Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus

Kulkarni, Sameer S.; Salehzadeh, Firoozeh; Fritz, Tomas; Zierath, Juleen R.; Krook, Anna; Osler, Megan E.

doi:10.1016/j.metabol.2011.06.014

Cited by 85 publications

(80 citation statements)

References 173 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, improvements in postprandial glucose were directly correlated with increased peripheral insulin-stimulated glucose uptake. The cellular mechanism responsible for attenuated improvements in peripheral insulin sensitivity in adults with IFG ϩ IGT is not readily apparent from our study design, but we propose that impaired mitochondrial oxidative capacity may play a role (16,20,29,32,49) since chronic hyperglycemia has been implicated in the dysregulation of mitochondrial capacity (28,41). In our study, exercise training increased metabolic flexibility in subjects with IFG or IGT alone, whereas those with IFG ϩ IGT remained metabolically inflexible.…”

Section: Discussionmentioning

confidence: 62%

“…In addition, in vitro work demonstrates that chronic hyperglycemia impairs metabolic flexibility by decreasing mitochondrial complex I activity in human myotubes (3). Skeletal muscle biopsies are needed to determine whether the presence of IFG alters in vivo mitochondrial oxidative capacity in adults with IGT (20,29,42). However, given that in vivo (29,42) and in vitro studies (3) report that chronic hyperglycemia overloads mitochondrial oxidative capacity, it appears plausible that exercising with a background of hyperglycemia impairs skeletal muscle glucose uptake through a metabolic stress/inflammatory-related pathway (36).…”

Section: Discussionmentioning

confidence: 99%

“…Skeletal muscle biopsies are needed to determine whether the presence of IFG alters in vivo mitochondrial oxidative capacity in adults with IGT (20,29,42). However, given that in vivo (29,42) and in vitro studies (3) report that chronic hyperglycemia overloads mitochondrial oxidative capacity, it appears plausible that exercising with a background of hyperglycemia impairs skeletal muscle glucose uptake through a metabolic stress/inflammatory-related pathway (36). This hypothesis is consistent with evidence that PGC-1␣ and AMPK expression are lower after exercise in insulin-resistant individuals (13,24,30).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Malin

Haus

Solomon

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Malin SK, Haus JM, Solomon TP, Blaszczak A, Kashyap SR, Kirwan JP. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes. Am J Physiol Endocrinol Metab 305: E1292-E1298, 2013. First published September 24, 2013; doi:10.1152/ajpendo.00441.2013.-Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG ϩ IGT is unknown. Twenty-four older (66.7 Ϯ 0.8 yr) obese (34.2 Ϯ 0.9 kg/m 2 ) adults were categorized as IFG (n ϭ 8), IGT (n ϭ 8), or IFG ϩ IGT (n ϭ 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ϳ85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m 2 ·min Ϫ1 ) with [6,6-2 H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG ϩ IGT (P Ͻ 0.05). Exercise reduced glucose iAUCOGTT in IGT only (P Ͻ 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity (P Ͻ 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P Ͻ 0.05). Adults with IFG ϩ IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training. obesity; prediabetes; insulin resistance; cardiometabolic; exercise APPROXIMATELY 79 MILLION ADULTS in the US have impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG ϩ IGT) and are collectively referred to as having prediabetes (2). Focusing on adults with IFG, IGT, and IFG ϩ IGT is clinically important since each phenotype has a unique pathology that promotes different degrees of cardiovascular disease risk (8, 31). The exact cause for the difference in disease risk is unclear, but the degree of insulin resistance in skeletal muscle or the liver is a likely candidate. Individuals with IGT [2-h oral glucose tolerance test (OGTT) values between 140 and 199 mg/dl] are typically characterized as having reduced skeletal muscle insulin sensitivity, whereas adults with IFG (fasting glucose 100 -125 mg/dl) generally h...

show abstract

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Malin

Haus

Solomon

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…Patients on insulin treatment and with symptomatic coronary heart disease were excluded. A muscle biopsy of the vastus lateralis and anthropomorphic measurements were taken at enrolment in the study (Barres et al 2012, Kulkarni et al 2012. In a separate cohort, 13 sedentary volunteers participated in an exercise training program consisting of 60 min a day, 5 days/week for 3 weeks.…”

Section: Human Subjectsmentioning

confidence: 99%

TWIST1 and TWIST2 regulate glycogen storage and inflammatory genes in skeletal muscle

Mudry

Massart

Szekeres

et al. 2015

Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

TWIST proteins are important for development of embryonic skeletal muscle and play a role in the metabolism of tumor and white adipose tissue. The impact of TWIST on metabolism in skeletal muscle is incompletely studied. Our aim was to assess the impact of TWIST1 and TWIST2 overexpression on glucose and lipid metabolism. In intact mouse muscle, overexpression of Twist reduced total glycogen content without altering glucose uptake. Expression of TWIST1 or TWIST2 reduced Pdk4 mRNA, while increasing mRNA levels of Il6, Tnfa, and Il1b. Phosphorylation of AKT was increased and protein abundance of acetyl CoA carboxylase (ACC) was decreased in skeletal muscle overexpressing TWIST1 or TWIST2. Glycogen synthesis and fatty acid oxidation remained stable in C2C12 cells overexpressing TWIST1 or TWIST2. Finally, skeletal muscle mRNA levels remain unaltered in ob/ob mice, type 2 diabetic patients, or in healthy subjects before and after 3 months of exercise training. Collectively, our results indicate that TWIST1 and TWIST2 are expressed in skeletal muscle. Overexpression of these proteins impacts proteins in metabolic pathways and mRNA level of cytokines. However, skeletal muscle levels of TWIST transcripts are unaltered in metabolic diseases.

show abstract

“…Epigenetics and T2DM: cause or effect? Over the past decade, evidence has emerged to suggest that the epigenetic landscape is altered in multiple organs in patients with T2DM, including pancreatic islets [75][76][77][78] , skeletal muscle [79][80][81] , adipose tissue 82 and liver 83,84 . Perhaps unsurprisingly, given the nature of the underlining pathophysiology of the disease, unbiased screens have identified differential methylation and expression of subsets of genes associated with a wide range of metabolic processes and mitochondrial functions in peripheral tissues of patients with T2DM 79,81 .…”

Section: Epigenomic Modifications In T2dmmentioning

confidence: 99%

The role of diet and exercise in the transgenerational epigenetic landscape of T2DM

2016

Self Cite

View full text Add to dashboard Cite

Epigenetic changes are caused by biochemical regulators of gene expression that can be transferred across generations or through cell division. Epigenetic modifications can arise from a variety of environmental exposures including undernutrition, obesity, physical activity, stress and toxins. Transient epigenetic changes across the entire genome can influence metabolic outcomes and might or might not be heritable. These modifications direct and maintain the cell-type specific gene expression state. Transient epigenetic changes can be driven by DNA methylation and histone modification in response to environmental stressors. A detailed understanding of the epigenetic signatures of insulin resistance and the adaptive response to exercise might identify new therapeutic targets that can be further developed to improve insulin sensitivity and prevent obesity. This Review focuses on the current understanding of mechanisms by which lifestyle factors affect the epigenetic landscape in type 2 diabetes mellitus and obesity. Evidence from the past few years about the potential mechanisms by which diet and exercise affect the epigenome over several generations is discussed.

show abstract

Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus

Cited by 85 publications

References 173 publications

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

TWIST1 and TWIST2 regulate glycogen storage and inflammatory genes in skeletal muscle

The role of diet and exercise in the transgenerational epigenetic landscape of T2DM

Contact Info

Product

Resources

About