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Results: 11 to 20 of 1222

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Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo.
Williams IM, McClatchey PM, Bracy DP, Valenzuela FA, Wasserman DH
(2018) Diabetes 67: 1962-1975
MeSH Terms: Animals, Biological Transport, Blood Pressure, Blotting, Western, Glucose, Insulin, Male, Mice, Inbred C57BL, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Transendothelial and Transepithelial Migration
Show Abstract · Added March 26, 2019
Before insulin can stimulate glucose uptake in muscle, it must be delivered to skeletal muscle (SkM) through the microvasculature. Insulin delivery is determined by SkM perfusion and the rate of movement of insulin across the capillary endothelium. The endothelium therefore plays a central role in regulating insulin access to SkM. Nitric oxide (NO) is a key regulator of endothelial function and stimulates arterial vasodilation, which increases SkM perfusion and the capillary surface area available for insulin exchange. The effects of NO on transendothelial insulin efflux (TIE), however, are unknown. We hypothesized that acute reduction of endothelial NO would reduce TIE. However, intravital imaging of TIE in mice revealed that reduction of NO by l--nitro-l-arginine methyl ester (l-NAME) enhanced the rate of TIE by ∼30% and increased total extravascular insulin delivery. This accelerated TIE was associated with more rapid insulin-stimulated glucose lowering. Sodium nitroprusside, an NO donor, had no effect on TIE in mice. The effects of l-NAME on TIE were not due to changes in blood pressure alone, as a direct-acting vasoconstrictor (phenylephrine) did not affect TIE. These results demonstrate that acute NO synthase inhibition increases the permeability of capillaries to insulin, leading to an increase in delivery of insulin to SkM.
© 2018 by the American Diabetes Association.
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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
Glycine -methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates.
Hughey CC, Trefts E, Bracy DP, James FD, Donahue EP, Wasserman DH
(2018) J Biol Chem 293: 11944-11954
MeSH Terms: Animals, Carbon, Citric Acid Cycle, Energy Metabolism, Fatty Liver, Gene Deletion, Gluconeogenesis, Glucose, Glycine N-Methyltransferase, Liver, Male, Metabolic Flux Analysis, Methionine, Mice, Mice, Knockout, S-Adenosylmethionine
Show Abstract · Added March 26, 2019
Glycine -methyltransferase (GNMT) is the most abundant liver methyltransferase regulating the availability of the biological methyl donor, -adenosylmethionine (SAM). Moreover, GNMT has been identified to be down-regulated in hepatocellular carcinoma (HCC). Despite its role in regulating SAM levels and association of its down-regulation with liver tumorigenesis, the impact of reduced GNMT on metabolic reprogramming before the manifestation of HCC has not been investigated in detail. Herein, we used H/C metabolic flux analysis in conscious, unrestrained mice to test the hypothesis that the absence of GNMT causes metabolic reprogramming. GNMT-null (KO) mice displayed a reduction in blood glucose that was associated with a decline in both hepatic glycogenolysis and gluconeogenesis. The reduced gluconeogenesis was due to a decrease in liver gluconeogenic precursors, citric acid cycle fluxes, and anaplerosis and cataplerosis. A concurrent elevation in both hepatic SAM and metabolites of SAM utilization pathways was observed in the KO mice. Specifically, the increase in metabolites of SAM utilization pathways indicated that hepatic polyamine synthesis and catabolism, transsulfuration, and lipogenesis pathways were increased in the KO mice. Of note, these pathways utilize substrates that could otherwise be used for gluconeogenesis. Also, this metabolic reprogramming occurs before the well-documented appearance of HCC in GNMT-null mice. Together, these results indicate that GNMT deletion promotes a metabolic shift whereby nutrients are channeled away from glucose formation toward pathways that utilize the elevated SAM.
© 2018 Hughey et al.
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Engagement with a Text-Messaging Intervention Improves Adherence in Adolescents with Type 1 Diabetes: Brief Report.
Zhang S, Hamburger E, Kahanda S, Lyttle M, Williams R, Jaser SS
(2018) Diabetes Technol Ther 20: 386-389
MeSH Terms: Adolescent, Blood Glucose, Diabetes Mellitus, Type 1, Female, Humans, Hypoglycemic Agents, Insulin, Male, Medication Adherence, Text Messaging, Treatment Outcome
Show Abstract · Added January 30, 2019
Adherence to diabetes management is a challenge for adolescents with type 1 diabetes (T1D). Positive psychology interventions have improved adherence to treatment recommendations in adults with chronic health conditions but have not been widely tested in pediatric populations. We hypothesized that higher engagement with a text-messaging intervention to promote positive affect would increase the effects on diabetes management among adolescents with T1D. Adolescents with T1D (n = 48) and their caregivers were randomized to either an attention control condition or a novel positive psychology intervention delivered through personalized automated text messaging. We examined rates of engagement (percent response to text messages) in relation to demographic factors, and we explored the effect of engagement in relation to adherence and glycemic control. Adolescent engagement was good (mean response rate of 76%) over the 8-week intervention. Engagement was related to adolescents' gender, race, baseline glycemic control, and blood glucose monitoring, but not to treatment type (pump vs. injection), diabetes duration, age, or household income. There was a significant effect of level of engagement on better caregiver-reported adherence, but adolescents' engagement was not related to self-reported adherence or glycemic control. These results indicate feasibility and initial efficacy of using automated text-messaging to deliver an intervention aimed at promoting adherence in adolescents with T1D.
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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
Regional differences in brain glucose metabolism determined by imaging mass spectrometry.
Kleinridders A, Ferris HA, Reyzer ML, Rath M, Soto M, Manier ML, Spraggins J, Yang Z, Stanton RC, Caprioli RM, Kahn CR
(2018) Mol Metab 12: 113-121
MeSH Terms: Adenosine Triphosphate, Animals, Basal Metabolism, Brain, Fasting, Glucose, Glycolysis, Male, Mass Spectrometry, Mice, Mice, Inbred C57BL, Organ Specificity, Pentose Phosphate Pathway
Show Abstract · Added March 26, 2019
OBJECTIVE - Glucose is the major energy substrate of the brain and crucial for normal brain function. In diabetes, the brain is subject to episodes of hypo- and hyperglycemia resulting in acute outcomes ranging from confusion to seizures, while chronic metabolic dysregulation puts patients at increased risk for depression and Alzheimer's disease. In the present study, we aimed to determine how glucose is metabolized in different regions of the brain using imaging mass spectrometry (IMS).
METHODS - To examine the relative abundance of glucose and other metabolites in the brain, mouse brain sections were subjected to imaging mass spectrometry at a resolution of 100 μm. This was correlated with immunohistochemistry, qPCR, western blotting and enzyme assays of dissected brain regions to determine the relative contributions of the glycolytic and pentose phosphate pathways to regional glucose metabolism.
RESULTS - In brain, there are significant regional differences in glucose metabolism, with low levels of hexose bisphosphate (a glycolytic intermediate) and high levels of the pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) and PPP metabolite hexose phosphate in thalamus compared to cortex. The ratio of ATP to ADP is significantly higher in white matter tracts, such as corpus callosum, compared to less myelinated areas. While the brain is able to maintain normal ratios of hexose phosphate, hexose bisphosphate, ATP, and ADP during fasting, fasting causes a large increase in cortical and hippocampal lactate.
CONCLUSION - These data demonstrate the importance of direct measurement of metabolic intermediates to determine regional differences in brain glucose metabolism and illustrate the strength of imaging mass spectrometry for investigating the impact of changing metabolic states on brain function at a regional level with high resolution.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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13 MeSH Terms
Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca Sensitivity of Insulin Secretion Vesicles.
Huang C, Walker EM, Dadi PK, Hu R, Xu Y, Zhang W, Sanavia T, Mun J, Liu J, Nair GG, Tan HYA, Wang S, Magnuson MA, Stoeckert CJ, Hebrok M, Gannon M, Han W, Stein R, Jacobson DA, Gu G
(2018) Dev Cell 45: 347-361.e5
MeSH Terms: Animals, Biological Transport, Calcium, Cell Differentiation, Female, Gene Expression Regulation, Glucose, Humans, Hypoglycemic Agents, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Sweetening Agents, Synaptotagmins
Show Abstract · Added April 17, 2018
Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca concentrations, suggesting differences in the Ca sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca binding paralog of the β cell Ca sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca sensing plays in regulating β cell maturation.
Copyright © 2018 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Cytosolic phosphoenolpyruvate carboxykinase as a cataplerotic pathway in the small intestine.
Potts A, Uchida A, Deja S, Berglund ED, Kucejova B, Duarte JA, Fu X, Browning JD, Magnuson MA, Burgess SC
(2018) Am J Physiol Gastrointest Liver Physiol 315: G249-G258
MeSH Terms: Amino Acids, Animals, Blood Glucose, Cytosol, Energy Metabolism, Gluconeogenesis, Glucose, Intestine, Small, Lipid Metabolism, Mice, Phosphoenolpyruvate Carboxykinase (ATP)
Show Abstract · Added May 1, 2018
Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is a gluconeogenic enzyme that is highly expressed in the liver and kidney but is also expressed at lower levels in a variety of other tissues where it may play adjunct roles in fatty acid esterification, amino acid metabolism, and/or TCA cycle function. PEPCK is expressed in the enterocytes of the small intestine, but it is unclear whether it supports a gluconeogenic rate sufficient to affect glucose homeostasis. To examine potential roles of intestinal PEPCK, we generated an intestinal PEPCK knockout mouse. Deletion of intestinal PEPCK ablated ex vivo gluconeogenesis but did not significantly affect glycemia in chow, high-fat diet, or streptozotocin-treated mice. In contrast, postprandial triglyceride secretion from the intestine was attenuated in vivo, consistent with a role in fatty acid esterification. Intestinal amino acid profiles and C tracer appearance into these pools were significantly altered, indicating abnormal amino acid trafficking through the enterocyte. The data suggest that the predominant role of PEPCK in the small intestine of mice is not gluconeogenesis but rather to support nutrient processing, particularly with regard to lipids and amino acids. NEW & NOTEWORTHY The small intestine expresses gluconeogenic enzymes for unknown reasons. In addition to glucose synthesis, the nascent steps of this pathway can be used to support amino acid and lipid metabolisms. When phosphoenolpyruvate carboxykinase, an essential gluconeogenic enzyme, is knocked out of the small intestine of mice, glycemia is unaffected, but mice inefficiently absorb dietary lipid, have abnormal amino acid profiles, and inefficiently catabolize glutamine. Therefore, the initial steps of intestinal gluconeogenesis are used for processing dietary triglycerides and metabolizing amino acids but are not essential for maintaining blood glucose levels.
3 Communities
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11 MeSH Terms
[F]fallypride characterization of striatal and extrastriatal D receptors in Parkinson's disease.
Stark AJ, Smith CT, Petersen KJ, Trujillo P, van Wouwe NC, Donahue MJ, Kessler RM, Deutch AY, Zald DH, Claassen DO
(2018) Neuroimage Clin 18: 433-442
MeSH Terms: Aged, Aged, 80 and over, Benzamides, Brain Mapping, Corpus Striatum, Dopamine D2 Receptor Antagonists, Female, Fluorodeoxyglucose F18, Humans, Magnetic Resonance Imaging, Male, Parkinson Disease, Positron-Emission Tomography, Receptors, Dopamine D2
Show Abstract · Added March 21, 2018
Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [F]fallypride, a high affinity D receptor ligand, to measure striatal and extrastriatal D nondisplaceable binding potential (BP). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BP reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D receptors, where reduced BP was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.
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14 MeSH Terms