Residual insulin secretion at diagnosis of type 1 diabetes is independently associated with both, age of onset and HLA genotype

Petrone, Antonio; Galgani, Andrea; Spoletini, Marialuisa; Alemanno, Irene; Cola, Simone Di; Bassotti, Gabrio; Picardi, Antonio; Manfrini, Silvia; Osborn, John; Pozzilli, Paolo; Buzzetti, Raffaella

doi:10.1002/dmrr.549

Cited by 42 publications

(37 citation statements)

References 24 publications

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“…We have previously demonstrated that C-peptide levels are significantly higher in patients with low HLA DRB1-DQB1 risk genotypes compared with those with high and moderate risk at disease diagnosis (17), underlining the importance of the genetic component in the preservation of ␤-cell function.…”

Section: Conclusion -T H I Smentioning

confidence: 98%

The PTPN22 1858T Gene Variant in Type 1 Diabetes Is Associated With Reduced Residual β-Cell Function and Worse Metabolic Control

Petrone

Spoletini²,

Zampetti³

et al. 2008

Diabetes Care

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FOR THE IMMUNOTHERAPY DIABETES (IMDIAB) GROUP 3OBJECTIVE -Evidence has been reported for a new susceptible locus for type 1 diabetes, the protein tyrosine phosphatase nonreceptor type 2 (PTPN22), which encodes a lymphoidspecific phosphatase. The aim of the study was to evaluate the influence of the C1858T variant of the PTPN22 gene on ␤-cell function as measured by C-peptide levels from time of disease diagnosis through 12 months follow-up in a prospective series of 120 consecutive type 1 diabetic subjects.RESEARCH DESIGN AND METHODS -The C1858T polymorphism was genotyped using TaqMan. Fasting C-peptide, A1C, and insulin requirements were determined at diagnosis and every 3 months for 12 months; their change during follow-up was analyzed using the general linear model repeated-measures procedure.RESULTS -Fasting C-peptide levels were significantly lower and A1C levels were significantly higher in subjects carrying the PTPN22 1858T variant than in subjects homozygous for C1858 from time of disease diagnosis through 12 months of intensive insulin therapy follow-up (P ϭ 0.008 and P ϭ 0.01, respectively). These findings were independent of age at onset, sex, and HLA risk groups. The trend in C-peptide and A1C levels in the 12-month period did not differ significantly between subjects with or without the 1858T variant. Insulin dose was similar in the 1858T carriers and noncarriers.CONCLUSIONS -Type 1 diabetic subjects carrying the 1858T variant show significantly lower ␤-cell function and worse metabolic control at diagnosis and throughout the study period than subjects homozygous for C1858; these differences remain unchanged over the course of the first year after diagnosis.

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Section: Conclusion -T H I Smentioning

confidence: 98%

The PTPN22 1858T Gene Variant in Type 1 Diabetes Is Associated With Reduced Residual β-Cell Function and Worse Metabolic Control

Petrone

Spoletini²,

Zampetti³

et al. 2008

Diabetes Care

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“…The disease risk is transmitted through the altered antigen-presenting function of dendritic cells (that express high levels of LYP), the altered activation of helper T cells and likely also via the decreased function of self-reactive regulatory T cells [48]. The c.1858C>T polymorphism of PTPN22 is associated with decreased residual β-cell function at the onset of T1DM [49,50]. The recent discovery of the expression of islet cell autoantibodies in 17-25% of MODY patients of Czech, German and Austrian origin [29,30,31] raises the question of whether the islet cell autoantibodies are present in a fraction of MODY patients because of their susceptibility to autoimmune disorders or whether these autoantibodies appear physiologically only as a transient result of β-cell destruction.…”

Section: Discussionmentioning

confidence: 99%

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Heneberg¹,

Malá²,

Yorifuji³

et al. 2015

Int Arch Allergy Immunol

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Background: The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid tyrosine phosphatase (LYP), which is expressed primarily in lymphoid tissues. The functional but geographically highly variable PTPN22 single-nucleotide polymorphisms (SNPs), particularly c.1858C>T, contribute to the onset and progression of autoimmunity-associated diseases and facilitate the expression of disease-associated autoantibodies. In Central Europe, 17-25% of patients with monogenic diabetes (maturity-onset diabetes of the young, MODY) transiently express islet cell autoantibodies. Methods: We addressed the links between the functional and geographically variable PTPN22 SNPs with MODY manifestation and the expression of islet cell autoantibodies in 276 MODY patients who originated from four regions (the Czech Republic, Israel, Japan and Brazil). Results: The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception of c.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1). A barely significant increase in the c.788G>A minor allele was also detected in the islet cell autoantibody-positive Czech MODY patients. However, c.788A behaves as a loss-of-function mutant in T cells, and thus protects against autoimmunity. Conclusions: MODY patients (including islet cell autoantibody-positive cases) do not display any increase in autoimmunity-associated PTPN22 alleles. The absence of autoimmunity-associated PTPN22 alleles was also demonstrated in latent autoimmune diabetes in adults, which suggests that the slow kinetics of the onset of autoantibodies is subject to a regulation that is different from that experienced in type 1 diabetes and other autoimmune disorders.

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“…Antibodies were determined at the screening visit, month 2, 7, 13 and 18. HLA typing was performed at a central laboratory in Italy as described [17] in all patients of study p520 and p521 for whom HLA type was not already known.…”

Section: Antibodies and Hlamentioning

confidence: 99%

Effect of heat shock protein peptide DiaPep277 on ß‐cell function in paediatric and adult patients with recent‐onset diabetes mellitus type 1: two prospective, randomized, double‐blind phase II trials

Schloot

Meierhoff

Lengyel

et al. 2006

Diabetes Metabolism Res

100

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Residual insulin secretion at diagnosis of type 1 diabetes is independently associated with both, age of onset and HLA genotype

Abstract: The degree of beta-cell destruction at diagnosis of T1DM is independently associated with both, age of onset and HLA genotypes, the two variables exert a similar quantitative effect on residual beta-cell function at diagnosis.

Cited by 42 publications

References 24 publications

The PTPN22 1858T Gene Variant in Type 1 Diabetes Is Associated With Reduced Residual β-Cell Function and Worse Metabolic Control

The PTPN22 1858T Gene Variant in Type 1 Diabetes Is Associated With Reduced Residual β-Cell Function and Worse Metabolic Control

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Effect of heat shock protein peptide DiaPep277 on ß‐cell function in paediatric and adult patients with recent‐onset diabetes mellitus type 1: two prospective, randomized, double‐blind phase II trials

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