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Publication Record


Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans.
Tamboli RA, Antoun J, Sidani RM, Clements A, Harmata EE, Marks-Shulman P, Gaylinn BD, Williams B, Clements RH, Albaugh VL, Abumrad NN
(2017) Diabetes Obes Metab 19: 1267-1275
MeSH Terms: Acylation, Anti-Obesity Agents, Cohort Studies, Combined Modality Therapy, Cross-Over Studies, Energy Metabolism, Gastric Bypass, Ghrelin, Gluconeogenesis, Glucose Clamp Technique, Human Growth Hormone, Humans, Infusions, Intravenous, Insulin Resistance, Liver, Muscle, Skeletal, Obesity, Morbid, Pancreatic Polypeptide, Pancreatic Polypeptide-Secreting Cells, Pituitary Gland, Anterior, Postoperative Care, Preoperative Care, Protein Precursors, Single-Blind Method
Show Abstract · Added April 3, 2017
AIMS - Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB).
MATERIALS AND METHODS - We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg  min ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp.
RESULTS - Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion.
CONCLUSIONS - These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB.
© 2017 John Wiley & Sons Ltd.
0 Communities
3 Members
0 Resources
24 MeSH Terms
SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration.
Masuzaki R, Zhao S, Valerius MT, Tsugawa D, Oya Y, Ray KC, Karp SJ
(2016) J Biol Chem 291: 3346-58
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Gene Expression Regulation, Growth Hormone, Hepatectomy, Immunohistochemistry, Insulin-Like Growth Factor I, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Mice, Knockout, Pituitary Gland, Protein Transport, Proteolysis, Receptors, Somatotropin, Suppressor of Cytokine Signaling Proteins, Ubiquitination
Show Abstract · Added April 11, 2016
After significant injury, the liver must maintain homeostasis during the regenerative process. We hypothesized the existence of mechanisms to limit hepatocyte proliferation after injury to maintain metabolic and synthetic function. A screen for candidates revealed suppressor of cytokine signaling 2 (SOCS2), an inhibitor of growth hormone (GH) signaling, was strongly induced after partial hepatectomy. Using genetic deletion and administration of various factors we investigated the role of SOCS2 during liver regeneration. SOCS2 preserves liver function by restraining the first round of hepatocyte proliferation after partial hepatectomy by preventing increases in growth hormone receptor (GHR) via ubiquitination, suppressing GH pathway activity. At later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum insulin-like growth factor 1 (IGF-1) that allows GH release from the pituitary. SOCS2, therefore, plays a dual role in modulating the rate of hepatocyte proliferation. In particular, this is the first demonstration of an endogenous mechanism to limit hepatocyte proliferation after injury.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone.
Oropeza D, Jouvet N, Budry L, Campbell JE, Bouyakdan K, Lacombe J, Perron G, Bergeron V, Neuman JC, Brar HK, Fenske RJ, Meunier C, Sczelecki S, Kimple ME, Drucker DJ, Screaton RA, Poitout V, Ferron M, Alquier T, Estall JL
(2015) Diabetes 64: 3798-807
MeSH Terms: Animals, Blood Glucose, Diabetes Mellitus, Experimental, Homeostasis, Human Growth Hormone, Humans, Hyperglycemia, Insulin, Insulin-Secreting Cells, Male, Mice, Mice, Transgenic, Phenotype
Show Abstract · Added August 2, 2016
There is growing concern over confounding artifacts associated with β-cell-specific Cre-recombinase transgenic models, raising questions about their general usefulness in research. The inducible β-cell-specific transgenic (MIP-CreERT(1Lphi)) mouse was designed to circumvent many of these issues, and we investigated whether this tool effectively addressed concerns of ectopic expression and disruption of glucose metabolism. Recombinase activity was absent from the central nervous system using a reporter line and high-resolution microscopy. Despite increased pancreatic insulin content, MIP-CreERT mice on a chow diet exhibited normal ambient glycemia, glucose tolerance and insulin sensitivity, and appropriate insulin secretion in response to glucose in vivo and in vitro. However, MIP-CreERT mice on different genetic backgrounds were protected from high-fat/ streptozotocin (STZ)-induced hyperglycemia that was accompanied by increased insulin content and islet density. Ectopic human growth hormone (hGH) was highly expressed in MIP-CreERT islets independent of tamoxifen administration. Circulating insulin levels remained similar to wild-type controls, whereas STZ-associated increases in α-cell number and serum glucagon were significantly blunted in MIP-CreERT(1Lphi) mice, possibly due to paracrine effects of hGH-induced serotonin expression. These studies reveal important new insight into the strengths and limitations of the MIP-CreERT mouse line for β-cell research.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
0 Communities
1 Members
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13 MeSH Terms
Effects of Antecedent GABA A Receptor Activation on Counterregulatory Responses to Exercise in Healthy Man.
Hedrington MS, Tate DB, Younk LM, Davis SN
(2015) Diabetes 64: 3253-61
MeSH Terms: Adult, Alprazolam, Autonomic Nervous System, Bicycling, Blood Glucose, Epinephrine, Exercise, Female, GABA-A Receptor Agonists, Glucagon, Glucose Clamp Technique, Human Growth Hormone, Humans, Hydrocortisone, Lipolysis, Male, Norepinephrine, Pituitary-Adrenal System, Receptors, GABA-A
Show Abstract · Added July 30, 2015
The aim of this study was to determine whether antecedent stimulation of γ-aminobutyric acid (GABA) A receptors with the benzodiazepine alprazolam can blunt physiologic responses during next-day moderate (90 min) exercise in healthy man. Thirty-one healthy individuals (16 male/15 female aged 28 ± 1 year, BMI 23 ± 3 kg/m(2)) were studied during separate, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hyperinsulinemic-euglycemic or hypoglycemic clamps with or without 1 mg alprazolam given 30 min before a clamp. Day 2 consisted of 90-min euglycemic cycling exercise at 50% VO2max. Despite similar euglycemia (5.3 ± 0.1 mmol/L) and insulinemia (46 ± 6 pmol/L) during day 2 exercise studies, GABA A activation with alprazolam during day 1 euglycemia resulted in significant blunting of plasma epinephrine, norepinephrine, glucagon, cortisol, and growth hormone responses. Lipolysis (glycerol, nonesterified fatty acids) and endogenous glucose production during exercise were also reduced, and glucose infusion rates were increased following prior euglycemia with alprazolam. Prior hypoglycemia with alprazolam resulted in further reduction of glucagon and cortisol responses during exercise. We conclude that prior activation of GABA A pathways can play a significant role in blunting key autonomous nervous system, neuroendocrine, and metabolic physiologic responses during next-day exercise in healthy man.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
0 Communities
0 Members
2 Resources
19 MeSH Terms
Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression.
Brouwers B, de Faudeur G, Osipovich AB, Goyvaerts L, Lemaire K, Boesmans L, Cauwelier EJ, Granvik M, Pruniau VP, Van Lommel L, Van Schoors J, Stancill JS, Smolders I, Goffin V, Binart N, in't Veld P, Declercq J, Magnuson MA, Creemers JW, Schuit F, Schraenen A
(2014) Cell Metab 20: 979-90
MeSH Terms: Animals, Female, Human Growth Hormone, Humans, Islets of Langerhans, Male, Mice, Mice, Transgenic, Receptors, Prolactin, Tryptophan Hydroxylase
Show Abstract · Added December 11, 2014
The human growth hormone (hGH) minigene is frequently used in the derivation of transgenic mouse lines to enhance transgene expression. Although this minigene is present in the transgenes as a secondcistron, and thus not thought to be expressed, we found that three commonly used lines, Pdx1-Cre(Late), RIP-Cre, and MIP-GFP, each expressed significant amounts of hGH in pancreatic islets. Locally secreted hGH binds to prolactin receptors on β cells, activates STAT5 signaling, and induces pregnancy-like changes in gene expression, thereby augmenting pancreatic β cell mass and insulin content. In addition, islets of Pdx1-Cre(Late) mice have lower GLUT2 expression and reduced glucose-induced insulin release and are protected against the β cell toxin streptozotocin. These findings may be important when interpreting results obtained when these and other hGH minigene-containing transgenic mice are used.
Copyright © 2014 Elsevier Inc. All rights reserved.
2 Communities
2 Members
0 Resources
10 MeSH Terms
Sorption and mineral-promoted transformation of synthetic hormone growth promoters in soil systems.
Qu S, Kolodziej EP, Cwiertny DM
(2014) J Agric Food Chem 62: 12277-86
MeSH Terms: Adsorption, Growth Hormone, Kinetics, Melengestrol Acetate, Minerals, Oxidation-Reduction, Soil, Soil Pollutants, Trenbolone Acetate, Zeranol
Show Abstract · Added December 4, 2014
This work examines the fate of synthetic growth promoters (trenbolone acetate, melengestrol acetate, and zeranol) in sterilized soil systems, focusing on their sorption to organic matter and propensity for mineral-promoted reactions. In organic-rich soil matrices (e.g., Pahokee Peat), the extent and reversibility of sorption did not generally correlate with compound hydrophobicity (e.g., K(ow) values), suggesting that specific binding interactions (e.g., potentially hydrogen bonding through C17 hydroxyl groups for the trenbolone and melengestrol families) can also contribute to uptake. In soils with lower organic carbon contents (1-5.9% OC), evidence supports sorption occurring in parallel with surface reaction on inorganic mineral phases. Subsequent experiments with pure mineral phases representative of those naturally abundant in soil (e.g., iron, silica, and manganese oxides) suggest that growth promoters are prone to mineral-promoted oxidation, hydrolysis, and/or nucleophilic (e.g., H2O or OH(-)) addition reactions. Although reaction products remain unidentified, this study shows that synthetic growth promoters can undergo abiotic transformation in soil systems, a previously unidentified fate pathway with implications for their persistence and ecosystem effects in the subsurface.
1 Communities
0 Members
0 Resources
10 MeSH Terms
Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice.
Cordoba-Chacon J, Gahete MD, McGuinness OP, Kineman RD
(2014) Am J Physiol Endocrinol Metab 307: E928-34
MeSH Terms: Acromegaly, Animals, Glucose, Glucose Clamp Technique, Growth Hormone, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Transgenic, Muscle, Skeletal
Show Abstract · Added October 7, 2014
A reciprocal relationship between insulin sensitivity and glucose tolerance has been reported in some mouse models and humans with isolated changes in growth hormone (GH) production and signaling. To determine if this could be explained in part by tissue-specific changes in insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed in mice with adult-onset, isolated GH deficiency and in mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors. Our results demonstrate that circulating GH levels are negatively correlated with insulin-mediated glucose uptake in muscle but positively correlated with insulin-mediated suppression of hepatic glucose production. A positive relationship was also observed between GH levels and endpoints of hepatic lipid metabolism known to be regulated by insulin. These results suggest hepatic insulin resistance could represent an early metabolic defect in GH deficiency.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Optimal nutrition in hemodialysis patients.
Ikizler TA
(2013) Adv Chronic Kidney Dis 20: 181-9
MeSH Terms: Appetite Stimulants, Dietary Supplements, Exercise Therapy, Growth Hormone, Humans, Inflammation, Insulin Resistance, Nutritional Status, Parenteral Nutrition, Protein-Energy Malnutrition, Renal Dialysis, Renal Insufficiency, Chronic, Wasting Syndrome
Show Abstract · Added August 15, 2013
Protein-energy wasting (PEW) is highly prevalent in patients undergoing maintenance hemodialysis (MHD). It is important to note that there is a robust association between the extent of PEW and the risk of hospitalization and death in these patients, regardless of the nutritional marker used. The multiple etiologies of PEW in advanced kidney disease are still being elucidated. Apart from the multiple mechanisms that might lead to PEW, it appears that the common pathway for all of the derangements is related to exaggerated protein degradation along with decreased protein synthesis. The hemodialysis procedure per se is an important contributor to this process. Metabolic and hormonal derangements such as acidosis, inflammation, and resistance to anabolic properties of insulin resistance and growth hormone are all implicated for the development of PEW in MHD patients. Appropriate management of MHD patients at risk for PEW requires a comprehensive combination of strategies to diminish protein and energy depletion and to institute therapies that will avoid further losses. The mainstay of nutritional treatment in MHD patients is provision of an adequate amount of protein and energy, using oral supplementation as needed. Intradialytic parenteral nutrition should be attempted in patients who cannot efficiently use the gastrointestinal tract. Other anabolic strategies such as exercise, anabolic hormones, anti-inflammatory therapies, and appetite stimulants can be considered as complementary therapies in suitable patients.
Published by Elsevier Inc.
0 Communities
1 Members
0 Resources
13 MeSH Terms
A Rab11a-Rab8a-Myo5B network promotes stretch-regulated exocytosis in bladder umbrella cells.
Khandelwal P, Prakasam HS, Clayton DR, Ruiz WG, Gallo LI, van Roekel D, Lukianov S, Peränen J, Goldenring JR, Apodaca G
(2013) Mol Biol Cell 24: 1007-19
MeSH Terms: Actin Cytoskeleton, Animals, Exocytosis, Female, Green Fluorescent Proteins, Human Growth Hormone, Humans, Microscopy, Confocal, Microscopy, Electron, Myosins, Rats, Rats, Sprague-Dawley, Signal Transduction, Stress, Mechanical, Urinary Bladder, rab GTP-Binding Proteins
Show Abstract · Added September 3, 2013
Multiple Rabs are associated with secretory granules/vesicles, but how these GTPases are coordinated to promote regulated exocytosis is not well understood. In bladder umbrella cells a subapical pool of discoidal/fusiform-shaped vesicles (DFVs) undergoes Rab11a-dependent regulated exocytosis in response to bladder filling. We show that Rab11a-associated vesicles are enmeshed in an apical cytokeratin meshwork and that Rab11a likely acts upstream of Rab8a to promote exocytosis. Surprisingly, expression of Rabin8, a previously described Rab11a effector and guanine nucleotide exchange factor for Rab8, stimulates stretch-induced exocytosis in a manner that is independent of its catalytic activity. Additional studies demonstrate that the unconventional motor protein myosin5B motor (Myo5B) works in association with the Rab8a-Rab11a module to promote exocytosis, possibly by ensuring transit of DFVs through a subapical, cortical actin cytoskeleton before fusion. Our results indicate that Rab11a, Rab8a, and Myo5B function as part of a network to promote stretch-induced exocytosis, and we predict that similarly organized Rab networks will be common to other regulated secretory pathways.
0 Communities
1 Members
0 Resources
16 MeSH Terms
OPPORTUNITY™: a large-scale randomized clinical trial of growth hormone in hemodialysis patients.
Kopple JD, Cheung AK, Christiansen JS, Djurhuus CB, El Nahas M, Feldt-Rasmussen B, Mitch WE, Wanner C, Göthberg M, Ikizler TA
(2011) Nephrol Dial Transplant 26: 4095-103
MeSH Terms: Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, Human Growth Hormone, Humans, Hypoalbuminemia, Male, Middle Aged, Renal Dialysis, Young Adult
Show Abstract · Added September 29, 2014
BACKGROUND - Adult maintenance hemodialysis (MHD) patients experience high mortality and morbidity and poor quality of life (QoL). Markers of protein-energy wasting are associated with these poor outcomes. The OPPORTUNITY™ Trial examined whether recombinant human growth hormone (hGH) reduces mortality in hypoalbuminemic MHD patients. Secondary end points were effects on number of hospitalizations, cardiovascular events, lean body mass (LBM), serum proteins, exercise capacity, QoL and adverse events.
METHODS - We performed a randomized, double-blind, placebo-controlled, multicenter multinational trial stratified for diabetic status. Clinically, stable adult MHD patients with serum albumin <4.0 g/dL were randomized to subcutaneous injections of hGH, 20 μg/kg/day, or placebo. Planned treatment duration was 24 months for 2500 patients. The trial was terminated early due to slow recruitment.
RESULTS - Seven hundred and twelve patients were randomized until trial termination; 695 patients received at least one dose of trial medication. Mean treatment duration was 20 weeks (no completers). There were no differences between groups in all-cause mortality, cardiovascular morbidity or mortality, serum albumin, LBM, physical exercise capacity or QoL. The hGH group, compared to placebo, displayed a reduction in body weight, total body fat, serum high-sensitivity C-reactive protein and possibly homocysteine and an increase in serum high-density lipoprotein-cholesterol and transferrin levels.
CONCLUSIONS - Although the OPPORTUNITY™ Trial was terminated early, treatment with hGH, compared to placebo, improved certain cardiovascular risk factors but did not reduce mortality, cardiovascular events or improve nutritional factors or QoL. The power for showing differences was substantially reduced due to the marked decrease in treatment duration and sample size.
0 Communities
1 Members
0 Resources
12 MeSH Terms