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

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 9/2011

01-09-2011 | Article

Deletion of Ia-2 and/or Ia-2β in mice decreases insulin secretion by reducing the number of dense core vesicles

Authors: T. Cai, H. Hirai, G. Zhang, M. Zhang, N. Takahashi, H. Kasai, L. S. Satin, R. D. Leapman, A. L. Notkins

Published in: Diabetologia | Issue 9/2011

Login to get access

Abstract

Aims/hypothesis

Islet antigen 2 (IA-2) and IA-2β are dense core vesicle (DCV) transmembrane proteins and major autoantigens in type 1 diabetes. The present experiments were initiated to test the hypothesis that the knockout of the genes encoding these proteins impairs the secretion of insulin by reducing the number of DCV.

Methods

Insulin secretion, content and DCV number were evaluated in islets from single knockout (Ia-2 [also known as Ptprn] KO, Ia-2β [also known as Ptprn2] KO) and double knockout (DKO) mice by a variety of techniques including electron and two-photon microscopy, membrane capacitance, Ca2+ currents, DCV half-life, lysosome number and size and autophagy.

Results

Islets from single and DKO mice all showed a significant decrease in insulin content, insulin secretion and the number and half-life of DCV (p < 0.05 to 0.001). Exocytosis as evaluated by two-photon microscopy, membrane capacitance and Ca2+ currents supports these findings. Electron microscopy of islets from KO mice revealed a marked increase (p < 0.05 to 0.001) in the number and size of lysosomes and enzymatic studies showed an increase in cathepsin D activity (p < 0.01). LC3 protein, an indicator of autophagy, also was increased in islets of KO compared with wild-type mice (p < 0.05 to 0.01) suggesting that autophagy might be involved in the deletion of DCV.

Conclusions/interpretation

We conclude that the decrease in insulin content and secretion, resulting from the deletion of Ia-2 and/or Ia-2β, is due to a decrease in the number of DCV.
Appendix
Available only for authorised users
Literature
1.
Lan MS, Lu J, Goto Y, Notkins AL (1994) Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol 13:505–514PubMedCrossRef
2.
Lu J, Li Q, Xie H et al (1996) Identification of a second transmembrane protein tyrosine phosphatase, IA-2beta, as an autoantigen in insulin-dependent diabetes mellitus: precursor of the 37-kDa tryptic fragment. Proc Natl Acad Sci USA 93:2307–2311PubMedCrossRef
3.
Notkins AL, Lernmark A (2001) Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest 108:1247–1252PubMed
4.
Verge CF, Gianani R, Kawasaki E et al (1996) Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45:926–933PubMedCrossRef
5.
6.
Kulmala P, Savola K, Petersen JS et al (1998) Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes. A population-based study. The Childhood Diabetes in Finland Study Group. J Clin Invest 101:327–336PubMedCrossRef
7.
Solimena M, Dirkx R Jr, Hermel JM et al (1996) ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. EMBO J 15:2102–2114PubMed
8.
Nishimura T, Kubosaki A, Ito Y, Notkins AL (2009) Disturbances in the secretion of neurotransmitters in IA-2/IA-2beta null mice: changes in behavior, learning and lifespan. Neuroscience 159:427–437PubMedCrossRef
9.
Caromile LA, Oganesian A, Coats SA, Seifert RA, Bowen-Pope DF (2010) The neurosecretory vesicle protein phogrin functions as a phosphatidylinositol phosphatase to regulate insulin secretion. J Biol Chem 285:10487–10496PubMedCrossRef
10.
Cai T, Krause MW, Odenwald WF, Toyama R, Notkins AL (2001) The IA-2 gene family: homologs in Caenorhabditis elegans, Drosophila and zebrafish. Diabetologia 44:81–88PubMedCrossRef
11.
Saeki K, Zhu M, Kubosaki A, Xie J, Lan MS, Notkins AL (2002) Targeted disruption of the protein tyrosine phosphatase-like molecule IA-2 results in alterations in glucose tolerance tests and insulin secretion. Diabetes 51:1842–1850PubMedCrossRef
12.
Kubosaki A, Gross S, Miura J et al (2004) Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice. Diabetes 53:1684–1691PubMedCrossRef
13.
Kubosaki A, Nakamura S, Notkins AL (2005) Dense core vesicle proteins IA-2 and IA-2beta: metabolic alterations in double knockout mice. Diabetes 54(Suppl 2):S46–S51PubMedCrossRef
14.
Kubosaki A, Nakamura S, Clark A, Morris JF, Notkins AL (2006) Disruption of the transmembrane dense core vesicle proteins IA-2 and IA-2beta causes female infertility. Endocrinology 147:811–815PubMedCrossRef
15.
Kim SM, Power A, Brown TM et al (2009) Deletion of the secretory vesicle proteins IA-2 and IA-2beta disrupts circadian rhythms of cardiovascular and physical activity. FASEB J 23:3226–3232PubMedCrossRef
16.
Harashima S, Clark A, Christie MR, Notkins AL (2005) The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion. Proc Natl Acad Sci USA 102:8704–8709PubMedCrossRef
17.
Gotoh M, Maki T, Kiyoizumi T, Satomi S, Monaco AP (1985) An improved method for isolation of mouse pancreatic islets. Transplantation 40:437–438PubMedCrossRef
18.
Zhang G, Hirai H, Cai T et al (2007) RESP18, a homolog of the luminal domain IA-2, is found in dense core vesicles in pancreatic islet cells and is induced by high glucose. J Endocrinol 195:313–321PubMedCrossRef
19.
Goping G, Pollard HB, Srivastava M, Leapman R (2003) Mapping protein expression in mouse pancreatic islets by immunolabeling and electron energy loss spectrum-imaging. Microsc Res Tech 61:448–456PubMedCrossRef
20.
Takahashi N, Kishimoto T, Nemoto T, Kadowaki T, Kasai H (2002) Fusion pore dynamics and insulin granule exocytosis in the pancreatic islet. Science 297:1349–1352PubMedCrossRef
21.
Takahashi N, Hatakeyama H, Okado H et al (2004) Sequential exocytosis of insulin granules is associated with redistribution of SNAP25. J Cell Biol 165:255–262PubMedCrossRef
22.
Zhang M, Goforth P, Bertram R, Sherman A, Satin L (2003) The Ca2+ dynamics of isolated mouse beta-cells and islets: implications for mathematical models. Biophys J 84:2852–2870PubMedCrossRef
23.
Kinard TA, Satin LS (1996) Temperature modulates the Ca2+ current of HIT-T15 and mouse pancreatic beta-cells. Cell Calcium 20:475–482PubMedCrossRef
24.
Horrigan FT, Bookman RJ (1994) Releasable pools and the kinetics of exocytosis in adrenal chromaffin cells. Neuron 13:1119–1129PubMedCrossRef
25.
Henquin JC, Nenquin M, Szollosi A, Kubosaki A, Louis Notkins A (2008) Insulin secretion in islets from mice with a double knockout for the dense core vesicle proteins islet antigen-2 (IA-2) and IA-2{beta}. J Endocrinol 196:573–581PubMedCrossRef
26.
Yang SN, Berggren PO (2006) The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology. Endocr Rev 27:621–676PubMedCrossRef
27.
Tian Y, Corkey RF, Yaney GC, Goforth PB, Satin LS, Moitoso de Vargas L (2008) Differential modulation of L-type calcium channel subunits by oleate. Am J Physiol Endocrinol Metab 294:E1178–E1186PubMedCrossRef
28.
Mears D (2004) Regulation of insulin secretion in islets of Langerhans by Ca(2+)channels. J Membr Biol 200:57–66PubMedCrossRef
29.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075PubMedCrossRef
30.
Marsh BJ, Soden C, Alarcon C et al (2007) Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine beta-cells. Mol Endocrinol 21:2255–2269PubMedCrossRef
31.
Speidel D, Salehi A, Obermueller S et al (2008) CAPS1 and CAPS2 regulate stability and recruitment of insulin granules in mouse pancreatic beta cells. Cell Metab 7:57–67PubMedCrossRef
32.
Wiser O, Trus M, Hernandez A et al (1999) The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci USA 96:248–253PubMedCrossRef
33.
Ji J, Muinuddin A, Kang Y, Diamant NE, Gaisano HY (2003) SNAP-25 inhibits L-type Ca2+ channels in feline esophagus smooth muscle cells. Biochem Biophys Res Commun 306:298–302PubMedCrossRef
34.
Nunemaker CS, Bertram R, Sherman A, Tsaneva-Atanasova K, Daniel CR, Satin LS (2006) Glucose modulates [Ca2+]i oscillations in pancreatic islets via ionic and glycolytic mechanisms. Biophys J 91:2082–2096PubMedCrossRef
35.
Trus M, Corkey RF, Nesher R et al (2007) The L-type voltage-gated Ca2+ channel is the Ca2+ sensor protein of stimulus-secretion coupling in pancreatic beta cells. Biochemistry 46:14461–14467PubMedCrossRef
36.
Cai T, Hirai H, Fukushige T et al (2009) Loss of the transcriptional repressor PAG-3/Gfi-1 results in enhanced neurosecretion that is dependent on the dense-core vesicle membrane protein IDA-1/IA-2. PLoS Genet 5:e1000447PubMedCrossRef
37.
Mziaut H, Trajkovski M, Kersting S et al (2006) Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5. Nat Cell Biol 8:435–445PubMedCrossRef
38.
Brunner Y, Coute Y, Iezzi M et al (2007) Proteomics analysis of insulin secretory granules. Mol Cell Proteomics 6:1007–1017PubMedCrossRef
39.
Chernysheva A, Tsitlidze NM, Savost'ianov KV et al (2008) Association of the chromosomal region 2q35 with type 1 diabetes mellitus in the Russian patients from Moscow. Genetika 44:232–235PubMed
40.
Yang JH, Downes K, Howson JM et al (2011) Evidence of association with type 1 diabetes in the SLC11A1 gene region. BMC Med Genet 12:59PubMedCrossRef
41.
An P, Freedman BI, Hanis CL et al (2005) Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis. Diabetes 54:909–914PubMedCrossRef
42.
Schelling JR, Abboud HE, Nicholas SB et al (2008) Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes 57:235–243PubMedCrossRef
43.
Menasche G, Pastural E, Feldmann J et al (2000) Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 25:173–176PubMedCrossRef
Metadata
Title
Deletion of Ia-2 and/or Ia-2β in mice decreases insulin secretion by reducing the number of dense core vesicles
Authors
T. Cai
H. Hirai
G. Zhang
M. Zhang
N. Takahashi
H. Kasai
L. S. Satin
R. D. Leapman
A. L. Notkins
Publication date
01-09-2011
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2011
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-011-2221-6

Other articles of this Issue 9/2011

Diabetologia 9/2011 Go to the issue

Article

Associations between single-nucleotide polymorphisms (+45T>G, +276G>T, −11377C>G, −11391G>A) of adiponectin gene and type 2 diabetes mellitus: a systematic review and meta-analysis

Letter

Risk scores for predicting type 2 diabetes: using the optimal tool

Article

Incidence and progression of diabetic retinopathy in Japanese adults with type 2 diabetes: 8 year follow-up study of the Japan Diabetes Complications Study (JDCS)

Commentary

Diagnosing gestational diabetes: can expert opinions replace scientific evidence?

Commentary

New approaches for the evaluation of renal vascular function in diabetes

Erratum

Erratum to: Dynamic evaluation of renal resistive index in normoalbuminuric patients with newly diagnosed hypertension or type 2 diabetes
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 discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

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

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