Autoimmunity against INS-IGF2 Protein Expressed in Human Pancreatic Islets*

Kanatsuna, Norio; Taneera, Jalal; Vaziri-Sani, Fariba; Wierup, Nils; Larsson, Helena Elding; Delli, Ahmed J.; Skärstrand, Hanna; Balhuizen, Alexander; Bennet, Hedvig; Steiner, Donald F.; Törn, Carina; Fex, Malin; Lernmark, Åke

doi:10.1074/jbc.m113.478222

Cited by 34 publications

(34 citation statements)

References 59 publications

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“…This transcript, mainly found in beta cells of the pancreas, encodes for a fusion consisting of the first 138 amino acids of the IGF2 gene along with 62 amino acids of the insulin gene (19).…”

Section: Gene Structure Of Igf2mentioning

confidence: 99%

IGF2 signaling and regulation in cancer

Brouwer‐Visser¹,

Huang

2015

Cytokine & Growth Factor Reviews

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Section: Gene Structure Of Igf2mentioning

confidence: 99%

IGF2 signaling and regulation in cancer

Brouwer‐Visser¹,

Huang

2015

Cytokine & Growth Factor Reviews

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“…Preparation of 35 S‐INS‐IGF2 including the pThINS‐IGF2 vector, the coupled in vitro transcription – translation of pThINS‐IGF2 and the preparation of both labelled and unlabelled INS‐IGF2 were previously described in detail .…”

Section: Methodsmentioning

confidence: 99%

“…The insulin B‐chain is also present in INS‐IGF2, a transcriptional splice variant of INS and the coding sequences of the two proximal open reading frame (ORF) of the IGF2 gene . The two ORFs of the IGF2 gene are normally non‐coding exons but insert a novel 138 amino acid c‐terminal region unrelated to pre‐pro‐IGF2 . Therefore, INS‐IGF2 consists of the preproinsulin signal peptide, the insulin B‐chain and eight amino acids of the C‐peptide in addition to 138 amino acids from the unemployed ORFs in the IGF2 gene .…”

Section: Introductionmentioning

confidence: 99%

“…We recently reported that INS‐IGF2 was expressed primarily in human islet beta cells and showed higher levels of expression in islets from normal compared to donors with either type 2 diabetes or high HbA1c levels . Newly diagnosed patients with type 1 diabetes selected to be either very young or young adults had autoantibodies able to recognize both insulin and INS‐IGF2 (doubly reactive autoantibodies) . INS‐IGF2 and insulin autoantibodies may therefore share binding sites on both INS‐IGF2 and insulin, respectively, thus complicating the understanding of these two autoantigens in type 1 diabetes .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Doubly Reactive INS‐IGF2 Autoantibodies in Children with Newly Diagnosed Autoimmune (type 1) Diabetes

et al. 2015

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The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.

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“…1). Both those studies have been important for the understanding of autoimmunity and genes for the diagnosis of pediatric diabetes (7,8), relations between specific autoantibodies and genes (9, 10), discovery of new autoantigens (11)(12)(13), prevalence and genetic predisposition for other autoimmune diseases (14,15). However, in order to understand the process from development of islet autoimmunity to type 1 diabetes and find factors triggering islet autoimmunity, we needed to follow children before the diagnosis of diabetes.…”

Section: Introductionmentioning

confidence: 99%

A Swedish approach to the prevention of type 1 diabetes

Larsson

2016

Pediatr Diabetes

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Background The autoimmune destruction of beta cells, resulting in clinical type 1 diabetes, may start early in life and last for several months or years. During this period of time, we have an opportunity to try to prevent or delay further beta‐cell destruction and clinical onset of type 1 diabetes. Objectives Ongoing prediction and prevention studies in Skåne, Sweden are described. Methods During September 2000 to August 2004, 35 000 children were screened at birth for genetic type 1 diabetes risk in the Diabetes Prediction in Skåne Study (DiPiS). In August 2004, the screening continued within the Enviromnental Determinants of Diabetes in the Young study (TEDDY). In the clinical trial Diabetes Prevention – Immune Tolerance (DiAPREV‐IT), children with multiple islet autoimmunity have been included to investigate if immune tolerance with Alum‐formulated GAD65 may prevent further beta‐cell loss. Results In DiPiS and TEDDY, a large number of children are followed in order to find the factors that trigger the autoimmune process leading to type 1 diabetes. Children followed in the studies develop diabetes at an early stage of disease, with few symptoms and a low frequency of diabetes ketoacidosis. DiAPREV‐IT is still blinded and results will be available in December 2016. Conclusion Large prospective studies will be needed to understand the complex process leading to type 1 diabetes. Secondary prevention may be possible in children with islet autoimmunity, but the studies are complicated by the variability of glucose metabolism and beta‐cell loss.

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Autoimmunity against INS-IGF2 Protein Expressed in Human Pancreatic Islets*

Cited by 34 publications

References 59 publications

IGF2 signaling and regulation in cancer

IGF2 signaling and regulation in cancer

Doubly Reactive INS‐IGF2 Autoantibodies in Children with Newly Diagnosed Autoimmune (type 1) Diabetes

A Swedish approach to the prevention of type 1 diabetes

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