Abstract
Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by irreversible destruction of pancreatic secretory parenchyma, fibrosis, exocrine atrophy, and endocrine insufficiency leading to diabetes. Secondary diabetes occurring in CP subsequent to destruction of pancreatic β-cells is distinct, since it involves β-cell dysfunction amidst an inflammatory milieu. Even though considerable knowledge is available on the pathophysiology and clinical management of CP, relatively much less is known about the molecular events leading to β-cell dysfunction. Investigators have demonstrated that altered morphology, reduced β-cell mass, and β-cell numbers result in endocrine insufficiency. However, recent reports and our observations suggest that β-cell dysfunction develops in the early stages of CP while clinical diabetes manifests later, when there is profound fibrosis. In the early stages, altered internal milieu and physiology arising due to inflammation and release of cytokines might lead to deranged signaling pathways and islet dysfunction. Subsequently, development of fibrosis causes islet destruction. This suggests that endocrine deficiency in CP is multifactorial. Although the role of transcription factors (Pdx-1, MafA, NeuroD) on β-cell functions is understood, alterations in internal milieu of pancreatic tissue that affects β-cell functions in CP has not been elucidated. In this review, we summarize the factors that have an effect on islet functions. Understanding molecular events of β-cell dysfunction in CP can lead to the development of targeted preventive and therapeutic modalities.
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References
Garg PK, Tandon RK. Survey on CP in the Asia–Pacific region. J Gastroenterol Hepatol. 2004;19:998–1004.
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1998;21:5–19.
Lankisch PG. Natural course of CP. Pancreatology. 2001;1:3–14.
Mitchell RMS, Byrne MF, Baillie J. Pancreatitis. Lancet. 2003;361:1447–1455.
Blondet J, Carlson A, Kobayashi T, et al. The role of total pancreatectomy and islet autotransplantation for CP. Surg Clin N Am. 2007;87:1477–1501.
Kobayashi T, Manivel JC, Bellin MD, et al. Correlation of pancreatic histopathologic findings and islet yield in children with CP undergoing total pancreatectomy and islet autotransplantation. Pancreas. 2010;39:57–63.
Kobayashi T, Manivel JC, Carlson AM, et al. Correlation of histopathology, islet Yield, and islet graft function after islet autotransplantation in CP. Pancreas. 2011;40:193–199.
Bellin MD, Sutherland DE. Pediatric islet autotransplantation: indication, technique, and outcome. Curr Diab Rep. 2010;10:326–331.
Crawford JM, Cotran RS. The pancreas. In: Cotran et al., eds. Robbins Pathologic basis of Disease. 6th ed. Philadelphia: W.B. Saunders company; 1999:902–929.
Pipeleers D. The biosociology of pancreatic β-cells. Diabetologia. 1987;30:277–291.
Pipeleers D, Van De Winkel M. Cellular endogenous fluorescence: a basis for preparing subpopulations of functionally homogenous cells. In: Kohen E, ed. Cell Structure and Function by Microspectrofluorometry. USA: Academic Press; 1989:391–404.
Kiekens R, In’t Veld R, Mahler T, Schuit F, Van De Winkel M, Pipeleers D. Differences in glucose recognition by individual rat pancreatic B cells are associated with intercellular differences in glucose-induced biosynthetic activity. J Clin Invest. 1992;89:117–125.
Stubbs M, Aiston S, Agius L. Subcellular localization, mobility, and kinetic activity of glucokinase in glucose-responsive insulin-secreting cells. Diabetes. 2000;49:2048–2055.
Poitout V, Rouault C, Guerre-Millo M, Briaud I, Reach G. Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans. Endocrinology. 1998;139:822–826.
Szecówka J, Sandberg E, Efendić S. The interaction of Vasoactive Intestinal Polypeptide (VIP), glucose and arginine on the secretion of insulin, glucagon and somatostatin in the perfused rat pancreas. Diabetologia. 1980;19:137–142.
Adrych K, Smoczynski M, Goyke E, Stelmanska E, Swierczynski J. Decreased serum leptin concentration in patients with CP. Pancreas. 2007;34:417–422.
Domschke S, Bloom SR, Adrian TE, Lux G, Domschke W. Chronic pancreatitis and diabetes mellitus: plasma and gastroduodenal mucosal profiles of regulatory peptides (gastrin, motilin, secretin, cholecystokinin, gastric inhibitory polypeptide, somatostatin, VIP, substance P, pancreatic polypeptide, glucagon, enteroglucagon, neurotensin). Hepatogastroenterology. 1988;35:229–237.
Miyahara T, Kawabuchi M, Goto M, et al. Morphological study of pancreatic endocrine in an experimental CP with diabetes induced by stress and cerulein. Ultrastruct Pathol. 1999;23:171–180.
Schrader H, Menge BA, Scneider S, et al. Reduced pancreatic volume and β- cell area in patients with CP. Gastroenterology. 2009;136:513–522.
Sasikala M, Pondugula PK, Guduru VR, et al. Reduced expression of Pdx-1 is associated with decreased beta cell function in CP. Pancreas. 2010;39:856–862.
Nyboe Andersen B, Krarup T, Thorsgaard Pedersen N, et al. B cell function in patients with CP and its relation to exocrine pancreatic function. Diabetolgia. 1982;23:86–89.
Knop FK, Vilsboll T, Hojberg PV, et al. Reduced incretin effect in type 2 diabetes; cause or consequence of the diabetic state? Diabetes. 2007;56:1951–1959.
Larsen S, Hilsted J, Tronier B, et al. Pancreatic hormone secretion in CP without residual beta cell function. Acta Endocrinol (Copenh). 1988;118:357–364.
Linde J, Nilsson LHS, Barany FR. Diabetes and hypoglycemia in CP. Scand J Gastroenterol. 1977;12:369–373.
Kannan V, Nabarro JDN, Cotton PB. Glucagon secretion in CP. Horm Res. 1979;11:203–212.
Al-Eryani S, Duris I, Payer J, et al. Plasma cholecystokinin and somatostatin levels in CP patients. Hepatogastroenterology. 2000;47:869–874.
Mahurkar S, Bhaskar S, Reddy DN, et al. Comprehensive screening for reg1alpha gene rules out association with tropical calcific pancreatitis. World J Gastroenterol. 2007;13:5938–5943.
Reddy DN, Prasad SS. Genetic basis of CP in Asia Pacific region. J Gastroenterol Hepatol. 2011;26:2–5.
Hawrami K, Mohan V, Bone A, Hitman GA. Analysis of islet regenerating (reg) gene polymorphisms in fibrocalculous pancreatic diabetes. Pancreas. 1997;14:122–125.
Mahurkar S, Bhaskar S, Reddy DN, et al. TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes. BMC Med Genet. 2008;9:80.
Chen R, Brentnall TA, Pan S, et al. Quantitative proteomics analysis reveals that proteins differentially expressed in CP are also frequently involved in pancreatic cancer. Mol Cell Proteomics. 2007;6:1331–1342.
Walker MD. Role of miRNA in pancreatic β Cells. Diabetes. 2008;57:2567.
Joglekar MV, Parekh VS, Hardikar AA. New pancreas from old: microregulators of pancreas regeneration. Trends Endocrinol Metab. 2007;18:393–400.
Poy MN, Eliasson L, Krutzfeldt J, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432:226–230.
Joglekar MV, Joglekar VM, Hardikar AA. Expression of islet-specific microRNAs during human pancreatic development. Gene Exp Patterns. 2009;9:109–113.
Modak MA, Parab PB, Ghaskadbi SS. Control of hyperglycemia significantly improves oxidative stress profile of pancreatic islets. Islets. 2011;3. Epub. 09/01/2011.
Mews P, Phillips P, Fahmy R, et al. Pancreatic stellate cells respond to inflammatory cytokines: potential role in CP. Gut. 2002;50:535–541.
Andersson AK, Flodström M, Sandler S. Cytokine induced inhibition of insulin release from mouse pancreatic β-cells deficient in inducible nitric oxide synthase. Biochem Biophys Res Commun. 2001;28:396–403.
Pavan kumar P, Sasikala M, Radhika G, Tandan M, Rao GV, Nageshwar Reddy D. Interferon gamma is a potent inhibitor of expression and nuclear translocation of homeodomain transcription factor Pdx-1 causing reduced β cell area in CP. Abstract presented at annual meeting of the Indian Society of Gastroenterology, 2010.
Hasel C, Durr S, Rau B, et al. In CP, widespread emergence of TRAIL receptors in epitheliacoincides with neoexpression of TRAIL by pancreatic stellate cells of early fibrotic areas. Lab Invest. 2003;83:825–836.
Donath MY, Storling J, Berchtold LA, et al. Cytokines and β-cell biology: from concept to clinical translation. Endocr Rev. 2008;29:334–350.
Corbett JA, Sweetland MA, Wang JL, et al. Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc Natl Acad Sci U S A. 1993;90:1731–1735.
Eizirik D, Mandrup-Poulsen T. A choice of death-the signal transduction of immune-mediated β-cell apoptosis. Diabetologia. 2001;44:2115–2133.
Maedler K, Schumann DM, Sauter N, et al. Low concentrations of interleukin-1β induces FLICE-inhibitory protein-mediated β-cell proliferation in human pancreatic islets. Diabetes. 2006;55:2713–2722.
Butler AE, Janson J, Bonner-Weir S, et al. β cell deficit and increased β cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–110.
Korc M, Friess H, Yamanaka Y, et al. CP is associated with increased concentrations of epidermal growth factor receptor, transforming growth factor α and phospholipase C γ. Gut. 1994;35:1468–1473.
Soga Y, Konori H, Miyazaki T, et al. Toll-like receptor 3 signaling induces CP through the Fas/Fas ligand mediated cytotoxicity. Tohoku J Exptl Med. 2009;217:175–184.
Maedler K, Fontana A, Ris F, et al. FLIP switches Fas-mediated glucose signaling in human pancreatic β cells from apoptosis to cell replication. Proc Natl Acad Sci USA. 2002;99:8236–8241.
Jasmin J-F, Mercier I, Sotgia F, et al. SOCS proteins and caveolin-1 as negative regulators of endocrine signaling. Trends Endocrinol Metab. 2006;17:150–158.
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This work was supported by grants from the Indian Council of Medical Research (ICMR 5/4/3-10/09-NCD-II) to MS. The authors acknowledge P Balkumar Reddy for technical assistance.
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Sasikala, M., Talukdar, R., Pavan kumar, P. et al. β-Cell Dysfunction in Chronic Pancreatitis. Dig Dis Sci 57, 1764–1772 (2012). https://doi.org/10.1007/s10620-012-2086-7
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DOI: https://doi.org/10.1007/s10620-012-2086-7