ResearchPad - endocrine-and-metabolic-conditons-disorders-and-treatments https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Metabolic changes during pregnancy in glucose‐intolerant NZO mice: A polygenic model with prediabetic metabolism]]> https://www.researchpad.co/article/N7d1aff3c-4c37-44e4-a38a-f0102ec2938b The aim of this work was to evaluate metabolic changes during pregnancy within the polygenic NZO mouse model and if it is a suitable one for the human disease. NZO mice showed early alterations in glucose homeostasis and insulin secretion, but no overt diabetes. Interestingly, the preconceptionally impaired glucose tolerance did not deteriorate during gestation despite a proliferation defect of Langerhans islets.

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<![CDATA[Carvedilol and metoprolol are both able to preserve myocardial function in type 2 diabetes]]> https://www.researchpad.co/article/Nc22c2d6a-231f-4c0c-bb28-d9eb3abccb66

Abstract

Purpose

Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as β‐blockers. β‐blocker efficacy is heterogenous, with second generation β‐blocker metoprolol selectively inhibiting β1‐AR, while third generation β‐blocker carvedilol has α1‐AR inhibition, antioxidant, and anti‐apoptotic actions alongside nonselective β‐AR inhibition. These additional properties have led to the hypothesis that carvedilol may improve cardiac contractility in the diabetic heart to a greater extent than metoprolol. The present study aimed to compare the efficacy of metoprolol and carvedilol on myocardial function in animal models and cardiac tissue from patients with type 2 diabetes and preserved ejection fraction.

Methods

Echocardiographic examination of cardiac function and assessment of myocardial function in isolated trabeculae was carried out in patients with and without diabetes undergoing coronary artery bypass grafting (CABG) who were prescribed metoprolol or carvedilol. Equivalent measures were undertaken in Zucker Diabetic Fatty (ZDF) rats following 4 weeks treatment with metoprolol or carvedilol.

Results

Patients receiving carvedilol compared to metoprolol had no difference in cardiac function, and no difference was apparent in myocardial function between β‐blockers. Both β‐blockers similarly improved myocardial function in diabetic ZDF rats treated for 4 weeks, without significantly affecting in vivo cardiac function.

Conclusions

Metoprolol and carvedilol were found to have no effect on cardiac function in type 2 diabetes with preserved ejection fraction, and were similarly effective in preventing myocardial dysfunction in ZDF rats.

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<![CDATA[Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin in db/db diabetic mice]]> https://www.researchpad.co/article/N6cd1cde1-618b-49a8-83b3-032fa1668c80

Abstract

Alteration in renin‐angiotensin system (RAS) has been implicated in the pathophysiology of diabetic kidney disease (DKD). The deleterious actions of angiotensin II (Ang II) could be antagonized by the formation of Ang‐(1–7), generated by the actions of angiotensin‐converting enzyme 2 (ACE2) and neprilysin (NEP). NEP degrades several peptides, including natriuretic peptides, bradykinin, amyloid beta, and Ang I. Although combination of Ang II receptor and NEP inhibitor treatment benefits patients with heart failure, the role of NEP in renal pathophysiology is a matter of active research. NEP pathway is a potent enzyme in Ang I to Ang‐(1–7) conversion in the kidney of ACE2‐deficient mice, suggesting a renoprotective role of NEP. The aim of the study is to test the hypothesis that chronic hyperglycemia downregulates renal NEP protein expression and activity in db/db diabetic mice and treatment with rosiglitazone normalizes hyperglycemia, renal NEP expression, and attenuates albuminuria. Mice received rosiglitazone (20 mg kg−1 day−1) for 10 weeks. Western blot analysis, immunohistochemistry, and enzyme activity revealed a significant decrease in renal and urinary NEP expression and activity in 16‐wk db/db mice compared with lean control (p < .0001). Rosiglitazone also attenuated albuminuria and increased renal and urinary NEP expressions (p < .0001). In conclusion, data support the hypothesis that diabetes decreases intrarenal NEP, which could have a pivotal role in the pathogenesis of DKD. Urinary NEP may be used as an index of intrarenal NEP status. The renoprotective effects of rosiglitazone could be mediated by upregulation of renal NEP expression and activity in db/db diabetic mice.

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<![CDATA[Glucose‐induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs]]> https://www.researchpad.co/article/Na22d6eab-5378-421e-9004-747778d2064f

Abstract

Diabetic complications cause significant morbidity and mortality. Dysfunction of vascular endothelial cells (ECs), caused by oxidative stress, is a main mechanism of cellular damage. Oxidative stress accelerates EC senescence and DNA damage. In this study, we examined the role of mitochondrial sirtuins (SIRTs) in glucose‐induced oxidative stress, EC senescence, and their regulation by miRNAs. Human retinal microvascular endothelial cells (HRECs) were exposed to 5 mmol/L (normoglycemia; NG) or 25 mmol/L glucose (hyperglycemia; HG) with or without transfection of miRNA antagomirs (miRNA‐1, miRNA‐19b, and miRNA‐320; specific SIRT‐targeting miRNAs). Expressions of SIRT3, 4 and 5 and their targeting miRNAs were examined using qRT‐PCR and ELISAs were used to study SIRT proteins. Cellular senescence was investigated using senescence‐associated β‐gal stain; while, oxidative stress and mitochondrial alterations were examined using 8‐OHdG staining and cytochrome B expressions, respectively. A streptozotocin‐induced diabetic mouse model was also used and animal retinas and hearts were collected at 2 months of diabetes. In HRECs, HG downregulated the mRNAs of SIRTs, while SIRT‐targeting miRNAs were upregulated. ELISA analyses confirmed such downregulation of SIRTs at the protein level. HG additionally caused early senescence, endothelial‐to‐mesenchymal transition and oxidative DNA damage in ECs. These changes were prevented by the transfection of specific miRNA antagomirs and by resveratrol. Retinal and cardiac tissues from diabetic mice also showed similar reductions of mitochondrial SIRTs. Collectively, these findings demonstrate a novel mechanism in which mitochondrial SIRTs regulate glucose‐induced cellular aging through oxidative stress and how these SIRTs are regulated by specific miRNAs. Identifying such mechanisms may lead to the discovery of novel treatments for diabetic complications.

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<![CDATA[Hepatic insulin sensitivity is improved in high‐fat diet‐fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis]]> https://www.researchpad.co/article/Ndfc3e4dc-b4b9-4509-b217-fb1c52000c0f

Abstract

Park2 is an E3 ubiquitin ligase known for its role in mitochondrial quality control via the mitophagy pathway. Park2 KO mice are protected from diet‐induced obesity and hepatic insulin sensitivity is improved in high‐fat diet (HFD)‐fed Park2 KO mice even under body weight‐matched conditions. In order to better understand the cellular mechanism by which Park2 KO mice are protected from diet‐induced hepatic insulin resistance, we determined changes in multiple pathways commonly associated with the pathogenesis of insulin resistance, namely levels of bioactive lipid species, activation of the endoplasmic reticulum (ER) stress response and changes in cytokine levels and signaling. We report for the first time that whole‐body insulin sensitivity is unchanged in regular chow (RC)‐fed Park2 KO mice, and that liver diacylglycerol levels are reduced and very‐long‐chain ceramides are increased in Park2 KO mice fed HFD for 1 week. Hepatic transcriptional markers of the ER stress response were reduced and plasma tumor necrosis factor‐α (TNFα), interleukin‐6 and −10 (IL6, IL10) were significantly increased in HFD‐fed Park2 KO mice; however, there were no detectable differences in hepatic inflammatory signaling pathways between groups. Interestingly, hepatic adenylate charge was reduced in HFD‐fed Park2 KO liver and was associated increased activation of AMPK. These data suggest that negative energy balance that contributed to protection from obesity during chronic HFD manifested at the level of the hepatocyte during short‐term HFD feeding and contributed to the improved hepatic insulin sensitivity.

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<![CDATA[Role of lactic acidosis as a mediator of sprint‐mediated nausea]]> https://www.researchpad.co/article/Nccda5935-0d0b-456c-9455-152a0d3d3f2c

Abstract

This study aims to determine whether there is a relationship between nausea level and lactic acidosis during recovery from sprinting. In all, 13 recreationally active males completed a 60 s bout of maximal intensity cycling. Prior to and for 45 min following exercise, blood pH, pCO2, and lactate levels were measured together with nausea. In response to sprinting, nausea, lactate, and H+ concentrations increased and remained elevated for at least 10 min (p < .001), whereas pCO2 increased only transiently (p < .001) before falling below pre‐exercise levels (p < .001), with all these variables returning toward pre‐exercise levels during recovery. Both measures of nausea adopted for analyses (nausea profile, NP; visual analogue scale, VAS), demonstrated significant repeated measures correlation (rmcorr) post‐exercise between nausea and plasma lactate (VAS and NPrrm> 0.595, p < .0001) and H+ concentrations (VAS and NPrrm> 0.689, p < .0001), but an inconsistent relationship with pCO2 (VAS rrm = 0.250, p = .040; NP rrm = 0.144, p = .248) and bicarbonate levels (VAS rrm = −0.252, p = .095; NP rrm = −0.397, p = .008). Linear mixed modeling was used to predict the trajectory of nausea over time, with both lactate and H+ concentrations found to be key predictors of nausea (p < .0001). In conclusion, this study reveals a strong positive relationship between nausea and both H+ and lactate concentrations during recovery from sprinting, a finding consistent with H+ and lactate being potential mediators of nausea post‐sprinting. However, as the timing of the recovery of both H+ and lactate was delayed, compared to that of nausea, further research is required to confirm these findings and investigate other potential mechanisms.

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<![CDATA[Plasma amino acid levels are elevated in young, healthy low birth weight men exposed to short‐term high‐fat overfeeding]]> https://www.researchpad.co/article/5b35f386463d7e4e15c1f832

Abstract

Low birth weight (LBW) individuals exhibit a disproportionately increased, incomplete fatty acid oxidation and a decreased glucose oxidation, compared with normal birth weight (NBW) individuals, and furthermore have an increased risk of developing insulin resistance and type 2 diabetes. We hypothesized that changes in amino acid metabolism may occur parallel to alterations in fatty acid and glucose oxidation, and could contribute to insulin resistance. Therefore, we measured fasting plasma levels of 15 individual or pools of amino acids in 18 LBW and 25 NBW men after an isocaloric control diet and after a 5‐day high‐fat, high‐calorie diet. We demonstrated that LBW and NBW men increased plasma alanine levels and decreased valine and leucine/isoleucine levels in response to overfeeding. Also, LBW men had higher alanine, proline, methionine, citrulline, and total amino acid levels after overfeeding compared with NBW men. Alanine and total amino acid levels tended to be negatively associated with the insulin‐stimulated glucose uptake after overfeeding. Therefore, the higher amino acid levels in LBW men could be a consequence of their reduction in skeletal muscle insulin sensitivity due to overfeeding with a possible increased skeletal muscle proteolysis and/or could potentially contribute to an impaired insulin sensitivity. Furthermore, the alanine level was negatively associated with the plasma acetylcarnitine level and positively associated with the hepatic glucose production after overfeeding. Thus, the higher alanine level in LBW men could be accompanied by an increased anaplerotic formation of oxaloacetate and thereby an enhanced tricarboxylic acid cycle activity and as well an increased gluconeogenesis.

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<![CDATA[Intestine‐specific expression of human chimeric intestinal alkaline phosphatase attenuates Western diet‐induced barrier dysfunction and glucose intolerance]]> https://www.researchpad.co/article/5c09e692d5eed0c484348ee6

Abstract

Intestinal epithelial cell derived alkaline phosphatase (IAP) dephosphorylates/detoxifies bacterial endotoxin lipopolysaccharide (LPS) in the gut lumen. We have earlier demonstrated that consumption of high‐fat high‐cholesterol containing western type‐diet (WD) significantly reduces IAP activity, increases intestinal permeability leading to increased plasma levels of LPS and glucose intolerance. Furthermore, oral supplementation with curcumin that increased IAP activity improved intestinal barrier function as well as glucose tolerance. To directly test the hypothesis that targeted increase in IAP would protect against WD‐induced metabolic consequences, we developed intestine‐specific IAP transgenic mice where expression of human chimeric IAP is under the control of intestine‐specific villin promoter. This chimeric human IAP contains domains from human IAP and human placental alkaline phosphatase, has a higher turnover number, narrower substrate specificity, and selectivity for bacterial LPS. Chimeric IAP was specifically and uniformly overexpressed in these IAP transgenic (IAPTg) mice along the entire length of the intestine. While IAP activity reduced from proximal P1 segment to distal P9 segment in wild‐type (WT) mice, this activity was maintained in the IAPTg mice. Dietary challenge with WD impaired glucose tolerance in WT mice and this intolerance was attenuated in IAPTg mice. Significant decrease in fecal zonulin, a marker for intestinal barrier dysfunction, in WD fed IAPTg mice and a corresponding decrease in translocation of orally administered nonabsorbable 4 kDa FITC dextran to plasma suggests that IAP overexpression improves intestinal barrier function. Thus, targeted increase in IAP activity represents a novel strategy to improve WD‐induced intestinal barrier dysfunction and glucose intolerance.

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