Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors
Alexandra E Butler, Martha Campbell-Thompson, Tatyana Gurlo, David W Dawson, Mark Atkinson, Peter C Butler, Alexandra E Butler, Martha Campbell-Thompson, Tatyana Gurlo, David W Dawson, Mark Atkinson, Peter C Butler
Abstract
Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic β-cells versus possible adverse pancreatic proliferative effects. Examination of pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by incretin therapy (n = 8) or other therapy (n = 12) and nondiabetic control subjects (n = 14) reveals an ∼40% increased pancreatic mass in DM treated with incretin therapy, with both increased exocrine cell proliferation (P < 0.0001) and dysplasia (increased pancreatic intraepithelial neoplasia, P < 0.01). Pancreata in DM treated with incretin therapy were notable for α-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. β-Cell mass was reduced by ∼60% in those with DM, yet a sixfold increase was observed in incretin-treated subjects, although DM persisted. Endocrine cells costaining for insulin and glucagon were increased in DM compared with non-DM control subjects (P < 0.05) and markedly further increased by incretin therapy (P < 0.05). In conclusion, incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumors.
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References
- Klöppel G, Löhr M, Habich K, Oberholzer M, Heitz PU. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res 1985;4:110–125
- Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110
- Rahier J, Guiot Y, Goebbels RM, Sempoux C, Henquin JC. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab 2008;10(Suppl. 4):32–42
- Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999;48:2270–2276
- Matveyenko AV, Dry S, Cox HI, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes 2009;58:1604–1615
- Zulewski H, Abraham EJ, Gerlach MJ, et al. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 2001;50:521–533
- Tourrel C, Bailbé D, Meile MJ, Kergoat M, Portha B. Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 2001;50:1562–1570
- Tschen SI, Dhawan S, Gurlo T, Bhushan A. Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice. Diabetes 2009;58:1312–1320
- Tschen SI, Georgia S, Dhawan S, Bhushan A. Skp2 is required for incretin hormone-mediated β-cell proliferation. Mol Endocrinol 2011;25:2134–2143
- Parnaud G, Bosco D, Berney T, et al. Proliferation of sorted human and rat beta cells. Diabetologia 2008;51:91–100
- Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011;141:150–156
- Gier B, Matveyenko AV, Kirakossian D, Dawson D, Dry SM, Butler PC. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes 2012;61:1250–1262
- Campbell-Thompson M, Wasserfall C, Kaddis J, et al. Network for Pancreatic Organ Donors with Diabetes (nPOD): developing a tissue biobank for type 1 diabetes. Diabetes Metab Res Rev 2012;28:608–617
- Campbell-Thompson ML, Heiple T, Montgomery E, Zhang L, Schneider L. Staining protocols for human pancreatic islets. J Vis Exp 2012;(63):e4068.
- Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2004;28:977–987
- Saisho Y, Manesso E, Butler AE, et al. Ongoing beta-cell turnover in adult nonhuman primates is not adaptively increased in streptozotocin-induced diabetes. Diabetes 2011;60:848–856
- Soltani SM, O’Brien TD, Loganathan G, et al. Severely fibrotic pancreases from young patients with chronic pancreatitis: evidence for a ductal origin of islet neogenesis. Acta Diabetol 2011 Jul 20 [E-pub ahead of print]
- Henquin JC, Rahier J. Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia 2011;54:1720–1725
- Yoon KH, Ko SH, Cho JH, et al. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 2003;88:2300–2308
- Stefan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y, Unger RH. Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes 1982;31:694–700
- Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006;91:4612–4619
- Sakaki M, Sano T, Hirokawa M, Takahashi M, Kiyoku H. Immunohistochemical study of endocrine cells in ductal adenocarcinoma of the pancreas. Virchows Arch 2002;441:249–255
- Gelling RW, Du XQ, Dichmann DS, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 2003;100:1438–1443
- Yu R, Dhall D, Nissen NN, Zhou C, Ren SG. Pancreatic neuroendocrine tumors in glucagon receptor-deficient mice. PLoS ONE 2011;6:e23397.
- Zhou C, Dhall D, Nissen NN, Chen CR, Yu R. Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas 2009;38:941–946
- Henopp T, Anlauf M, Schmitt A, et al. Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas. J Clin Endocrinol Metab 2009;94:213–217
- Takeda Y, Fujita Y, Honjo J, et al. Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice. Diabetologia 2012;55:404–412
- Bramswig NC, Everett LJ, Schug J, et al. Epigenomic plasticity enables human pancreatic α to β cell reprogramming. J Clin Invest 2013;123:1275–1284
- Williams-Herman D, Johnson J, Teng R, et al. Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes. Diabetes Obes Metab 2010;12:442–451
- Bunck MC, Cornér A, Eliasson B, et al. Effects of exenatide on measures of β-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 2011;34:2041–2047
- Retnakaran R, Zinman B. Short-term intensified insulin treatment in type 2 diabetes: long-term effects on β-cell function. Diabetes Obes Metab 2012;14(Suppl. 3):161–166
- Xiang AH, Peters RK, Kjos SL, et al. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes 2006;55:517–522
- Meier JJ, Köhler CU, Alkhatib B, et al. Beta-cell development and turnover during prenatal life in humans. Eur J Endocrinol 2010;162:559–568
- Thorel F, Népote V, Avril I, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 2010;464:1149–1154
- Dhawan S, Georgia S, Tschen SI, Fan G, Bhushan A. Pancreatic β cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell 2011;20:419–429
Source: PubMed