Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and ...zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss.
Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between ...idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1
CD4
T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4
T cells. PD-1
T helper 17 cells are the predominant CD4
T cell subset expressing TGF-β. Coculture of PD-1
CD4
T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4
T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1
CD4
T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
The associations of low (<0.90) and high (>1.40) ankle brachial index (ABI) with risk of all-cause and cardiovascular disease (CVD) mortality have not been examined in a population-based setting.
We ...examined all-cause and CVD mortality in relation to low and high ABI in 4393 American Indians in the Strong Heart Study. Participants had bilateral ABI measurements at baseline and were followed up for 8.3+/-2.2 years (36 589 person-years). Cox regression was used to quantify mortality rates among participants with high and low ABI relative to those with normal ABI (0.90 < or =ABI < or =1.40). Death from all causes occurred in 1022 participants (23.3%; 27.9 deaths per 1000 person-years), and of these, 272 (26.6%; 7.4 deaths per 1000 person-years) were attributable to CVD. Low ABI was present in 216 participants (4.9%), and high ABI occurred in 404 (9.2%). Diabetes, albuminuria, and hypertension occurred with greater frequency among persons with low (60.2%, 44.4%, and 50.1%) and high (67.8%, 49.9%, and 45.1%) ABI compared with those with normal ABI (44.4%, 26.9%, and 36.5%), respectively (P<0.0001). Adjusted risk estimates for all-cause mortality were 1.69 (1.34 to 2.14) for low and 1.77 (1.48 to 2.13) for high ABI, and estimates for CVD mortality were 2.52 (1.74 to 3.64) for low and 2.09 (1.49 to 2.94) for high ABI.
The association between high ABI and mortality was similar to that of low ABI and mortality, highlighting a U-shaped association between this noninvasive measure of peripheral arterial disease and mortality risk. Our data suggest that the upper limit of normal ABI should not exceed 1.40.
Aims/hypothesis The aim of the study was to examine the association of existing diabetes (i.e. already diagnosed prior to pregnancy), gestational diabetes and glycosuria (both diagnosed and ...ascertained during pregnancy) with birthweight and future offspring BMI, waist circumference and fat mass (assessed by dual x-ray emission absorptiometry). Methods A prospective pregnancy/birth cohort study was performed using data from the Avon Longitudinal Study of Parents and Children. Results Among 10,591 mother-offspring pairs included in analyses with birth size, women with existing diabetes (n = 40), those diagnosed with gestational diabetes (n = 53) and those with at least two episodes of ++ glycosuria (n = 372) had greater mean birthweight and odds for macrosomia (birthweight > 4,000 g) than women with none of these. Adjusted odds ratios for macrosomia were 3.56 (95% CI 1.53-8.28), 5.50 (95% CI 1.18-10.30) and 1.58 (95% CI 1.18-2.12) for existing diabetes, gestational diabetes and glycosuria, respectively. Among 6,842 mother-offspring pairs with anthropometric measurements at age 9-11 years, maternal gestational diabetes and glycosuria (but not existing diabetes) were associated with increased offspring odds of general or central overweight/obesity. For gestational diabetes, these associations attenuated towards the null with adjustment for maternal prepregnancy BMI, but independent associations remained for glycosuria. The adjusted odds ratio for general overweight/obesity when comparing women with at least two episodes of ++ glycosuria with those with no evidence of diabetes or glycosuria was 1.35 (95% CI 1.00-1.82) and that for central obesity (top 10% waist circumference vs all others) was 1.31 (95% CI 1.00-1.72). Conclusions/interpretation These results provide some evidence for a long-term effect of maternal glycaemia in pregnancy on offspring obesity risk.
Aim
To evaluate the diagnostic and prognostic performance of alternative diagnostic strategies to oral glucose tolerance tests, including random plasma glucose, fasting plasma glucose and HbA1c, ...during the COVID‐19 pandemic.
Methods
Retrospective service data (Cambridge, UK; 17 736 consecutive singleton pregnancies, 2004–2008; 826 consecutive gestational diabetes pregnancies, 2014–2019) and 361 women with ≥1 gestational diabetes risk factor (OPHELIA prospective observational study, UK) were included. Pregnancy outcomes included gestational diabetes (National Institute of Health and Clinical Excellence or International Association of Diabetes and Pregnancy Study Groups criteria), diabetes in pregnancy (WHO criteria), Caesarean section, large‐for‐gestational age infant, neonatal hypoglycaemia and neonatal intensive care unit admission. Receiver‐operating characteristic curves and unadjusted logistic regression were used to compare random plasma glucose, fasting plasma glucose and HbA1c performance.
Results
Gestational diabetes diagnosis was significantly associated with random plasma glucose at 12 weeks area under the receiver‐operating characteristic curve for both criteria 0.81 (95% CI 0.79–0.83), fasting plasma glucose National Institute of Health and Clinical Excellence: area under the receiver‐operating characteristic curve 0.75 (95% CI 0.65–0.85); International Association of Diabetes and Pregnancy Study Groups: area under the receiver‐operating characteristic curve 0.92 (95% CI 0.85–0.98) and HbA1c at 28 weeks' gestation National Institute of Health and Clinical Excellence: 0.83 (95% CI 0.75–0.90); International Association of Diabetes and Pregnancy Study Groups: 0.84 (95% CI 0.77–0.91). Each measure predicts some, but not all, pregnancy outcomes studied. At 12 weeks, ~5% of women would be identified using random plasma glucose ≥8.5 mmol/l (sensitivity 42%; specificity 96%) and at 28 weeks using HbA1c ≥39 mmol/mol (sensitivity 26%; specificity 96%) or fasting plasma glucose ≥5.2–5.4 mmol/l (sensitivity 18–41%; specificity 97–98%).
Conclusions
Random plasma glucose at 12 weeks, and fasting plasma glucose or HbA1c at 28 weeks identify women with hyperglycaemia at risk of suboptimal pregnancy outcomes. These opportunistic laboratory tests perform adequately for risk stratification when oral glucose tolerance testing is not available.
Aims/hypothesis
Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture ...in women and men and compared the risk to that found with other drugs used in diabetes.
Methods
Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999–2008.
Results
There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28;
p
= 3 × 10
−5
), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%).
Conclusions/interpretation
Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.
Highlights ► The nematode Caenorhabditis elegans is an attractive system in which to seek biological mechanisms of decision making. ► Four basic paradigms of behavioral choice, a simple form of ...decision making, have been demonstrated in C. elegans . ► A recent series of pioneering studies has begun to elucidate the neuronal mechanisms of several choice paradigms. ► Peptide signaling seems to play a prominent role in behavioral choice in C. elegans.
Aims/hypothesis
The aim of this study was to examine the prevalence of and risk factors for diabetic retinopathy in people with newly diagnosed type 2 diabetes mellitus, using Scottish national data.
...Methods
We identified individuals diagnosed with type 2 diabetes mellitus in Scotland between January 2005 and May 2008 using data from the national diabetes database. We calculated the prevalence of retinopathy and ORs for risk factors associated with retinopathy at first screening.
Results
Of the 51,526 people with newly diagnosed type 2 diabetes mellitus identified, 91.4% had been screened by 31 December 2010. The median time to first screening was 315 days (interquartile range IQR 111–607 days), but by 2008 the median was 83 days (IQR 51–135 days). The prevalence at first screening of any retinopathy was 19.3%, and for referable retinopathy it was 1.9%. For individuals screened after a year the prevalence of any retinopathy was 20.5% and referable retinopathy was 2.3%. Any retinopathy at screening was associated with male sex (OR 1.19, 95% CI 1.14, 1.25), HbA
1c
(OR 1.07, 95% CI 1.06, 1.08 per 1% 11 mmol/mol increase), systolic BP (OR 1.06, 95% CI 1.05, 1.08 per 10 mmHg increase), time to screening (OR for screening >1 year post diagnosis = 1.12, 95% CI 1.07, 1.17) and obesity (OR 0.87, 95% CI 0.82, 0.93) in multivariate analysis.
Conclusions/interpretation
The prevalence of retinopathy at first screening is lower than in previous UK studies, consistent with earlier diagnosis of diabetes. Most newly diagnosed type 2 diabetic patients in Scotland are screened within an acceptable interval and the prevalence of referable disease is low, even in those with delayed screening.
Aims/hypothesis
To describe the associations between age, sex and BMI at diagnosis of type 2 diabetes, and test the hypothesis that men are diagnosed with diabetes at lower average BMI than women of ...similar age.
Methods
Linear regression was used to estimate and compare the relationship between age and BMI at diagnosis among 51,920 men and 43,137 women included in a population-based diabetes register in Scotland for whom an index BMI measurement was taken within 1 year of diabetes diagnosis. We also examined HbA
1c
values by sex within the same timescale.
Results
Mean BMI closest to date of diagnosis of type 2 diabetes mellitus was 31.83 kg/m
2
(SD 5.13) in men and 33.69 kg/m
2
(SD 6.43) in women. The inverse relationship between age and BMI at diagnosis of type 2 diabetes mellitus was significantly steeper in women than in men (slope estimate in men −0.12 kg/m
2
per year 95% CI −0.13, −0.12 women −0.18 kg/m
2
per year 95% CI −0.18, −0.17,
p
< 0.0001 for formal test of interaction). Mean BMI difference was most marked at younger ages and narrowed with advancing age. However, HbA
1c
levels within 1 year of diagnoses were broadly similar in men and women.
Conclusions/interpretation
Men are diagnosed with type 2 diabetes at lower BMI than women across the age range. This observation may help explain why type 2 diabetes is more common among middle-aged men in populations of European extraction. Whether the same pattern is also observed in other ethnic groups requires confirmation.
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