Endocrine pancreatic insufficiency in chronic pancreatitis

Angelopoulos, Nicholas; Dervenis, Christos; Goula, Anastasia; Rombopoulos, Grigorios; Livadas, Sarantis; Kaltsas, Dimitrios; Kaltzidou, Victoria; Tolis, George

doi:10.1159/000085264

Cited by 44 publications

(21 citation statements)

References 90 publications

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“…Most current estimates propose that only ϳ1% of diabetes cases are caused by pancreatitis (43). However, in several large studies, exocrine insufficiency (significantly lower fecal elastase) was measured in Ͼ50% of type 1 diabetic patients and ϳ35% of type 2 diabetic patients (44 -46).…”

Section: Discussionmentioning

confidence: 99%

Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration

et al. 2008

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OBJECTIVE-Chronic pancreatitis, characterized by pancreatic exocrine tissue destruction with initial maintenance of islets, eventually leads to insulin-dependent diabetes in most patients. Mice deficient for the transcription factors E2F1 and E2F2 suffer from a chronic pancreatitis-like syndrome and become diabetic. Surprisingly, onset of diabetes can be prevented through bone marrow transplantation. The goal of the described studies was to determine the hematopoietic cell type responsible for maintaining islets and the associated mechanism of this protection.RESEARCH DESIGN AND METHODS-Mouse models of acute and chronic pancreatitis, together with mice genetically deficient for macrophage production, were used to determine roles for macrophages in islet angiogenesis and maintenance.RESULTS-We demonstrate that macrophages are essential for preventing endocrine cell loss and diabetes. Macrophages expressing matrix metalloproteinase-9 migrate to the deteriorating pancreas. E2f1/E2f2 mutant mice transplanted with wild-type, but not macrophage-deficient colony stimulating factor 1 receptor mutant (Csf1r Ϫ/Ϫ ), bone marrow exhibit increased angiogenesis and proliferation within islets, coinciding with increased islet mass. A similar macrophage dependency for islet and islet vasculature maintenance is observed during caerulein-induced pancreatitis.CONCLUSIONS-These findings demonstrate that macrophages promote islet angiogenesis and protect against islet loss during exocrine degeneration, could explain why most patients with chronic pancreatitis develop diabetes, and suggest an avenue for preventing pancreatitis-associated diabetes.

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Section: Discussionmentioning

confidence: 99%

Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration

et al. 2008

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“…In pancreatic acini, GLP-1 may regulate enzyme secretion (38). Finally, the downregulation of GLP-1 receptors in islets in chronic pancreatitis suggests that the impaired glucose tolerance in these patients may be due not only to a loss of islets but also to a reduced responsiveness of b-cells to GLP-1 (39). No data are presently available on possible GLP-1 effects in duodenal Brunner's glands or in the breast.…”

Section: Discussionmentioning

confidence: 99%

GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting

Körner

Stöckli²,

Waser³

et al. 2007

Journal of Nuclear Medicine

406

303

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Peptide hormone receptors overexpressed in human tumors, such as somatostatin receptors, can be used for in vivo targeting for diagnostic and therapeutic purposes. A novel promising candidate in this field is the GLP-1 receptor, which was recently shown to be massively overexpressed in gut and lung neuroendocrine tumors-in particular, in insulinomas. Anticipating a major development of GLP-1 receptor targeting in nuclear medicine, our aim was to evaluate in vitro the GLP-1 receptor expression in a large variety of other tumors and to compare it with that in nonneoplastic tissues. Methods: The GLP-1 receptor protein expression was qualitatively and quantitatively investigated in a broad spectrum of human tumors (n 5 419) and nonneoplastic human tissues (n 5 209) with receptor autoradiography using 125 I-GLP-1(7-36)amide. Pharmacologic competition experiments were performed to provide proof of specificity of the procedure. Results: GLP-1 receptors were expressed in various endocrine tumors, with particularly high amounts in pheochromocytomas, as well as in brain tumors and embryonic tumors but not in carcinomas or lymphomas. In nonneoplastic tissues, GLP-1 receptors were present in generally low amounts in specific tissue compartments of several organs-namely, pancreas, intestine, lung, kidney, breast, and brain; no receptors were identified in lymph nodes, spleen, liver, or the adrenal gland. The rank order of potencies for receptor binding-namely, GLP-1(7-36)amide 5 exendin-4 GLP-2 5 glucagon(1-29)-provided proof of specific GLP-1 receptor identification. Conclusion: The GLP-1 receptors may represent a novel molecular target for in vivo scintigraphy and targeted radiotherapy for a variety of GLP-1 receptor-expressing tumors. For GLP-1 receptor scintigraphy, a low-background signal can be expected, on the basis of the low receptor expression in the normal tissues surrounding tumors. G protein-coupled peptide hormone receptors play an increasing role in cancer medicine. This role is based primarily on the peptide receptor overexpression on tumor cells, which allows specific receptor-targeted scintigraphic tumor imaging and tumor therapy with radiolabeled peptide analogs (1). The somatostatin receptors were the first peptide receptors identified for these purposes, and somatostatin receptor targeting has now become an integral part of the routine management of patients with gastroenteropancreatic neuroendocrine tumors. Somatostatin receptor scintigraphy (OctreoScan [ 111 In-pentetreotide]; Mallinckrodt, Inc.) detects these tumors with extremely high sensitivity and specificity (2). Moreover, recent results from clinical studies performing somatostatin receptor radionuclide therapy of these tumors are very promising (3,4).Prompted by the success of somatostatin receptor targeting, we have evaluated the overexpression of other peptide receptor families in tumors in vitro (1), with the aim, eventually, of being able to target in vivo a larger spectrum of tumors or individual tumors more efficiently with multiple pepti...

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“…There is a well-recognised correlation between hyperglycaemia and acute as well as chronic pancreatitis in patients [3,4]. For example, temporary hyperglycaemia can be observed in up to 50% of patients with AP, persistent diabetes may affect 1-15% of patients with AP, and the prevalence of diabetes in chronic pancreatitis varies between 30% and 83%, depending on the study [5,6].…”

Section: Introductionmentioning

confidence: 99%

Diabetes aggravates acute pancreatitis and inhibits pancreas regeneration in mice

et al. 2012

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Aims/hypothesis It is well established that acute pancreatitis often causes diabetes and that a high blood glucose level associated with pancreatitis is a marker of poor prognosis. The aim of this study was to evaluate if diabetes merely reflects the severity of pancreatitis or whether it can also aggravate the progression of this disease in a vicious circle. Methods Reversible acute oedematous pancreatitis was induced in untreated and streptozotocin-treated diabetic mice by injection of cerulein. Progression of pancreatitis was studied by immunohistochemistry, ELISA and various other enzyme assays. The production of regenerating isletderived 3β (REG3β) was determined by western blot and immunohistochemistry. Results While cerulein treatment in non-diabetic mice resulted in acute pancreatitis followed by regeneration of the pancreas within 7 days, diabetes aggravated pancreatitis, inhibited the regeneration of the exocrine tissue and led to strong atrophy of the pancreas. The aggravation of pancreatitis by diabetes was characterised by decreased production of the anti-inflammatory protein REG3β, increased inflammation, augmented oedema formation and increased cell death during the acute phase of pancreatitis (p < 0.05). During the regenerative phase, diabetes augmented inflammation, increased cell death, reduced acinar cell expansion and increased the expansion of duct as well as interstitial cells, resulting in the formation of tubular complexes (p<0.05). Administration of insulin reversed the observed phenotype in diabetic mice. Conclusions/interpretation Diabetes aggravates acute pancreatitis and suppresses regeneration of the exocrine tissue. Thus, diabetes is not just a concomitant phenomenon of pancreatitis, but can have a fundamental influence on the progression of acute pancreatitis.

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Endocrine pancreatic insufficiency in chronic pancreatitis

Cited by 44 publications

References 90 publications

Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration

Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration

GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting

Diabetes aggravates acute pancreatitis and inhibits pancreas regeneration in mice

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