Exocrine pancreatic insufficiency in diabetes mellitus: frequency, pathogenesis, diagnosis, treatment
PDF (Русский)

Keywords

pancreas, exocrine and endocrine functions of the pancreas, interrelations of exocrine and endocrine pancreatic insufficiency, treatment, replacement therapy

How to Cite

Gubergrits, N. B., Belyayeva, N. V., Klochkov, O. Y., & Fomenko, P. G. (2019). Exocrine pancreatic insufficiency in diabetes mellitus: frequency, pathogenesis, diagnosis, treatment. Herald of Pancreatic Club, 44(3), 7-22. https://doi.org/10.33149/vkp.2019.03.01

Abstract views: 14
PDF Downloads: 12

Abstract

The article represents a detailed literature review, which analyses normal physiological interrelations of exocrine and endocrine pancreatic parenchyma. Literature data regarding pathogenesis, clinical peculiarities, treatment of pancreatogenic diabetes mellitus (DM) and exocrine pancreatic insufficiency secondary to the DM are highlighted. Fecal elastase‑1 (FE‑1) is found to be a perfect biomarker to reflect the exocrine pancreatic insufficiency in patients with DM type 2. We demonstrate study results which highlighted a strong association of diabetes with low FE‑1 levels and positive correlation FE‑1 with C-peptide levels, lipase, C-reactive protein, body mass index, total 25-(OH)-vitamin D. Results of the studies which reveal the existence of two intra-pancreatic axes of communication are presented: one involved in the regulation of enzyme production by insulin via the insular-acinar axis; another involved in the regulation of insulin release by pancreatic enzymes via the acini-insular axis. The concept of acini-islet-acinar axis is introduced. Exocrine pancreatic insufficiency might be explained as a DM complication. A pathogenetic substantiation of reasonability of Creon indication in DM type 3 and for treatment of exocrine pancreatic insufficiency in patients with DM is presented. Pancreatin therapy can be used safely in patients with DM and exocrine pancreatic dysfunction.

https://doi.org/10.33149/vkp.2019.03.01
PDF (Русский)

References

1. Внешнесекреторная недостаточность поджелудочной железы. Что это такое? Как часто встречается? Как диагностируется и лечится? В вопросах и ответах гастроэнтеролога врачам и пациентам. Ред. В. Г. Передерий, С. М. Ткач, А. С. Ларин, С. В. Скопиченко. Киев: Твиса, 2005. 193 с.
2. Гдаль В., Морозова З., Чичула Ю. Діагностика зовнішньосекреторної недостатності підшлункової залози при хронічному панкреатиті та цукровому діабеті. Ліки України. 2001. № 10. С. 52–54.
3. Едва ли не каждый второй больной диабетом имеет недостаточную секрецию поджелудочной железы: обзор. Под ред. Б. Н. Маньковского. Діабет і життя. 2002. № 3. Репринт. С. 1–4.
4. Каган И. И., Железнов Л. М. Поджелудочная железа: микрохирургическая и компьютерно-томографическая анатомия. Москва: Медицина, 2004. 152 с.
5. Клер Х. У. Хронический панкреатит: современные аспекты патофизиологии и лечения. Материалы V Национальной Школы гастроэнтерологов, гепатологов Украины. Киев, 2003. С. 64–66.
6. Ларин А. С., Ткач С. М., Юзвенко Т. Ю. Диагностика и коррекция экзокринной недостаточности поджелудочной железы у больных сахарным диабетом. Сучасна гастроентерологія. 2006. № 3. С. 42–45.
7. Можейко Л. А. Эндокринно-экзокринные взаимоотношения поджелудочной железы: история вопроса. Журнал ГрГМУ. 2007. № 3. С. 7–11.
8. Передерий В. Г., Ткач С. М., Парунян Л. М. Частота и возможные причины экзокринной недостаточности поджелудочной железы при сахарном диабете. Укр. терапевт. журнал. 2004. № 2. С. 12–16.
9. Bennett P. H. Diabetes in the elderly: diagnosis and epidemiology. Geriatrics. 1984. Vol. 39. P. 37–41.
10. Büchler M. W., Uhl W., Malfertheiner P., Sarr M. G. Diseases of the pancreas. Basel; Freiburg; Paris et al.: Karger, 2004. 212 p.
11. Bytzer P., Talley N. J., Leemon M. Prevalence of the gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch. Intern Med. 2001. Vol. 161. P. 1989–1996.
12. Chey W. Y., Shay H., Shuman C. R. External pancreatic secretion in diabetes mellitus. Ann. Intern. Med. 1963. Vol. 59. P. 812–821.
13. Clinical Pancreatology for practicing gastroenterologists and surgeons. Ed. J. E. Dominguez-Munoz. Magdeburg: A Blackwell Publ. Co, 2005. 535 р.
14. Dyck W. P., Texter E. C. J., Lasater J. M. Influence of glucagons on pancreatic exocrine secretion in man. Gastroenterology. 1970. Vol. 58. P. 532–539.
15. El Newihi H., Dooley C. P., Saad C. Impaired exocrine pancreatic function in diabetes with diarrhea and peripheral neuropathy. Dig. Dis. Sci. 1988. Vol. 33. P. 705–710.
16. Emoto T., Miyata M, Izukura M. Simultaneous observation of endocrine and exocrine functions of the pancreas responding to somatostatin in man. Regul. Pept. 1997. Vol. 68. P. 1–8.
17. Ewald N., Raspe A., Kaufmann C., Bretzel G., Kloer H. U., Hardt P. D. Determinants of exocrine pancreatic function as measured by fecal elastase-1 concentrations (FEC) in patients with diabetes mellitus. Eur J Med Res. 2009. Vol. 14, No 3. P. 118–122
18. Ewald N., Bretzel R., Fantus I., Hollenhorst М., Kloer Н., Hardt Р. 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. Vol. 23. P. 386–391.
19. Ewald N., Hardt P., Andersen D. Pancreatogenic diabetes: peculiarities in diagnosis and treatment. Pancreatology. 2018. Vol. 18, No 4 (Suppl.). P. S39–S40.
20. Ferrer R., Medrano J., Diego M. Effect of exogenous insulin and glucagon on exocrine pancreatic secretion in rats in vivo. Int. J. Pancreatol. 2000. Vol. 28. P. 67–75.
21. Foulis A.K. Histology of the islet in insulin-dependent diabetes mellitus: a positive sequence of events. Textbook of diabetes. Ed. J.C. Pickup, G. Williams. 2nd ed. Oxford, 1997. Vol. 15. P. 24–29.
22. Frier B. M., Saunders J. H. B., Wormsley K. G., Bouchier I. A. D. Exocrine pancreatic function in juvenile-onset diabetes mellitus. Gut. 1976. Vol. 17. P. 685–691.
23. Gepts W. Pathology of the pancreas in juvenile diabetes. Diabetes. 1965. Vol. 14. P. 619–633.
24. Gilbeau J. P., Poncelet V., Libon E. The density, contour, and thickness of the pancreas in diabetics: CT findings in 57 patients. Am. J. Roentgenol. 1992. Vol. 159. P. 527–531.
25. Grandt D., Bein S., Beglinger C. Peptide YY inhibits interdigestive pancreatic enzyme secretion in humans. Pancreas. 1995. Vol. 11. P. 430.
26. Gröger G., Keller J., Bertram C. Pancreatic enzyme responses are altered in patients with insulin dependent diabetes mellitus. Digestion. 1999. Vol. 60. P. 378.
27. Hardt P., Kloer H. Diabetes mellitus and exocrine pancreatic disease. Pancreatic disease: towards the year 2000. Ed. C.D. Johnson, C.W. Imrie. London et al., 1999. P. 33–39.
28. Hardt P. D., Krauss A., Bretz L. Pancreatic exocrine function in patients with type 1 and type 2 diabetes mellitus. Acta Diabetol. 2000. Vol. 37. P. 105–110.
29. Hirota M., Hashimoto M., Hiratsuka M. Alterations of plasma immunoreactive glucagons-like peptide-1 behavior in non-insulin-dependent diabetics. Diabetes. Res. Clin. Pract. 1990. Vol. 9. P. 179–185.
30. Icks A., Haastert B., Giani G., Rathmann W. Low fecal elastase-1 in type 1 diabetes mellitus. Z. Gastroenterol. 2001. Vol. 39. P. 823–830.
31. Kangrga R., Ignjatovic S., Dragasevic М., Jovicic S., Singh N. Pancreatic elastase levels in feces as a marker of exocrine pancreatic function in patients with diabetes mellitus. Laboratory Medicine. 2016. Vol. 47, No 2. P. 140–148.
32. Keller J., Conrads H., Goebell H. Differential responses of human pancreatic and biliary secretion to graded ileal lipid perfusion. Digestion. 1998. Vol. 59. P. 206.
33. Keller J., Conrads H., Holst J. J. The ratios between pancreatic secretory enzymes are modulated by physiologic ileal lipid concentrations. Pancreas. 1998. Vol. 17. P. 442.
34. Keller J., Layer P. Acinar-islet interactions: Pancreatic exocrine insufficiency in diabetes mellitus. Pancreatic disease: basic science and clinical management. London et al., 2004. Vol. 21. P. 267–278.
35. Knop F. K., Vilsboll T., Larsen S. Increased postpran.dial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. Am J Physiol Endocrinol Metab. 2007. Vol. 292. P. E324–E330.
36. Kobayashi T., Nakanishi K., Kajio H. Pancreatic cytoceratin: an antigen of pancreatic exocrine cell autoantibodies in type-1 (insulin-dependent) diabetes mellitus. Diabetologia. 1990. Vol. 33. P. 363–370.
37. Kobayashi T., Nakanishi K., Sugimoto T. Histopathological changes of the pancreas in islet cell antibodies (ICA)-positive subjects before and after the clinical onset of insulin-dependent diabetes mellitus. Diabetes. 1988. Vol. 37. P. 24A.
38. Kondrashova A., Nurminen N., Lehtonen J., Hyoty M., Toppari J., Ilonen J., Veijola R., Knip M., Hyoty H. Exocrine pancreas function decreases during the progression of the beta-cell damaging process in young prediabetic children. Pediatric Diabetes. 2018. Vol. 19, No 3. P. 398–402.
39. Konturek S. J., Tasler J., Obulowicz W. Characteristics of inhibition of pancreatic secretion by glucagons. Digestion. 1974. Vol. 10. P. 138–149.
40. Lankisch P. G., Manthey G., Otto J. Exocrine pancreatic function in insulin-dependent diabetes mellitus. Digestion. 1982. Vol. 25. P. 210–216.
41. Layer P., Van Der O, Holst J. J. Altered postprandial motility in chronic pancreatitis: role of malabsorption. Gastroenterology. 1997. Vol. 112. P. 1624–1634.
42. Layer P., Keller J. Pancreatic enzymes: secretion and luminal nutrient digestin in health and disease. J. Clin. Gastroenterol. 1999. Vol. 28. P. 3–10.
43. Layer P., Ohe M., Groeger G. Luminal availability and digestive efficacy of substituted enzymes in pancreatic insufficiency. Pancreas. 1992. Vol. 7. P. 745.
44. Layer P., Peschel S., Schlesinger T. Human pancreatic secretion and intestinal motility: effects of ileal nutrient perfusion. Am. J. Physiol. 1990. Vol. 258. P. G196–G201.
45. 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.
46. Lohr M., Kloppel G. Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy. Diabetologia. 1987. Vol. 30. P. 757–762.
47. Lozinska L. Decreased insulin secretion and glucose clearance in exocrine pancreas‐insufficient pigs. Exp. Physiol. 2016. Vol. 101. P. 100–112.
48. Mally M., Cirulli V., Hayek A., Otonkosky T. ICA 69 is expressed equally in the human endocrine and exocrine pancreas. Diabetologica. 1996. Vol. 39. P. 474–480.
49. Mandel A. L., Breslin, P. A. High endogenous salivary amylase activity is associated with improved glycemic homeostasis following starch ingestion in adults. J. Nutr. Vol. 142. 2012. P. 853–858.
50. Mohapatra S., Majumder S., Smyrk T. C., Zhang L., Matveyenko A., Kudva Y. C., Chari S. T. Exocrine pancreatopathy: conclusions from a review of literature. Pancreas. 2016. Vol. 45, No 8. P. 1104–1110.
51. Morgenroth K., Kozuschek W. Pancreatitis. Berlin, New York: Walter de Gruyter, 1991. 120 p.
52. Murakami Т. Pancreatic Insulo-acinar portal systems in humans, rats, and some other mammals: scanning electron microscopy of vascular casts. Microscopy research and technique. 1997. Vol. 37. P. 478–488.
53. Nakajima K. Low serum amylase in association with metabolic syndrome and diabetes: a community-based study. Cardiovasc. Diabetol. 2011. Vol. 10. P. 34.
54. Nakanishi K., Kobayashi T., Miyashita H. Exocrine pancreatic ductograms in insulin-dependent diabetes mellitus. Am. J. Gastroenterol. 1994. Vol. 89. P. 762–766.
55. Panicot L., Mas E., Thivolet C. Circulating antibodies against an exocrine pancreatic enzyme in type 1 diabetes. Diabetes. 1999. Vol. 48. P. 2316–2323.
56. Pierzynowski S. G., Gregory P. C., Filip R., Woliński J., Pierzynowska K. G. Glucose homeostasis dependency on acini-islet-acinar (AIA) axis communication: a new possible pathophysiological hypothesis regarding diabetes mellitus. Nutr Diabetes. 2018. Vol. 8, No 1. P. 55.
57. Pierzynowski S. G. Experiments suggesting extra-digestive effects of enteral pancreatic amylase and its peptides on glucose homeostasis in a pig model. Sci. Rep. 2017. Vol. 86. P. 28.
58. Pollard H., Miller L., Brewer W. External secretion of the pancreas and diabetes (study of secretin test). Am. J. Dig. Dis. 1943. Vol. 10. P. 20.
59. Prasanna Kumar H. R., Gowdappa H. B., Hosmani T., Urs T. Exocrine dysfunction correlates with endocrinal impairment of pancreas in Type 2 diabetes mellitus. Indian J Endocr Metab. 2018. Vol. 22. P. 121–125.
60. Rathmann W., Haastert B., Icks A. Low fecal elastase 1 concentration in type 2 diabetes mellitus. Scand. J. Gastroenterol. 2001. Vol. 36. P. 1056–1061.
61. Ross J. J., Wasserfall C., Perry D. J., Mcgrail K. M., Posgai A. L., Brusko T. M., Schatz D., Haller M. J., Atkinson M. A., Ocala F. L., Gainesville F. L. Exocrine pancreatic function as a novel biomarker in pre-T1D. Diabetes. 2018. Vol. 67 (Suppl.). P. A412–A413.
62. Schäfer E., Fekete Á., Gasparics R. A comparatives study of diabetic complications in patients with pancreatic diabetes mellitus and chronic pancreatitis. Pancreatology. 2006. Vol. 6. P. 375
63. Semakula C., Vandewalle C. L., Van Schravendijk C. F. 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. Vol. 12. P. 321–333.
64. Suarez F., Fevitt M. D., Adshead J. Pancreatic supplements reduce symptomatic response of healthy subjects to a high fat meal. Dig. Dis. Sci. 1999. Vol. 44. P. 1317–1321.
65. Talley S. J., Bytzer P., Hammer J. Psychological distress is linked to gastrointestinal symptoms in diabetes mellitus. Am. J. Gastroenterol. 2001. Vol. 96. P. 1033–1038.
66. Talukdar R., Reddy D. N. Pancreatic exocrine insufficiency in type 1 and 2 diabetes: therapeutic implications. J Assoc Physicians India. 2017. Vol. 65, No 9. P. 64–70.
67. The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery. Ed. H. G. Beger, A. L. Warshaw, R. H. Hruban. Oxford: Willey Blackwell. 2018. 1173 p.
68. Tully G. T., Lowenthal J. J. The diabetic coma of acute pancreatitis. Ann. Intern. Med. 1958. Vol. 48. P. 310.
69. Van der O., Layer P., Wollny C. Somatostatin 28 and coupling of human interdigestive intestinal motility and pancreatic secretion. Gastroenterology. 1992. Vol. 103. P. 974–982.
70. Waguri M., Hanafusa T., Itoh N., Miyagawa J., Imagawa A., Kuwajima M., Kono N., Matsuzawa Y. Histopathologic study of the pancreas shows a characteristic lymphocytic infiltration in Japanese patients with IDDM. Endocr J. 1997. Vol. 44, No 1. P. 23–33.
71. Whitcomb D. C., Bodhani A., Beckmann K. Effcacy and safety of pancrealipase/pancreatin in patients with exocrine pancreatic insufficiency and a medical history of diabetes mellitus. Pancreas. 2016. Vol. 45. P. 676–686.
72. 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.