Insulin resistance in skeletal muscle
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 240-242
2025-12-01
41
13C- NMR spectroscopy permitted for the first time non- invasive, direct assessment of rates of insulin- stimulated muscle glycogen synthesis in vivo. Using this approach, it was found that muscle glycogen synthesis accounts for ~90% of insulin- stimulated whole- body glucose disposal and for virtually all the non- oxidative glucose disposal in healthy insulin- sensitive humans. People with type 2 diabetes exhibit a 60% reduction in insulin- stimulated muscle glycogen synthesis, which represents the main abnormality underlying their insulin resistance. Similarly, after the ingestion of mixed meals, the increase in muscle glycogen synthesis was ~30% lower in people with type 2 diabetes despite doubled serum insulin concentrations compared with insulin- sensitive individuals. Applying combined 13C/31P NMR spectroscopy to directly measure the time course of intracellular concentrations of key metabolites in the pathway of muscle glycogen synthesis (intramyocellular glucose, glucose- 6- phosphate, and glycogen) revealed diminished increases in glucose- 6- phosphate and intramyocellular glucose concentrations in skeletal muscle of type 2 diabetes during hyperinsulinaemia (Figure 1). This indicates that an abnormality in insulin- stimulated glucose trans port via glucose transporter 4 (GLUT 4) is the main abnormality responsible for muscle insulin resistance in people with type 2 diabetes and/or obesity and in insulin- resistant first- degree relatives of people with type 2 diabetes. Further studies to delineate the mechanism by which insulin resistance affects recruitment of GLUT4 have indicated that upstream defects in the insulin signalling cascade are responsible for the impaired GLUT 4 translocation.
Fig1. Cellular mechanism of insulin resistance in human skeletal muscle. Augmented lipid availability, mainly increased fatty acid flux, raises the intramyocellular pool of the long- chain fatty acyl (CoA) pool, which fuels mitochondrial oxidation or serves to synthesize diacylglycerols (DAGs) for storage as triglyceride (TAG) lipid droplets. When fatty acid delivery and uptake exceed the rates of mitochondrial long- chain fatty acyl- CoA oxidation and incorporation of DAGs into TAGs, the intramyocellular DAG content transiently or chronically increases. Specifically, increases in plasma membrane sn- 1,2- DAGs lead to activation of novel protein kinase C (nPKC) isoforms (PKCε and PKCθ). Translocation of the PKCε to the membrane leads to phosphorylation of the insulin receptor on threonine1160 (T1160), leading to inhibition of insulin receptor kinase (IRK) activity, whereas activation of PKCθ leads to increased serine phosphorylation of insulin receptor substrate 1 (IRS- 1) on critical sites (e.g. Ser1101), which in turn blocks insulin- stimulated tyrosine phosphorylation of IRS- 1 and the binding and activation of phosphatidylinositol 3- kinase (PI3K). Both of these events result in reduced insulin- stimulated recruitment of glucose transporter type 4 (GLUT 4) units to the membrane, leading to impaired insulin- stimulated glucose uptake and phosphorylation to glucose- 6- phosphate and ultimately decreased insulin- stimulated glycogen synthesis. Source: Shulman 2014. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
It has been suggested previously that hyperglycaemia may cause these abnormalities by a mechanism summarized as glucose toxicity, which seems to be supported by similar impairments of insulin- stimulated glycogen synthesis and glucose- 6- phosphate increases in skeletal muscle in individuals with suboptimally managed type 1 diabetes. However, since insulin- resistant but normoglycaemic humans, such as lean relatives of people with obesity or older people with type 2 diabetes exhibit identical effects, mechanisms other than glucose toxicity have to explain the insulin resistance in the skeletal muscle of these groups.
Most insulin- resistant but normoglycaemic humans feature dyslipidaemia with elevated very low- density lipoproteins (VLDLs), TAGs, and/or fatty acids, which also predict not only type 2 diabetes but also cardiovascular mortality. Excess lipid storage in the form of obesity has long been associated with insulin resistance, but 1H- NMR studies provided evidence for an even stronger relationship between intramuscular and intramyocellular TAG content and muscle insulin resistance than for body fat content. Intramyocellular TAG concentrations can be measured non- invasively by 1H NMR spectroscopy and increased concentrations have been termed ectopic lipid accumulation or metabolic obesity. The observation of augmented ectopic lipid deposition in insulin- resistant states infers that intracellular TAGs or lipid metabolites could mediate the effect of circulating lipids on insulin action (Figure 1). From early pre- clinical studies, Randle explained the impaired glucose metabolism in type 2 diabetes by an interaction with fatty acids, termed the glucose–fatty acid cycle. This hypothesis postulated that fatty acid oxidation first raises the mitochondrial concentration ratio of acetyl- coenzyme A (acetyl- CoA)/CoA, which would inhibit the pyruvate dehydrogenase (PDH) complex. The subsequent rise in citrate would inhibit phosphofructokinase- 1 and raise glucose- 6- phosphate, which would then inhibit hexokinase and finally increase intracellular glucose concentrations and reduce muscle glucose uptake. In contrast, short- term elevations of plasma TAGs and fatty acids resulted in marked muscle insulin resistance, but a blunted rise in intramyocellular glucose and glucose- 6- phosphate, as measured using 13C/31P NMR spectroscopy during insulin stimulation in healthy humans. Lipid- induced muscle insulin resistance in humans thereby results from reduction of insulin- stimulated glucose trans port into the muscle cells, with subsequently impaired glucose phosphorylation and decreased insulin- stimulated glycogen syn thesis (Figure 1). Thus, lipids cause insulin resistance in humans via direct inhibition of glucose transport, but not via inhibition of the PDH complex. Some studies, but not others, suggest that lipid- induced insulin resistance may be more pronounced in men than in women, which would support the known greater diabetes risk for men.
Increases in intramyocellular TAGs are an even better predictor of insulin resistance in muscle and liver than circulating plasma fatty acids. Indeed, lipid- induced insulin resistance is reflected by impaired insulin signalling via reduced tyrosine phosphorylation of insulin receptor substrate- 1 (IRS- 1), IRS- 1- dependent phosphatidylinositol 3- kinase (PI3K) activation, and serine phosphorylation of Akt . This could result from accumulation of intramyocellular long- chain fatty acyl- CoA (LCFA- CoA), diacylglycerols (DAGs), or ceramides (Figure 1). Studies on transgenic and knockout animal models provide compelling evidence that fatty acid elevation increases intramyocellular LCFA- CoA, CoA, and DAGs, but not ceramide content, along with stimulation of TAG synthesis by DAG O- acyltransferase- 1 (DGAT- 1) and of protein kinase C- θ (PKCθ), with subsequent serine phosphorylation of IRS- 1 via the serine–threonine kinase cascade. However, studies employing other animal models showed that the ceramide pathway could also be involved in lipid- induced insulin resistance. Several studies in humans reported conflicting results, likely due to differences in the design, cohorts, and analytical methods. A recent study shed more light on the time course of events of lipid- induced insulin resistance by performing serial biopsies in humans during lipid infusion and comparing the results obtained from biopsies from insulin- resistant individuals with obesity or type 2 diabetes. Lipid infusion resulted in a transient increase in intramyocellular DAGs, followed by activation of PKCθ and increased phosphorylation of the serine1101 residues of IRS- 1, with subsequent inhibition of insulin signalling and insulin- stimulated muscle glucose disposal (Figure 1). Similar increases in myocellular DAGs and PKCθ activation were found in individuals with type 2 diabetes and obesity without lipid infusion. DAG subspecies containing C18- acyl residues correlated best with insulin resistance in all conditions of insulin resistance, whereas total ceramides and their subspecies were not affected either by lipid infusion or in people with the insulin resistance of obesity and type 2 diabetes.
In addition to lipids, dietary excess of protein has been related to insulin resistance and circulating branched- chain amino acids predict type 2 diabetes. By analogy with fatty acids, short- term elevation of plasma amino acids reduces insulin- stimulated glucose- 6- phosphate and glycogen synthesis by activating the mammalian target of the rapamycin (mTOR)/p70 S60 kinase path way, with subsequent serine phosphorylation of IRS- 1. This pathway would further favour ectopic lipid storage.
In conclusion, the lipid- induced insulin resistance or lipotoxicity hypothesis proposes that in the absence of a balance between fatty acid delivery and muscle TAG synthesis via DGAT- 1 as well as oxidation in the mitochondria, lipotoxic species such as sn- 1,2- DAGs will accumulate in the plasma membrane and activate PKCε/PKCθ in skeletal muscle. This in turn will inhibit the insulin receptor kinase (IRK) activity (PKCε) and IRS- 1–associated PI3K (PKCθ), leading to impaired insulin signalling and impaired insulin- stimulated glucose uptake. Any mechanism by which lipid delivery to the muscle is reduced, lipid oxidation is increased, and/or TAG synthesis is stimulated will likely reduce LCFA- CoA and plasma membrane sn- 1,2- DAG concentrations and prevent lipid- induced muscle insulin resistance.
Consequently, decreases in muscle lipid oxidation could serve as another contributor to lipid accumulation in the skeletal muscle and thereby insulin resistance. Flux rates through muscle ATP synthase, reflecting basal mitochondrial phosphorylation, are ~40% lower in lean insulin- resistant first- degree relatives of individuals with type 2 diabetes than in insulin- sensitive but otherwise matched people. During insulin stimulation, muscle ATP synthase flux doubled in insulin- sensitive humans, but was almost abolished in the offspring of people with type 2 diabetes. Similarly, individuals with type 2 diabetes, but without obesity, featured ~25% lower mitochondrial phosphorylation rates in the basal (fasting) state and no increase during insulin stimulation, even in the presence of increased availability of glucose as a substrate. This may be due to reduced capacities of the electron- transport chain and/or the phosphorylation system and/or reduced insulin- stimulated phosphate transport into the myocytes.
Ageing, an important risk factor of type 2 diabetes, associates with impaired biogenesis and accelerated apoptosis of mitochondria. Non- obese older humans are not only frequently insulin resistant, but also feature higher intramyocellular TAG contents and ~30–40% lower rates of both muscle ATP synthase flux and tricarboxylic acid (TCA) cycle oxidation. Hence age- associated reductions in mitochondrial function may predispose older people to ectopic lipid accumulation and muscle insulin resistance, possibly owing to damage by accumulating reactive oxygen species (ROS). In line with this contention, similar reductions were reported for neural mitochondrial activity in healthy older individuals. The hypothesis of age- associated ROS- induced reductions in mitochondrial function contributing to age- associated muscle insulin resistance was further supported by findings in transgenic mice with overexpression of human catalase targeted to the mitochondria (MCAT mice). These mice were protected from age- associated abnormalities in muscle mitochondrial function and DAG/PKCθ- induced muscle insulin resistance, along with reduced mitochondrial oxidative damage, preserved muscle ATP synthesis, and adenosine 5′- monophosphate- activated protein kinase (AMPK)- induced mitochondrial biogenesis. Moreover, measurements of basal and insulin- stimulated rates of muscle PDH (VPDH) flux relative to citrate synthase flux (VCS) employing [1- 13C] glucose incorporation into glutamate relative to alanine in muscle biopsies from healthy, lean, old, and young humans revealed a blunted rise of insulin- stimulated VPDH/VCS fluxes in the old people, along with 25% lower muscle glucose uptake and 70% higher accumulation of intramyocellular TAGs. These findings indicate a marked inability of mitochondria to switch from lipid to glucose oxidation during insulin stimulation. Recent assessments of VPDH/VCS ratios in soleus or quadriceps muscles revealed that mitochondrial substrate preference, often referred to as metabolic inflexibility, is not essential for the pathogenesis of insulin resistance in humans. Taken together, combined acquired and age- associated reductions in features of mitochondrial function may promote intramyocellular lipid accumulation and insulin resistance in type 2 diabetes.
In addition to ageing per se, other metabolic factors such as hyperglycaemia and dyslipidaemia may impair mitochondrial function and thereby contribute to muscle insulin resistance. In this context, insulin- resistant individuals with type 1 diabetes have lower insulin- stimulated ATP synthase flux, which negatively relates to glucometabolic regulation. Short- term lipid infusion also leads to lower muscle ATP synthase flux, but only on the onset of insulin resistance in healthy humans. The reduced rates of insulin- stimulated ATP synthase flux were associated with impaired insulin- stimulated increases in muscle glucose- 6- phosphate concentrations due to lower insulin- stimulated glucose uptake. Lipid lowering via inhibition of lipoprotein lipase (LPL) by acipimox improves insulin resistance independently of changes in oxidative capacity in type 2 diabetes. These findings suggest that glucose- and lipid- induced abnormalities in muscle mitochondrial function are not primary events in the development of insulin resistance in common type 2 diabetes.
A series of studies addressed the role of mitochondrial function independently of age and glycaemic levels. Young, lean, but severely insulin- resistant first- degree relatives of people with type 2 diabetes were identified with 30% lower basal rates of muscle ATP synthase and TCA cycle fluxes compared to age- and body mass–matched insulin- sensitive individuals. This abnormality of mitochondrial oxidative phosphorylation was found in the presence of 38% lower mitochondrial density, indicating that the reduction in mitochondrial function may be attributed to lower muscle mitochondrial content. In contrast to previous reports on skeletal muscle of people with type 2 diabetes, this was not explained by reduced expression of the peroxisome proliferator- activated receptor (PPAR) γ- coactivator 1α (PGC1α), a key regulator of mitochondrial biogenesis. Likewise, in another cohort of first- degree relatives of individuals with type 2 diabetes, the stimulatory effect of exercise training on insulin sensitivity and ATP synthesis did not depend on common single- nucleotide polymorphisms (SNPs) of PGC1α, but was modified by a G/G- SNP of the gene encoding NADH dehydrogenase (ubiquinone) 1β subcomplex (NDUFB6), a component of complex I of the mitochondrial respiratory chain. The finding that the insulin resistance in relatives of individuals with type 2 diabetes is related to lower fasting and insulin- stimulated rates of muscle ATP synthesis in a similar fashion as in people with overt type 2 diabetes strongly underlines the role of inherited factors in the pathogenesis of insulin resistance and type 2 diabetes. Taken together, at least in this cohort of insulin- resistant first- degree relatives of individuals with type 2 diabetes, it is likely that a reduction in mitochondrial content, due to reduced mitochondrial biogenesis, is responsible for the reduced mitochondrial oxidative and phosphorylation activity and may be an acquired abnormality. Nevertheless, given the key role of mitochondrial activity in the regulation of fat metabolism in muscle cells, these data suggest that the reduced mitochondrial function may be an important predisposing factor that promotes plasma membrane sn- 1,2- DAG accumulation in muscle cells and insulin resistance in muscle among people with insulin resistance whose parents have type 2 diabetes.
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