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SIRT2 knockout exacerbates insulin resistance in high fat-fed mice.
Lantier L, Williams AS, Hughey CC, Bracy DP, James FD, Ansari MA, Gius D, Wasserman DH
(2018) PLoS One 13: e0208634
MeSH Terms: Acetylation, Animals, Diet, High-Fat, Energy Metabolism, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Muscle, Skeletal, Phosphorylation, Proto-Oncogene Proteins c-akt, Sirtuin 2
Show Abstract · Added January 8, 2019
The NAD+-dependent deacetylase SIRT2 is unique amongst sirtuins as it is effective in the cytosol, as well as the mitochondria. Defining the role of cytosolic acetylation state in specific tissues is difficult since even physiological effects at the whole body level are unknown. We hypothesized that genetic SIRT2 knockout (KO) would lead to impaired insulin action, and that this impairment would be worsened in HF fed mice. Insulin sensitivity was tested using the hyperinsulinemic-euglycemic clamp in SIRT2 KO mice and WT littermates. SIRT2 KO mice exhibited reduced skeletal muscle insulin-induced glucose uptake compared to lean WT mice, and this impairment was exacerbated in HF SIRT2 KO mice. Liver insulin sensitivity was unaffected in lean SIRT2 KO mice. However, the insulin resistance that accompanies HF-feeding was worsened in SIRT2 KO mice. It was notable that the effects of SIRT2 KO were largely disassociated from cytosolic acetylation state, but were closely linked to acetylation state in the mitochondria. SIRT2 KO led to an increase in body weight that was due to increased food intake in HF fed mice. In summary, SIRT2 deletion in vivo reduces muscle insulin sensitivity and contributes to liver insulin resistance by a mechanism that is unrelated to cytosolic acetylation state. Mitochondrial acetylation state and changes in feeding behavior that result in increased body weight correspond to the deleterious effects of SIRT2 KO on insulin action.
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16 MeSH Terms
Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery.
Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, Alikhan M, Clements BA, Abumrad NN, Flynn CR
(2019) Gastroenterology 156: 1041-1051.e4
MeSH Terms: Anastomosis, Surgical, Animals, Anticholesteremic Agents, Bariatric Surgery, Bile Acids and Salts, Blood Glucose, Cholestyramine Resin, Diet, High-Fat, Gallbladder, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose Tolerance Test, Ileum, Insulin Resistance, Intestines, Lymph, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Signal Transduction, Verrucomicrobia, Weight Loss
Show Abstract · Added January 4, 2019
BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity.
McDonnell WJ, Koethe JR, Mallal SA, Pilkinton MA, Kirabo A, Ameka MK, Cottam MA, Hasty AH, Kennedy AJ
(2018) Diabetes 67: 2361-2376
MeSH Terms: Adipose Tissue, Animals, CD8-Positive T-Lymphocytes, Complementarity Determining Regions, Diet, High-Fat, Glucose Tolerance Test, Insulin Resistance, Liver, Male, Mice, Obesity, Prostaglandins
Show Abstract · Added March 26, 2019
Adipose tissue (AT) CD4 and CD8 T cells contribute to obesity-associated insulin resistance. Prior studies identified conserved T-cell receptor (TCR) chain families in obese AT, but the presence and clonal expansion of specific TCR sequences in obesity has not been assessed. We characterized AT and liver CD8 and CD4 TCR repertoires of mice fed a low-fat diet (LFD) and high-fat diet (HFD) using deep sequencing of the TCRβ chain to quantify clonal expansion, gene usage, and CDR3 sequence. In AT CD8 T cells, HFD reduced TCR diversity, increased the prevalence of public TCR clonotypes, and selected for TCR CDR3 regions enriched in positively charged and less polarized amino acids. Although TCR repertoire alone could distinguish between LFD- and HFD-fed mice, these properties of the CDR3 region of AT CD8 T cells from HFD-fed mice led us to examine the role of negatively charged and nonpolar isolevuglandin (isoLG) adduct-containing antigen-presenting cells within AT. IsoLG-adducted protein species were significantly higher in AT macrophages of HFD-fed mice; isoLGs were elevated in M2-polarized macrophages, promoting CD8 T-cell activation. Our findings demonstrate that clonal TCR expansion that favors positively charged CDR3s accompanies HFD-induced obesity, which may be an antigen-driven response to isoLG accumulation in macrophages.
© 2018 by the American Diabetes Association.
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MeSH Terms
Increases in bioactive lipids accompany early metabolic changes associated with β-cell expansion in response to short-term high-fat diet.
Seferovic MD, Beamish CA, Mosser RE, Townsend SE, Pappan K, Poitout V, Aagaard KM, Gannon M
(2018) Am J Physiol Endocrinol Metab 315: E1251-E1263
MeSH Terms: Animals, Blood Glucose, Cell Proliferation, Diabetes Mellitus, Type 2, Diet, High-Fat, Insulin Resistance, Insulin-Secreting Cells, Lipid Metabolism, Lipids, Liver, Male, Mice, Muscle, Skeletal, Obesity
Show Abstract · Added April 15, 2019
Pancreatic β-cell expansion is a highly regulated metabolic adaptation to increased somatic demands, including obesity and pregnancy; adult β cells otherwise rarely proliferate. We previously showed that high-fat diet (HFD) feeding induces mouse β-cell proliferation in less than 1 wk in the absence of insulin resistance. Here we metabolically profiled tissues from a short-term HFD β-cell expansion mouse model to identify pathways and metabolite changes associated with β-cell proliferation. Mice fed HFD vs. chow diet (CD) showed a 14.3% increase in body weight after 7 days; β-cell proliferation increased 1.75-fold without insulin resistance. Plasma from 1-wk HFD-fed mice induced β-cell proliferation ex vivo. The plasma, as well as liver, skeletal muscle, and bone, were assessed by LC and GC mass-spectrometry for global metabolite changes. Of the 1,283 metabolites detected, 159 showed significant changes [false discovery rate (FDR) < 0.1]. The majority of changes were in liver and muscle. Pathway enrichment analysis revealed key metabolic changes in steroid synthesis and lipid metabolism, including free fatty acids and other bioactive lipids. Other important enrichments included changes in the citric acid cycle and 1-carbon metabolism pathways implicated in DNA methylation. Although the minority of changes were observed in bone and plasma (<20), increased p-cresol sulfate was increased >4 fold in plasma (the largest increase in all tissues), and pantothenate (vitamin B) decreased >2-fold. The results suggest that HFD-mediated β-cell expansion is associated with complex, global metabolite changes. The finding could be a significant insight into Type 2 diabetes pathogenesis and potential novel drug targets.
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14 MeSH Terms
Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes.
Li Z, Li Y, Overstreet JM, Chung S, Niu A, Fan X, Wang S, Wang Y, Zhang MZ, Harris RC
(2018) Diabetes 67: 1847-1857
MeSH Terms: Albuminuria, Animals, Biomarkers, Crosses, Genetic, Cytokines, Diabetes Mellitus, Type 2, Diabetic Nephropathies, ErbB Receptors, Erlotinib Hydrochloride, Fibrosis, Glomerulonephritis, Hypoglycemic Agents, Insulin Resistance, Kidney, Macrophages, Membrane Transport Modulators, Mice, Knockout, Mice, Mutant Strains, Nitric Oxide Synthase Type III, Oxidative Stress, Protein Kinase Inhibitors, T-Lymphocytes, Transforming Growth Factor alpha
Show Abstract · Added November 9, 2018
Previous studies by us and others have indicated that renal epidermal growth factor receptors (EGFR) are activated in models of diabetic nephropathy (DN) and that inhibition of EGFR activity protects against progressive DN in type 1 diabetes. In this study we examined whether inhibition of EGFR activation would affect the development of DN in a mouse model of accelerated type 2 diabetes (BKS with endothelial nitric oxide knockout [eNOS]). eNOS mice received vehicle or erlotinib, an inhibitor of EGFR tyrosine kinase activity, beginning at 8 weeks of age and were sacrificed at 20 weeks of age. In addition, genetic models inhibiting EGFR activity () and transforming growth factor-α () were studied in this model of DN in type 2 diabetes. Compared with vehicle-treated mice, erlotinib-treated animals had less albuminuria and glomerulosclerosis, less podocyte loss, and smaller amounts of renal profibrotic and fibrotic components. Erlotinib treatment decreased renal oxidative stress, macrophage and T-lymphocyte infiltration, and the production of proinflammatory cytokines. Erlotinib treatment also preserved pancreas function, and these mice had higher blood insulin levels at 20 weeks, decreased basal blood glucose levels, increased glucose tolerance and insulin sensitivity, and increased blood levels of adiponectin compared with vehicle-treated mice. Similar to the aforementioned results, both and diabetic mice also had attenuated DN, preserved pancreas function, and decreased basal blood glucose levels. In this mouse model of accelerated DN, inhibition of EGFR signaling led to increased longevity.
© 2018 by the American Diabetes Association.
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23 MeSH Terms
Insulin resistance is a significant determinant of sarcopenia in advanced kidney disease.
Deger SM, Hewlett JR, Gamboa J, Ellis CD, Hung AM, Siew ED, Mamnungu C, Sha F, Bian A, Stewart TG, Abumrad NN, Ikizler TA
(2018) Am J Physiol Endocrinol Metab 315: E1108-E1120
MeSH Terms: Adult, Body Composition, Cross-Sectional Studies, Female, Glucose, Glucose Clamp Technique, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Muscle, Skeletal, Phosphorylation, Renal Dialysis, Renal Insufficiency, Chronic, Sarcopenia
Show Abstract · Added September 24, 2018
Maintenance hemodialysis (MHD) patients display significant nutritional abnormalities. Insulin is an anabolic hormone with direct effects on skeletal muscle (SM). We examined the anabolic actions of insulin, whole-body (WB), and SM protein turnover in 33 MHD patients and 17 participants without kidney disease using hyperinsulinemic-euglycemic-euaminoacidemic (dual) clamp. Gluteal muscle biopsies were obtained before and after the dual clamp. At baseline, WB protein synthesis and breakdown rates were similar in MHD patients. During dual clamp, controls had a higher increase in WB protein synthesis and a higher suppression of WB protein breakdown compared with MHD patients, resulting in statistically significantly more positive WB protein net balance [2.02 (interquartile range [IQR]: 1.79 and 2.36) vs. 1.68 (IQR: 1.46 and 1.91) mg·kg fat-free mass·min for controls vs. for MHD patients, respectively, P < 0.001]. At baseline, SM protein synthesis and breakdown rates were higher in MHD patients versus controls, but SM net protein balance was similar between groups. During dual clamp, SM protein synthesis increased statistically significantly more in controls compared with MHD patients ( P = 0.03), whereas SM protein breakdown decreased comparably between groups. SM net protein balance was statistically significantly more positive in controls compared with MHD patients [67.3 (IQR: 46.4 and 97.1) vs. 15.4 (IQR: -83.7 and 64.7) μg·100 ml·min for controls and MHD patients, respectively, P = 0.03]. Human SM biopsy showed a positive correlation between glucose and leucine disposal rates, phosphorylated AKT to AKT ratio, and muscle mitochondrial markers in controls but not in MHD patients. Diminished response to anabolic actions of insulin in the stimulated setting could lead to muscle wasting in MHD patients.
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16 MeSH Terms
Acute effects of insulin on circulating natriuretic peptide levels in humans.
Bachmann KN, Deger SM, Alsouqi A, Huang S, Xu M, Ferguson JF, Su YR, Niswender KD, Ikizler TA, Wang TJ
(2018) PLoS One 13: e0196869
MeSH Terms: Adult, Aged, Atrial Natriuretic Factor, Female, Glucose Clamp Technique, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Natriuretic Peptide, Brain, Obesity, Peptide Fragments
Show Abstract · Added April 2, 2019
BACKGROUND - The natriuretic peptide hormones play an important role in salt and blood pressure regulation. In observational studies, obesity and insulin resistance have been consistently associated with lower concentrations of natriuretic peptides. It has been proposed that insulin influences natriuretic peptide production.
OBJECTIVE - We sought to determine the acute effects of insulin administration on natriuretic peptide concentrations.
METHODS - 31 men and women (11 lean, 10 overweight, and 10 obese), ages 30-70 years, without cardiovascular disease or overt diabetes underwent a hyperinsulinemic-euglycemic insulin clamp. Plasma concentrations of N-terminal pro atrial natriuretic peptide (NT-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured at baseline and steady-state (the final 30 minutes of the clamp protocol).
RESULTS - From baseline to steady-state, insulin levels increased from a mean level of 9.5 to 176.7 μU/ml (p<0.001). Over this period, circulating NT-proANP concentrations decreased by 9% (-1933 ng/L, p = 0.01). The changes in NT-proANP did not differ between lean, overweight, and obese individuals. Steady-state NT-proANP levels, adjusted for baseline, were lower in individuals with greater insulin resistance, independent of BMI. In contrast to NT-proANP, NT-proBNP levels did not change significantly during the clamp (p = 0.41).
CONCLUSION - Insulin administration was associated with a moderate decrease in circulating NT-proANP, but not NT-proBNP. The lowest NT-proANP concentrations were found in insulin-resistant individuals. Further investigations are warranted to elucidate potential mechanisms underlying the effects of insulin on the cardiac hormonal axis.
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Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling.
Samovski D, Dhule P, Pietka T, Jacome-Sosa M, Penrose E, Son NH, Flynn CR, Shoghi KI, Hyrc KL, Goldberg IJ, Gamazon ER, Abumrad NA
(2018) Diabetes 67: 1272-1284
MeSH Terms: Animals, CD36 Antigens, CHO Cells, Carbohydrate Metabolism, Cells, Cultured, Cricetinae, Cricetulus, Diabetes Mellitus, Type 2, Female, Glucose, Humans, Insulin, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Receptor, Insulin, Signal Transduction
Show Abstract · Added May 26, 2018
During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.
© 2018 by the American Diabetes Association.
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20 MeSH Terms
The Vasculature in Prediabetes.
Wasserman DH, Wang TJ, Brown NJ
(2018) Circ Res 122: 1135-1150
MeSH Terms: Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Vessels, Cardiovascular Diseases, Combined Modality Therapy, Diabetes Mellitus, Type 2, Diet, Reducing, Disease Progression, Endothelium, Vascular, Extracellular Matrix, Fatty Acids, Nonesterified, Fibrinolysis, Glucose, Humans, Hyperglycemia, Hypoglycemic Agents, Inflammation, Insulin Resistance, Life Style, Metabolic Syndrome, Mice, MicroRNAs, Microcirculation, Muscle, Skeletal, Obesity, Prediabetic State, Risk, Weight Loss
Show Abstract · Added March 26, 2019
The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.
© 2018 American Heart Association, Inc.
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28 MeSH Terms
Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS).
Gao C, Tabb KL, Dimitrov LM, Taylor KD, Wang N, Guo X, Long J, Rotter JI, Watanabe RM, Curran JE, Blangero J, Langefeld CD, Bowden DW, Palmer ND
(2018) Sci Rep 8: 5603
MeSH Terms: Adult, Apolipoprotein A-V, Atherosclerosis, Carrier Proteins, Female, Genetic Linkage, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Resistance, Lipids, Lipoproteins, HDL, Mexican Americans, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides, Whole Exome Sequencing
Show Abstract · Added April 10, 2018
Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h = 0.50), high-density lipoprotein (HDL, h = 0.57), total cholesterol (TC, h = 0.53), and triglyceride (TG, h = 0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, P = 3.67 × 10, LOD = 2.36, MAF = 14.2%). In addition, two correlated SNPs (r = 1.0) rs189547099 (P = 6.31 × 10, LOD = 3.13, MAF = 0.50%) and chr4:157997598 (P = 6.31 × 10, LOD = 3.13, MAF = 0.50%) reached exome-wide significance (P < 9.11 × 10). rs189547099 is an intronic SNP in FNIP2 and SNP chr4:157997598 is intronic in GLRB. Linkage analysis revealed 46 SNPs with a LOD > 3 with the strongest signal at rs1141070 (LOD = 4.30, P = 0.33, MAF = 21.6%) in DFFB. A total of 53 nominally associated variants (P < 5.00 × 10, MAF ≥ 1.0%) were selected for replication in six Mexican-American cohorts (N = 3,280). The strongest signal observed was a synonymous variant (rs1160983, P = 4.44 × 10, MAF = 2.7%) in TOMM40. Beyond primary findings, previously reported lipid loci were fine-mapped using exome sequencing in IRASFS. These results support that exome sequencing complements and extends insights into the genetics of lipid levels.
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17 MeSH Terms