Akt links insulin signaling to albumin endocytosis in proximal tubule epithelial cells

Diabetes mellitus (DM) has become an epidemic, causing a significant decline in quality of life of individuals due to its multisystem involvement. Kidney is an important target organ in DM accounting for the majority of patients requiring renal replacement therapy at dialysis units. Microalbuminuria (MA) has been a valuable tool to predict end-organ damage in DM but its low sensitivity has driven research efforts to seek other alternatives. Albumin is taken up by albumin receptors, megalin and cubilin in the proximal tubule epithelial cells. We demonstrated that insulin at physiological concentrations induce albumin endocytosis through activation of protein kinase B (Akt) in proximal tubule epithelial cells. Inhibition of Akt by a phosphorylation deficient construct abrogated insulin induced albumin endocytosis suggesting a role for Akt in insulin-induced albumin endocytosis. Furthermore we demonstrated a novel interaction between Akt substrate 160kDa (AS160) and cytoplasmic tail of megalin. Mice with type 1 DM (T1D) displayed decreased Akt, megalin, cubilin and AS160 expression in their kidneys in association with urinary cubilin shedding preceding significant MA. Patients with T1D who have developed MA in the EDC (The Pittsburgh Epidemiology of Diabetes Complications) study demonstrated urinary cubilin shedding prior to development of MA. We hypothesize that perturbed insulin-Akt cascade in DM leads to alterations in trafficking of megalin and cubilin, which results in urinary cubilin shedding as a prelude to MA in early diabetic nephropathy. We propose that utilization of urinary cubilin shedding, as a urinary biomarker, will allow us to detect and intervene in diabetic nephropathy (DN) at an earlier stage. Copyright

Type A behavior and risk of all-cause mortality, CAD, and CAD-related mortality, in a type 1 diabetes population: 22 years of follow-up in the Pittsburgh Epidemiology of Diabetes Complications Study

Objective To determine whether type A behavior predicts all cause mortality and incident coronary artery disease (CAD) in a type 1 diabetes population. Research Design and Methods Twenty-two year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood onset type 1 diabetes were analyzed for the 506 participants who completed the Bortner Rating Scale (measuring type A myocardial infarction as determined by hospital records/ Q waves on ECG, CAD death behavior) and Beck’s Depression Inventory (BDI) at baseline (1986-1988). CAD comprised (determined by a mortality classification committee), angiographic stenosis, ischemic ECG and angina. Results There were 128 deaths (25.3%) during follow-up. Univariate analysis showed an inverse relationship between Bortner scores and all cause mortality (p=0.01) which remained significant after allowing for age, sex, duration, HbA1c, education, smoking, BMI, and physical activity (p=0.03). However, the addition of BDI scores attenuated the relationship (p=0.11) with a significant interaction (p=0.03) such that any protective effect against mortality was limited among individuals with lower BDI scores (bottom 3 quintiles) (p=0.07), while no effect was seen in those with higher BDI (p=0.97). Bortner scores showed only a borderline association with incident CAD (p=0.09). Conclusions Those with higher type A behavior have lower all-cause mortality in our type 1 diabetes population, an effect that interacts with depressive symptomatology such that it is only operative in those with low BDI scores. Further research should focus on understanding this interaction

Risk of longer-term neurological conditions in the Deepwater Horizon Oil Spill Coast Guard Cohort Study – Five years of follow-up

Background: Long-term neurological health risks associated with oil spill cleanup exposures are largely unknown. We aimed to investigate risks of longer-term neurological conditions among U.S. Coast Guard (USCG) responders to the 2010 Deepwater Horizon (DWH) oil spill. Methods: We used data from active duty members of the DWH Oil Spill Coast Guard Cohort Study (N=45224). Self-reported oil spill exposures were ascertained from post-deployment surveys. Incident neurological outcomes were classified using International Classification of Diseases, 9th Revision, codes from military health encounter records up to 5.5 years post-DWH. We used Cox Proportional Hazards regression to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for various incident neurological diagnoses (2010–2015). Oil spill responder (n=5964) vs. non-responder (n= 39260) comparisons were adjusted for age, sex, and race, while within-responder comparisons were additionally adjusted for smoking. Results: Compared to those not responding to the spill, spill responders had reduced risks for headache (aHR=0.84, 95% CI: 0.74-0.96), syncope and collapse (aHR=0.74, 95% CI: 0.56-0.97), and disturbance of skin sensation (aHR=0.81, 95% CI: 0.68-0.96). Responders reporting ever (n=1068) vs. never (n=2424) crude oil inhalation exposure were at increased risk for several individual and grouped outcomes related to headaches and migraines (aHR range: 1.39-1.83). Crude oil inhalation exposure was also associated with elevated risks for an inflammatory nerve condition, mononeuritis of upper limb and mononeuritis multiplex (aHR=1.71, 95% CI: 1.04-2.83), and tinnitus (aHR=1.91, 95% CI: 1.23-2.96), a condition defined by ringing in one or both ears. Risk estimates for those neurological conditions were higher in magnitude among responders reporting exposure to both crude oil and oil dispersants than among those reporting crude oil only. Conclusion: In this large study of active duty USCG responders to the DWH disaster, self-reported spill cleanup exposures were associated with elevated risks for longer-term neurological conditions

The interactive role of type 2 diabetes mellitus and E-selectin S128R mutation on susceptibility to coronary heart disease

<p>Abstract</p> <p>Background</p> <p>The role of gene-environment interactions as risk factors for coronary heart disease (CAD) remains largely undefined. Such interactions may involve gene mutations and disease conditions such as type 2 diabetes mellitus (DM2) predisposing individuals to acquiring the disease.</p> <p>Methods</p> <p>In the present study, we assessed the possible interactive effect of DM2 and E-selectin S128R polymorphism with respect to its predisposing individuals to CAD, using as a study model a population of 1,112 patients and 427 angiographed controls of Saudi origin. E-selectin genotyping was accomplished by polymerase chain reaction (PCR) amplification followed by <it>Pst</it>I restriction enzyme digestion.</p> <p>Results</p> <p>The results show that DM2 is an independent risk factor for CAD. In the absence of DM2, the presence of the R mutant allele alone is not significantly associated with CAD (p = 0.431, OR 1.28). In contrast, in the presence of DM2 and the S allele, the likelihood of an individual acquiring CAD is significant (odds ratio = 5.44; p = < 0.001). This effect of DM2 becomes remarkably greater in the presence of the mutant 128R allele, as can be observed from the odds ratio of their interaction term (odds ratio = 6.11; p = < 0.001).</p> <p>Conclusion</p> <p>Our findings indicate therefore that the risk of acquiring CAD in patients with DM2 increases significantly in the presence of the 128R mutant allele of the E-selectin gene.</p

A comparison of dietary patterns derived by cluster and principal components analysis in a UK cohort of children

Background/Objectives: The objective of this study was to identify dietary patterns in a cohort of 7-year-old children through cluster analysis, compare with patterns derived by principal components analysis (PCA), and investigate associations with sociodemographic variables. Subjects/Methods: The main caregivers in the Avon Longitudinal Study of Parents and Children (ALSPAC) recorded dietary intakes of their children (8279 subjects) using a 94-item food frequency questionnaire. Items were then collapsed into 57 food groups. Dietary patterns were identified using k-means cluster analysis and associations with sociodemographic variables examined using multinomial logistic regression. Clusters were compared with patterns previously derived using PCA. Results: Three distinct clusters were derived: Processed (4177 subjects), associated with higher consumption of processed foods and white bread, Plant-based (2065 subjects), characterized by higher consumption of fruit, vegetables and non-white bread, and Traditional British (2037 subjects), associated with higher consumption of meat, vegetables and full-fat milk. Membership of the Processed cluster was positively associated with girls, younger mothers, snacking and older siblings. Membership of the Plant-based cluster was associated with higher educated mothers and vegetarians. The Traditional British cluster was associated with council housing and younger siblings. The three clusters were similar to the three dietary patterns obtained through PCA; each principal component score being higher on average in the corresponding cluster.Conclusions:Both cluster analysis and PCA identified three dietary patterns very similar both in the foods associated with them and sociodemographic characteristics. Both methods are useful for deriving meaningful dietary patterns. © 2011 Macmillan Publishers Limited All rights reserved

Retinal microvascular parameters are not associated with reduced renal function in a study of individuals with type 2 diabetes

Abstract The eye provides an opportunistic “window” to view the microcirculation. There is published evidence of an association between retinal microvascular calibre and renal function measured by estimated glomerular filtration rate (eGFR) in individuals with diabetes mellitus. Beyond vascular calibre, few studies have considered other microvascular geometrical features. Here we report novel null findings for measures of vascular spread (vessel fractal dimension), tortuosity, and branching patterns and their relationship with renal function in type 2 diabetes over a mean of 3 years. We performed a nested case-control comparison of multiple retinal vascular parameters between individuals with type 2 diabetes and stable (non-progressors) versus declining (progressors) eGFR across two time points within a subset of 1072 participants from the GoDARTS study cohort. Retinal microvascular were measured using VAMPIRE 3.1 software. In unadjusted analyses and following adjustment for age, gender, systolic blood pressure, HbA1C, and diabetic retinopathy, no associations between baseline retinal vascular parameters and risk of eGFR progression were observed. Cross-sectional analysis of follow-up data showed a significant association between retinal arteriolar diameter and eGFR, but this was not maintained following adjustment. These findings are consistent with a lack of predictive capacity for progressive loss of renal function in type 2 diabetes