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1.
J Phys Chem B ; 125(44): 12214-12227, 2021 11 11.
Article in English | MEDLINE | ID: mdl-34726915

ABSTRACT

The environment surrounding a chromophore can dramatically affect the energy absorption and relaxation process, as manifested in optical spectra. Simulations of nonlinear optical spectroscopy, such as two-dimensional electronic spectroscopy (2DES) and transient absorption (TA), will be influenced by the computational model of the environment. We here compare a fixed point charge molecular mechanics model and a quantum mechanical (QM) model of the environment in computed 2DES and TA spectra of Nile red in water and the chromophore of photoactive yellow protein (PYP) in water and protein environments. In addition to simulating these nonlinear optical spectra, we directly juxtapose the computed excitation energy correlation function to the dynamic Stokes shift function often used to analyze environment dynamics. Overall, we find that for the three systems studied here the mutual electronic polarization provided by the QM environment manifests in broader 2DES signals, as well as a larger reorganization energy and a larger static Stokes shift due to stronger coupling between the chromophore and the environment.


Subject(s)
Molecular Dynamics Simulation , Water , Electronics , Quantum Theory , Spectrum Analysis
2.
Philos Trans A Math Phys Eng Sci ; 379(2211): 20190467, 2021 Nov 29.
Article in English | MEDLINE | ID: mdl-34628943

ABSTRACT

Superionic solid electrolytes have widespread use in energy devices, but the fundamental motivations for fast ion conduction are often elusive. In this Perspective, we draw upon atomistic simulations of a wide range of superionic conductors to illustrate some ways frustration can lower diffusion cation barriers in solids. Based on our studies of halides, oxides, sulfides and hydroborates and a survey of published reports, we classify three types of frustration that create competition between different local atomic preferences, thereby flattening the diffusive energy landscape. These include chemical frustration, which derives from competing factors in the anion-cation interaction; structural frustration, which arises from lattice arrangements that induce site distortion or prevent cation ordering; and dynamical frustration, which is associated with temporary fluctuations in the energy landscape due to anion reorientation or cation reconfiguration. For each class of frustration, we provide detailed simulation analyses of various materials to show how ion mobility is facilitated, resulting in stabilizing factors that are both entropic and enthalpic in origin. We propose the use of these categories as a general construct for classifying frustration in superionic conductors and discuss implications for future development of suitable descriptors and improvement strategies. This article is part of the Theo Murphy meeting issue 'Understanding fast-ion conduction in solid electrolytes'.

3.
Annu Rev Phys Chem ; 72: 165-188, 2021 04 20.
Article in English | MEDLINE | ID: mdl-33395546

ABSTRACT

Including both environmental and vibronic effects is important for accurate simulation of optical spectra, but combining these effects remains computationally challenging. We outline two approaches that consider both the explicit atomistic environment and the vibronic transitions. Both phenomena are responsible for spectral shapes in linear spectroscopy and the electronic evolution measured in nonlinear spectroscopy. The first approach utilizes snapshots of chromophore-environment configurations for which chromophore normal modes are determined. We outline various approximations for this static approach that assumes harmonic potentials and ignores dynamic system-environment coupling. The second approach obtains excitation energies for a series of time-correlated snapshots. This dynamic approach relies on the accurate truncation of the cumulant expansion but treats the dynamics of the chromophore and the environment on equal footing. Both approaches show significant potential for making strides toward more accurate optical spectroscopy simulations of complex condensed phase systems.

4.
Pediatr Diabetes ; 19(7): 1322-1330, 2018 11.
Article in English | MEDLINE | ID: mdl-29927039

ABSTRACT

OBJECTIVES: The primary objective was to investigate the mediating effects of diabetes management in the relationship between diabetes symptoms and generic health-related quality of life (HRQOL) in adolescents and young adults (AYAs) with type 1 diabetes. The secondary objective explored patient health communication and perceived treatment adherence barriers as mediators in a serial multiple mediator model. METHODS: The PedsQL 3.2 Diabetes Module 15-item diabetes symptoms summary score, 18-item diabetes management summary score, and PedsQL 4.0 generic core scales were completed in a 10-site national field test study by 418 AYA aged 13 to 25 years with type 1 diabetes. Diabetes symptoms and diabetes management were tested for bivariate and multivariate linear associations with overall generic HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of diabetes management as an intervening variable between diabetes symptoms and generic HRQOL. RESULTS: The predictive effects of diabetes symptoms on HRQOL were mediated in part by diabetes management. In predictive analytics models utilizing multiple regression analyses, demographic and clinical covariates, diabetes symptoms, and diabetes management significantly accounted for 53% of the variance in generic HRQOL (P < 0.001), demonstrating a large effect size. Patient health communication and perceived treatment adherence barriers were significant mediators in an exploratory serial multiple mediator model. CONCLUSIONS: Diabetes management explains in part the effects of diabetes symptoms on HRQOL in AYA with type 1 diabetes. Patient health communication to healthcare providers and perceived treatment adherence barriers further explain the mechanism in the relationship between diabetes symptoms and overall HRQOL.


Subject(s)
Diabetes Mellitus, Type 1/psychology , Disease Management , Quality of Life , Adolescent , Factor Analysis, Statistical , Female , Health Communication , Humans , Male , Surveys and Questionnaires , Treatment Adherence and Compliance , Young Adult
5.
Qual Life Res ; 27(9): 2295-2303, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29785681

ABSTRACT

OBJECTIVES: The objective was to investigate the patient-reported diabetes symptoms predictors of generic health-related quality of life (HRQOL) in adolescents and young adults (AYA) with type 1 or type 2 diabetes. METHODS: The 15-item PedsQL™ 3.2 Diabetes Module Diabetes Symptoms Summary Score and PedsQL™ 4.0 Generic Core Scales were completed in a 10-site national field test study by 513 AYA ages 13-25 years with type 1 (n = 424) or type 2 (n = 89) diabetes. Diabetes symptoms were tested for bivariate and multivariate linear associations with generic HRQOL. RESULTS: Diabetes symptoms were associated with decreased HRQOL in bivariate analyses. In predictive analytics models utilizing hierarchical multiple regression analyses controlling for relevant demographic and clinical covariates, diabetes symptoms accounted for 38 and 39% of the variance in patient-reported generic HRQOL for type 1 and type 2 diabetes, respectively, reflecting large effect sizes. The diabetes symptoms facets hyperglycemia symptoms, hypoglycemia symptoms, and nonspecific diabetes symptoms individually accounted for a significant percentage of the variance in separate exploratory predictive analytics models after controlling for demographic and clinical covariates, with small-to-large effect sizes. CONCLUSIONS: Diabetes symptoms are potentially modifiable predictors of generic HRQOL in AYA with diabetes. Identifying specific diabetes symptoms or symptoms facets that are the most important predictors from the patient perspective facilitates a patient-centered approach in clinical research, clinical trials, and practice designed to enhance overall generic HRQOL in AYA with diabetes.


Subject(s)
Diabetes Mellitus, Type 2/psychology , Quality of Life/psychology , Adolescent , Adult , Diabetes Mellitus, Type 2/pathology , Female , Humans , Male , Surveys and Questionnaires , Young Adult
6.
J Pediatr Gastroenterol Nutr ; 62(5): 751-6, 2016 05.
Article in English | MEDLINE | ID: mdl-26628442

ABSTRACT

OBJECTIVE: The objective of the present study was to report on the health-related quality of life (HRQOL) of infants with chronic liver disease using the PedsQL (Pediatric Quality of Life Inventory) Infant Scales. METHODS: The 36-item (ages 1-12 months) and 45-item (ages 13-24 months) PedsQL Infant Scales (physical functioning, physical symptoms, emotional functioning, social functioning, cognitive functioning) were completed by 50 parents of infants with chronic liver disease. RESULTS: Infants ages 1 to 12 months had significantly lower HRQOL scores compared with a matched healthy sample. Infants 13 to 24 months trended to lower physical HRQOL scores that did not reach statistical significance. Recent hospitalizations had an impact on the majority of HRQOL subscales, as did ascites, and failure to thrive. CONCLUSIONS: Infants ages 1 to 12 months with chronic liver disease demonstrate lower HRQOL compared with healthy children with physical subscales being most severely affected. The PedsQL Infant Scales allow the definition of HRQOL during a critical period of an infants' development that has been heretofore difficult to measure.


Subject(s)
Liver Diseases/psychology , Parents , Quality of Life , Adult , Child Health Services , Child, Preschool , Chronic Disease/psychology , Cross-Sectional Studies , Female , Humans , Infant , Infant, Newborn , Male , Psychometrics , Reproducibility of Results
7.
PLoS One ; 10(10): e0139960, 2015.
Article in English | MEDLINE | ID: mdl-26445459

ABSTRACT

BACKGROUND & AIMS: Leptin, the protein product of the ob gene, increases energy expenditure and reduces food intake, thereby promoting weight reduction. Leptin also regulates glucose homeostasis and hepatic insulin sensitivity via hypothalamic proopiomelanocortin neurons in mice. Roux-en-Y gastric bypass (RYGB) induces weight loss that is substantial and sustained despite reducing plasma leptin levels. In addition, patients who fail to undergo diabetes remission after RYGB are hypoletinemic compared to those who do and to lean controls. We have previously demonstrated that the beneficial effects of RYGB in mice require the melanocortin-4 receptor, a downstream effector of leptin action. Based on these observations, we hypothesized that leptin is required for sustained weight reduction and improved glucose homeostasis observed after RYGB. METHODS: To investigate this hypothesis, we performed RYGB or sham operations on leptin-deficient ob/ob mice maintained on regular chow. To investigate whether leptin is involved in post-RYGB weight maintenance, we challenged post-surgical mice with high fat diet. RESULTS: RYGB reduced total body weight, fat and lean mass and caused reduction in calorie intake in ob/ob mice. However, it failed to improve glucose tolerance, glucose-stimulated plasma insulin, insulin tolerance, and fasting plasma insulin. High fat diet eliminated the reduction in calorie intake observed after RYGB in ob/ob mice and promoted weight regain, although not to the same extent as in sham-operated mice. We conclude that leptin is required for the effects of RYGB on glucose homeostasis but not body weight or composition in mice. Our data also suggest that leptin may play a role in post-RYGB weight maintenance.


Subject(s)
Glucose/metabolism , Leptin/metabolism , Animals , Blood Glucose/analysis , Diet, High-Fat , Enzyme-Linked Immunosorbent Assay , Gastric Bypass , Glucose Tolerance Test , Insulin/analysis , Insulin/metabolism , Insulin Resistance , Leptin/deficiency , Leptin/genetics , Liver/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Receptor, Melanocortin, Type 4/metabolism , Triglycerides/analysis
8.
Mol Metab ; 4(5): 427-36, 2015 May.
Article in English | MEDLINE | ID: mdl-25973390

ABSTRACT

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) is an effective method of weight loss and remediation of type-2 diabetes; however, the mechanisms leading to these improvements are unclear. Additionally, adipocytes within white adipose tissue (WAT) depots can manifest characteristics of brown adipocytes. These 'BRITE/beige' adipocytes express uncoupling protein 1 (UCP1) and are associated with improvements in glucose homeostasis and protection from obesity. Interestingly, atrial and B-type natriuretic peptides (NPs) promote BRITE/beige adipocyte enrichment of WAT depots, an effect known as "browning." Here, we investigate the effect of RYGB surgery on NP, NP receptors, and browning in the gonadal adipose tissues of female mice. We propose that such changes may lead to improvements in metabolic homeostasis commonly observed following RYGB. METHODS: Wild type, female, C57/Bl6 mice were fed a 60% fat diet ad libitum for six months. Mice were divided into three groups: Sham operated (SO), Roux-en-Y gastric bypass (RYGB), and Weight matched, sham operated (WM-SO). Mice were sacrificed six weeks following surgery and evaluated for differences in body weight, glucose homeostasis, adipocyte morphology, and adipose tissue gene expression. RESULTS: RYGB and calorie restriction induced similar weight loss and improved glucose metabolism without decreasing food intake. ß3-adrenergic receptor expression increased in gonadal adipose tissue, in addition to Nppb (BNP), and NP receptors, Npr1, and Npr2. The ratio of Npr1:Npr3 and Npr2:Npr3 increased in RYGB, but not WM-SO groups. Ucp1 protein and mRNA, as well as additional markers of BRITE/beige adipose tissue and lipolytic genes increased in RYGB mice to a greater extent than calorie-restricted mice. CONCLUSIONS: Upregulation of Nppb, Npr1, Npr2, and ß3-adrenergic receptors in gonadal adipose tissue following RYGB was associated with increased markers of browning. This browning of gonadal adipose tissue may underpin the positive effect of RYGB on metabolic parameters and may in part be mediated through upregulation of natriuretic peptides.

9.
Mol Metab ; 3(7): 717-30, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25353000

ABSTRACT

The current study examined potential mechanisms for altered circulating ghrelin levels observed in diet-induced obesity (DIO) and following weight loss resulting from Roux-en-Y gastric bypass (RYGB). We hypothesized that circulating ghrelin levels were altered in obesity and after weight loss through changes in ghrelin cell responsiveness to physiological cues. We confirmed lower ghrelin levels in DIO mice and demonstrated elevated ghrelin levels in mice 6 weeks post-RYGB. In both DIO and RYGB settings, these changes in ghrelin levels were associated with altered ghrelin cell responsiveness to two key physiological modulators of ghrelin secretion - glucose and norepinephrine. In DIO mice, increases in ghrelin cell density within both the stomach and duodenum and in somatostatin-immunoreactive D cell density in the duodenum were observed. Our findings provide new insights into the regulation of ghrelin secretion and its relation to circulating ghrelin within the contexts of obesity and weight loss.

10.
Gastroenterology ; 147(1): 184-195.e3, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24727021

ABSTRACT

BACKGROUND & AIMS: Activation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings. METHODS: We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-κB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. RESULTS: In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. CONCLUSIONS: Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Colitis/prevention & control , Colitis/physiopathology , Colonic Neoplasms/prevention & control , Colonic Neoplasms/physiopathology , Inflammation/genetics , Inflammation/physiopathology , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Azoxymethane/adverse effects , Biopsy , Case-Control Studies , Colitis/chemically induced , Colon/metabolism , Colon/pathology , Colonic Neoplasms/chemically induced , Dextran Sulfate/adverse effects , Disease Models, Animal , Humans , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Mice , Mice, Knockout , NF-kappa B/metabolism , Polymorphism, Single Nucleotide/genetics , RNA, Messenger/metabolism
11.
Mol Metab ; 3(2): 191-201, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24634822

ABSTRACT

Glucagon-like peptide-1 (GLP-1) secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB). While intact GLP-1exerts its metabolic effects via the classical GLP-1 receptor (GLP-1R), proteolytic processing of circulating GLP-1 yields metabolites such as GLP-1(9-36)amide/GLP-1(28-36)amide, that exert similar effects independent of the classical GLP-1R. We investigated the hypothesis that GLP-1, acting via these metabolites or through its known receptor, is required for the beneficial effects of RYGB using two models of functional GLP-1 deficiency - α-gustducin-deficient (α-Gust (-/-)) mice, which exhibit attenuated nutrient-stimulated GLP-1 secretion, and GLP-1R-deficient mice. We show that the effect of RYGB to enhance glucose-stimulated GLP-1 secretion was greatly attenuated in α-Gust (-/-) mice. In both genetic models, RYGB reduced body weight and improved glucose homeostasis to levels observed in lean control mice. Therefore, GLP-1, acting through its classical GLP-1R or its bioactive metabolites, does not seem to be involved in the effects of RYGB on body weight and glucose homeostasis.

12.
Gastroenterology ; 144(3): 580-590.e7, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23159449

ABSTRACT

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB) improves glucose homeostasis independently of changes in body weight by unknown mechanisms. Melanocortin-4 receptors (MC4R) have weight-independent effects on glucose homeostasis, via autonomic neurons, and also might contribute to weight loss after RYGB. We investigated whether MC4Rs mediate effects of RYGB, such as its weight-independent effects on glucose homeostasis, in mice and humans. METHODS: We studied C57BL/6 mice with diet-induced obesity, MC4R-deficient mice, and mice that re-express MC4R specifically in autonomic neurons after RYGB or sham surgeries. We also sequenced the MC4R locus in patients undergoing RYGB to investigate diabetes resolution in carriers of rare MC4R variants. RESULTS: MC4Rs in autonomic brainstem neurons (including the parasympathetic dorsal motor vagus) mediated improved glucose homeostasis independent of changes in body weight. In contrast, MC4Rs in cholinergic preganglionic motor neurons (sympathetic and parasympathetic) mediated RYGB-induced increased energy expenditure and weight loss. Increased energy expenditure after RYGB is the predominant mechanism of weight loss and confers resistance to weight gain from a high-fat diet, the effects of which are MC4R-dependent. MC4R-dependent effects of RYGB still occurred in mice with Mc4r haplosufficiency, and early stage diabetes resolved at a similar rate in patients with rare variants of MC4R and noncarriers. However, carriers of MC4R (I251L), a rare variant associated with increased weight loss after RYGB and increased basal activity in vitro, were more likely to have early and weight-independent resolution of diabetes than noncarriers, indicating a role for MC4Rs in the effects of RYGB. CONCLUSIONS: MC4Rs in autonomic neurons mediate beneficial effects of RYGB, including weight-independent improved glucose homeostasis, in mice and humans.


Subject(s)
Blood Glucose/metabolism , Gastric Bypass , Homeostasis , Motor Neurons/metabolism , Receptor, Melanocortin, Type 4/metabolism , Vagus Nerve/metabolism , Weight Loss , Animals , Cholinergic Neurons/metabolism , Diet, High-Fat/adverse effects , Energy Metabolism , Heterozygote , Humans , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Receptor, Melanocortin, Type 4/genetics
13.
J Clin Child Adolesc Psychol ; 41(3): 370-7, 2012.
Article in English | MEDLINE | ID: mdl-22420771

ABSTRACT

The goal of this study is to examine levels of oppositional defiant disorder (ODD) and conduct disorder (CD) in four groups of children: attention-deficit/hyperactivity disorder (ADHD) only, anxiety only, ADHD and anxiety, and controls (i.e., non-ADHD youth). Although children with ADHD exhibit more ODD and CD than non-ADHD youth, it is unknown if anxiety is associated with increased or decreased ODD and CD in children with ADHD. We examined parent and teacher ratings of ODD and CD from the Disruptive Behavior Disorder Rating Scale in 203 school age children (ages 6-9); 70% were male, and 47% were Caucasian. Children were divided into four diagnostic groups based on ADHD and anxiety status from the Diagnostic Interview Scale for Children. According to parents, children with ADHD and anxiety had the highest levels of ODD/CD, followed by children with ADHD only (i.e., without anxiety). Children with anxiety only and controls had lowest ODD and CD scores, and these groups did not differ from each other. The same patterns were found according to teacher report, except that the anxiety only group had significantly lower levels of ODD than non-ADHD controls. Further, combined type ADHD youth with anxiety exhibited the highest levels of ODD and CD compared to all other groups. Comorbid anxiety may strengthen the association of ADHD and ODD/CD, particularly in the combined subtype. We discuss the importance of comorbid anxiety to the development of externalizing problems as well as potential explanatory factors underlying elevated ODD and CD among children with ADHD and anxiety.


Subject(s)
Anxiety Disorders/complications , Anxiety/complications , Attention Deficit Disorder with Hyperactivity/complications , Conduct Disorder/complications , Child , Family , Female , Humans , Male , Psychiatric Status Rating Scales , Severity of Illness Index
14.
Psychiatry Res ; 197(1-2): 90-6, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22455859

ABSTRACT

Although attention-deficit/hyperactivity disorder (ADHD) is frequently comorbid with disruptive behavior disorders, less is known about ADHD and comorbid anxiety. To improve understanding about the association of anxiety and social functioning, we studied 223 6 to 9 year-old ethnically diverse boys and girls (M=7.4 years) with and without ADHD. According to parents, children with ADHD and anxiety (n=46) and ADHD only (n=71) were consistently less socially competent than comparison children (i.e., no anxiety and ADHD: n=80) and children with anxiety only (n=26), who did not differ from one another. A similar pattern emerged for teacher ratings where youth with ADHD only and ADHD with anxiety exhibited the most social problems, but they did not differ from each other. These data suggest that comorbid anxiety does not exacerbate social dysfunction among 6 to 9 year-old children with ADHD. We consider findings within a developmental psychopathology framework to further understand social development in children with ADHD and anxiety.


Subject(s)
Anxiety/epidemiology , Anxiety/psychology , Attention Deficit Disorder with Hyperactivity/epidemiology , Social Behavior , Child , Comorbidity , Female , Humans , Male , Psychiatric Status Rating Scales , Social Behavior Disorders/epidemiology , Statistics as Topic
17.
Obesity (Silver Spring) ; 16(12): 2585-92, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19279655

ABSTRACT

To investigate the contributions of two surgical gut manipulations-exclusion of the proximal intestine from alimentary flow and exposure of the jejunum to partially digested nutrients-to body weight regulation and metabolism, we have developed a rat model of an investigational device, the endoluminal sleeve (ELS). The ELS is a 10 cm, nutrient-impermeable, flexible tube designed for endoluminal implantation. ELS devices were surgically implanted in the duodenal bulb of rats with diet-induced obesity. Body weight, food intake, stool caloric content, and glucose homeostasis were subsequently evaluated. ELS-implanted rats demonstrated a 20% reduction of body weight compared to sham-operated (SO) controls. ELS-treated animals consumed an average of 27% fewer kcal/day than SO, and there was no evidence of malabsorption. ELS treatment improved fasting glycemia and glucose tolerance after oral and intraperitoneal (IP) administration. ELS treatment enhanced insulin sensitivity, as demonstrated by decreased fasting and glucose-stimulated insulin levels and confirmed by calculation of homeostasis model assessment of insulin resistance (IR). These data suggest that selective bypass of the proximal intestine by ELS, with enhanced delivery of partially digested nutrients to the jejunum, mimics many of the effects of Roux-en-Y gastric bypass (RYGB) on body weight and glucose metabolism. Thus, ELS implantation may be an effective treatment for obesity and diabetes. Since the ELS device is amenable to endoscopic placement, it may offer a valuable alternative to more invasive surgical approaches in selected patients with obesity and its metabolic complications.


Subject(s)
Blood Glucose/metabolism , Energy Intake , Intestinal Absorption , Intestine, Small/surgery , Obesity/surgery , Weight Loss , Animals , Bariatric Surgery , Diet , Feces/chemistry , Gastric Bypass , Ghrelin/blood , Homeostasis , Implants, Experimental , Injections, Intraperitoneal/methods , Insulin/blood , Insulin Resistance , Insulin-Secreting Cells/metabolism , Male , Models, Animal , Obesity/metabolism , Rats , Rats, Sprague-Dawley
18.
J Biol Chem ; 277(2): 1531-7, 2002 Jan 11.
Article in English | MEDLINE | ID: mdl-11606564

ABSTRACT

Serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits insulin signal transduction in a variety of cell backgrounds, which might contribute to peripheral insulin resistance. However, because of the large number of potential phosphorylation sites, the mechanism of inhibition has been difficult to determine. One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser(307) in rat IRS-1 or Ser(312) in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. During a yeast tri-hybrid assay, phosphorylation of Ser(307) by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. In 32D myeloid progenitor cells, phosphorylation of Ser(307) inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling.


Subject(s)
Insulin/metabolism , Mitogen-Activated Protein Kinases/metabolism , Phosphoproteins/metabolism , Receptor, Insulin/metabolism , Animals , Anisomycin/pharmacology , Anti-Bacterial Agents/pharmacology , Cell Line , Humans , Insulin Receptor Substrate Proteins , Mitogen-Activated Protein Kinase 8 , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Rats , Recombinant Fusion Proteins/metabolism , Signal Transduction/physiology , Tumor Necrosis Factor-alpha/pharmacology , Two-Hybrid System Techniques
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