Prediction of impending type 1 diabetes through automated dual-label measurement of proinsulin:C-peptide ratio

Background : The hyperglycemic clamp test, the gold standard of beta cell function, predicts impending type 1 diabetes in islet autoantibody-positive individuals, but the latter may benefit from less invasive function tests such as the proinsulin: C-peptide ratio (PI:C). The present study aims to optimize precision of PI:C measurements by automating a dual-label trefoil-type time-resolved fluorescence immunoassay (TT-TRFIA), and to compare its diagnostic performance for predicting type 1 diabetes with that of clamp-derived C-peptide release. Methods : Between-day imprecision (n = 20) and split-sample analysis (n = 95) were used to compare TT-TRFIA (Auto Delfia, Perkin-Elmer) with separate methods for proinsulin (in-house TRFIA) and C-peptide (Elecsys, Roche). High-risk multiple autoantibody-positive firstdegree relatives (n = 49; age 5-39) were tested for fasting PI:C, HOMA2-IR and hyperglycemic clamp and followed for 20-57 months (interquartile range). Results : TT-TRFIA values for proinsulin, C-peptide and PI:C correlated significantly (r(2) = 0.96-0.99; P<0.001) with results obtained with separate methods. TT-TRFIA achieved better between-day % CV for PI:C at three different levels (4.5-7.1 vs 6.7-9.5 for separate methods). In high-risk relatives fasting PI:C was significantly and inversely correlated ( r(s) = -0.596; P<0.001) with first-phase C-peptide release during clamp ( also with second phase release, only available for age 12-39 years; n = 31), but only after normalization for HOMA2-IR. In ROC- and Cox regression analysis, HOMA2-IR-corrected PI:C predicted 2-year progression to diabetes equally well as clamp-derived C-peptide release. Conclusions : The reproducibility of PI:C benefits from the automated simultaneous determination of both hormones. HOMA2-IR-corrected PI:C may serve as a minimally invasive alternative to the more tedious hyperglycemic clamp test

Fasting insulin sensitivity indices are not better than routine clinical variables at predicting insulin sensitivity among Black Africans: a clamp study in sub-Saharan Africans

BACKGROUND: We aimed to evaluate the predictive utility of common fasting insulin sensitivity indices, and non-laboratory surrogates [BMI, waist circumference (WC) and waist-to-height ratio (WHtR)] in sub-Saharan Africans without diabetes. METHODS: We measured fasting glucose and insulin, and glucose uptake during 80/mU/m2/min euglycemic clamp in 87 Cameroonians (51 men) aged (SD) 34.6 (11.4) years. We derived insulin sensitivity indices including HOMA-IR, quantitative insulin sensitivity check index (QUICKI), fasting insulin resistance index (FIRI) and glucose-to-insulin ratio (GIR). Indices and clinical predictors were compared to clamp using correlation tests, robust linear regressions and agreement of classification by sex-specific thirds. RESULTS: The mean insulin sensitivity was M =10.5+/-3.2mg/kg/min. Classification across thirds of insulin sensitivity by clamp matched with non-laboratory surrogates in 30-48% of participants, and with fasting indices in 27-51%, with kappa statistics ranging from 0.10 to 0.26. Fasting indices correlated significantly with clamp (/r/=0.23-0.30), with GIR performing less well than fasting insulin and HOMA-IR (both p <0.02). BMI, WC and WHtR were equal or superior to fasting indices (/r/=0.38-0.43). Combinations of fasting indices and clinical predictors explained 25-27% of variation in clamp values. CONCLUSION: Fasting insulin sensitivity indices are modest predictors of insulin sensitivity measured by euglycemic clamp, and do not perform better than clinical surrogates in this population

Incidence, prevalence and genetic determinants of neonatal diabetes mellitus: a systematic review and meta-analysis protocol

Abstract Background In the absence of existing data, the present review intends to determine the incidence, prevalence and/or genetic determinants of neonatal diabetes mellitus (NDM), with expected contribution to disease characterization. Methods We will include cross-sectional, cohort or case-control studies which have reported the incidence, prevalence and/or genetic determinants of NDM between January 01, 2000 and May 31, 2016, published in English or French languages and without any geographical limitation. PubMed and EMBASE will be extensively screened to identify potentially eligible studies, completed by manual search. Two authors will independently screen, select studies, extract data, and assess the risk of bias; disagreements will be resolved by consensus. Clinical heterogeneity will be investigated by examining the design and setting (including geographic region), procedure used for genetic testing, calculation of incidence or prevalence, and outcomes in each study. Studies found to be clinically homogeneous will be pooled together through a random effects meta-analysis. Statistical heterogeneity will be assessed using the chi-square test of homogeneity and quantified using the I2 statistic. In case of substantial heterogeneity, subgroup analyses will be undertaken. Publication bias will be assessed with funnel plots, complemented with the use of Egger’s test of bias. Discussion This systematic review and meta-analysis is expected to draw a clear picture of phenotypic and genotypic presentations of NDM in order to better understand the condition and adequately address challenges in respect with its management. Systematic review registration PROSPERO CRD4201603976

Genetic factors contributing to hypertension in African-based populations : a systematic review and meta-analysis

In a systematic review, the authors explored genetic association studies of essential hypertension in African populations. Studies reporting on the association of polymorphism(s) with hypertension in African populations were included. Appropriate studies were pooled using random effects model meta-analysis, under six potential inheritance models. In all, 46 polymorphisms in 33 genes were investigated for their association with hypertension or blood pressure levels. Meta-analysis was possible for three single nucleotide polymorphisms: rs4340, rs699, and rs5186. An association was found between rs5186, rs699, and hypertension under allele contrast and homozygous codominant models (odds ratio, 1.63 [95% confidence interval, 1.04-2.54] and 4.01 [95% confidence interval, 1.17-13.80] for rs5186, respectively; and 1.80 [95% confidence interval, 1.13-2.87] for rs699). Findings were mostly robust in sensitivity analyses. According to the systematic review, there is currently insufficient evidence on the specific polymorphisms that pose the risk of hypertension in African populations. Large-scale genetic studies are warranted to better understand susceptibility polymorphisms that may be specific to African populations

Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin: C-Peptide Ratio (vol 11, e0166702, 2016)

[This corrects the article DOI: 10.1371/journal.pone.0166702.].status: publishe

Twenty-Year Progression Rate to Clinical Onset According to Autoantibody Profile, Age, and HLA-DQ Genotype in a Registry-Based Group of Children and Adults With a First-Degree Relative With Type 1 Diabetes

OBJECTIVE: We investigated whether islet autoantibody profile, HLA-DQ genotype, and age influenced a 20-year progression to diabetes from first autoantibody positivity (autoAb+) in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Persistently islet autoAb+ siblings and offspring (n = 462) under 40 years of age were followed by the Belgian Diabetes Registry. AutoAbs against insulin (IAA), GAD (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A) were determined by radiobinding assay. RESULTS: The 20-year progression rate of multiple-autoAb+ relatives (n = 194) was higher than that for single-autoAb+ participants (n = 268) (88% vs. 54%; P < 0.001). Relatives positive for IAA and GADA (n = 54) progressed more slowly than double-autoAb+ individuals carrying IA-2A and/or ZnT8A (n = 38; P = 0.001). In multiple-autoAb+ relatives, Cox regression analysis identified the presence of IA-2A or ZnT8A as the only independent predictors of more rapid progression to diabetes (P < 0.001); in single-autoAb+ relatives, it identified younger age (P < 0.001), HLA-DQ2/DQ8 genotype (P < 0.001), and IAA (P = 0.028) as independent predictors of seroconversion to multiple positivity for autoAbs. In time-dependent Cox regression, younger age (P = 0.042), HLA-DQ2/DQ8 genotype (P = 0.009), and the development of additional autoAbs (P = 0.012) were associated with more rapid progression to diabetes. CONCLUSIONS: In single-autoAb+ relatives, the time to multiple-autoAb positivity increases with age and the absence of IAA and HLA-DQ2/DQ8 genotype. The majority of multiple-autoAb+ individuals progress to diabetes within 20 years; this occurs more rapidly in the presence of IA-2A or ZnT8A, regardless of age, HLA-DQ genotype, and number of autoAbs. These data may help to refine the risk stratification of presymptomatic type 1 diabetes.status: publishe

Twenty-year progression rate to clinical onset according to autoantibody profile, age, and HLA-dq genotype in a registry-based group of children and adults with a first-degree relative with type 1 diabetes

OBJECTIVE We investigated whether islet autoantibody profile, HLA-DQ genotype, and age influenced a 20-year progression to diabetes from first autoantibody positivity (autoAb+) in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Persistently islet autoAb+ siblings and offspring (n = 462) under 40 years of agewere followed by the Belgian Diabetes Registry. AutoAbs against insulin (IAA), GAD (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A) were determined by radiobinding assay. RESULTS The 20-year progression rate ofmultiple-autoAb+ relatives (n = 194) was higher than that for single-autoAb+ participants (n = 268) (88% vs. 54%; P < 0.001). Relatives positive for IAA and GADA (n = 54) progressed more slowly than double-autoAb+ individuals carrying IA-2A and/or ZnT8A (n = 38; P = 0.001). In multiple-autoAb+ relatives, Cox regression analysis identified the presence of IA-2A or ZnT8A as the only independent predictors of more rapid progression to diabetes (P < 0.001); in single-autoAb+ relatives, it identified younger age (P < 0.001), HLA-DQ2/DQ8 genotype (P < 0.001), and IAA (P = 0.028) as independent predictors of seroconversion to multiple positivity for autoAbs. In time-dependent Cox regression, younger age (P = 0.042), HLA-DQ2/DQ8 genotype (P = 0.009), and the development of additional autoAbs (P = 0.012) were associated with more rapid progression to diabetes. CONCLUSIONS In single-autoAb+ relatives, the time tomultiple-autoAb positivity increaseswith age and the absence of IAA and HLA-DQ2/DQ8 genotype. The majority of multipleautoAb+ individuals progress to diabetes within 20 years; this occurs more rapidly in the presence of IA-2A or ZnT8A, regardless of age, HLA-DQ genotype, and number of autoAbs. These data may help to refine the risk stratification of presymptomatic type 1 diabetes.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Accelerated progression to type 1 diabetes in the presence of HLA-A∗24 and-B∗18is restricted to multiple islet autoantibody-positive individuals with distinct HLA-DQ and autoantibody risk profiles

OBJECTIVE: We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ, -A∗24, -B∗18, and -B∗39 status. Genetic markers were determined by PCR sequence-specific oligotyping. RESULTS: Unlike HLA-B∗18 or -B∗39, HLA-A∗24 was associated with delayed progression from single- to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurredindependently from olderage(P<0.001)and absence of HLA-DQ2/DQ8 or -DQ8 (P < 0.001 and P = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, HLA-A∗24 was associated with accelerated progression from multiple-autoantibody positivity to clinical onset (P = 0.006), but its effects were restricted to HLA-DQ8+relatives with IA-2 or zinctransporter8 autoantibodies (P = 0.002). HLA-B∗18, but not -B∗39, was also associated with more rapid progression, but only in HLA-DQ2 carriers with double positivity for GAD and insulin autoantibodies (P = 0.004). CONCLUSIONS: HLA-A∗24 predisposes to a delayed antigen spreading of humoral autoimmunity, whereas HLA-A∗24 and -B∗18 are associated with accelerated progression of advanced subclinical autoimmunity in distinct risk groups. The relation of these alleles to the underlying disease process requires further investigation. Their typing should be relevant for the preparation and interpretation of observational and interventional studies in asymptomatic type 1 diabetes.SCOPUS: ar.jinfo:eu-repo/semantics/publishe