Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Gastroenterology
Published in: Journal of Gastroenterology 2/2013

01-02-2013 | Original Article—Liver, Pancreas, and Biliary Tract

Decreased expression of insulin and increased expression of pancreatic transcription factor PDX-1 in islets in patients with liver cirrhosis: a comparative investigation using human autopsy specimens

Authors: Masahiro Sakata, Akihiko Kawahara, Takumi Kawaguchi, Jun Akiba, Tomoki Taira, Eitaro Taniguchi, Mitsuhiko Abe, Hironori Koga, Masayoshi Kage, Michio Sata

Published in: Journal of Gastroenterology | Issue 2/2013

Login to get access

Abstract

Background

Glucose intolerance in patients with liver cirrhosis (LC), known as hepatogenous diabetes, is thought to be distinct from type 2 diabetes (T2DM) in some aspects. Hyperinsulinemia and/or insulin resistance in liver disease is associated with hepatocarcinogenesis, growth of hepatocellular carcinoma, and poor prognosis. However, the pathophysiological processes in islets that are responsible for hyperinsulinemia in LC are still not precisely known. Therefore, we investigated the histopathological differences in islets of Langerhans cells between LC and T2DM.

Methods

A total of 35 human autopsy pancreatic tissue samples were used in this study (control, n = 18; T2DM, n = 6; LC, n = 11). The expression of insulin, glucagon, somatostatin, pancreatic duodenal homeobox-1 (PDX-1), proliferating cell nuclear antigen (PCNA), and Ki-67 was examined using immunohistochemistry and quantitated by image analysis.

Results

Islet hypertrophy and a significant increase in PCNA-positive cells in islets were observed in the tissues from LC cases. The insulin-positive areas in islets were significantly decreased in LC cases compared with control and T2DM cases (P = 0.001, P = 0.035, respectively), whereas the PDX-1-positive area was significantly increased in LC cases (P = 0.001) compared with the control. Furthermore, disorganization of pancreatic endocrine cells and nucleocytoplasmic translocation of PDX-1 were both seen in the LC subjects.

Conclusions

In LC, islets undergo hypertrophy and exhibit paradoxical expression of insulin and PDX-1. In the subjects autopsied, insulin expression was decreased, whereas expression of the pancreatic transcription factor PDX-1 was increased in LC. These results point to important distinctions between LC and T2DM.
Literature
1.
Chang-Chen KJ, Mullur R, Bernal-Mizrachi E. Beta-cell failure as a complication of diabetes. Rev Endocr Metab Disord. 2008;9:329–43.PubMedCrossRef
2.
Roden M, Petersen KF, Shulman GI. Nuclear magnetic resonance studies of hepatic glucose metabolism in humans. Recent Prog Horm Res. 2001;56:219–37.PubMedCrossRef
3.
Roden M, Bernroider E. Hepatic glucose metabolism in humans—its role in health and disease. Best Pract Res Clin Endocrinol Metab. 2003;17:365–83.PubMedCrossRef
4.
Radziuk J, Pye S. Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis. Diabetes Metab Res Rev. 2001;17:250–72.PubMedCrossRef
5.
Ishida T, Chap Z, Chou J, Lewis R, Hartley C, Entman M, et al. Differential effects of oral, peripheral intravenous, and intraportal glucose on hepatic glucose uptake and insulin and glucagon extraction in conscious dogs. J Clin Invest. 1983;72:590–601.PubMedCrossRef
6.
Tappy L, Minehira K. New data and new concepts on the role of the liver in glucose homeostasis. Curr Opin Clin Nutr Metab Care. 2001;4:273–7.PubMedCrossRef
7.
Cotrozzi G, Casini Raggi V, Relli P, Buzzelli G. Role of the liver in the regulation of glucose metabolism in diabetes and chronic liver disease. Ann Ital Med Int. 1997;12:84–91.PubMed
8.
Nielsen MF, Caumo A, Aagaard NK, Chandramouli V, Schumann WC, Landau BR, et al. Contribution of defects in glucose uptake to carbohydrate intolerance in liver cirrhosis: assessment during physiological glucose and insulin concentrations. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1135–43.PubMedCrossRef
9.
Megyesi C, Samols E, Marks V. Glucose tolerance and diabetes in chronic liver disease. Lancet. 1967;2:1051–6.PubMedCrossRef
10.
Iwasaki Y, Ohkubo A, Kajinuma H, Akanuma Y, Kosaka K. Degradation and secretion of insulin in hepatic cirrhosis. J Clin Endocrinol Metab. 1978;47:774–9.PubMedCrossRef
11.
Johnson DG, Alberti KG, Faber OK, Binder C. Hyperinsulinism of hepatic cirrhosis: diminished degradation or hypersecretion? Lancet. 1977;1:10–3.PubMedCrossRef
12.
Hashimoto N, Ashida H, Kotoura Y, Nishioka A, Nishiwaki M, Utsunomiya J. Analysis of hepatic encephalopathy after distal splenorenal shunt—PTP image and pancreatic hormone kinetics. Hepatogastroenterology. 1993;40:360–4.PubMed
13.
Narita R, Abe S, Kihara Y, Akiyama T, Tabaru A, Otsuki M. Insulin resistance and insulin secretion in chronic hepatitis C virus infection. J Hepatol. 2004;41:132–8.PubMedCrossRef
14.
Greco AV, Mingrone G, Mari A, Capristo E, Manco M, Gasbarrini G. Mechanisms of hyperinsulinaemia in Child’s disease grade B liver cirrhosis investigated in free living conditions. Gut. 2002;51:870–5.PubMedCrossRef
15.
Picardi A, Gentilucci UV, Zardi EM, Caccavo D, Petitti T, Manfrini S, et al. TNF-alpha and growth hormone resistance in patients with chronic liver disease. J Interferon Cytokine Res. 2003;23:229–35.PubMedCrossRef
16.
Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–8.PubMedCrossRef
17.
Persico M, Russo R, Persico E, Svelto M, Spano D, Andolfo I, et al. SOCS3 and IRS-1 gene expression differs between genotype 1 and genotype 2 hepatitis C virus-infected HepG2 cells. Clin Chem Lab Med. 2009;47:1217–25.PubMedCrossRef
18.
Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–508.PubMedCrossRef
19.
Saito K, Inoue S, Saito T, Kiso S, Ito N, Tamura S, et al. Augmentation effect of postprandial hyperinsulinaemia on growth of human hepatocellular carcinoma. Gut. 2002;51:100–4.PubMedCrossRef
20.
Kaji K, Yoshiji H, Kitade M, Ikenaka Y, Noguchi R, Yoshii J, et al. Impact of insulin resistance on the progression of chronic liver diseases. Int J Mol Med. 2008;22:801–8.PubMed
21.
Balkau B, Kahn HS, Courbon D, Eschwege E, Ducimetiere P. Hyperinsulinemia predicts fatal liver cancer but is inversely associated with fatal cancer at some other sites: the Paris Prospective Study. Diabetes Care. 2001;24:843–9.PubMedCrossRef
22.
Miuma S, Ichikawa T, Taura N, Shibata H, Takeshita S, Akiyama M, et al. The level of fasting serum insulin, but not adiponectin, is associated with the prognosis of early stage hepatocellular carcinoma. Oncol Rep. 2009;22:1415–24.PubMedCrossRef
23.
Komura T, Mizukoshi E, Kita Y, Sakurai M, Takata Y, Arai K, et al. Impact of diabetes on recurrence of hepatocellular carcinoma after surgical treatment in patients with viral hepatitis. Am J Gastroenterol. 2007;102:1939–46.PubMedCrossRef
24.
Kawaguchi T, Taniguchi E, Morita Y, Shirachi M, Tateishi I, Nagata E, et al. Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection. Liver Int. 2010;30:479–86.PubMedCrossRef
25.
Donadon V, Balbi M, Ghersetti M, Grazioli S, Perciaccante A, Della Valentina G, et al. Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol. 2009;15:2506–11.PubMedCrossRef
26.
Lebovitz HE. Insulin secretagogues: old and new. Diabetes Rev. 1999;7:139–53.
27.
Stock MJ. An automatic, closed-circuit oxygen consumption apparatus for small animals. J Appl Physiol. 1975;39:849–50.PubMed
28.
Abdel-Halim SM, Guenifi A, Khan A, Larsson O, Berggren PO, Ostenson CG, et al. Impaired coupling of glucose signal to the exocytotic machinery in diabetic GK rats: a defect ameliorated by cAMP. Diabetes. 1996;45:934–40.PubMedCrossRef
29.
Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest. 2004;114:828–36.PubMed
30.
Hui H, Perfetti R. Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. Eur J Endocrinol. 2002;146:129–41.PubMedCrossRef
31.
Saitoh M. Studies on histopathology of pancreas in portal hypertension. Nippon Shokakibyo Gakkai Zasshi. 1984;81:1444–52.PubMed
32.
Nagy I, Hajnal F, Mohacsi G, Nemeth J, Laszik Z, Pap A. Pancreatic trophism in experimental liver cirrhosis. Int J Pancreatol. 1993;14:157–66.PubMed
33.
Takei K, Suda K. Study of mechanisms of pancreatic fibrosis and structural changes in liver cirrhotic patients. Nippon Shokakibyo Gakkai Zasshi. 1997;94:92–100.PubMed
34.
Bishop AE, Polak JM. The anatomy, organization and ultrastructure of the islets of Langerhans. In: Pickup JC, Williams G, editors. Textbook of diabetes. Oxford: Blackwell Science; 2002.
35.
Kawahara A, Hattori S, Akiba J, Nakashima K, Taira T, Watari K, et al. Infiltration of thymidine phosphorylase-positive macrophages is closely associated with tumor angiogenesis and survival in intestinal type gastric cancer. Oncol Rep. 2010;24:405–15.PubMedCrossRef
36.
Lehr HA, Mankoff DA, Corwin D, Santeusanio G, Gown AM. Application of photoshop-based image analysis to quantification of hormone receptor expression in breast cancer. J Histochem Cytochem. 1997;45:1559–65.PubMedCrossRef
37.
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;52:102–10.PubMedCrossRef
38.
Bates HE, Sirek A, Kiraly MA, Yue JT, Riddell MC, Matthews SG, et al. Adaptation to intermittent stress promotes maintenance of beta-cell compensation: comparison with food restriction. Am J Physiol Endocrinol Metab. 2008;295:E947–58.PubMedCrossRef
39.
40.
Lingohr MK, Buettner R, Rhodes CJ. Pancreatic beta-cell growth and survival—a role in obesity-linked type 2 diabetes? Trends Mol Med. 2002;8:375–84.PubMedCrossRef
41.
Xue Y, Liu C, Xu Y, Yuan Q, Xu K, Mao X, et al. Study on pancreatic islet adaptation and gene expression during pregnancy in rats. Endocrine. 2010;37:83–97.PubMedCrossRef
42.
Finegood DT, McArthur MD, Kojwang D, Thomas MJ, Topp BG, Leonard T, et al. Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes. 2001;50:1021–9.PubMedCrossRef
43.
Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6:87–97.PubMed
44.
Bluher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell. 2002;3:25–38.PubMedCrossRef
45.
Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998;2:559–69.PubMedCrossRef
46.
Imai J, Katagiri H, Yamada T, Ishigaki Y, Suzuki T, Kudo H, et al. Regulation of pancreatic beta cell mass by neuronal signals from the liver. Science. 2008;322:1250–4.PubMedCrossRef
47.
48.
Duvillie B, Currie C, Chrones T, Bucchini D, Jami J, Joshi RL, et al. Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to beta-cell hyperplasia in mutant mice lacking insulin. Endocrinology. 2002;143:1530–7.PubMedCrossRef
49.
Brennand K, Huangfu D, Melton D. All beta cells contribute equally to islet growth and maintenance. PLoS Biol. 2007;5:e163.PubMedCrossRef
50.
Guz Y, Montminy MR, Stein R, Leonard J, Gamer LW, Wright CV, et al. Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Development. 1995;121:11–8.PubMed
51.
Kawamori D, Kajimoto Y, Kaneto H, Umayahara Y, Fujitani Y, Miyatsuka T, et al. Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH(2)-terminal kinase. Diabetes. 2003;52:2896–904.PubMedCrossRef
52.
Marco J, Diego J, Villanueva ML, Diaz-Fierros M, Valverde I, Segovia JM. Elevated plasma glucagon levels in cirrhosis of the liver. N Engl J Med. 1973;289:1107–11.PubMedCrossRef
53.
Gragnoli G, Signorini AM, Tanganelli I. Plasma levels of insulin, C-peptide and glucagon in liver cirrhosis. J Endocrinol Invest. 1981;4:1–5.PubMed
54.
Antoniello S, La Rocca S, Cavalcanti E, Auletta M, Salvatore F, Cacciatore L. Insulin and glucagon degradation in liver are not affected by hepatic cirrhosis. Clin Chim Acta. 1989;183:343–50.PubMedCrossRef
55.
Raskin P. Islet-cell abnormalities in non-insulin-dependent diabetes mellitus. Am J Med. 1985;79:2–5.PubMedCrossRef
56.
Iguchi H, Ikeda Y, Okamura M, Tanaka T, Urashima Y, Ohguchi H, et al. SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice. J Biol Chem. 2005;280:37669–80.PubMedCrossRef
57.
Wang H, Zhang W, Cai H, Xu S, Sui W, Jiang Y, et al. Alpha-cell loss from islet impairs its insulin secretion in vitro and in vivo. Islets. 2011;3:58–65.PubMedCrossRef
58.
Schauder P, McIntosh C, Arends J, Arnold R, Frerichs H, Creutzfeldt W. Somatostatin and insulin release from isolated rat pancreatic islets stimulated by glucose. FEBS Lett. 1976;68:225–7.PubMedCrossRef
59.
Patel YC, Weir GC. Increased somatostatin content of islets from streptozotocin-diabetic rats. Clin Endocrinol (Oxf). 1976;5:191–4.CrossRef
60.
Matsushima Y, Makino H, Kanatsuka A, Yamamoto M, Kumagai A. Immunohistochemical changes of somatostatin cells in the pancreatic islets of rats after streptozotocin administration. Endocrinol Jpn. 1978;25:111–5.PubMedCrossRef
Metadata
Title
Decreased expression of insulin and increased expression of pancreatic transcription factor PDX-1 in islets in patients with liver cirrhosis: a comparative investigation using human autopsy specimens
Authors
Masahiro Sakata
Akihiko Kawahara
Takumi Kawaguchi
Jun Akiba
Tomoki Taira
Eitaro Taniguchi
Mitsuhiko Abe
Hironori Koga
Masayoshi Kage
Michio Sata
Publication date
01-02-2013
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 2/2013
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-012-0633-9

Other articles of this Issue 2/2013

Journal of Gastroenterology 2/2013 Go to the issue

Erratum

Erratum to: Evaluation of a new immunochromatographic test for Helicobacter pylori IgG antibodies in elderly symptomatic patients

Original Article—Alimentary Tract

Gastric hypochlorhydria is associated with an exacerbation of dyspeptic symptoms in female patients

Original Article—Alimentary Tract

Hepatocyte growth factor stimulates the migration of gastric epithelial cells by altering the subcellular localization of the tight junction protein ZO-1

Review

Culture systems for hepatitis E virus

Original Article—Liver, Pancreas, and Biliary Tract

Butein inhibits ethanol-induced activation of liver stellate cells through TGF-β, NFκB, p38, and JNK signaling pathways and inhibition of oxidative stress

Original Article—Liver, Pancreas, and Biliary Tract

The efficacy of nocturnal administration of branched-chain amino acid granules to improve quality of life in patients with cirrhosis
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits