scholarly journals Altered Activity of 11β-Hydroxysteroid Dehydrogenase Types 1 and 2 in Skeletal Muscle Confers Metabolic Protection in Subjects with Type 2 Diabetes

2007 ◽  
Vol 92 (8) ◽  
pp. 3314-3320 ◽  
Author(s):  
Christina Jang ◽  
Varuni R. Obeyesekere ◽  
Rodney J. Dilley ◽  
Zygmunt Krozowski ◽  
Warrick J. Inder ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Enzyme Activity ◽  
Vastus Lateralis ◽  
Hydroxysteroid Dehydrogenase ◽  
Significant Negative Correlation ◽  
University Teaching ◽  
Mrna Levels ◽  
Percent Conversion

Abstract Context: There is little information regarding the regulation of 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes in skeletal muscle in the setting of type 2 diabetes. Objective: Our objective was to investigate whether there is differential mRNA expression and enzyme activity of 11β-HSD1 and 11β-HSD2 in the skeletal muscle of diabetic subjects compared with controls at baseline and in response to dexamethasone. Design: Participants underwent muscle biopsy of vastus lateralis at baseline and after dexamethasone. Setting: The study took place at a university teaching hospital. Participants: Twelve subjects with type 2 diabetes and 12 age- and sex-matched controls participated. Intervention: Subjects were given oral dexamethasone, 4 mg/d for 4 d. Main Outcome Measures: We assessed 11β-HSD1, 11β-HSD2, and H6PDH mRNA levels by quantitative RT-PCR and enzyme activity by percent conversion of [3H]cortisone and [3H]cortisol, respectively. Results: At baseline, mRNA levels were similar in diabetic and control subjects for 11β-HSD1, 11β-HSD2, and H6PDH. 11β-HSD1 activity was reduced in diabetic subjects (percent conversion of [3H]cortisone to [3H]cortisol was 11.4 ± 2.5% vs. 18.5 ± 2.2%; P = 0.041), and 11β-HSD2 enzyme activity was higher in diabetic subjects (percent conversion of [3H]cortisone to [3H]cortisol was 17.2 ± 2.6% vs. 9.2 ± 1.3%; P = 0.012). After dexamethasone, 11β-HSD1 mRNA increased in both groups (P < 0.001), whereas 11β-HSD2 mRNA decreased (P = 0.002). 11β-HSD1 activity increased in diabetic subjects (P = 0.021) but not in controls, whereas 11β-HSD2 activity did not change in either group. At baseline, there was a significant negative correlation between 11β-HSD1 and 11β-HSD2 enzyme activity (r = −0.463; P = 0.026). Conclusions: The activities of skeletal muscle 11β-HSD1 and 11β-HSD2 are altered in diabetes, which together may reduce intracellular cortisol generation, potentially conferring metabolic protection.

scholarly journals Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1

2017 ◽  
Vol 122 (1) ◽  
pp. 38-47 ◽  
Author(s):  
Leryn J. Reynolds ◽  
Daniel P. Credeur ◽  
Camila Manrique ◽  
Jaume Padilla ◽  
Paul J. Fadel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Vastus Lateralis ◽  
Glucose Disposal ◽  
Endothelin 1 ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)−1·min−1] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM−1·min−1) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P < 0.05). peNOS/eNOS content was higher in Lean under basal conditions and, although not increased by insulin, remained higher in Lean during the insulin clamp than in obese T2D ( P < 0.05). ET-1 mRNA and peptide were 2.25 ± 0.50- and 1.52 ± 0.11-fold higher in obese T2D compared with Lean at baseline, and ET-1 peptide remained 2.02 ± 1.9-fold elevated in obese T2D after insulin infusion ( P < 0.05) but did not increase with insulin in either group ( P > 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 ( P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients. NEW & NOTEWORTHY Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.

scholarly journals 4126 Intermuscular adipose tissue secretes pro-inflammatory, extracellular matrix, and lipid signals related to insulin resistance and type 2 diabetes

2020 ◽  
Vol 4 (s1) ◽  
pp. 9-9
Author(s):  
Darcy Kahn ◽  
Simona Zarini ◽  
Emily Macias ◽  
Amanda Garfield ◽  
Kathleen Harrison ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Functional Role ◽  
Vastus Lateralis ◽  
Laparoscopic Bariatric Surgery ◽  
Intermuscular Adipose Tissue

OBJECTIVES/GOALS: Intermuscular adipose tissue (IMAT) has been associated with insulin resistance and type 2 diabetes, yet mechanistic studies addressing the functional role of IMAT are lacking. The aim of this work was to identify novel mechanisms by which IMAT may directly impact skeletal muscle metabolism. METHODS/STUDY POPULATION: We quantified the secretome of IMAT, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) to determine if there are differences between depots in the secretion of cytokines, eicosanoids, FFAs and proteins that influence metabolic function. SAT and VAT biopsies from patients undergoing laparoscopic bariatric surgery and IMAT extracted from vastus lateralis biopsies of individuals with Obesity were cultured for 48 hours in DMEM, and the conditioned media was analyzed using nanoflow HPLC-MS, multiplex ELISAs and LC/MS/MS for proteins, cytokines and eicosanoids/FFA, respectively. RESULTS/ANTICIPATED RESULTS: IMAT secretion of various extracellular matrix proteins (fibrinogen-β, collagenV1a3, fibronectin) was significantly different than VAT and SAT. Pro-inflammatory cytokine secretion of IFNg, TNFa, IL-8 and IL-13 from IMAT was higher than VAT and significantly higher than SAT (p < 0.05). IMAT secretes significantly more pro-inflammatory eicosanoids TXB2 and PGE2 than VAT (p = 0.02, 0.05) and SAT (p = 0.01, 0.04). IMAT and VAT have significantly greater basal lipolysis assessed by FFA release rates compared to SAT (p = 0.01, 0.04). DISCUSSION/SIGNIFICANCE OF IMPACT: These data begin to characterize the disparate secretory properties of SAT, VAT and IMAT and suggest a metabolically adverse secretome of IMAT, that due to its proximity to skeletal muscle may play an important functional role in the pathogenesis of insulin resistance and type 2 diabetes.

scholarly journals Decreased Thioredoxin-1 and Increased HSP90 Expression in Skeletal Muscle in Subjects with Type 2 Diabetes or Impaired Glucose Tolerance

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
M. Venojärvi ◽  
A. Korkmaz ◽  
S. Aunola ◽  
K. Hällsten ◽  
K. Virtanen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Insulin Signalling ◽  
Vastus Lateralis ◽  
Diabetes Research ◽  
Insulin Signalling Pathway ◽  
Thioredoxin 1

In diabetes, the endogenous defence systems are overwhelmed, causing various types of stress in tissues. In this study, newly diagnosed or diet-treated type 2 diabetics (T2D) (n=10) were compared with subjects with impaired glucose tolerance (IGT) (n=8). In both groups, at resting conditions, blood samples were drawn for assessing metabolic indices and skeletal muscle samples (m. vastus lateralis) were taken for the measurements of cellular defence markers: thioredoxin-1 (TRX-1) and stress proteins HSP72, HSP90. The protein level of TRX-1 was 36.1% lower (P=0.031) and HSP90 was 380% higher (P<0.001) in the T2D than in the IGT subjects, with no significant changes in HSP72. However, after the adjustment of both analyses with HOMA-IR only HSP90 difference remained significant. In conclusion, level of TRX-1 in skeletal muscle tissue was lower while that of HSP90 was higher in T2D than in IGT subjects. This may impair antioxidant defence and lead to disruptions of protein homoeostasis and redox regulation of cellular defences. Because HSP90 may be involved in sustaining functional insulin signalling pathway in type 2 diabetic muscles and higher HSP90 levels can be a consequence of type 2 diabetes, our results are potentially important for the diabetes research.

scholarly journals Skeletal muscle 11β hydroxysteroid dehydrogenase type 1 activity is upregulated following elective abdominal surgery

2009 ◽  
Vol 160 (2) ◽  
pp. 249-255 ◽  
Author(s):  
Christina Jang ◽  
Varuni R Obeyesekere ◽  
Frank P Alford ◽  
Warrick J Inder
Keyword(s):  
Skeletal Muscle ◽  
Enzyme Activity ◽  
Abdominal Surgery ◽  
Plasma Cortisol ◽  
Vastus Lateralis ◽  
Mrna Levels ◽  
Glucose Levels ◽  
Post Surgery ◽  
Elective Abdominal Surgery ◽  
Factor Α

ObjectiveCortisol has been traditionally implicated in the causation of peri-operative skeletal muscle (SkM) insulin resistance, but cortisol levels return to normal within 72 h of surgery. Tissue cortisol bioactivity may be prolonged by local upregulation of the enzyme 11βHSD1. We aimed to investigate the changes of SkM 11βHSD1 enzyme activity and mRNA expression, relative to plasma cortisol, insulin and glucose levels following elective abdominal surgery.Patients and designEight non-diabetic subjects (two male, six female) underwent serial plasma hormone sampling and muscle biopsy of vastus lateralis at baseline and on day 5 following elective laparoscopic cholecystectomy.MethodsSkM 11βHSD1 and H6PDH mRNA levels were measured by quantitative RT-PCR and enzyme activity by % conversion of 3H cortisone to cortisol. Plasma glucose, insulin, free fatty acids (FFA), tumour necrosis factor-α and cortisol by standardised assays.ResultsCompared with baseline, SkM 11βHSD1 activity was significantly increased on day 5 after surgery (14.7±2.1 vs 20.4±3.2%, P=0.005). Neither 11βHSD1 nor H6PDH mRNA levels were altered after surgery. Plasma cortisol (P=0.027), FFA (P=0.01) and glucose (P=0.004) rose rapidly following surgery and had returned to baseline values by 24 h post-surgery. There was no significant change in plasma insulin.ConclusionsThis is the first study to demonstrate an upregulation of SkM 11βHSD1 activity in response to a physiological stressor. Sustained activation of this enzyme may increase tissue cortisol bioactivity.

scholarly journals Type 2 Diabetes Modifies Skeletal Muscle Gene Expression Response to Gastric Bypass Surgery

2021 ◽  
Author(s):  
Matthew D. Barberio ◽  
G. Lynis Dohm ◽  
Walter J. Pories ◽  
Natalie A. Gadaleta ◽  
Joseph A. Houmard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Gastric Bypass ◽  
Clinical Symptoms ◽  
Vastus Lateralis ◽  
Gene Expression Response ◽  
Muscle Health ◽  
The Impact

AbstractRoux-en-Y gastric bypass (RYGB) is an effective treatment for type 2 diabetes mellitus (T2DM) which can result in remission of clinical symptoms, yet mechanisms for improved skeletal muscle health are poorly understood. We sought to define the impact of existing T2DM on RYGB-induced muscle transcriptome changes.MethodsVastus lateralis biopsy transcriptomes were generated pre- and 1-yr post-RYGB in black adult females with (T2D; n = 5, age=51±6 yr, BMI=53.0±5.8 kg/m2) and without (CON; n = 7,43±6 yr,51.0±9.2 kg/m2) T2DM. Insulin, glucose, and HOMA-IR were measured in blood at the same time points. ANCOVA detected differentially expressed genes (p< 0.01, Fold change<|1.2|), which were used to identify enriched biological pathways.ResultsPre-RYGB, 95 probes were downregulated with T2D including subunits of mitochondrial complex I. Post-RYGB, the T2D group had normalized gene expression when compared to their non-diabetic counterparts with only 3 probes remaining significantly different. In the T2D, we identified 52 probes upregulated from pre- to post-RYGB, including NDFUB7 and NDFUA1.ConclusionBlack females with T2DM show extensive down regulation of genes across aerobic metabolism pathways prior to RYGB, which resolves 1 year post-RYGB and is related to improvements in clinical markers. These data support efficacy of RYGB for improving skeletal muscle health, especially in patients with T2DM.

scholarly journals Associations of Haplotypes Upstream ofIRS1with Insulin Resistance, Type 2 Diabetes, Dyslipidemia, Preclinical Atherosclerosis, and Skeletal MuscleLOC646736mRNA Levels

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Selma M. Soyal ◽  
Thomas Felder ◽  
Simon Auer ◽  
Hannes Oberkofler ◽  
Bernhard Iglseder ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Lipid Profile ◽  
Mrna Levels ◽  
Tissue Mass ◽  
Cross Sectional ◽  
Adipose Tissue Mass

The genomic region ~500 kb upstream ofIRS1has been implicated in insulin resistance, type 2 diabetes, adverse lipid profile, and cardiovascular risk. To gain further insight into this chromosomal region, we typed four SNPs in a cross-sectional cohort and subjects with type 2 diabetes recruited from the same geographic region. From 16 possible haplotypes, 6 haplotypes with frequencies >0.01 were observed. We identified one haplotype that was protective against insulin resistance (determined by HOMA-IR and fasting plasma insulin levels), type 2 diabetes, an adverse lipid profile, increased C-reactive protein, and asymptomatic atherosclerotic disease (assessed by intima media thickness of the common carotid arteries). BMI and total adipose tissue mass as well as visceral and subcutaneous adipose tissue mass did not differ between the reference and protective haplotypes. In 92 subjects, we observed an association of the protective haplotype with higher skeletal muscle mRNA levels ofLOC646736, which is located in the same haplotype block as the informative SNPs and is mainly expressed in skeletal muscle, but only at very low levels in liver or adipose tissues. These data suggest a role forLOC646736in human insulin resistance and warrant further studies on the functional effects of this locus.

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