Insulin resistance and altered glucose transporter 4 expression in experimental uremia

Aksentijević, Dunja; Bhandari, Sunil; Seymour, Anne-Marie L.

doi:10.1038/ki.2008.691

Cited by 22 publications

(21 citation statements)

References 46 publications

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“…The magnitude of elevation of both serum creatinine and urea in the uremic group at 12 wk was comparable to previous studies (1,66). Uremia was associated with anemia, but not with impaired growth (preserved tibia length) ( Table 1).…”

Section: Uremia Is Associated With Compensated Ventricular Hypertrophsupporting

confidence: 85%

“…Serum urea and creatinine were analyzed at the Clinical Biochemistry Department, Hull Royal Infirmary, Hull and East Yorkshire Hospitals NHS Trust. The homeostasis model assessment-immunoreactivity (HOMA-IR) has been used previously to assess insulin resistance in rat models (1,15) and was calculated by the following equation: HOMA-IR ϭ [fasting serum glucose] ‫ء‬ [fasting serum insulin]/22.5.…”

Section: Hematocrit and Serum Metabolite Analysismentioning

confidence: 99%

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Uremic cardiomyopathy is characterized by loss of the cardioprotective effects of insulin

Semple

Bhandari

Seymour

2012

American Journal of Physiology-Renal Physiology

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Chronic kidney disease is associated with a unique cardiomyopathy, characterized by a combination of structural and cellular remodeling, and an enhanced susceptibility to ischemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway due to insulin resistance. The susceptibility of the uremic heart to ischemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Uremia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischemia was investigated in vitro in control and uremic hearts ± insulin ± rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by (13)C-NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immunoprecipitation. Insulin improved postischemic rate pressure product in control but not uremic hearts, [recovered rate pressure product (%), control 59.6 ± 10.7 vs. 88.9 ± 8.5, P < 0.05; uremic 19.3 ± 4.6 vs. 28.5 ± 10.4, P = ns]. Rosiglitazone resensitized uremic hearts to insulin-mediated cardioprotection [recovered rate pressure product (%) 12.7 ± 7.0 vs. 61.8 ± 15.9, P < 0.05]. Myocardial carbohydrate metabolism remained responsive to insulin in uremic hearts. Uremia was associated with increased phosphorylation of Akt (1.00 ± 0.08 vs. 1.31 ± 0.11, P < 0.05) in normoxia, but no change in postischemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased postischemia in uremic hearts (P < 0.05). Uremia is associated with enhanced susceptibility to ischemia-reperfusion injury and a loss of insulin-mediated cardioprotection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uremic hearts post-ischemia-reperfusion and impaired activation of the reperfusion injury salvage kinase pathway may underlie these findings.

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Section: Uremia Is Associated With Compensated Ventricular Hypertrophsupporting

confidence: 85%

Section: Hematocrit and Serum Metabolite Analysismentioning

confidence: 99%

Uremic cardiomyopathy is characterized by loss of the cardioprotective effects of insulin

Semple

Bhandari

Seymour

2012

American Journal of Physiology-Renal Physiology

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“…Although simple, our study comprises what to our knowledge is the first characterization of human hepatocytes under uremic conditions to date, and it evoked a phenotype surprisingly like that seen in the clinical setting (5,7,11,14) and in rodent models of uremia (1,3,8).…”

Section: Discussionmentioning

confidence: 99%

Changes in gluconeogenesis and intracellular lipid accumulation characterize uremic human hepatocytes ex vivo

Ellis

Johansson

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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It is well known that reduced glomerular filtration rate (GFR) leads to an increased risk of dyslipidemia, insulin resistance, and cardiovascular mortality. The liver is a central organ for metabolism, but its function in the uremic setting is still poorly characterized. We used human primary hepatocytes isolated from livers of nine donors with normal renal function to investigate perturbations in key metabolic pathways following exposure to uremic (n ϭ 8) or healthy (n ϭ 8) sera, and to serum-free control medium. Both uremic and healthy elicited consistent responses from hepatocytes from multiple donors and compared with serum-free control. However, at physiological insulin concentrations, uremic cells accumulated 56% more intracellular lipids. Also, when comparing uremic with healthy medium after culture, it contained more very-low-density lipoprotein-triglyceride and glucose. These changes were accompanied by decreased phosphorylation of AktS473. mRNA levels of key regulators of gluconeogenesis in uremic sera-treated hepatocytes such as phosphoenolpyruvate carboxykinase 1 and glucose 6-phosphate were elevated. We also found increased expression of 11␤-hydroxysteroid dehydrogenase mRNA in uremic cells, along with high phosphorylation of downstream p53 and phospholipase C-␥1Y783. Thus our ex vivo data suggest that the uremic hepatocytes rapidly develop a glycogenic and lipogenic condition accompanied by perturbations in a large number of signaling networks.human primary hepatocytes; kidney disease; dyslipidemia; insulin signaling REGARDLESS OF ETIOLOGY, the loss of renal function (uremia) is also a state of dyslipidemia (7) and insulin resistance (5, 11). Despite that nondiabetic uremic patients are commonly euglycemic, they exhibit increased circulating insulin levels and impaired glucose disposal rate (5, 11). Furthermore, circulating lipids in uremic subjects are prevalently characterized by an elevated presence of triglycerides (TGs), a reduced highdensity lipoprotein (HDL) concentration, and increased lowdensity lipoprotein (LDL) concentration (7, 11).Notwithstanding its central role in metabolism, relatively little is known about hepatic function under conditions of impaired renal functionality. Indirect measures appear to show a normal glucose uptake and glycogen synthesis rate in the uremic liver (5), whereas decreased levels of hepatic lecithincholesterol acyltransferase (LCAT) have been linked to low circulating HDL in the same patient group (10).Recently, Chapagain et al. (3) reported a central role for elevated hepatic 11␤-hydroxysteroid dehydrogenase (HSD) type 1, a determinant of intracellular cortisone signaling, in the development of insulin resistance and dyslipidemia in two nondiabetic rodent models of uremia. Notably, short-term administration of carbenoxolone, a specific 11␤-HSD1 inhibitor, resulted in normalization of glucose tolerance and circulating insulin levels, along with an altered hepatic expression of gluconeogenic and lipogenic genes.Despite these advances, our understanding of th...

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“…Evidence from animal studies has shown that kidney failure led to hyperglycemia and hyperinsulinemia 44,45…”

Section: Mets and Kidney Disease: A Bidirectional Relationship?mentioning

confidence: 99%

Relationship between chronic kidney disease and metabolic syndrome: current perspectives

Nashar¹,

Egan²

2014

DMSO

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Both metabolic syndrome (MetS) and chronic kidney disease (CKD) are increasing in incidence and lead to significant cardiovascular morbidity and mortality. The relationship between these two entities is complex. Individual components of the MetS are known risk factors for incident kidney disease, but it is not clear how the clustering of these components is linked to the development and progression of kidney disease. Cross-sectional studies show an association of the MetS and prevalent CKD; however, one cannot draw conclusions as to which came first – the MetS or the kidney disease. Observational studies suggest a relationship between MetS and incident CKD, but they also demonstrate the development of MetS in patients with established CKD. These observations suggest a bidirectional relationship. A better understanding of the relationship between components of the MetS and whether and how these components contribute to progression of CKD and incident cardiovascular disease could inform more effective prevention strategies.

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Insulin resistance and altered glucose transporter 4 expression in experimental uremia

Cited by 22 publications

References 46 publications

Uremic cardiomyopathy is characterized by loss of the cardioprotective effects of insulin

Uremic cardiomyopathy is characterized by loss of the cardioprotective effects of insulin

Changes in gluconeogenesis and intracellular lipid accumulation characterize uremic human hepatocytes ex vivo

Relationship between chronic kidney disease and metabolic syndrome: current perspectives

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