Gestational diabetes mellitus in Cameroon: prevalence, risk factors and screening strategies.

Background: The burden of gestational diabetes (GDM) and the optimal screening strategies in African populations are yet to be determined. We assessed the prevalence of GDM and the performance of various screening tests in a Cameroonian population. Methods: We carried out a cross-sectional study involving the screening of 983 women at 24-28 weeks of pregnancy for GDM using serial tests, including fasting plasma (FPG), random blood glucose (RBG), a 1-hour 50g glucose challenge test (GCT), and standard 2-hour oral glucose tolerance test (OGTT). GDM was defined using the World Health Organization (WHO 1999), International Association of Diabetes and Pregnancy Special Group (IADPSG 2010), and National Institute for Health Care Excellence (NICE 2015) criteria. GDM correlates were assessed using logistic regressions, and c-statistics were used to assess the performance of screening strategies. Findings: GDM prevalence was 5·9%, 17·7%, and 11·0% using WHO, IADPSG, and NICE criteria, respectively. Previous stillbirth [odds ratio: 3·14, 95%CI: 1·27-7·76)] was the main correlate of GDM. The optimal cut-points to diagnose WHO-defined GDM were 5·9 mmol/L for RPG (c-statistic 0·62) and 7·1 mmol/L for 1-hour 50g GCT (c-statistic 0·76). The same cut-off value for RPG was applicable for IADPSG-diagnosed GDM while the threshold was 6·5 mmol/L (c-statistic 0·61) for NICE-diagnosed GDM. The optimal cut-off of 1-hour 50g GCT was similar for IADPSG and NICE-diagnosed GDM. WHO-defined GDM was always confirmed by another diagnosis strategy while IADPSG and GCT independently identified at least 66·9 and 41·0% of the cases. Interpretation: GDM is common among Cameroonian women. Effective detection of GDM in under-resourced settings may require simpler algorithms including the initial use of FPG, which could substantially increase screening yield.

Clinical features of Legionnaires' disease at three Belgian university hospitals, a retrospective study.

INTRODUCTION: Legionnaires' disease (LD) is a recognised cause of community-acquired pneumonia. However, Legionella is an overlooked pathogen in hospital-acquired pneumonia. The European Surveillance System 2008-2017 found 23% of the Belgian LD reported cases being healthcare-related, with a higher death-rate than in community-acquired patients. This study aims to describe patients admitted for community-acquired LD or affected by hospital-acquired LD and investigate discriminants associated with lethality. METHODS: Medical records were retrospectively reviewed at three Belgian University Hospitals, between 1 January 2016 up to 31 January 2019. Hospital-acquired LD was defined as symptom onset at 10 days or more after admission, according to the Centres for Disease Control and prevention. Community-acquired LD was defined as diagnosis at admission or within 10 days after admission. RESULTS: Fifty patients were included in the study, among them 26% were diagnosed with hospital-acquired LD. The case-fatality rate was 22%, with eight of the eleven deceased patients (73%) being in the hospital-acquired LD group. Medical history of asthma or chronic obstructive pulmonary disease and higher sequential organ failure assessment (SOFA) score at diagnosis were more frequently observed in the hospital-acquired LD group. Furthermore, significantly lower SOFA score at diagnosis of LD and higher rates of treatment with levofloxacin or moxifloxacin were observed in survivors. CONCLUSION: In the current cohort, LD death-rate was mainly driven by hospital-acquired LD patients. Hospital-acquired LD might especially affect patients with chronic respiratory disease. Respiratory fluoroquinolones treatment and lower SOFA score at diagnosis may be associated with favourable outcomes.

Metabolic effects of exposure to pesticides during gestation in female Wistar rats and their offspring: a risk factor for diabetes?

Some pesticides increase the risk of type 2 diabetes, but whether fetal exposure carries transgenerational risk remains unknown. We evaluated the metabolic effects of gestational exposure to chlorpyrifos and imidacloprid in female Wistar rats and their offspring. We studied female nulliparous Wistar rats, including six exposed to imidacloprid (IMI) and six to chlorpyrifos (CPF) once daily throughout gestation at 1/10 lethal dose 50, while six (control group) received distilled water. These were explored 1 month after the birth of the offspring, while their offspring were explored at weaning (4 weeks) and adult age (12 weeks). Blood glucose, insulin and lipid profile were determined at each stage, while glucose transporter 4 (GLUT4) and nuclear factor kappa beta (NFkß) protein expression was measured in skeletal muscle at the end of follow up. Exposure to pesticides was associated with significantly higher fasting glucose (+25.4 to 30.9%) and insulin (> 100%) levels, with > 100% increased insulin resistance (HOMA-IR), - 18.3 to - 21.1% reduced HDL-cholesterol and + 60.9 to + 102.6% increased LDL-cholesterol in mothers. GLUT4 expression was reduced by 28.9-42.3% while NFkß expression increased by 32.8-35.4% in mothers. In offspring, similar abnormalities were observed at weaning (+ 18.4 to 67.4% fasting glucose, + 57.1 to 72.2% LDL-cholesterol, + 72.3 to 78.2% fasting insulin), persisting at adult age with decreased expression of GLUT4 (- 52.8 to 54.5%) and increased expression of NFkß (+ 30.5 to 30.7%). Gestational exposure to imidacloprid and chlorpyrifos induces hyperglycemia, insulin resistance and dyslipidemia in female Wistar rats and their offspring. The effects on offspring persist until adult age, suggesting intergenerational adverse effects.

Gestational Exposure to Pesticides Induces Oxidative Stress and Lipid Peroxidation in Offspring that Persist at Adult Age in an Animal Model.

Pesticide exposure may induce biochemical alterations including oxidative stress and lipid peroxidation. However, in the context of developmental origin of health and disease, putative trans-generational effect of exposure to pesticides are insufficiently studied. We therefore aimed to evaluate the biochemical effect of gestational exposure to four pesticides on female Wistar rats and their offspring at adult age. We studied 30 female nulliparous Wistar rats divided into 5 equal groups. Group 1 served as the control group and received distilled water while group 2, 3, 4 and 5 received orally pesticide 1 (imidacloprid), pesticide 2 (chlorpyrifos), pesticide 3 (imidacloprid + lambda cyhalothrin) and pesticide 4 (oxamyl) respectively once daily throughout gestation at a dose equivalent to 1/10 lethal dose 50. The mothers were followed up until one month post gestation. The offspring were followed up from birth until adult age (12 weeks). In all animals at each time point we evaluated malondialdehyde (MDA), oxidative stress and liver function enzymes. There was similar variation of total body weight in all the groups during and after gestation. However, Female Wistar rats of the exposed groups had significant alterations in liver SOD (-30.8% to +64.1%), catalase (-38.8% to -85.7%) and GSH (-29.2% to -86.5%) and; kidney catalase (> 100%), GSH (> 100%). Moreover, MDA, alanine transaminase (ALT) and aspartate transaminase (AST) levels were significantly higher in pesticide exposed rats compared to the control group. Similar alterations in antioxidant enzymes, MDA and liver function enzymes were observed in offspring of treated rats evidenced at weaning and persisting until adult age. Exposure to pesticides causes oxidative stress and lipid peroxidation in exposed female Wistar rats and their offspring. The persistence in offspring at adult age suggests transgenerational adverse effects.

Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D.

Aim: Several biomarkers have been proposed to detect pancreatic ß cell destruction in vivo but so far have not been compared for sensitivity and significance. Methods: We used islet transplantation as a model to compare plasma concentrations of miR-375, 65-kDa subunit of glutamate decarboxylase (GAD65), and unmethylated insulin DNA, measured at subpicomolar sensitivity, and study their discharge kinetics, power for outcome prediction, and detection of graft loss during follow-up. Results: At 60 minutes after transplantation, GAD65 and miR-375 consistently showed near-equimolar and correlated increases proportional to the number of implanted ß cells. GAD65 and miR-375 showed comparable power to predict poor graft outcome at 2 months, with areas under the curve of 0.833 and 0.771, respectively (P = 0.53). Using receiver operating characteristic analysis, we defined likelihood ratios (LRs) for rationally selected result intervals. In GADA-negative recipients (n = 28), GAD65 <4.5 pmol/L (LR = 0.15) and >12.2 pmol/L (LR = ∞) predicted good and poor outcomes, respectively. miR-375 could be used in all recipients irrespective of GAD65 autoantibody status (n = 46), with levels <1.4 pmol/L (LR = 0.14) or >7.6 pmol/L (LR = 9.53) as dual thresholds. The posttransplant surge of unmethylated insulin DNA was inconsistent and unrelated to outcome. Combined measurement of these three biomarkers was also tested as liquid biopsy for ß cell death during 2-month follow-up; incidental surges of GAD65, miR-375, and (un)methylated insulin DNA, alone or combined, were confidently detected but could not be related to outcome. Conclusions: GAD65 and miR-375 performed equally well in quantifying early graft destruction and predicting graft outcome, outperforming unmethylated insulin DNA.

Human herpesvirus 8 infection DNA positivity is associated with low insulin secretion: A case-control study in a sub-Saharan African population with diabetes.

BACKGROUND: Viruses have been considered potential triggers for the development of diabetes. This study assessed insulin secretion and insulin sensitivity in human herpesvirus 8 (HHV8)-infected and uninfected sub-Saharan African people with diabetes. METHODS: In all, 173 people with non-autoimmune diabetes were enrolled consecutively: 124 with type 2 diabetes mellitus (T2DM) and 49 with ketosis-prone diabetes (KPD) admitted in hyperglycemic crisis. Those with KPD were further subdivided into those with new-onset ketotic-phase KPD (n = 34) or non-ketotic phase KPD (n = 15). All participants were screened for HHV8-specific antibodies and genomic DNA. Blood samples were collected for analysis of fasting glucose, HbA1c, lipid profile, and C-peptide, with insulin resistance and secretion estimated by homeostasis model assessment. RESULTS: Among the 173 diabetic participants, 88 (50.9%) were positive for HHV8 antibodies (Ac-HHV8+), including 15 (8.7%) positive for HHV8 DNA (DNA-HHV8+). The seroprevalence of HHV8 was similar between T2DM (55.6%) and KPD (61.2%) subjects. Of those with and without ketotic-phase KPD, 35.3% and 46.7% were Ac-HHV8+, respectively. Body mass index was significantly in lower DNA-HHV8+ than DNA-HHV8- subjects. Low-density lipoprotein and total cholesterol were significantly higher, but C-peptide and homeostatic model assessment of ß-cell function (HOMA-ß) were significantly lower in DNA-HHV8+ than DNA-HHV8- participants. After excluding DNA-HHV8+ participants, triglyceride concentrations were significantly higher in Ac-HHV8+ (n = 73) than Ac-HHV8- (n = 85) subjects. In contrast, HOMA-ß was significantly higher among Ac-HHV8+ than Ac-HHV8- participants. CONCLUSIONS: In the present study, HHV8 DNA positivity was associated with low insulin secretion in this sub-Saharan African diabetes population.

Accelerated Progression to Type 1 Diabetes in the Presence of HLA-A*24 and -B*18 Is 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 occurred independently from older age (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 zinc transporter 8 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.

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.

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.

Correction: Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin:C-Peptide Ratio.

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

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 (AutoDelfia, Perkin-Elmer) with separate methods for proinsulin (in-house TRFIA) and C-peptide (Elecsys, Roche). High-risk multiple autoantibody-positive first-degree 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 (r2 = 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 (rs = -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.

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

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 I 2 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 CRD42016039765.

Genetic risk of type 2 diabetes in populations of the African continent: A systematic review and meta-analyses.

BACKGROUND: Type 2 diabetes (T2D) is growing faster in Africa than anywhere else, driven by the dual effects of genetic and environmental factors. We conducted a systematic review and meta-analyses of published studies on genetic markers of T2D in populations within Africa. METHODS: Multiple databases were searched for studies of genetic variants associated with T2D in populations living in Africa. Studies reporting on the association of a genetic marker with T2D or indicators of glycaemia were included. Data were extracted on study design and characteristics, genetic determinants, effect estimates of associations with T2D. FINDINGS: Overall, 100 polymorphisms in 57 genes have been investigated in relation with T2D in populations within Africa, in 60 studies. Almost all studies used the candidate gene approach, with >88% published during 2006-2014 and 70% (42/60) originating from Tunisia and Egypt. Polymorphisms in ACE, AGRP, eNOS, GSTP1, HSP70-2, MC4R, MTHFR, PHLPP, POL1, TCF7L2, and TNF-α gene were found to be associated with T2D, with overlapping effect on various cardiometabolic traits. The polymorphisms investigated in multiple studies mostly had consistent effects across studies, with only modest or no statistical heterogeneity. Effect sizes were modestly significant [e.g., odd ratio 1.49 (95%CI 1.33-1.66) for TCF7L2 (rs7903146)]. Underpowered genome-wide studies revealed no diabetes risk loci specific to African populations. INTERPRETATION: Current evidence on the genetic markers of T2D in African populations mostly originate from North African countries, is overall scanty and largely insufficient to reliably inform the genetic architecture of T2D across Africa.

Relationship between glycaemic variability and hyperglycaemic clamp-derived functional variables in (impending) type 1 diabetes.

AIMS/HYPOTHESIS: We examined whether measures of glycaemic variability (GV), assessed by continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG), can complement or replace measures of beta cell function and insulin action in detecting the progression of preclinical disease to type 1 diabetes. METHODS: Twenty-two autoantibody-positive (autoAb(+)) first-degree relatives (FDRs) of patients with type 1 diabetes who were themselves at high 5-year risk (50%) for type 1 diabetes underwent CGM, a hyperglycaemic clamp test and OGTT, and were followed for up to 31 months. Clamp variables were used to estimate beta cell function (first-phase [AUC5-10 min] and second-phase [AUC120-150 min] C-peptide release) combined with insulin resistance (glucose disposal rate; M 120-150 min). Age-matched healthy volunteers (n = 20) and individuals with recent-onset type 1 diabetes (n = 9) served as control groups. RESULTS: In autoAb(+) FDRs, M 120-150 min below the 10th percentile (P10) of controls achieved 86% diagnostic efficiency in discriminating between normoglycaemic FDRs and individuals with (impending) dysglycaemia. M 120-150 min outperformed AUC5-10 min and AUC120-150 min C-peptide below P10 of controls, which were only 59-68% effective. Among GV variables, CGM above the reference range was better at detecting (impending) dysglycaemia than elevated SMBG (77-82% vs 73% efficiency). Combined CGM measures were equally efficient as M 120-150 min (86%). Daytime GV variables were inversely correlated with clamp variables, and more strongly with M 120-150 min than with AUC5-10 min or AUC120-150 min C-peptide. CONCLUSIONS/INTERPRETATION: CGM-derived GV and the glucose disposal rate, reflecting both insulin secretion and action, outperformed SMBG and first- or second-phase AUC C-peptide in identifying FDRs with (impending) dysglycaemia or diabetes. Our results indicate the feasibility of developing minimally invasive CGM-based criteria for close metabolic monitoring and as outcome measures in trials.

Fructosamine measurement for diabetes mellitus diagnosis and monitoring: a systematic review and meta-analysis protocol.

INTRODUCTION: Fructosamine is a marker of glucose control reflecting the average glycaemic level over the preceding 2-3 weeks. Fructosamine has not gained as much popularity as glycated haemoglobin (HbA1c) for diabetes mellitus (DM) control monitoring, and the related underlying reasons remain unclear. We aim to search for and summarise available evidence on the accuracy of fructosamine measurements to diagnose and monitor DM. METHODS AND ANALYSIS: This systematic review will include randomised control trials, controlled before-and-after studies, time series designs, cohort studies, case-control studies and cross-sectional surveys reporting the diagnosis and/or monitoring of DM (type 1 DM, type 2 DM and gestational DM) with fructosamine compared with other measures of glycaemia (fasting glucose, oral glucose tolerance test, random glucose, HbA1c), without any language restriction. We will perform electronic searches in PubMed, Scopus and other databases, supplemented with manual searches. Articles published from 1 January 1980 to 30 June 2015 will be eligible for inclusion in this review. Two authors will independently screen, select studies, extract data and assess the risk of bias with discrepancies resolved by consensus. We will assess clinical heterogeneity by examining the types of interventions and outcomes in each study, and pool studies judged to be clinically homogeneous. We will also assess statistical heterogeneity using the χ(2) test of homogeneity and quantify it using the I(2) statistic. Absolute accuracy measures (sensitivity, specificity) will be pooled in a bivariate random-effects model, allowing for intersetting variability. Negative and positive predictive values will be computed for fructosamine, compared with another measure of glycaemia from the pooled estimates of sensitivity and specificity, using Bayes' theorem. ETHICS AND DISSEMINATION: This systematic review will use data from published studies and does not require ethics approval. Findings will be published in a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: PROSPERO (ID=CRD42015015930).

Study of the effect of altitude on the measurement of glycated haemoglobin using point-of-care instruments.

We measured the glycated haemoglobin (HbA1c) levels of a total of 24 non-diabetic volunteers and diabetic patients using a point-of-care (POC) analyser in three Cameroonian cities at different altitudes. Although 12 to 25% of duplicates had more than 0.5% (8 mmol/mol) difference across the sites, HbA1c values correlated significantly (r = 0.89-0.96). Further calibration studies against gold-standard measures are warranted.

Preexisting insulin autoantibodies predict efficacy of otelixizumab in preserving residual ß-cell function in recent-onset type 1 diabetes.

OBJECTIVE: Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose. RESEARCH DESIGN AND METHODS: In the included patients (n = 40 otelixizumab, n = 40 placebo), ß-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization. (Auto)antibodies against insulin (I[A]A), GAD (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A) were determined on stored sera by liquid-phase radiobinding assay. RESULTS: At baseline, only better preserved AUC C-peptide release and higher levels of IAA were associated with better preservation of ß-cell function and lower insulin needs under anti-CD3 treatment. In multivariate analysis, IAA (P = 0.022) or the interaction of IAA and C-peptide (P = 0.013) independently predicted outcome together with treatment. During follow-up, good responders to anti-CD3 treatment (i.e., IAA(+) participants with relatively preserved ß-cell function [≥ 25% of healthy control subjects]) experienced a less pronounced insulin-induced rise in I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3 treatment, and their changes showed no relation to functional outcome. CONCLUSIONS: There is important specificity of IAA among other diabetes autoantibodies to predict good therapeutic response of recent-onset type 1 diabetic patients to anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 diabetes should consider both relatively preserved functional ß-cell mass and presence of IAA as inclusion criteria.

Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients.

CONTEXT AND OBJECTIVE: In preparation of future prevention trials, we aimed to identify predictors of 3-year diabetes onset among oral glucose tolerance test (OGTT)- and hyperglycemic clamp-derived metabolic markers in persistently islet autoantibody positive (autoAb(+)) offspring and siblings of patients with type 1 diabetes (T1D). DESIGN: The design is a registry-based study. SETTING: Functional tests were performed in a hospital setting. PARTICIPANTS: Persistently autoAb(+) first-degree relatives of patients with T1D (n = 81; age 5-39 years). MAIN OUTCOME MEASURES: We assessed 3-year predictive ability of OGTT- and clamp-derived markers using receiver operating characteristics (ROC) and Cox regression analysis. Area under the curve of clamp-derived first-phase C-peptide release (AUC(5-10 min); min 5-10) was determined in all relatives and second-phase release (AUC(120-150 min); min 120-150) in those aged 12-39 years (n = 62). RESULTS: Overall, the predictive ability of AUC(5-10 min) was better than that of peak C-peptide, the best predictor among OGTT-derived parameters (ROC-AUC [95%CI]: 0.89 [0.80-0.98] vs 0.81 [0.70-0.93]). Fasting blood glucose (FBG) and AUC(5-10 min) provided the best combination of markers for prediction of diabetes within 3 years; (ROC-AUC [95%CI]: 0.92 [0.84-1.00]). In multivariate Cox regression analysis, AUC(5-10 min)) (P = .001) was the strongest independent predictor and interacted significantly with all tested OGTT-derived parameters. AUC(5-10 min) below percentile 10 of controls was associated with 50-70% progression to T1D regardless of age. Similar results were obtained for AUC(120-150 min). CONCLUSIONS: Clamp-derived first-phase C-peptide release can be used as an efficient and simple screening strategy in persistently autoAb(+) offspring and siblings of T1D patients to predict impending diabetes.

Association of HLA class II markers with autoantibody-negative ketosis-prone atypical diabetes compared to type 2 diabetes in a population of sub-Saharan African patients.

AIM: We investigated the association of HLA DRB1 and DQB1 alleles, haplotypes and genotypes with unprovoked antibody-negative ketosis-prone atypical diabetes (A(-) KPD) in comparison to type 2 diabetes (T2D). METHODS: A(-) KPD and T2D sub-Saharan African patients aged 19-63 years were consecutively recruited. Patients positive for cytoplasmic islet cell, insulin, glutamic acid decarboxylase or islet antigen-2 autoantibodies were excluded. Odds ratios were obtained via logistic regression after considering alleles with a minimum frequency of 5% in the study population. Bonferroni correction was used in the case of multiple comparisons. RESULTS: Among the 130 participants, 35 (27%) were women and 57 (44%) were A(-) KPD. DRB1 and DQB1 allele frequencies were similar for both A(-) KPD and T2D patients; they did not confer any substantial risk even after considering type 1 diabetes susceptibility and resistance alleles. We found no association between A(-) KPD and the derived DRB1*07-DQB1*02:02 (OR: 0.55 [95%CI: 0.17-1.85], P=0.336); DRB1*11-DQB1*03:01 (OR: 2.42 [95%CI: 0.79-7.42], P=0.123); DRB1*15-DQB1*06:02 (OR: 0.87 [95%CI: 0.39-1.95], P=0.731) and DRB1*03:01-DQB1*02:01 (OR: 1.48 [95%CI: 0.55-3.96], P=0.437) haplotypes. Overall, we did not find any evidence of susceptibility to ketosis associated with DRB1 and DQB1 genotypes (all P>0.05) in A(-) KPD compared to T2D. Similar results were obtained after adjusting the analysis for age and sex. CONCLUSION: Factors other than DRB1 and DQB1 genotype could explain the propensity to ketosis in A(-) KPD. These results need to be confirmed in a larger population with the perspective of improving the classification and understanding of the pathophysiology of A(-) KPD.

Air pollution and risk of type 2 diabetes mellitus: a systematic review and meta-analysis.

AIM: Whether exposure to relatively high levels of air pollution is associated with diabetes occurrence remains unclear. We sought to assess and quantify the association between exposure to major air pollutants and risk of type 2 diabetes. METHODS: PubMed and EMBASE databases (through September 2013) were searched using a combination of terms related to exposure to gaseous (NO2 and NOx) or particulate matter pollutants (PM2.5, PM10 and PM10-2.5) and type 2 diabetes. Descriptive and quantitative information were extracted from selected studies. We used random-effects models meta-analysis to derive overall risk estimates per type of pollutant. RESULTS: We included ten studies (five cross-sectional and five prospective), assessing the effects of air pollutants on the occurrence of diabetes. In prospective investigations, the overall effect on diabetes occurrence was significant for both NO2 (adjusted hazard ratio [HR], 1.13; 95% confidence interval [95%CI], 1.01-1.22; p < 0.001; I(2) = 36.4%, pheterogeneity = 0.208) and PM2.5 (HR, 1.11; 95%CI, 1.03-1.20; p < 0.001; I(2) = 0.0%, pheterogeneity = 0.827). Odds ratios were reported by two cross-sectional studies which revealed similar associations between both NO2 and PM2.5 with type 2 diabetes. Across studies, risk estimates were generally adjusted for age, gender, body mass index and cigarette smoking. CONCLUSIONS: Available evidence supports a prospective association of main air pollutants with an increased risk for type 2 diabetes. This finding may have implications for population-based strategies to reduce diabetes risk.