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

2021 ◽  
Vol 12 ◽  
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

IntroductionRoux-en-Y gastric bypass (RYGB) is an effective treatment for type 2 diabetes mellitus (T2DM) that 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-year post-RYGB in black adult females with (T2D; n = 5, age = 51 ± 6 years, BMI = 53.0 ± 5.8 kg/m2) and without (CON; n = 7, 43 ± 6 years, 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 three 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 downregulation 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 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 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 Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes

Diabetologia ◽  
2021 ◽  
Author(s):  
Rasmus J. O. Sjögren ◽  
David Rizo-Roca ◽  
Alexander V. Chibalin ◽  
Elin Chorell ◽  
Regula Furrer ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Amino Acid ◽  
Glucose Homeostasis ◽  
Gene Set ◽  
Branched Chain Amino Acid ◽  
Human Myotubes ◽  
Branched Chain ◽  
The Impact

Abstract Aims/hypothesis Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified. Methods Plasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor α (ERRα) knockdown on leucine oxidation. Results Impairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37–56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific Ppargc1a knockout mice. ESRRA (encoding ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes. Conclusions/interpretation Metabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1α is ERRα-dependent. Graphical abstract

scholarly journals Type 2 diabetes mellitus in the Goto-Kakizaki rat impairs microvascular function and contributes to premature skeletal muscle fatigue

2019 ◽  
Vol 126 (3) ◽  
pp. 626-637 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
Matthew T. Lewis ◽  
Jonathan D. Kasper ◽  
Paul D. Chantler ◽  
Robert W. Wiseman
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Type 2 Diabetes Mellitus ◽  
Structure Function ◽  
Vascular Structure ◽  
Gk Rats ◽  
The Impact

Despite extensive investigation into the impact of metabolic disease on vascular function and, by extension, tissue perfusion and organ function, interpreting results for specific risk factors can be complicated by the additional risks present in most models. To specifically determine the impact of type 2 diabetes without obesity on skeletal muscle microvascular structure/function and on active hyperemia with elevated metabolic demand, we used 17-wk-old Goto-Kakizaki (GK) rats to study microvascular function at multiple levels of resolution. Gracilis muscle arterioles demonstrated blunted dilation to acetylcholine (both ex vivo proximal and in situ distal arterioles) and elevated shear (distal arterioles only). All other alterations to reactivity appeared to reflect compromised endothelial function associated with increased thromboxane (Tx)A2 production and oxidant stress/inflammation rather than alterations to vascular smooth muscle function. Structural changes to the microcirculation of GK rats were confined to reduced microvessel density of ~12%, with no evidence for altered vascular wall mechanics. Active hyperemia with either field stimulation of in situ cremaster muscle or electrical stimulation via the sciatic nerve for in situ gastrocnemius muscle was blunted in GK rats, primarily because of blunted functional dilation of skeletal muscle arterioles. The blunted active hyperemia was associated with impaired oxygen uptake (V̇o2) across the muscle and accelerated muscle fatigue. Acute interventions to reduce oxidant stress (TEMPOL) and TxA2 action (SQ-29548) or production (dazmegrel) improved muscle perfusion, V̇o2, and muscle performance. These results suggest that type 2 diabetes mellitus in GK rats impairs skeletal muscle arteriolar function apparently early in the progression of the disease and potentially via an increased reactive oxygen species/inflammation-induced TxA2 production/action on network function as a major contributing mechanism. NEW & NOTEWORTHY The impact of type 2 diabetes mellitus on vascular structure/function remains an area lacking clarity. Using diabetic Goto-Kakizaki rats before the development of other risk factors, we determined alterations to vascular structure/function and skeletal muscle active hyperemia. Type 2 diabetes mellitus reduced arteriolar endothelium-dependent dilation associated with increased thromboxane A2 generation. Although modest microvascular rarefaction was evident, there were no other alterations to vascular structure/function. Skeletal muscle active hyperemia was blunted, although it improved after antioxidant or anti-thromboxane A2 treatment.

scholarly journals Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats

2005 ◽  
Vol 34 (2) ◽  
pp. 299-315 ◽  
Author(s):  
Young Ho Suh ◽  
Younyoung Kim ◽  
Jeong Hyun Bang ◽  
Kyoung Suk Choi ◽  
June Woo Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats

Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

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 Skeletal Muscle DNA Methylation Changes following Gastric Bypass in Women with Type 2 Diabetes

2018 ◽  
Vol 50 (5S) ◽  
pp. 150
Author(s):  
Matthew D. Barberio ◽  
G. Lynis Dohm ◽  
Walter J. Pories ◽  
Evan P. Nadler ◽  
Monica J. Hubal
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Dna Methylation ◽  
Gastric Bypass

scholarly journals The Impact of Antidiabetic Agents on Sarcopenia in Type 2 Diabetes: A Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Chen-Ning Wu ◽  
Kai-Jen Tien
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Geriatric Syndrome ◽  
Contributing Factors ◽  
Antidiabetic Agents ◽  
The Impact

Sarcopenia is a geriatric syndrome characterized by decline of skeletal muscle mass and function. Contributing factors include nutritional, genetic, inflammatory, and endocrinal factors. The reported prevalence of sarcopenia in type 2 diabetes mellitus is high, especially in patients with poor glycemic control. Additionally, antidiabetic agents may alter the balance between protein synthesis and degradation through various mechanisms of skeletal muscle mass regulation. This study reviewed the literature on the pathogenesis of sarcopenia in diabetes mellitus and the current understanding of whether antidiabetic agents contribute positively or negatively to sarcopenia and muscle wasting.

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