- ICH GCP
- Registro degli studi clinici negli Stati Uniti
- Sperimentazione clinica NCT00579813
Mechanisms Underlying Metabolic Syndrome in Obesity
Panoramica dello studio
Stato
Condizioni
Intervento / Trattamento
Descrizione dettagliata
Obesity is the most common and powerful force for creating insulin resistance and metabolic syndrome, however, the molecular basis of this association is not well understood. In this proposal, three independently funded researchers-Philip Kern, MD a clinical investigator, and Charlotte Peterson, PhD and Robert McGehee, PhD, with significant experience in muscle and adipocyte biology, respectively-will formalize a collaborative effort as a natural extension of previous work and shared interests in the fields of obesity, insulin resistance, and tissue lipid accumulation. Our overall hypothesis is that insulin resistance in humans stems largely from ectopic accumulation of intramyocellular lipid (IMCL) during the development of obesity. Further, we hypothesize that excess IMCL accumulation is dependent on secretory proteins derived from a complex interplay between adipocytes and macrophages in adipose tissue. To test these hypotheses, we will examine the interactions among adipocytes, macrophages, and muscle cells isolated and cultured from subjects that are obese with insulin resistance and impaired glucose tolerance (IGT), and from some with Type 2 Diabetes. This study population has elevated IMCL and is at high risk for obesity complications, but avoids the pathophysiologic complications of glucotoxicity. These subjects will be compared to obese subjects with normal glucose tolerance (NGT).
Aim 1 will explore mechanisms that contribute to IMCL and elucidate its role in the development of IGT. Cultured muscle cells will be used to determine whether obese subjects with IGT versus NGT demonstrate intrinsic differences in muscle gene expression and metabolic activity under differing extracellular fatty acid concentrations. Lipid accumulation and oxidation, and insulin-mediated glycogen synthesis and signaling will be assessed.
Aim 2 will determine if the IMCL accumulation is dependent on adipose tissue secretory proteins. We will use co-cultures of adipocytes, myoblasts, and adipose stromal vascular cells to examine IMCL and the development of insulin resistance.
Aim 3 will determine whether the stromal fraction from IGT subjects promotes IMCL more effectively than that from NGT subjects in co-cultures with muscle cells. We will compare the stromal vascular fractions with regard to monocyte/macrophage accumulation and cytokine expression.
Aim 4 will determine if improved glucose tolerance in response to a 10-week treatment with pioglitazone results in decreased IMCL and identify cellular mechanisms involved. Co-culture studies will also be used with muscle and stromal cells, before and after pioglitazone treatment. These experiments will provide mechanistic insight into the link between obesity and muscle function leading to metabolic syndrome.
Tipo di studio
Iscrizione (Effettivo)
Fase
- Fase 4
Contatti e Sedi
Luoghi di studio
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Arkansas
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Little Rock, Arkansas, Stati Uniti, 72205
- University of Arkansas for Medical Sciences
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Kentucky
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Lexington, Kentucky, Stati Uniti, 40536
- University of Kentucky
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Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
Inclusion Criteria:
- 18-65 years of age
- BMI 28+
- diabetes, impaired glucose tolerance or normal glucose tolerance
Exclusion Criteria:
- AST >2x normal
- congestive heart failure
- history of coronary artery disease
- chronic renal insufficiency (creatinine > 1.4mg/dl)
- use of gemfibrozil, ACE inhibitors, and angiotensin receptor II blockers, or anticoagulants
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Scienza basilare
- Assegnazione: Non randomizzato
- Modello interventistico: Assegnazione di gruppo singolo
- Mascheramento: Nessuno (etichetta aperta)
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
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Nessun intervento: 1
Baseline studies (OGTT, DXA, RMR, FSIGT, and biopsies) on normal control subjects.
Oral glucose tolerance tests, body composition assessment, resting metabolic rate, insulin sensitivity measurement with the frequently sampled method and Minimal Model.
These studies will establish baseline data in lean subjects on adipose tissue gene expression, insulin sensitivity, glucose tolerance, metabolic rate and body composition.
There is no intervention.
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Comparatore attivo: 2
Baseline studies (OGTT, DXA, RMR, FSIGT, biopsies), then 10 weeks treatment on Pioglitazone.
Baseline tests are repeated at the end of medication treatment.
All of the studies described in arm 1 are repeated after treatment.
The subjects in this group have impaired glucose tolerance.
After the measurement of adipose tissue gene expression, insulin sensitivity, glucose tolerance, metabolic rate and body composition, subjects are treated with pioglitazone, working up to 45 mg/day, for 10 weeks.
After this time, adipose tissue gene expression, insulin sensitivity, glucose tolerance, metabolic rate and body composition are repeated.
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Pioglitazone 30mg for 2 weeks, then Pioglitazone 45mg for 8 weeks.
Altri nomi:
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Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
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Change in Insulin Sensitivity Using FSIGT
Lasso di tempo: Baseline and 10 weeks
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The frequently sampled intravenous glucose tolerance test (FSIGT) involves the injection of IV glucose and the frequent measurement of glucose and insulin.
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Baseline and 10 weeks
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Effects of Pioglitazone on Changes in BMI
Lasso di tempo: Baseline and 10 weeks
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Body Mass Index (BMI) is measured at baseline, in lean and obese subjects, and after pioglitazone in obese subjects
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Baseline and 10 weeks
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Changes in Muscle Lipid After Pioglitazone
Lasso di tempo: At baseline and 10 weeks
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Muscle lipid following biopsy using oil red-O staining.
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At baseline and 10 weeks
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Changes in Fat Inflammation Following Pioglitazone
Lasso di tempo: Baseline and 10 weeks
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macrophages in fat at baseline, in lean and obese participants, and obese after pioglitazone (in obese)
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Baseline and 10 weeks
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Collaboratori e investigatori
Sponsor
Collaboratori
Investigatori
- Investigatore principale: Philip Kern, MD, University of Kentucky
Studiare le date dei record
Studia le date principali
Inizio studio
Completamento primario (Effettivo)
Completamento dello studio (Effettivo)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Stima)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Processi patologici
- Disturbi del metabolismo del glucosio
- Malattie metaboliche
- Patologia
- Ipernutrizione
- Disturbi della nutrizione
- Sovrappeso
- Peso corporeo
- Iperinsulinismo
- Sindrome
- Obesità
- Sindrome metabolica
- Resistenza all'insulina
- Agenti ipoglicemizzanti
- Effetti fisiologici delle droghe
- Pioglitazone
Altri numeri di identificazione dello studio
- 32677
- R01DK071277 (Sovvenzione/contratto NIH degli Stati Uniti)
Piano per i dati dei singoli partecipanti (IPD)
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Descrizione del piano IPD
Informazioni su farmaci e dispositivi, documenti di studio
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