Impaired postprandial skeletal muscle vascular responses to a mixed meal challenge in normoglycaemic people with a parent with type 2 diabetes

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.

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A Mixed Meal Potentiates the Insulin Sensitivity of Glucose Transport and Metabolism in Adipocytes from Patients with Type 2 Diabetes Mellitus

Diabetic Medicine ◽

10.1111/j.1464-5491.1988.tb01104.x ◽

1988 ◽

Vol 5 (8) ◽

pp. 761-765

Author(s):

A. Lange ◽

J. Bak ◽

P. H. Andersen ◽

B. Richelsen ◽

O. Pedersen

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Sensitivity ◽

Glucose Transport ◽

Mixed Meal

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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 ◽

10.1007/s00125-021-05481-9 ◽

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

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Effects of Whey Protein on Skeletal Muscle Microvascular and Mitochondrial Plasticity Following 10-Weeks of Exercise Training in Men with Type-2 Diabetes

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2020-0943 ◽

2021 ◽

Author(s):

Kim Gaffney ◽

Adam Lucero ◽

Donia Macartney-Coxson ◽

Jane Clapham ◽

Patricia Whitfield ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Exercise Training ◽

Whey Protein ◽

Controlled Trial ◽

Protein Supplementation ◽

Microvascular Blood Flow ◽

Glucose Disposal ◽

Altered Expression

Skeletal muscle microvascular dysfunction and mitochondrial rarefaction feature in type-2 diabetes mellitus (T2DM) linked to low tissue glucose disposal rate (GDR). Exercise training and milk protein supplementation independently promote microvascular and metabolic plasticity in muscle associated with improved nutrient delivery, but combined effects are unknown. In a randomised-controlled trial, 24 men (55.6 y, SD5.7) with T2DM ingested whey protein drinks (protein/carbohydrate/fat: 20/10/3 g; WHEY) or placebo (carbohydrate/fat: 30/3 g; CON) before/after 45 mixed-mode intense exercise sessions over 10 weeks, to study effects on insulin-stimulated (hyperinsulinemic clamp) skeletal-muscle microvascular blood flow (mBF) and perfusion (near-infrared spectroscopy), and histological, genetic, and biochemical markers (biopsy) of microvascular and mitochondrial plasticity. WHEY enhanced insulin-stimulated perfusion (WHEY-CON 5.6%; 90%CI -0.1, 11.3), while mBF was not altered (3.5%; -17.5, 24.5); perfusion, but not mBF, associated (regression) with increased GDR. Exercise training increased mitochondrial (range of means: 40-90%) and lipid density (20-30%), enzyme activity (20-70%), capillary:fiber ratio (~25%), and lowered systolic (~4%) and diastolic (4-5%) blood pressure, but without WHEY effects. WHEY dampened PGC1α -2.9% (90%CI -5.7, -0.2) and NOS3 -6.4% (-1.4, -0.2) expression, but other mRNA were unclear. Skeletal muscle microvascular and mitochondrial exercise adaptations were not accentuated by whey protein ingestion in men with T2DM. Clinical Trial Registration Number: ACTRN12614001197628 Novelty Bullets: • Chronic whey ingestion in T2DM with exercise altered expression of several mitochondrial and angiogenic mRNA. • Whey added no additional benefit to muscle microvascular or mitochondrial adaptations to exercise. • Insulin-stimulated perfusion increased with whey but was without impact on glucose disposal.

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