Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, ...homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic CLPP allele: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), or an experimentally demonstrated splice-donor-site mutation, c.270+4A>G. CLPP, a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase encoded by CLPP and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response (UPRmt) stress signaling pathway. Crystal-structure modeling suggests that both substitutions would alter the structure of the CLPP barrel chamber that captures unfolded proteins and exposes them to proteolysis. Together with the previous identification of mutations in HARS2, encoding mitochondrial histidyl-tRNA synthetase, mutations in CLPP expose dysfunction of mitochondrial protein homeostasis as a cause of Perrault syndrome.
Context:
Observational studies report consistent associations between low vitamin D concentration and increased glycemia and risk of type 2 diabetes, but results of randomized controlled trials ...(RCTs) are mixed.
Objective:
The objective of the study was to systematically review RCTs that report on the effects of vitamin D supplementation on glucose homeostasis or diabetes prevention.
Data Sources:
Sources of data for the study were MEDLINE, EMBASE, SCOPUS, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment, and Science Citation Index from inception to June 2013.
Study Selection:
Study selection was trials that compared vitamin D3 supplementation with placebo or a non-vitamin D supplement in adults with normal glucose tolerance, prediabetes, or type 2 diabetes.
Data Extraction and Synthesis:
Two reviewers collected data and assessed trial quality using the Cochrane Risk of Bias tool. Random-effects models were used to estimate mean differences (MDs) and odds ratios. The main outcomes of interest were homeostasis model assessment of insulin resistance, homeostasis model assessment of β-cell function, hemoglobin A1c levels, fasting blood glucose, incident diabetes, and adverse events.
Data Synthesis:
Thirty-five trials (43 407 patients) with variable risk of bias were included. Vitamin D had no significant effects on insulin resistance homeostasis model assessment of insulin resistance: MD −0.04; 95% confidence interval (CI) −0.30 to 0.22, I-squared statistic (I2) = 45%, insulin secretion (homeostasis model of β-cell function: MD 1.64; 95% CI −25.94 to 29.22, I2 = 40%), or hemoglobin A1c (MD −0.05%; 95% CI −0.12 to 0.03, I2 = 55%) compared with controls. Four RCTs reported on the progression to new diabetes and found no effect of vitamin D (odds ratio 1.02; 95% CI 0.94 to 1.10, I2 = 0%). Adverse events were rare, and there was no evidence of publication bias.
Conclusions:
Evidence from available trials shows no effect of vitamin D3 supplementation on glucose homeostasis or diabetes prevention. Definitive conclusions may be limited in the context of the moderate degree of heterogeneity, variable risk of bias, and short-term follow-up duration of the available evidence to date.
Characterizing C+ ions in the Martian ionosphere is important for understanding the history of the Martian atmosphere and surface due to its place in understanding carbon escape. Measuring minor ...ions, like C+, which are close in mass to major atmospheric ions, in this case O+, is difficult, requiring fitting algorithms and accurate background subtraction. Accurate measurement of these species is essential for understanding chemistry and transport in the ionosphere. In this paper, we use data from the Mars Atmospheric and Volatile EvolutioN SupraThermal And Thermal Ion Composition (MAVEN‐STATIC) sensor to report the first C+ fluxes measured in the Martian magnetotail. We will describe a multistep method of background subtraction as well as fitting routines that are used to extract C+ fluxes from a 40‐orbit subset of STATIC data. Our results show tailward fluxes in both optical shadow and the adjacent sunlit magnetotail at high altitudes (> $ > $3,000 km) and Mars‐ward at low altitudes (< $< $2,000 km) in shadow. These local flux values are similar to estimates of neutral carbon fluxes from photochemical escape. However, total carbon loss comparisons will require a more comprehensive study of integrated C+ loss over a larger data set from the Martian magnetotail.
Key Points
C+ fluxes were detected 27% of the time above a 2.2 sigma noise threshold during 40 orbits throughout the Mars magnetotail
Typical C+ fluxes (104 − 105/cm2 s) are 1–2 orders of magnitude lower than either O+ or O2+ fluxes
Fluxes are tailward at altitudes > $ > $3,000 km and Mars‐ward at < $< $2,000 km
Acute-phase biomarkers such as C-reactive protein (CRP) and IL-6 have emerged as predictors of incident type 2 diabetes mellitus, implicating chronic subclinical inflammation as a factor in the ...pathophysiology of diabetes. Gestational diabetes (GDM) identifies a population of women at high risk of subsequent type 2 diabetes mellitus, representing an early stage in the natural history of the disease. In this context, we performed a cross-sectional study to determine whether markers of subclinical inflammation are elevated in patients with GDM. We studied 180 healthy pregnant women undergoing oral glucose tolerance testing in the late second or early third trimester. Based on oral glucose tolerance testing and prepregnancy body mass index (BMI), participants were stratified into four groups: 1) normal glucose tolerance (NGT) lean (BMI, <25 kg/m2) (n = 65); 2) NGT overweight (n = 28); 3) impaired glucose tolerance (n = 39); and 4) GDM (n = 48). Median CRP level was highest in overweight NGT subjects (8.8 mg/liter), followed by GDM (5.5 mg/liter), impaired glucose tolerance (4.4 mg/liter), and lean NGT (4.4 mg/liter) (overall P = 0.0297). CRP was significantly correlated with prepregnancy BMI (r = 0.38, P < 0.0001), followed by fasting insulin (r = 0.27, P = 0.0002) and fasting blood glucose (r = 0.18, P = 0.016). In multivariate linear regression analysis, prepregnancy BMI emerged as the most important determinant of CRP concentration, whereas glycemic tolerance status was not a significant factor. Furthermore, the observed stepwise increase in CRP per tertile of prepregnancy BMI was not significantly attenuated by glycemic tolerance status or factors known to be associated with GDM. In summary, we demonstrate that maternal serum levels of CRP are not related to GDM but rather correlate significantly with prepregnancy obesity. An independent contribution of CRP to risk of GDM could not be confirmed. These data suggest a model in which obesity mediates a systemic inflammatory response, with possible downstream metabolic sequelae, including insulin resistance and glucose dysregulation.
Gout and serum uric acid are associated with mortality but their simultaneous contributions have not been fully evaluated in the general population.
To explore the independent and conjoint ...relationships of gout and uric acid with mortality in the US population.
Mortality risks of gout and serum uric acid were determined for 15 773 participants, aged 20 years or older, in the Third National Health and Nutrition Examination Survey by linking baseline information collected during 1988-1994 with mortality data up to 2006. Multivariable Cox proportional hazards regression determined adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each exposure and all analyses were conducted in 2011 and 2012.
Compared with subjects without a history of gout, the multivariable HR for subjects with gout were 1.42 (CI 1.12-1.82) for total and 1.58 (CI 1.13-2.19) for cardiovascular mortality. Adjusted HRs per 59.5 µmol/l (1 mg/dl) increase in uric acid were 1.16 (CI 1.10-1.22) for total and cardiovascular mortality and this pattern was consistent across disease categories. In the conjoint analysis, the adjusted HRs for mortality in the highest two uric acid quartiles were 1.64 (CI 1.08-2.51) and 1.77 (CI 1.23-2.55), respectively, for subjects with gout, and were 1.09 (CI 0.87-1.37) and 1.37 (CI (1.11-1.70), respectively, for subjects without gout, compared with those without gout in the lowest quartile. A similar pattern emerged for cardiovascular mortality.
Gout and serum uric acid independently associate with total and cardiovascular mortality. These risks increase with rising uric acid concentrations.
OBJECTIVE:-- The objective of the present analysis was to evaluate the association of alanine aminotransferase (ALT) with directly measured insulin sensitivity (Si) in a large, multiethnic cohort of ...U.S. adults and to determine whether ALT adds to existing metabolic risk definitions in identifying subjects with insulin resistance. RESEARCH DESIGN AND METHODS-- Si was directly measured from frequently sampled intravenous glucose tolerance tests among 999 nondiabetic African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years who were participating in the Insulin Resistance Atherosclerosis Study. Subjects also received an oral glucose tolerance test, and fasting insulin, ALT, and alcohol intake were determined. RESULTS:-- ALT was associated with Si after adjustment for age, sex, ethnicity, impaired fasting glucose, triglycerides, HDL, blood pressure, and waist (clinical model) (P < 0.0001). The association remained significant after further adjustment for fasting insulin and impaired glucose tolerance (P = 0.004). In logistic regression analysis, elevated ALT (upper quartile) was associated with insulin resistance (lowest quartile of Si) after adjustment for age, sex, and ethnicity (odds ratio 3.0 95% CI 2.2-4.1). Elevated ALT was independently associated with insulin resistance when included in models with waist circumference, National Cholesterol Education Program criteria for metabolic syndrome, hypertriglyceridemic waist, elevated triglyceride-to-HDL ratio, or homeostasis model assessment of insulin resistance (HOMA-IR) (all P < 0.01). Finally, the addition of elevated ALT improved classification of insulin resistance by area under the receiver operating characteristic curve criteria for all models except HOMA-IR. CONCLUSIONS:-- ALT was associated with insulin resistance independently of conventional and more detailed metabolic measures. These findings suggest that the addition of ALT to existing clinically based metabolic risk definitions is an inexpensive way to improve the identification of subjects with insulin resistance.
Gestational diabetes mellitus (GDM) identifies a population of young women at high risk of developing type 2 diabetes and thus provides an excellent model for studying early events in the natural ...history of this disease. Adiponectin, a novel adipocyte-derived protein with insulin-sensitising properties, has been proposed as a factor linking insulin resistance and beta cell dysfunction in the pathogenesis of type 2 diabetes. We conducted the current investigation to determine whether adiponectin is associated with beta cell dysfunction in GDM.
We studied 180 women undergoing OGTT in late pregnancy. Based on the OGTT results, participants were stratified into three groups: (1) NGT (n=93); (2) IGT (n=39); and (3) GDM (n=48). First-phase insulin secretion was determined using a validated index previously proposed by Stumvoll. Insulin sensitivity was assessed using the validated OGTT insulin sensitivity index of Matsuda and DeFronzo (IS(OGTT)).
To evaluate beta cell function in relation to ambient insulin sensitivity, an insulin secretion-sensitivity index (ISSI) was derived from the product of the Stumvoll index and the IS(OGTT), based on the existence of the predicted hyperbolic relationship between these two measures. Mean ISSI was highest in the NGT group (6,731), followed by that in the IGT group (4,976) and then that in the GDM group (3,300) (overall p<0.0001), compatible with the notion of declining beta cell function across these glucose tolerance groups. Importantly, adiponectin was significantly correlated with ISSI (r=0.34, p<0.0001), with a stepwise increase in mean ISSI observed per tertile of adiponectin concentration (trend p<0.0001). In multivariate linear regression analysis, ISSI was positively correlated with adiponectin and negatively correlated with GDM, IGT and C-reactive protein (r(2)=0.54).
Adiponectin concentration is an independent correlate of beta cell function in late pregnancy. As such, adiponectin may play a key role in mediating insulin resistance and beta cell dysfunction in the pathogenesis of diabetes.
The proliferative response of autoreactive rheumatoid factor (RF) B cells to mammalian chromatin-containing immune complexes (ICs) results from the sequential engagement of the B cell receptor (BCR) ...and Toll-like receptor 9 (TLR9). We have used ICs constructed from anti-hapten antibodies and defined haptenated dsDNA fragments to determine the form of mammalian DNA that mediates this process. Despite their relatively low abundance in mammalian DNA, we found that inclusion of hypomethylated CpG motifs in these ICs was necessary for effective activation. In the absence of antibody, the same fragments could efficiently stimulate low-affinity hapten-specific and DNA-reactive 3H9 B cells, but not RF B cells. These results extend the BCR/TLR9 coengagement paradigm to a second major class of autoreactive B cells, further confirm the critical role of the BCR in chromatin ligand delivery to TLR9, and implicate hypomethylated CpG motifs as ligand elements necessary for the initiation of systemic autoimmune disease.
Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant ...pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth.
Objective: Previous studies reported independent associations of hematological parameters with risk of incident type 2 diabetes, although limited data are available on associations of these ...parameters with insulin resistance (IR) and (especially) pancreatic β-cell dysfunction in large epidemiological studies. Our objective was to evaluate the associations of hematological parameters, including hematocrit (HCT), hemoglobin (Hgb), red blood cell count (RBC), and white blood cell count with IR and β-cell dysfunction in a cohort of nondiabetic subjects at high metabolic risk.
Methods: Nondiabetic subjects (n = 712) were recruited in Toronto and London, Ontario, Canada, between 2004 and 2006, based on the presence of one or more risk factors for type 2 diabetes mellitus including obesity, hypertension, a family history of diabetes, and/or a history of gestational diabetes. Fasting blood samples were collected and oral glucose tolerance tests administered, with additional samples for glucose and insulin drawn at 30 and 120 min. Measures of IR included the homeostasis model assessment (HOMA-IR) and Matsuda’s insulin sensitivity index, whereas measures of β-cell dysfunction included the insulinogenic index divided by HOMA-IR as well as the insulin secretion-sensitivity index-2. Associations of hematological parameters with IR and β-cell dysfunction were assessed using multiple linear regression and analysis of covariance with adjustments for age, gender, ethnicity, smoking, cardiovascular disease, systolic and diastolic blood pressure, and waist circumference.
Results: HOMA-IR increased across quartiles of HCT, Hgb, RBC, and white blood cell count after adjustment for age, gender, ethnicity, and smoking (all P (trend) <0.0001). Similarly, there was a strong stepwise decrease in the Matsuda’s insulin sensitivity index across increasing quartiles of these hematological measures (all P (trend) <0.0001). The associations remained significant after further adjustment for previous cardiovascular disease, blood pressure, and waist circumference (all P (trend) <0.0001). Similarly, there was a strong pattern of decreasing β-cell function across increasing quartiles of all hematological patterns (all P (trend) <0.0001). The findings for HCT, Hgb, and RBC were attenuated slightly after full multivariate adjustment, although the trend across quartiles remained highly significant.
Conclusion: These findings suggest that standard, clinically relevant hematological variables may be related to the underlying pathophysiological changes associated with type 2 diabetes mellitus.
In a large sample of non-diabetic subjects with metabolic risk factors, hematological parameters were significantly associated with insulin sensitivity and β-cell dysfunction, the main physiological disorders underlying type 2 diabetes.
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