rss-каталоги, яндекс новости rss, habr rss, яндекс новости rss лента, рбк rss, медуза rss, rss новости мира, rss яндекс новости, rss яндекс, rss новости, rbc rss, meduza rss, rss mail ru, адрес rss ленты новостей яндекса, yandex news rss, yandex rss, каталог rss каналов, ixbt rss, rss каналы новостей, rss habr, rss rbc, rss yandex новости, коммерсант rss, lenta.ru rss, яндекс rss, rss yandex новости ссылка, rbc rss канал, rss yandex, rss погода, rss lenta ru, 3dnews ноутбук, rss российские каналы, 3d news rss, военно-промышленный курьер rss, rss лента яндекс, rss рбк, каталог rss, рбк rss канал, яндекс rss новости, список rss лент новостей, rss каталоги, tass rss, rss новости яндекс, список rss каналов, lenta rss, тасс rss, rss ленты новостей, эхо москвы rss, яндекс новости рсс, lenta ru rss, интерфакс rss, yandex новости rss, rss лента новостей яндекс для сайта, новости rss, anekdot ru rss, 3dnews rss, яндекс новости rss ссылка, список rss, анекдоты rss, rss ленты каталог, rbc rss ссылка, рецепты rss, rss каталог, rss каналы ссылки, pikabu rss, лента ру rss, список rss лент, рбк rss лента, rss habrahabr, rss ссылка на яндекс новости, rss lenta, каталог rss лент, tjournal rss, яндекс rss каналы, рбк rss ссылка, rss tass, новости спорта rss, топ rss лент, rss лента яндекс новости, яндекс новости rss xml, rss ленты новостей список, rss канал рбк, rss тасс, rss 3dnews, дождь rss, яндекс новости rss feed, ixbt.com rss, rss лента.ру, rss комсомольская правда, новости яндекс rss, rss.rbc.ru, rss беларусь минск, rss новости кино, rss яндекс новости ссылка, рбк rrs, пикабу rss, каталог rss новостей, rss ленты яндекса, 3dnews ноутбуки, news yandex ru rss, rbc rss feed, комсомольская правда rss, fontanka.ru rss, rss каналы, rss каналы новостей, rss лента новостей, rss новости, новости rss, каталог rss-каналов, каталог rss-лент, каталог rss, россии, заявил, школе, октября, вс, страны, новости, стрельбу, рассказал, сообщил, цена, сообщает, новых, москве, российского, северного, время, украины, коронавируса, пермском, поток, риа, нитка, тысяч, крае, работы, впервые, словам, ученик, мужчине, рф, овсяные, данные, победил, первая, президента, газом, рекордно, медведчук, рост, песков, пермью, рублей, начала, пробег, оценил, представляет, глава, неделю, заполнена, зеленский, отметил, открыл, млрд, covid-19, техническим, хлопья, обмена, города, ребенком, района, рбк, lenta, ссылкой, чтобы, устроил, назвал, пресс-службе, всего, мира, полиция, составил, власти, команды, поселке, других, нефть, подорожали, своем, последний, газопровода, татарстане, некоторые, пострадавший, правила, владимир, понедельник, торгов, появился, rss каналы, rss каналы новостей, rss лента новостей, rss новости, новости rss, каталог rss-каналов, каталог rss-лент, каталог rss, россии, российская, рассказал, октября, команда, сообщает, победу, spirit, рф, team, зеленский, главы, заявил, президента, украины, dota, страны, чемпионат, белоруссии, американской, сообщил, начала, области, путин, свою, выиграла, мира, словам, воскресенье, принудительное, журналистка, турнире, владимир, international, время, полиция, москве, шлеменко, туристов, медведчука, неделе, призвал, прошли, франции, взыскание, объяснил, мкс, рублей, александр, приставы, новости, отравления, дома, данным, lenta, покинул, человек, задержали, facebook, албании, прокомментировал, матче, возможность, него, гибели, компании, место, получил, сша, посол, оценил, совета, поражение, петербуржцы, гусейновым, версию, работы, составила, песков, тасс, всего, краснодар, игре, николя, дела
 
 Diabetes Journal current issueнет даты
Diabetes Journal current issue

 
 
1. Probing {beta}-Cell Biology in Space and TimeЧт, 30 сен[−]
Автор(?)

β-Cells in the islet of Langerhans have a central role in maintaining energy homeostasis. Understanding the physiology of β-cells and other islet cells requires a deep understanding of their structural and functional organization, their interaction with vessels and nerves, the layout of paracrine interactions, and the relationship between subcellular compartments and protein complexes inside each cell. These elements are not static; they are dynamic and exert their biological actions at different scales of time. Therefore, scientists must be able to investigate (and visualize) short- and long-lived events within the pancreas and β-cells. Current technological advances in microscopy are able to bridge multiple spatiotemporal scales in biology to reveal the complexity and heterogeneity of β-cell biology. Here, I briefly discuss the historical discoveries that leveraged microscopes to establish the basis of β-cell anatomy and structure, the current imaging platforms that allow the study of islet and β-cell biology at multiple scales of resolution, and their challenges and implications. Lastly, I outline how the remarkable longevity of structural elements at different scales in biology, from molecules to cells to multicellular structures, could represent a previously unrecognized organizational pattern in developing and adult β-cells and pancreas biology.


2. What Regulates Basal Insulin Secretion and Causes Hyperinsulinemia?Чт, 30 сен[−]
Автор(?)

We hypothesize that basal hyperinsulinemia is synergistically mediated by an interplay between increased oxidative stress and excess lipid in the form of reactive oxygen species (ROS) and long-chain acyl-CoA esters (LC-CoA). In addition, ROS production may increase in response to inflammatory cytokines and certain exogenous environmental toxins that mislead β-cells into perceiving nutrient excess when none exists. Thus, basal hyperinsulinemia is envisioned as an adaptation to sustained real or perceived nutrient excess that only manifests as a disease when the excess demand can no longer be met by an overworked β-cell. In this article we will present a testable hypothetical mechanism to explain the role of lipids and ROS in basal hyperinsulinemia and how they differ from glucose-stimulated insulin secretion (GSIS). The model centers on redox regulation, via ROS, and S-acylation–mediated trafficking via LC-CoA. These pathways are well established in neural systems but not β-cells. During GSIS, these signals rise and fall in an oscillatory pattern, together with the other well-established signals derived from glucose metabolism; however, their precise roles have not been defined. We propose that failure to either increase or decrease ROS or LC-CoA appropriately will disturb β-cell function.


3. Annexin 1 Mimetic Ac2-26 Holds Promise for the Treatment of Diabetic NephropathyЧт, 30 сен[−]
Автор(?)
Нет описания

4. Found in Translation: Novel Insights Into Type 1 Diabetes and {beta}-Cell BiologyЧт, 30 сен[−]
Автор(?)
Нет описания

5. Type 2 Diabetes, Glycemia, and Brain Health: The Complexity of CausalityЧт, 30 сен[−]
Автор(?)
Нет описания

6. Perirenal Fat and Chronic Kidney Disease in Patients With DiabetesЧт, 30 сен[−]
Автор(?)
Нет описания

7. The Attenuation of Diabetic Nephropathy by Annexin A1 via Regulation of Lipid Metabolism Through the AMPK/PPAR{alpha}/CPT1b PathwayЧт, 30 сен[−]
Автор(?)

Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. In this study, we assess the effects of ANXA1 in diabetic mice and proximal tubular epithelial cells (PTECs) treated with high glucose plus palmitate acid (HGPA) and explore the association of ANXA1 with lipid accumulation in patients with DN. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion, and tubulointerstitial lesions in high-fat diet/streptozotocin–induced diabetic mice. ANXA1 deficiency promotes intrarenal lipid accumulation and drives mitochondrial alterations in kidneys. In addition, Ac2-26, an ANXA1 mimetic peptide, has a therapeutic effect against lipid toxicity in diabetic mice. In HGPA-treated human PTECs, ANXA1 silencing causes FPR2/ALX-driven deleterious effects, which suppress phosphorylated Thr172 AMPK, resulting in decreased peroxisome proliferator–activated receptor α and carnitine palmitoyltransferase 1b expression and increased HGPA-induced lipid accumulation, apoptosis, and elevated expression of proinflammatory and profibrotic genes. Last but not least, the extent of lipid accumulation correlates with renal function, and the level of tubulointerstitial ANXA1 expression correlates with ectopic lipid deposition in kidneys of patients with DN. These data demonstrate that ANXA1 regulates lipid metabolism of PTECs to ameliorate disease progression; hence, it holds great potential as a therapeutic target for DN.


8. Prohibitin Inactivation in Adipocytes Results in Reduced Lipid Metabolism and Adaptive Thermogenesis ImpairmentЧт, 30 сен[−]
Автор(?)

Prohibitin-1 (PHB) is a multifunctional protein previously reported to be important for adipocyte function. PHB is expressed on the surface of adipose cells, where it interacts with a long-chain fatty acid (LCFA) transporter. Here, we show that mice lacking PHB in adipocytes (PHB adipocyte [Ad]-knockout [KO]) have a defect in fat tissue accumulation despite having larger lipid droplets in adipocytes due to reduced lipolysis. Although PHB Ad-KO mice do not display glucose intolerance, they are insulin resistant. We show that PHB Ad-KO mice are lipid intolerant due to a decreased capacity of adipocytes for LCFA uptake. Instead, PHB Ad-KO mice have increased expression of GLUT1 in various tissues and use glucose as a preferred energy source. We demonstrate that PHB Ad-KO mice have defective brown adipose tissue, are intolerant to cold, and display reduced basal energy expenditure. Systemic repercussions of PHB inactivation in adipocytes were observed in both males and females. Consistent with lower cellular mitochondrial content and reduced uncoupling protein 1 protein expression, brown adipocytes lacking PHB display decreased proton leak and switch from aerobic metabolism to glycolysis. Treatment of differentiating brown adipocytes with small molecules targeting PHB suppressed mitochondrial respiration and uncoupling. Our results demonstrate that PHB in adipocytes is essential for normal fatty acid uptake, oxidative metabolism, and adaptive thermogenesis. We conclude that PHB inhibition could be investigated as an approach to altering energy substrate utilization.


9. Mutations of NRG4 Contribute to the Pathogenesis of Nonalcoholic Fatty Liver Disease and Related Metabolic DisordersЧт, 30 сен[−]
Автор(?)

Neuregulin 4 (Nrg4), an adipose tissue–enriched endocrine factor, participates in adipocyte-to-hepatocyte communication, eliciting beneficial metabolic effects in nonalcoholic fatty liver disease (NAFLD). We evaluate the physiological roles of NRG4 in humans and unravel the role of NRG4 variants in the pathogenesis of NAFLD and related metabolic disorders. We identified two rare missense mutations—p.R44H and p.E47Q—in the NRG4 EGF-like domain by whole-exome sequencing in 224 severely obese subjects and exome genotyping in 2,388 subjects from the Shanghai Obesity Study. The overexpression animal models showed that wild-type (WT) Nrg4 could attenuate high-fat diet–induced hepatic lipogenesis and improve energy metabolism. Nrg4 E47Q enhanced the protective effect, whereas Nrg4 R44H lost this function. Unlike Nrg4 R44H, Nrg4 E47Q activated the phosphorylation of ErbB4 and negatively regulated de novo lipogenesis through the ErbB4-STAT5-SREBP-1C pathway. The surface plasmon resonance experiments revealed a higher affinity of E47Q Nrg4 than WT to bind ErbB4, while R44H showed no binding. In conclusion, the study suggests that genetic variations in NRG4 could produce mutant proteins with aberrant functions and that impaired or enhanced Nrg4 function could be either a risk factor or a protective factor for NAFLD and associated metabolic disorders.


10. Subcutaneous Adipose Tissue Metabolic Function and Insulin Sensitivity in People With ObesityЧт, 30 сен[−]
Автор(?)

We used stable isotope–labeled glucose and palmitate tracer infusions, a hyperinsulinemic-euglycemic clamp, positron emission tomography of muscles and adipose tissue after [18F]fluorodeoxyglucose and [15O]water injections, and subcutaneous adipose tissue (SAT) biopsy to test the hypotheses that 1) increased glucose uptake in SAT is responsible for high insulin-stimulated whole-body glucose uptake in people with obesity who are insulin sensitive and 2) putative SAT factors thought to cause insulin resistance are present in people with obesity who are insulin resistant but not in those who are insulin sensitive. We found that high insulin-stimulated whole-body glucose uptake in insulin-sensitive participants with obesity was not due to channeling of glucose into SAT but, rather, was due to high insulin-stimulated muscle glucose uptake. Furthermore, insulin-stimulated muscle glucose uptake was not different between insulin-sensitive obese and lean participants even though adipocytes were larger, SAT perfusion and oxygenation were lower, and markers of SAT inflammation, fatty acid appearance in plasma in relation to fat-free mass, and plasma fatty acid concentration were higher in the insulin-sensitive obese than in lean participants. In addition, we observed only marginal or no differences in adipocyte size, SAT perfusion and oxygenation, and markers of SAT inflammation between insulin-resistant and insulin-sensitive obese participants. Plasma fatty acid concentration was also not different between insulin-sensitive and insulin-resistant obese participants, even though SAT was resistant to the inhibitory effect of insulin on lipolysis in the insulin-resistant obese group. These data suggest that several putative SAT factors commonly implicated in causing insulin resistance are normal consequences of SAT expansion unrelated to insulin resistance.


11. Modulation of Glucose Production by Central Insulin Requires IGF-1 Receptors in AgRP NeuronsЧт, 30 сен[−]
Автор(?)
Similar to insulin, central administration of IGF-1 can suppress hepatic glucose production (HGP), but it is unclear whether this effect is mediated via insulin receptors (InsRs) or IGF-1 receptors (IGF-1Rs) in the brain. To this end, we used pharmacologic and genetic approaches in combination with hyperinsulinemic-euglycemic clamps to decipher the role of these receptors in mediating central effects of IGF-1 and insulin on HGP. In rats, we observed that intracerebroventricular (ICV) administration of IGF-1 or insulin markedly increased the glucose infusion rate (GIR) by >50% and suppressed HGP (P < 0.001). However, these effects were completely prevented by preemptive ICV infusion with an IGF-1R and InsR/IGF-1R hybrid (HybridR) blocking antibody. Likewise, ICV infusion of the InsR antagonist, S961, which also can bind HybridRs, interfered with the ability of central insulin, but not IGF-1, to increase the GIR. Furthermore, hyperinsulinemic clamps in mice lacking IGF-1Rs in AgRP neurons revealed ~30% reduction in the GIR in knockout animals, which was explained by an impaired ability of peripheral insulin to completely suppress HGP (P < 0.05). Signaling studies further revealed an impaired ability of peripheral insulin to trigger ribosomal S6 phosphorylation or phosphatidylinositol (3,4,5)-trisphosphate production in AgRP neurons lacking IGF-1Rs. In summary, these data suggest that attenuation of IGF-1R signaling in the mediobasal hypothalamus, and specifically in AgRP neurons, can phenocopy impaired regulation of HGP as previously demonstrated in mice lacking InsRs in these cells, suggesting a previously unappreciated role for IGF-1Rs and/or HybridRs in the regulation of central insulin/IGF-1 signaling in glucose metabolism.

12. The Choline Metabolite TMAO Inhibits NETosis and Promotes Placental Development in GDM of Humans and MiceЧт, 30 сен[−]
Автор(?)

Choline metabolite trimethylamine N-oxide (TMAO) has been recognized as a risk factor of gestational diabetes mellitus (GDM), but its exact role in GDM has not been reported. In this study, we focused on the placenta development to reveal the role of TMAO in GDM. We found that the TMAO levels in peripheral and cord plasma were increased in women with GDM and that TMAO levels were positively correlated with newborn weight and placental thickness. Neutrophil extracellular traps (NETs) in the peripheral and cord plasma and the myeloperoxidase expression in the placenta of women with GDM also increased. NETs could inhibit the proliferation, migration, invasion, and angiogenesis of HTR-8/Svneo cells. However, TMAO not only could inhibit the formation of NETs but also could enhance the biological function of HTR-8/Svneo cells. With induction of GDM in NETs-deficient PAD4–/– and wild-type mice, the placental weight of PAD4–/– mice increased significantly. TMAO feeding also inhibited the formation of NETs and further increased the weight of the placenta and fetuses, and this increase did not affect the placental structure. Our data indicate that higher TMAO levels and the formation of abnormal NETs were associated with GDM. TMAO not only could promote the development of the placenta and fetuses but also could inhibit the formation of NETs.


13. Chronic Antidiabetic Actions of Leptin: Evidence From Parabiosis Studies for a CNS-Derived Circulating Antidiabetic FactorЧт, 30 сен[−]
Автор(?)

We used parabiosis to determine whether the central nervous system (CNS)-mediated antidiabetic effects of leptin are mediated by release of brain-derived circulating factors. Parabiosis was surgically induced at 4 weeks of age, and an intracerebroventricular (ICV) cannula was placed in the lateral cerebral ventricle at 12 weeks of age for ICV infusion of leptin or saline vehicle. Ten days after surgery, food intake, body weight, and blood glucose were measured for 5 consecutive days, and insulin-deficiency diabetes was induced in all rats by a single streptozotocin (STZ) injection (40 mg/kg). Five days after STZ injection, leptin or vehicle was infused ICV for 7 days, followed by 5-day recovery period. STZ increased blood glucose and food intake. Chronic ICV leptin infusion restored normoglycemia in leptin-infused rats while reducing blood glucose by ~27% in conjoined vehicle-infused rats. This glucose reduction was caused mainly by decreased hepatic gluconeogenesis. Chronic ICV leptin infusion also reduced net cumulative food intake and increased GLUT4 expression in skeletal muscle in leptin/vehicle compared with vehicle/vehicle conjoined rats. These results indicate that leptin’s CNS-mediated antidiabetic effects are mediated, in part, by release into the systemic circulation of leptin-stimulated factors that enhance glucose utilization and reduce liver gluconeogenesis.


14. Inhibition of lncRNA TCONS_00077866 Ameliorates the High Stearic Acid Diet-Induced Mouse Pancreatic {beta}-Cell Inflammatory Response by Increasing miR-297b-5p to Downregulate SAA3 ExpressionЧт, 30 сен[−]
Автор(?)

Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on β-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of long noncoding (lnc)RNA TCONS_00077866 (lnc866) in SA-induced β-cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic β-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and β-cell inflammation. According to lncRNA-miRNAs-mRNA coexpression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in β-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced β-cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect β-cells against the effects of SA during the development of type 2 diabetes.


15. Sleeve Gastrectomy Suppresses Hepatic Glucose Production and Increases Hepatic Insulin Clearance Independent of Weight LossЧт, 30 сен[−]
Автор(?)

Bariatric operations induce weight loss, which is associated with an improvement in hepatic steatosis and a reduction in hepatic glucose production. It is not clear whether these outcomes are entirely due to weight loss, or whether the new anatomy imposed by the surgery contributes to the improvement in the metabolic function of the liver. We performed vertical sleeve gastrectomy (VSG) on obese mice provided with a high-fat high-sucrose diet and compared them to diet and weight-matched sham-operated mice (WMS). At 40 days after surgery, VSG-operated mice displayed less hepatic steatosis compared with WMS. By measuring the fasting glucose and insulin levels in the blood vessels feeding and draining the liver, we showed directly that hepatic glucose production was suppressed after VSG. Insulin levels were elevated in the portal vein, and hepatic insulin clearance was elevated in VSG-operated mice. The hepatic expression of genes associated with insulin clearance was upregulated. We repeated the experiment in lean mice and observed that portal insulin and glucagon are elevated, but only insulin clearance is increased in VSG-operated mice. In conclusion, direct measurement of glucose and insulin in the blood entering and leaving the liver shows that VSG affects glucose and insulin metabolism through mechanisms independent of weight loss and diet.


16. Long RNA Sequencing and Ribosome Profiling of Inflamed {beta}-Cells Reveal an Extensive Translatome LandscapeЧт, 30 сен[−]
Автор(?)

Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell–mediated destruction of the insulin-producing pancreatic β-cells. Increasing evidence suggest that the β-cells themselves contribute to their own destruction by generating neoantigens through the production of aberrant or modified proteins that escape central tolerance. We recently demonstrated that ribosomal infidelity amplified by stress could lead to the generation of neoantigens in human β-cells, emphasizing the participation of nonconventional translation events in autoimmunity, as occurring in cancer or virus-infected tissues. Using a transcriptome-wide profiling approach to map translation initiation start sites in human β-cells under standard and inflammatory conditions, we identify a completely new set of polypeptides derived from noncanonical start sites and translation initiation within long noncoding RNA. Our data underline the extreme diversity of the β-cell translatome and may reveal new functional biomarkers for β-cell distress, disease prediction and progression, and therapeutic intervention in T1D.


17. Relationship Between Glycemia and Cognitive Function, Structural Brain Outcomes, and Dementia: A Mendelian Randomization Study in the UK BiobankЧт, 30 сен[−]
Автор(?)

We investigated the relationship between glycemia and cognitive function, brain structure and incident dementia using bidirectional Mendelian randomization (MR). Data were from the UK Biobank (n= ~500,000). Our exposures were genetic instruments for type 2 diabetes (157 variants) and HbA1c (51 variants) and our outcomes were reaction time (RT), visual memory, hippocampal volume (HV), white matter hyperintensity volume (WMHV), and Alzheimer dementia (AD). We also investigated associations between genetic variants for RT (43 variants) and diabetes and HbA1c. We used conventional inverse-variance–weighted (IVW) MR alongside MR sensitivity analyses. Using IVW, genetic liability to type 2 diabetes was not associated with RT (exponentiated β [expβ]= 1.00 [95% CI 1.00; 1.00]), visual memory (expβ= 1.00 [95% CI 0.99; 1.00]), WMHV (expβ= 0.99 [95% CI 0.97; 1.01]), HV (β-coefficient mm3= –2.30 [95% CI –12.39; 7.78]) or AD (odds ratio [OR] 1.15 [95% CI 0.87; 1.52]). HbA1c was not associated with RT (expβ= 1.00 [95% CI 0.99; 1.02]), visual memory (expβ= 0.99 [95% CI 0.96; 1.02]), WMHV (expβ= 1.03 [95% CI 0.88; 1.22]), HV (β= –21.31 [95% CI –82.96; 40.34]), or risk of AD (OR 1.09 [95% CI 0.42; 2.83]). IVW showed that reaction time was not associated with diabetes risk (OR 0.94 [95% CI 0.54; 1.65]), or with HbA1c (β-coefficient mmol/mol= –0.88 [95% CI= –1.88; 0.13]) after exclusion of a pleiotropic variant. Overall, we observed little evidence of causal association between genetic instruments for type 2 diabetes or peripheral glycemia and some measures of cognition and brain structure in midlife.


18. Perirenal Fat Thickness Is Significantly Associated With the Risk for Development of Chronic Kidney Disease in Patients With DiabetesЧт, 30 сен[−]
Автор(?)

Perirenal fat is adjacent to kidneys and active in metabolism and adipokine secretion. We aimed to investigate whether perirenal fat is an independent predictor for chronic kidney disease (CKD) and compared it with total, subcutaneous, or visceral fat in patients with diabetes. Perirenal fat thickness (PRFT) was measured by computed tomography, and total body fat (TBF), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were assessed by DEXA. In cross-sectional analysis, patients with higher PRFT had a lower estimated glomerular filtration rate (eGFR). Multiple linear regression analysis showed a negative correlation between PRFT and eGFR after confounders adjustment. No association between eGFR and TBF, SAT, or VAT was observed. Longitudinally, 190 patients with type 2 diabetes mellitus (T2DM) without CKD at baseline were followed for 2 years. A total of 29 participants developed CKD. After VAT-based multivariate adjustment, each SD (per-SD) increment in baseline PRFT was associated with a higher incidence of CKD (hazard ratio 1.67, 95% CI 1.04–2.68), while TBF, SAT, and VAT were not. Furthermore, PRFT predicted CKD, with a C-statistic (95% CI) of 0.668 (0.562, 0.774), which was higher than that of TPF [0.535 (0.433, 0.637)], SAT [0.526 (0.434, 0.618)], and VAT [0.602 (0.506, 0.698)]. In conclusion, with perirenal fat there was a higher predictive value for CKD than with total, subcutaneous, or visceral fat in T2DM.


19. Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic StressЧт, 30 сен[−]
Автор(?)

Obesity and type 2 diabetes mellitus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, anecdotal evidence contradicts this common belief. Accordingly, obese patients with cardiovascular disease have better prognoses relative to leaner patients with the same diagnoses, whereas treatment of T2DM patients with thiazolidinedione, one of the popular insulin-sensitizer drugs, significantly increases the risk of heart failure. Using mice with skeletal musclespecific ablation of the insulin receptor gene (MIRKO), we addressed this paradox by demonstrating that insulin signaling in skeletal muscles specifically mediated cross talk with the heart, but not other metabolic tissues, to prevent cardiac dysfunction in response to metabolic stress. Despite severe hyperinsulinemia and aggregating obesity, MIRKO mice were protected from myocardial insulin resistance, mitochondrial dysfunction, and metabolic reprogramming in response to diet-induced obesity. Consequently, the MIRKO mice were also protected from myocardial inflammation, cardiomyopathy, and left ventricle dysfunction. Together, our findings suggest that insulin resistance in skeletal muscle functions as a double-edged sword in metabolic diseases.


20. Intraglomerular Dysfunction Predicts Kidney Failure in Type 2 DiabetesЧт, 30 сен[−]
Автор(?)

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (RA) and efferent (RE) arteriolar resistance and intraglomerular pressure (PGLO) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the RA-to-RE ratio and PGLO with ESKD incidence in 237 Pima Indian individuals with T2D who underwent serial measures of GFR (iothalamate) and RPF (p-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants. Of the 237 participants (mean age 42 years, diabetes duration 11 years, and GFR 153 mL/min and median urine albumin–to–creatinine ratio 36 mg/g), 69 progressed to ESKD during a median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing RA-to-RE ratio (HR 4.60, 95% CI 2.55–8.31) or elevated PGLO followed by a rapid decline (HR 2.96, 95% CI 1.45–6.02) strongly predicted incident ESKD. PGLO (R2= 21%, P < 0.0001) and RA-to-RE ratio (R2= 15%, P < 0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression. In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.


21. Contributions of Sodium-Hydrogen Exchanger 1 and Mitogen-Activated Protein Kinases to Enhanced Retinal Venular Constriction to Endothelin-1 in DiabetesЧт, 30 сен[−]
Автор(?)

Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide. However, mechanisms contributing to ET-1–induced constriction of retinal venules are incompletely understood. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca2+) in retinal venular constriction to ET-1 and the impact of diabetes on these signaling molecules. Retinal venules were isolated from control pigs and pigs with streptozocin-induced diabetes for in vitro studies. ET-1–induced vasoconstriction was abolished in the absence of extracellular Ca2+ and sensitive to c-Jun N-terminal kinase (JNK) inhibitor SP600125 but unaffected by extracellular signal–regulated kinase (ERK) inhibitor PD98059, p38 kinase inhibitor SB203580, or broad-spectrum PKC inhibitor Gö 6983. Diabetes (after 2 weeks) enhanced venular constriction to ET-1, which was insensitive to PD98059 and Gö 6983 but was prevented by NHE1 inhibitor cariporide, SB203580, and SP600125. In conclusion, extracellular Ca2+ entry and activation of JNK, independent of ERK and PKC, mediate constriction of retinal venules to ET-1. Diabetes activates p38 MAPK and NHE1, which cause enhanced venular constriction to ET-1. Treatments targeting these vascular molecules may lessen retinal complications in early diabetes.


22. SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in HumansЧт, 30 сен[−]
Автор(?)

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.


23. Profile of Podocyte Translatome During Development of Type 2 and Type 1 Diabetic Nephropathy Using Podocyte-Specific TRAP mRNA RNA-seqЧт, 30 сен[−]
Автор(?)

Podocyte injury is important in development of diabetic nephropathy (DN). Although several studies have reported single-cell-based RNA sequencing (RNA-seq) of podocytes in type 1 DN (T1DN), the podocyte translating mRNA profile in type 2 DN (T2DN) has not previously been compared with that of T1DN. We analyzed the podocyte translatome in T2DN in podocin-Cre; Rosa26fsTRAP; eNOS–/–; db/db mice and compared it with that of streptozotocin-induced T1DN in podocin-Cre; Rosa26fsTRAP; eNOS–/– mice using translating ribosome affinity purification (TRAP) and RNA-seq. More than 125 genes were highly enriched in the podocyte ribosome. More podocyte TRAP genes were differentially expressed in T2DN than in T1DN. TGF-β signaling pathway genes were upregulated, while MAPK pathway genes were downregulated only in T2DN, while ATP binding and cAMP-mediated signaling genes were downregulated only in T1DN. Genes regulating actin filament organization and apoptosis increased, while genes regulating VEGFR signaling and glomerular basement membrane components decreased in both type 1 and type 2 diabetic podocytes. A number of diabetes-induced genes not previously linked to podocyte injury were confirmed in both mouse and human DN. On the basis of differences and similarities in the podocyte translatome in T2DN and T1DN, investigators can identify factors underlying the pathophysiology of DN and novel therapeutic targets to treat diabetes-induced podocyte injury.


24. The Low-Expression Variant of FABP4 Is Associated With Cardiovascular Disease in Type 1 DiabetesЧт, 30 сен[−]
Автор(?)

Fatty acid binding protein 4 (FABP4) is implicated in the pathogenesis of cardiometabolic disorders. Pharmacological inhibition or genetic deletion of FABP4 improves cardiometabolic health and protects against atherosclerosis in preclinical models. As cardiovascular disease (CVD) is common in type 1 diabetes, we examined the role of FABP4 in the development of complications in type 1 diabetes, focusing on a functional, low-expression variant (rs77878271) in the promoter of the FABP4 gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease, and mortality using Cox proportional hazards models for the FABP4 rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G allele of rs77878271 increased the risk of CVD, independent of confounders. Findings were tested for replication in 852 Danish and 3,678 Finnish individuals with type 1 diabetes. In the meta-analysis, each G allele increased the risk of stroke by 26% (P= 0.04), CAD by 26% (P= 0.006), and CVD by 17% (P= 0.003). In Mendelian randomization, a 1-SD unit decrease in FABP4 increased risk of CAD 2.4-fold. Hence, in contrast with the general population, among patients with type 1 diabetes the low-expression G allele of rs77878271 increased CVD risk, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes.


25. Differential DNA Methylation and Expression of miRNAs in Adipose Tissue From Twin Pairs Discordant for Type 2 DiabetesЧт, 30 сен[−]
Автор(?)

The prevalence of type 2 diabetes (T2D) is increasing worldwide, but current treatments have limitations. miRNAs may play a key role in the development of T2D and can be targets for novel therapies. Here, we examined whether T2D is associated with altered expression and DNA methylation of miRNAs using adipose tissue from 14 monozygotic twin pairs discordant for T2D. Four members each of the miR-30 and let-7-families were downregulated in adipose tissue of subjects with T2D versus control subjects, which was confirmed in an independent T2D case-control cohort. Further, DNA methylation of five CpG sites annotated to gene promoters of differentially expressed miRNAs, including miR-30a and let-7a-3, was increased in T2D versus control subjects. Luciferase experiments showed that increased DNA methylation of the miR-30a promoter reduced its transcription in vitro. Silencing of miR-30 in adipocytes resulted in reduced glucose uptake and TBC1D4 phosphorylation; downregulation of genes involved in demethylation and carbohydrate/lipid/amino acid metabolism; and upregulation of immune system genes. In conclusion, T2D is associated with differential DNA methylation and expression of miRNAs in adipose tissue. Downregulation of the miR-30 family may lead to reduced glucose uptake and altered expression of key genes associated with T2D.


26. Pancreatic Differentiation of Stem Cells Reveals Pathogenesis of a Syndrome of Ketosis-Prone DiabetesЧт, 30 сен[−]
Автор(?)

Genetic analysis of an adult patient with an unusual course of ketosis-prone diabetes (KPD) and lacking islet autoantibodies demonstrated a nucleotide variant in the 5'-untranslated region (UTR) of PDX1, a β-cell development gene. When differentiated to the pancreatic lineage, his induced pluripotent stem cells stalled at the definitive endoderm (DE) stage. Metabolomics analysis of the cells revealed that this was associated with leucine hypersensitivity during transition from the DE to the pancreatic progenitor (PP) stage, and RNA sequencing showed that defects in leucine-sensitive mTOR pathways contribute to the differentiation deficiency. CRISPR/Cas9 manipulation of the PDX1 variant demonstrated that it is necessary and sufficient to confer leucine sensitivity and the differentiation block, likely due to disruption of binding of the transcriptional regulator NFY to the PDX1 5'-UTR, leading to decreased PDX1 expression at the early PP stage. Thus, the combination of an underlying defect in leucine catabolism characteristic of KPD with a functionally relevant heterozygous variant in a critical β-cell gene that confers increased leucine sensitivity and inhibits endocrine cell differentiation resulted in the phenotype of late-onset β-cell failure in this patient. We define the molecular pathogenesis of a diabetes syndrome and demonstrate the power of multiomics analysis of patient-specific stem cells for clinical discovery.


27. Issues and EventsЧт, 30 сен[−]
Нет описания


 
Каталог RSS-каналов (RSS-лент) — RSSfeedReader
Top.Mail.Ru
Яндекс.Метрика
© 2009–2021 Михаил Смирнов
Сайт использует cookie и javascript. Никакая личная информация не собирается
Всего заголовков: 27
По категориям:
• Все заголовки
По датам:
• Все заголовки
• 2021-09-30, Чт (27)
По авторам:
• Все заголовки
• Arrojo e Drigo, R (1)
• Ben-Haroush Schyr, R.; Al-Kurd, A.; Moalem, B.; Permyakova, A.; Israeli, H… (1)
• Chen, X.; Mao, Y.; Hu, J.; Han, S.; Gong, L.; Luo, T.; Yang, S.; Qing, H… (1)
• Chen, Y.-L.; Ren, Y.; Rosa, R. H.; Kuo, L.; Hein, T. W (1)
• Corkey, B. E.; Deeney, J. T.; Merrins, M. J (1)
• da Silva, A. A.; Hall, J. E.; Dai, X.; Wang, Z.; Salgado, M. C.; do Carmo… (1)
• Dahlström, E. H.; Saksi, J.; Forsblom, C.; Uglebjerg, N.; Mars, N… (1)
• Farias Quipildor, G.; Mao, K.; Beltran, P. J.; Barzilai, N.; Huffman, D. M (1)
• Gao, Z.; Daquinag, A. C.; Fussell, C.; Djehal, A.; Desaubry, L.; Kolonin, M… (1)
• Garfield, V.; Farmaki, A.-E.; Fatemifar, G.; Eastwood, S. V.; Mathur, R… (1)
• Jia, D.; Zhang, J.; Liu, X.; Andersen, J.-P.; Tian, Z.; Nie, J.; Shi, Y (1)
• Koh, H.-C. E.; van Vliet, S.; Pietka, T. A.; Meyer, G. A.; Razani, B… (1)
• Li, Y.; Jin, L.; Jiang, F.; Yan, J.; Lu, Y.; Yang, Q.; Zhang, Y.; Zhang, H… (1)
• Lin, X.; Zhang, Y.; He, X.; Chen, Y.; Chen, N.; Liu, J.; Wang, M.; Li, Y… (1)
• Lu, H.; Guo, R.; Zhang, Y.; Su, S.; Zhao, Q.; Yu, Y.; Shi, H.; Sun, H… (1)
• Nilsson, E.; Vavakova, M.; Perfilyev, A.; Säll, J.; Jansson, P.-A… (1)
• Nishizaki, H.; Matsuoka, O.; Kagawa, T.; Kobayashi, A.; Watanabe, M… (1)
• Pan, Y.; Zhang, M.-Z.; Harris, R. C (1)
• Roever, L.; Tse, G.; Biondi-Zoccai, G (1)
• Russ, H. A.; Davidson, H. W (1)
• Saulnier, P. J.; Looker, H. C.; Mauer, M.; Najafian, B.; Gand, E.; Ragot, S… (1)
• Srikanth, V (1)
• Thomaidou, S.; Slieker, R. C.; van der Slik, A. R.; Boom, J.; Mulder, F… (1)
• Wang, Y.; Niu, A.; Pan, Y.; Cao, S.; Terker, A. S.; Wang, S.; Fan, X.; Toth… (1)
• Wu, L.; Liu, C.; Chang, D.-Y.; Zhan, R.; Zhao, M.; Man Lam, S.; Shui, G… (1)
• Yang, D.; Patel, S.; Szlachcic, W. J.; Chmielowiec, J.; Scaduto, D… (1)