Intrafamilial Variability of Early-Onset Diabetes due to an INS Mutation

Aim. The objective of this study was to describe the clinical characteristics of two siblings and their father carrying a C95Y mutation in the insulin (INS) gene. Methods/Results. A Danish patient, his sister, and his father were identified to carry the C95Y mutation in the preproinsulin molecule causing permanent neonatal diabetes. All three were diagnosed before 29 weeks of age, were born at term with near-normal birth weight, and were negative for GAD, ICA, IA-2, and IAA autoantibodies. The daily insulin requirement the first six months after diagnosis was <0.5 U kg−1 day−1 for both children. The father, insulin treated for over 40 years, has bilateral preproliferative retinopathy. Conclusions. These three cases further confirm the essential features of diabetes caused by INS mutations with proteotoxic effect. We conclude that patients with similar features must be investigated for mutations of INS gene

Skap2, a candidate gene for type 1 diabetes, regulates b-cell apoptosis and glycemic control in newly diagnosed patients

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D), suggesting SKAP2 as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the b-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual b-cell function during the 1st year after diagnosis. In INS-1E cells and rat and human islets, proinflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an antiapoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced ap-optosis, which correlated with reduced nuclear content of S536-phosphorylated nuclear factor-kB (NF-kB) subunit p65, lower nitric oxide production, and diminished CHOP expression indicative of decreased endoplasmic reticu-lum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls b-cell sensitivity to cytokines possibly by affecting the NF-kB–inducible nitric oxide synthase– endoplasmic reticulum stress pathway.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Complex multi-block analysis identifies new immunologic and genetic disease progression patterns associated with the residual β-cell function 1 year after diagnosis of type 1 diabetes

The purpose of the present study is to explore the progression of type 1 diabetes (T1D) in Danish children 12 months after diagnosis using Latent Factor Modelling. We include three data blocks of dynamic paraclinical biomarkers, baseline clinical characteristics and genetic profiles of diabetes related SNPs in the analyses. This method identified a model explaining 21.6% of the total variation in the data set. The model consists of two components: (1) A pattern of declining residual β-cell function positively associated with young age, presence of diabetic ketoacidosis and long duration of disease symptoms (P = 0.0004), and with risk alleles of WFS1, CDKN2A/2B and RNLS (P = 0.006). (2) A second pattern of high ZnT8 autoantibody levels and low postprandial glucagon levels associated with risk alleles of IFIH1, TCF2, TAF5L, IL2RA and PTPN2 and protective alleles of ERBB3 gene (P = 0.0005). These results demonstrate that Latent Factor Modelling can identify associating patterns in clinical prospective data--future functional studies will be needed to clarify the relevance of these patterns

Diagram of a single factor/component from a -block model examining biomarkers over time (Biomarkers) in relation to baseline characteristics (Baseline) and Genetic background (Genes).

<p>The pattern indicates that e.g. the biomarker <i>A</i> increases- and the biomarker <i>B</i> decreases over time. This pattern is e.g. related to high values of the baseline characteristics <i>B1</i> and high number of risk alleles for gene <i>G1</i> and low number of risk alleles for gene <i>G2.</i></p

The course of stimulated C-peptide (pmol/L), HbA_1c (%) and IDAA1c for each child during the 12 months follow-up colored according to age.

<p><b>A</b>. Raw values of stimulated C-peptide (pmol/L). Stimulated C-peptide was lowest in the youngest age groups. <b>B</b>. Raw values of HbA_1c (%). The HbA_1c level in the very young age group was lower at onset compared with the older age groups. <b>C</b>. Raw values of IDAA1c. The children with points below the black are in partial remission at that time point defined as IDAA1c ≤9. Very few of the very young children were in partial remission during the 12 months follow up (21.1% after 3 months).</p

Stimulated C-peptide (pmol/L), HbA_1c (%) and IDAA1c during 12 months follow up.

<p>Stimulated C-peptide (pmol/L), HbA_1c (%) and IDAA1c during 12 months follow up.</p

Complex <i>Multi</i>-<i>Block Analysis</i> Identifies New Immunologic and Genetic Disease Progression Patterns Associated with the Residual β-Cell Function 1 Year after Diagnosis of Type 1 Diabetes - Figure 3

<p><b>Multi-block analyses: A. ‘β-cell function’-component: (I)</b> Pattern of the paraclinical biomarkers forming the ‘β-cell function’-component and the progression of this biomarker pattern during the first 12 months after diagnosis. (<b>II</b>) The pattern of baseline (the time of diagnosis) characteristics predictive for the biomarker pattern of the ‘β-cell function’-component over time (p = 0.001), were long duration of symptoms, younger age and DKA and consequently high blood glucose and low level of standard bicarbonate. (<b>III</b>) The pattern of type 1- and T2D associated SNPs associated with the biomarker pattern of the ‘β-cell function’-component over time (I) (p = 0.006) and the pattern of baseline characteristics in (II). The best genetic predictors for the biomarker pattern of the ‘β-cell function’-component over time were a combination of more risk alleles of the <i>INS (</i>rs689 and rs3842753), <i>RNLS</i> (rs10509540), <i>WFS1</i> (rs10010131) and <i>CDKN2A/2B</i> (rs564398) variants; and less risk alleles of the <i>TSPAN8-LGR5</i> (rs7961581) variant. <b>B. ‘ZnT8’-component:</b> (<b>I</b>) Pattern of biomarkers forming the ‘ZnT8-component’ and the progression of this biomarker pattern during the first 12 months after diagnosis. (<b>II</b>) This component was not significantly associated with baseline characteristics. (<b>III</b>) The pattern of T1D and T2D associated SNPs associated with the biomarker pattern of the ‘ZnT8’-component over time (I) (p = 0.0005). The best genetic predictors for the biomarker pattern of the ‘ZnT8Ab’-component were a combination of more risk alleles of the <i>IFIH1</i> (rs1990760), <i>TAF5L</i> (rs3753886), <i>HNF1B</i> (TCF2, rs4430796), <i>IL2RA</i> (rs11594656), <i>PTPN2</i> (rs1893217) and <i>CDKAL1</i> (rs10946398) variants; and less risk alleles of the <i>ERBB3</i> (rs2292239) variant.</p

CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients

Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat β-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh-/- mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower β-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of β-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic β-cells, the target cells of the autoimmune assault.SCOPUS: ar.jinfo:eu-repo/semantics/publishe