinct autoantibodies against exocrine pancreatic antigens in European patients with type 1 diabetes mellitus and non-alcoholic chronic pancreatitis. JOP. 2008;9:683–9.PubMedGoogle Scholar
  132. 132.
    di Cesare E, Previti M, Lombardo F, Mazzù N, di Benedetto A, Cucinotta D. Prevalence of autoantibodies to carbonic anhydrase II and lactoferrin in patients with type 1 diabetes. Ann N Y Acad Sci. 2004;1037:131–2.CrossRefPubMedGoogle Scholar
  133. 133.
    Kobayashi T, Nakanishi K, Kajio H, Morinaga S, Sugimoto T, Murase T, et al. Pancreatic cytokeratin: an antigen of pancreatic exocrine cell autoantibodies in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1990;33:363–70.CrossRefPubMedGoogle Scholar
  134. 134.
    Panicot L, Mas E, Thivolet C, Lombardo D. Circulating antibodies against an exocrine pancreatic enzyme in type 1 diabetes. Diabetes. 1999;48:2316–23.CrossRefPubMedGoogle Scholar
  135. 135.
    Yamada T, Hiraoka E, Miyazaki T, Sato J, Ban N. Diabetes as first manifestation of autoimmune pancreatitis. Am J Med Sci. 2017;353:498–9.CrossRefPubMedGoogle Scholar
  136. 136.
    Ennazk L, Mghari GE, Ansari NE. Association of newly diagnosed type 1 diabetes and autoimmune pancreatitis. Endocrinol Diabetes Metab Case Rep. 2016;2016.Google Scholar
  137. 137.
    Papaccio G, Chieffi-Baccari G, Mezzogiorno V, Esposito V. Extraislet infiltration in NOD mouse pancreas: observations after immunomodulation. Pancreas. 1993;8:459–64.CrossRefPubMedGoogle Scholar
  138. 138.
    Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TWH, Atkinson MA, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med. 2012;209:51–60.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Culina S, Lalanne AI, Afonso G, Cerosaletti K, Pinto S, Sebastiani G, et al. Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Sci Immunol. 2018;3.Google Scholar
  140. 140.
    Gonzalez-Duque S, Azoury ME, Colli ML, Afonso G, Turatsinze J-V, Nigi L, et al. Conventional and neo-antigenic peptides presented by β cells are targeted by circulating Naïve CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab. 2018.Google Scholar
  141. 141.
    Radenkovic M, Silver C, Arvastsson J, Lynch K, Lernmark Å, Harris RA, et al. Altered regulatory T cell phenotype in latent autoimmune diabetes of the adults (LADA). Clin Exp Immunol. 2016;186:46–56.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Schenkel JM, Masopust D. Tissue-resident memory T cells. Immunity. 2014;41:886–97.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Valle A, Giamporcaro GM, Scavini M, Stabilini A, Grogan P, Bianconi E, et al. Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes. 2013;62:2072–7.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Semakula C, Vandewalle CL, Van Schravendijk CF, Sodoyez JC, Schuit FC, Foriers A, et al. Abnormal circulating pancreatic enzyme activities in more than twenty-five percent of recent-onset insulin-dependent diabetic patients: association of hyperlipasemia with high-titer islet cell antibodies. Belgian diabetes registry. Pancreas. 1996;12:321–33.CrossRefPubMedGoogle Scholar
  145. 145.
    Rowe P, Wasserfall C, Croker B, Campbell-Thompson M, Pugliese A, Atkinson M, et al. Increased complement activation in human type 1 diabetes pancreata. Diabetes Care. 2013;36:3815–7.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Sarkar SA, Lee CE, Victorino F, Nguyen TT, Walters JA, Burrack A, et al. Expression and regulation of chemokines in murine and human type 1 diabetes. Diabetes. 2012;61:436–46.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Zhang Q, Fillmore TL, Schepmoes AA, Clauss TRW, Gritsenko MA, Mueller PW, et al. Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes. J Exp Med. 2013;210:191–203.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Burch TC, Morris MA, Campbell-Thompson M, Pugliese A, Nadler JL, Nyalwidhe JO. Proteomic analysis of disease stratified human pancreas tissue indicates unique signature of type 1 diabetes. PLoS One. 2015;10:e0135663.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Lewis MP, Reber HA, Ashley SW. Pancreatic blood flow and its role in the pathophysiology of pancreatitis. J Surg Res. 1998;75:81–9.CrossRefPubMedGoogle Scholar
  150. 150.
    El-Gohary Y, Tulachan S, Branca M, Sims-Lucas S, Guo P, Prasadan K, et al. Whole-mount imaging demonstrates hypervascularity of the pancreatic ducts and other pancreatic structures. Anat Rec (Hoboken). 2012;295:465–73.CrossRefGoogle Scholar
  151. 151.
    Saladino CFJ. Age changes in the canine pancreas: histomorphological, electron microscopic, and biochemical study. 1971;246.Google Scholar
  152. 152.
    Funk HU. Veränderungen an Pankreaskapillaren bei Diabetikern. Diabetologia. 1966;1:228–32.CrossRefPubMedGoogle Scholar
  153. 153.
    Levy BI, Schiffrin EL, Mourad J-J, Agostini D, Vicaut E, Safar ME, et al. Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus. Circulation. 2008;118:968–76.CrossRefPubMedGoogle Scholar
  154. 154.
    Pollak OJ. Human pancreatic atherosclerosis. Ann N Y Acad Sci. 1968;149:928–39.CrossRefPubMedGoogle Scholar
  155. 155.
    Blumenthal HT, Probstein JG, Berns AW. Interrelationship of diabetes mellitus and pancreatitis. Arch Surg. 1963;87:844–50.CrossRefPubMedGoogle Scholar
  156. 156.
    Berns AW, Owens CT, Blumenthal HT. A histo- and immunopathologic study of the vessels and islets of langerhans of the pancreas in diabetes mellitus. J Gerontol. 1964;19:179–89.CrossRefPubMedGoogle Scholar
  157. 157.
    Reiner L, Jimenez FA, Rodriguez FL. Atherosclerosis in the mesenteric circulation. Observations and correlations with aortic and coronary atherosclerosis. Am Heart J. 1963;66:200–9.CrossRefPubMedGoogle Scholar
  158. 158.
    Clair JRS, Ramirez D, Passman S, Benninger RKP. Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models. Nat Commun. 2018;9:1742.CrossRefGoogle Scholar
  159. 159.
    Kivisaari L. The effect of experimental pancreatitis and diabetes on the microvasculature of the rat pancreas. Scand J Gastroenterol. 1979;14:689–95.CrossRefPubMedGoogle Scholar
  160. 160.
    Canzano JS, Nasif LH, Butterworth EA, Fu DA, Atkinson MA, Campbell-Thompson M. Islet Microvasculature Alterations With Loss of Beta-cells in Patients With Type 1 Diabetes. J Histochem Cytochem. 2018;22155418778546.Google Scholar
  161. 161.
    Sasson A, Rachi E, Sakhneny L, Baer D, Lisnyansky M, Epshtein A, et al. Islet Pericytes are required for β-cell maturity. Diabetes. 2016;65:3008–14.CrossRefPubMedGoogle Scholar
  162. 162.
    Almaça J, Weitz J, Rodriguez-Diaz R, Pereira E, Caicedo A. The Pericyte of the pancreatic islet regulates capillary diameter and local blood flow. Cell Metab. 2018;27:630–644.e4.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Babic T, Browning KN, Kawaguchi Y, Tang X, Travagli RA. Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat. J Physiol Lond. 2012;590:3611–22.CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Love JA, Yi E, Smith TG. Autonomic pathways regulating pancreatic exocrine secretion. Auton Neurosci. 2007;133:19–34.CrossRefPubMedGoogle Scholar
  165. 165.
    Solomon TE, Grossman MI. Effect of atropine and vagotomy on response of transplanted pancreas. Am J Phys. 1979;236:E186–90.Google Scholar
  166. 166.
    Valenzuela JE, Weiner K, Saad C. Cholinergic stimulation of human pancreatic secretion. Dig Dis Sci. 1986;31:615–9.CrossRefPubMedGoogle Scholar
  167. 167.
    Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J, et al. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell. 2006;127:1123–35.CrossRefPubMedGoogle Scholar
  168. 168.
    Lundberg M, Lindqvist A, Wierup N, Krogvold L, Dahl-Jørgensen K, Skog O. The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes. PLoS One. 2017;12:e0179911.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Masamune A, Watanabe T, Kikuta K, Shimosegawa T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol. 2009;7:S48–54.CrossRefPubMedGoogle Scholar
  170. 170.
    Czakó L, Hegyi P, Rakonczay Z, Wittmann T, Otsuki M. Interactions between the endocrine and exocrine pancreas and their clinical relevance. Pancreatology. 2009;9:351–9.CrossRefPubMedGoogle Scholar
  171. 171.
    Nomiyama Y, Tashiro M, Yamaguchi T, Watanabe S, Taguchi M, Asaumi H, et al. High glucose activates rat pancreatic stellate cells through protein kinase C and p38 mitogen-activated protein kinase pathway. Pancreas. 2007;34:364–72.CrossRefPubMedGoogle Scholar
  172. 172.
    Watanabe S, Nagashio Y, Asaumi H, Nomiyama Y, Taguchi M, Tashiro M, et al. Pressure activates rat pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1175–81.CrossRefPubMedGoogle Scholar
  173. 173.
    Zang G, Sandberg M, Carlsson P-O, Welsh N, Jansson L, Barbu A. Activated pancreatic stellate cells can impair pancreatic islet function in mice. Ups J Med Sci. 2015;120:169–80.CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Foulis AK, Farquharson MA, Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987;30:333–43.CrossRefPubMedGoogle Scholar
  175. 175.
    Skog O, Korsgren S, Wiberg A, Danielsson A, Edwin B, Buanes T, et al. Expression of human leukocyte antigen class I in endocrine and exocrine pancreatic tissue at onset of type 1 diabetes. Am J Pathol. 2015;185:129–38.CrossRefPubMedGoogle Scholar
  176. 176.
    Battaglia M, Atkinson MA. The streetlight effect in type 1 diabetes. Diabetes. 2015;64:1081–90.CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Magalhaes I, Pingris K, Poitou C, Bessoles S, Venteclef N, Kiaf B, et al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J Clin Invest. 2015;125:1752–62.CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Kuric E, Krogvold L, Hanssen KF, Dahl-Jørgensen K, Skog O, Korsgren O. No evidence for presence of mucosal-associated invariant T cells in the Insulitic lesions in patients recently diagnosed with type 1 diabetes. Am J Pathol. 2018;188:1744–8.CrossRefPubMedGoogle Scholar
  179. 179.
    Stechova K, Kolouskova S, Sumnik Z, Cinek O, Kverka M, Faresjo MK, et al. Anti-GAD65 reactive peripheral blood mononuclear cells in the pathogenesis of cystic fibrosis related diabetes mellitus. Autoimmunity. 2005;38:319–23.CrossRefPubMedGoogle Scholar
  180. 180.
    Bizzarri C, Giannone G, Benevento D, Montemitro E, Alghisi F, Cappa M, et al. ZnT8 antibodies in patients with cystic fibrosis: an expression of secondary beta-cell damage? J Cyst Fibros. 2013;12:803–5.CrossRefPubMedGoogle Scholar
  181. 181.
    Scuro LA, Bovo P, Sandrini T, Angelini G, Cavallini G, Mirakian R. Autoimmunity and diabetes associated with chronic pancreatitis. Lancet. 1983;1:424.CrossRefPubMedGoogle Scholar
  182. 182.
    Cummings MH, Chong L, Hunter V, Kar PS, Meeking DR, Cranston IC. Gastrointestinal symptoms and pancreatic exocrine insufficiency in type 1 and type 2 diabetes. Practical Diabetes. 2015;32:54–8.CrossRefGoogle Scholar
  183. 183.
    Gotfried J, Priest S, Schey R. Diabetes and the small intestine. Curr Treat Options Gastroenterol. 2017;15:490–507.CrossRefPubMedGoogle Scholar
  184. 184.
    Cavalot F, Bonomo K, Fiora E, Bacillo E, Salacone P, Chirio M, et al. Does pancreatic elastase-1 in stools predict steatorrhea in type 1 diabetes? Diabetes Care. 2006;29:719–21.CrossRefPubMedGoogle Scholar
  185. 185.
    Hardt PD, Hauenschild A, Jaeger C, Teichmann J, Bretzel RG, Kloer HU, et al. High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations: a prospective multicenter study. Dig Dis Sci. 2003;48:1688–92.CrossRefPubMedGoogle Scholar
  186. 186.
    Lindkvist B, Domínguez-Muñoz JE, Luaces-Regueira M, Castiñeiras-Alvariño M, Nieto-Garcia L, Iglesias-Garcia J. Serum nutritional markers for prediction of pancreatic exocrine insufficiency in chronic pancreatitis. Pancreatology. 2012;12:305–10.CrossRefPubMedGoogle Scholar
  187. 187.
    Lindkvist B, Nilsson C, Kvarnström M, Oscarsson J. Importance of pancreatic exocrine dysfunction in patients with type 2 diabetes: a randomized crossover study. Pancreatology. 2018.Google Scholar
  188. 188.
    Alexandre-Heymann L, Lemoine AY, Nakib S, Kapel N, Ledoux S, Larger E. Nutritional markers in patients with diabetes and pancreatic exocrine failure. Acta Diabetol. 2019.Google Scholar
  189. 189.
    Tignor AS, Wu BU, Whitlock TL, Lopez R, Repas K, Banks PA, et al. High prevalence of low-trauma fracture in chronic pancreatitis. Am J Gastroenterol. 2010;105:2680–6.CrossRefPubMedGoogle Scholar
  190. 190.
    Mohan V, Poongothai S, Pitchumoni CS. Oral pancreatic enzyme therapy in the control of diabetes mellitus in tropical calculous pancreatitis. Int J Pancreatol. 1998;24:19–22.PubMedGoogle Scholar
  191. 191.
    Whitcomb DC, Bodhani A, Beckmann K, Sander-Struckmeier S, Liu S, Fuldeore M, et al. Efficacy and safety of Pancrelipase/Pancreatin in patients with exocrine pancreatic insufficiency and a medical history of diabetes mellitus. Pancreas. 2016;45:679–86.CrossRefPubMedGoogle Scholar
  192. 192.
    Knop FK, Vilsbøll T, Larsen S, Højberg PV, Vølund A, Madsbad S, et al. Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. Am J Physiol Endocrinol Metab. 2007;292:E324–30.CrossRefGoogle Scholar
  193. 193.
    Ebert R, Creutzfeldt W. Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution. Diabetologia. 1980;19:198–204.CrossRefPubMedGoogle Scholar
  194. 194.
    Suzuki S, Miura J, Shimizu K, Tokushige K, Uchigata Y, Yamamoto M. Clinicophysiological outcomes after total pancreatectomy. Scand J Gastroenterol. 2016;51:1526–31.CrossRefPubMedGoogle Scholar
  195. 195.
    Ewald N, Bretzel RG, Fantus IG, Hollenhorst M, Kloer HU, Hardt PD, et al. Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-Centre trial. Diabetes Metab Res Rev. 2007;23:386–91.CrossRefPubMedGoogle Scholar
  196. 196.
    Keller J, Aghdassi AA, Lerch MM, Mayerle JV, Layer P. Tests of pancreatic exocrine function - clinical significance in pancreatic and non-pancreatic disorders. Best Pract Res Clin Gastroenterol. 2009;23:425–39.CrossRefPubMedGoogle Scholar
  197. 197.
    Zsóri G, Illés D, Terzin V, Ivány E, Czakó L. Exocrine pancreatic insufficiency in type 1 and type 2 diabetes mellitus: do we need to treat it? A systematic review. Pancreatology. 2018;Google Scholar
  198. 198.
    Struyvenberg MR, Martin CR, Freedman SD. Practical guide to exocrine pancreatic insufficiency - breaking the myths. BMC Med. 2017;15:29.CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Löhr J-M, Oliver MR, Frulloni L. Synopsis of recent guidelines on pancreatic exocrine insufficiency. United European Gastroenterol J. 2013;1:79–83.CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Working Party of the Australasian Pancreatic Club, Smith RC, Smith SF, Wilson J, Pearce C, Wray N, et al. Summary and recommendations from the Australasian guidelines for the management of pancreatic exocrine insufficiency. Pancreatology. 2016;16:164–80.CrossRefGoogle Scholar
  201. 201.
    Piciucchi M, Capurso G, Archibugi L, Delle Fave MM, Capasso M, Delle Fave G. Exocrine pancreatic insufficiency in diabetic patients: prevalence, mechanisms, and treatment. Int J Endocrinol. 2015;2015:595649.CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    O’Keefe SJ, Cariem AK, Levy M. The exacerbation of pancreatic endocrine dysfunction by potent pancreatic exocrine supplements in patients with chronic pancreatitis. J Clin Gastroenterol. 2001;32:319–23.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Service de DiabétologieHôpital CochinParisFrance
  2. 2.Département Hospitalo Universitaire, INSERM U 1016Université Paris DescartesParisFrance

Personalised recommendations