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
Diabetologia
Published in: Diabetologia 12/2007

01-12-2007 | Article

The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients

Authors: P. Marchetti, M. Bugliani, R. Lupi, L. Marselli, M. Masini, U. Boggi, F. Filipponi, G. C. Weir, D. L. Eizirik, M. Cnop

Published in: Diabetologia | Issue 12/2007

Login to get access

Abstract

Aims/hypothesis

Pancreatic beta cells have highly developed endoplasmic reticulum (ER) due to their role in insulin secretion. Since ER stress has been associated with beta cell dysfunction, we studied several features of beta cell ER in human type 2 diabetes.

Methods

Pancreatic samples and/or isolated islets from non-diabetic controls (ND) and type 2 diabetes patients were evaluated for insulin secretion, apoptosis (electron microscopy and ELISA), morphometric ER assessment (electron microscopy), and expression of ER stress markers in beta cell prepared by laser capture microdissection and in isolated islets.

Results

Insulin release was lower and beta cell apoptosis higher in type 2 diabetes than ND islets. ER density volume was significantly increased in type 2 diabetes beta cells. Expression of alpha-mannosidase (also known as mannosidase, alpha, class 1A, member 1) and UDP-glucose glycoprotein glucosyl transferase like 2 (UGCGL2), assessed by microarray and/or real-time reverse transcriptase polymerase chain reaction (RT-PCR), differed between ND and type 2 diabetes beta cells. Expression of immunoglobulin heavy chain binding protein (BiP, also known as heat shock 70 kDa protein 5 [glucose-regulated protein, 78 kDa] [HSPA5]), X-box binding protein 1 (XBP-1, also known as XBP1) and C/EBP homologous protein (CHOP, also known as damage-inducible transcript 3 [DDIT3]) was not higher in type 2 diabetes beta cell or isolated islets cultured at 5.5 mmol/l glucose (microarray and real-time RT-PCR) than in ND samples. When islets were cultured for 24 h at 11.1 mmol/l glucose, there was induction of BiP and XBP-1 in type 2 diabetes islets but not in ND islets.

Conclusions/interpretation

Beta cell in type 2 diabetes showed modest signs of ER stress when studied in pancreatic samples or isolated islets maintained at physiological glucose concentration. However, exposure to increased glucose levels induced ER stress markers in type 2 diabetes islet cells, which therefore may be more susceptible to ER stress induced by metabolic perturbations.
Literature
1.
American Diabetes Association (2007) Diagnosis and classification of diabetes mellitus. Diabetes Care 30:S42–S47CrossRef
2.
Hossain P, Kawar B, El Nahas M (2007) Obesity and diabetes in the developing world—a growing challenge. N Engl J Med 356:213–215PubMedCrossRef
3.
Yach D, Stuckler D, Brownell KD (2006) Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nat Med 12:62–66PubMedCrossRef
4.
Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846PubMedCrossRef
5.
Ferrannini E, Mari A (2004) Beta cell function and its relation to insulin action in humans: a critical appraisal. Diabetologia 47:943–956PubMedCrossRef
6.
Prentki M, Nolan CJ (2006) Islet beta cell failure in type 2 diabetes. J Clin Invest 116:1802–1812PubMedCrossRef
7.
Weir GC, Bonner-Weir S (2004) Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 53(Suppl 3):S16–S21PubMedCrossRef
8.
Donath MY, Halban PA (2004) Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia 47:581–589PubMedCrossRef
9.
10.
Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107PubMedCrossRef
11.
Cnop M, Ladriere L, Hekerman P et al (2007) Selective inhibition of eukaryotic translation initiation factor 2α dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic β-cell dysfunction and apoptosis. J Biol Chem 282:3989–3997PubMedCrossRef
12.
Oyadomari S, Araki E, Mori M (2002) Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells. Apoptosis 7:335–345PubMedCrossRef
13.
Karaskov E, Scott C, Zhang L, Teodoro T, Ravazzola M, Volchuk A (2006) Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic β-cell apoptosis. Endocrinology 147:3398–3407PubMedCrossRef
14.
Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63PubMed
15.
Shi Y, Taylor SI, Seng-Lai T, Sonenberg N (2003) When translation meets metabolism: multiple links to diabetes. Endocr Rev 24:91–101PubMedCrossRef
16.
Marciniak SJ, Ron D (2006) Endoplasmic reticulum stress signalling in disease. Physiol Rev 86:1133–1149PubMedCrossRef
17.
Wang J, Takeuchi T, Tanaka S et al (1999) A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. J Clin Invest 103:27–37PubMedCrossRef
18.
Oyadomari S, Takeda K, Takiguchi M et al (2001) Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci USA 98:10845–10850PubMedCrossRef
19.
Cardozo AK, Ortis F, Storling J et al (2005) Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. Diabetes 54:452–461PubMedCrossRef
20.
Kharroubi I, Ladriere L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL (2004) Free fatty acid and cytokines induce pancreatic β-cell apoptosis by different mechanisms: role of nuclear factor-κB and endoplasmic reticulum stress. Endocrinology 145:5087–5096PubMedCrossRef
21.
Araki E, Oyadomari S, Mori M (2003) Impact of endoplasmic reticulum stress pathway on pancreatic β-cells and diabetes mellitus. Exp Biol Med 228:1213–1217
22.
Iyer S, Korada M, Rainbow L et al (2004) Wolcott–Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature. Acta Paediatr 93:1195–1201PubMedCrossRef
23.
Harding HP, Zeng H, Zhang Y et al (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163PubMedCrossRef
24.
Scheuner D, Vander Mierde D, Song B et al (2005) Control of mRNA translation preserves endoplasmic reticulum function in beta-cells and maintains glucose homeostasis. Nat Med 11:757–764PubMedCrossRef
25.
Laybutt DR, Preston AM, Akerfeldt MC et al (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50:752–763PubMedCrossRef
26.
Huang C, Lin C, Haatajal L et al (2007) High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress-mediated beta cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes 56:2016–2027PubMedCrossRef
27.
Del Guerra S, Lupi R, Marselli L et al (2005) Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54(3):727–735PubMedCrossRef
28.
Marchetti P, Del Guerra S, Marselli L et al (2004) Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 89:5535–5541PubMedCrossRef
29.
Lupi R, Dotta F, Marselli L et al (2002) Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51:1437–1442PubMedCrossRef
30.
Fukui K, Yang Q, Cao Y et al (2005) The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. Cell Metab 2:373–384PubMedCrossRef
31.
Marselli L, Sgroi DC, Ahn Y-B, Sharma A, Bonner-Weir G, Weir G (2005) Laser capture microdissection provides marked enrichment of beta-cell tissue from human pancreas. Diabetes 54(Suppl 1):A403
32.
Ahn YB, Xu G, Marselli L et al (2007) Changes in gene expression in beta cells after islet isolation and transplantation using laser-capture microdissection. Diabetologia 50:334–342PubMedCrossRef
33.
Pirot P, Naamane N, Libert F et al (2007) Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs. Diabetologia 50:1006–1014PubMedCrossRef
34.
Back Sh, Schroder M, Lee K, Zhang K, Kaufman RJ (2005) ER stress signalling by regulated splicing: IRE1/HAC1/XBP1. Methods 35:395–416PubMedCrossRef
35.
Deng S, Vatamaniuk M, Huang X et al (2004) Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes 53:624–632PubMedCrossRef
36.
Lin JM, Fabregat ME, Gomis R, Bergsten P (2002) Pulsatile insulin release from islets isolated from three subjects with type 2 diabetes. Diabetes 51:988–993PubMedCrossRef
37.
Fernandez-Alvarez J, Conget I, Rasschaert J, Sener A, Gomis R, Malaisse WJ (1994) Enzymatic, metabolic and secretory patterns in human islets of type 2 (non-insulin-dependent) diabetic patients. Diabetologia 37:177–181PubMedCrossRef
38.
Ostenson CG, Gaisano H, Sheu L, Tibell A, Bartfai T (2006) Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients. Diabetes 55:435–440PubMedCrossRef
39.
Chehter EZ, Duarte MI, Takakura CF, Longo MA, Laudanna AA (2003) Ultrastructural study of the pancreas in AIDS. Pancreas 26:153–159PubMedCrossRef
40.
Junger E, Herberg L, Jeruschke K, Leiter EH (2002) The diabetes-prone NZO/Hl strain. II. Pancreatic immunopathology. Lab Invest 82:843–853PubMed
41.
Zuber C, Fan JY, Guhl B, Roth J (2004) Misfolded proinsulin accumulates in expanded pre-Golgi intermediates and endoplasmic reticulum subdomains in pancreatic beta cells of Akita mice. FASEB J 18:917–919PubMed
42.
Karaveg K, Siriwardena A, Tempel W et al (2005) Mechanism of class 1 (glycosylhydrolase family 47) α-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J Biol Chem 280:16197–16207PubMedCrossRef
43.
Totani K, Ihara Y, Matsuo I, Koshino H, Ito Y (2005) Synthetic substrates for an endoplasmic reticulum protein-folding sensor, UDP-glucose: glycoprotein glucosyltransferase. Angew Chem Int Ed Engl 44:7950–7954PubMedCrossRef
44.
Dejgaard S, Nicolay J, Taheri M, Thomas DY, Bergeron JJ (2004) The ER glycoprotein quality control system. Curr Issues Mol Biol 6:29–42PubMed
45.
Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389PubMedCrossRef
46.
Loffler M, Bilban M, Reimers M, Waldhausl W, Stulnig TM (2006) Blood glucose-lowering nuclear receptor agonists only partially normalize hepatic gene expression in db/db mice. J Pharmacol Exp Ther 316:797–804PubMedCrossRef
47.
Kuchenmeister U, Kuhn G, Wegner J, Nurnberg G, Ender K (1999) Post mortem changes in Ca2+ transporting proteins of sarcoplasmic reticulum in dependence on malignant hyperthermia status in pigs. Mol Cell Biochem 195:37–46PubMedCrossRef
48.
Wang H, Kouri G, Wollheim CB (2005) ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity. J Cell Sci 118:3905–3915PubMedCrossRef
49.
Robertson RP (2004) Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 279:42351–42354PubMedCrossRef
50.
Lortz S, Tiedge M, Nachtwey T, Karlsen AE, Nerup J, Lenzen S (2000) Protection of insulin-producing RINm5F cells against cytokine-mediated toxicity through overexpression of antioxidant enzymes. Diabetes 49:1123–1130PubMedCrossRef
Metadata
Title
The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients
Authors
P. Marchetti
M. Bugliani
R. Lupi
L. Marselli
M. Masini
U. Boggi
F. Filipponi
G. C. Weir
D. L. Eizirik
M. Cnop
Publication date
01-12-2007
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 12/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-007-0816-8

Other articles of this Issue 12/2007

Diabetologia 12/2007 Go to the issue

Article

Renal carcinogenesis in models of diabetes in rats—metabolic changes are closely related to neoplastic development

Letter

Increased physical activity is a cornerstone in the prevention of type 2 diabetes in high-risk individuals

Erratum

Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus

Article

Notch signalling suppresses apoptosis in adult human and mouse pancreatic islet cells

Article

Early mortality in EURODIAB population-based cohorts of type 1 diabetes diagnosed in childhood since 1989

Article

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts
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