We summarize the existing literature data concerning the involvement of skeletal muscle (SM) in whole body glucose homeostasis and the contribution of SM insulin resistance (IR) to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS), adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.
Insulin resistance (IR) constitutes a common and broadly prevalent metabolic disorder, which seems to govern the pathophysiology of diabetes mellitus, metabolic syndrome, and obesity [
In general, IR indicates the presence of an impaired peripheral tissue response to endogenously secreted insulin. It is typically manifested as both decreased insulin-mediated glucose uptake (IMGU) at the level of adipose and skeletal muscle (SM) tissue, and as an impaired suppression of hepatic glucose output. A significant body of evidence supports the critical role of SM for the development of IR, most commonly through an interactive cross-talk with adipose and liver tissue [
SM plays a crucial role in maintaining systemic glucose metabolism, accounting for 85% of whole body insulin-stimulated glucose uptake [
The activated insulin-signaling cascade results in the release of GLUT4 from an intracellular reservoir compartment and its translocation and final fusion with the plasma membrane. This is the rate-limiting step for the uptake of glucose, which is transported across the plasma membrane and further processed by either oxidative (glycolysis) or nonoxidative pathways (glycogen synthesis) [
However, glucose disposal in SM is not entirely independent from the metabolic effects of insulin on other peripheral tissues, such as adipose tissue (AT). It seems that IR at the level of SM might be also secondarily induced to adipose tissue IR. More specifically, it has been shown that mice with AT-specific knockout of GLUT4 had an impaired IMGU in SM as well, despite preserved GLUT4 expression in this tissue [
SM is a principal tissue responsible for IMGU which has recently gained a lot of interest, as a major site involved in peripheral IR. Most of the available data have derived from studies in type 2 diabetes mellitus (T2DM), where SM has emerged as an important insulin-resistant peripheral tissue, via molecular mechanisms that are currently being extensively investigated.
In vitro and in vivo data from humans and laboratory animals support a selective insulin-signaling defect at the level of glucose transport in SM. In type 2 diabetic patients, IMGU in SM has been found to be significantly reduced by about 50%, without clarifying whether this is a permanent defect or rather a short-term downregulation secondary to the diabetic state. Furthermore, an additional possible explanation for the development of IR in SM is related to specific alterations in the insulin-signal transduction pathway, including decreased IRS-1 protein content, impaired IRS-1 phosphorylation, reduced PI3K activity, or altered protein expression of the regulatory subunit of PI3K [
Despite the considerable body of evidence supporting the critical role of SM for the development of IR in many clinical entities, the exact underlying mechanisms have not been fully delineated and most commonly represent a complex interaction between multiple extrinsic and intrinsic factors.
Most commonly, IR in SM is considered to be the end result of a complex interaction involving several different tissues. AT can induce IR at the level of SM via secretion of adipokines, inflammatory mediators, and growth factors. Tumor necrosis factor
TNF
In addition, adiponectin, a protective adipokine secreted by adipocytes, plays a pivotal role for SM insulin sensitivity. Adiponectin stimulates FFA catabolism, either directly or indirectly through stimulation of PPAR
The primary site of postabsorptive glucose disposal is SM and the primary mechanism of glucose storage is through its conversion to glycogen. In states of IR, a deficiency in the nonoxidative glucose disposal has been primarily related to a defect in glycogen synthesis. Freymond et al. studied biopsies of vastus lateralis muscle, both before and during a hyperinsulinemic-euglycemic clamp, and demonstrated that human subjects with IR display decreased insulin-stimulated glycogen synthase activity [
Chronic glucocorticoid excess, a typical biochemical feature of Cushing’s syndrome, has been traditionally associated with IR in general. However, recent experimental observations suggest that glucocorticoids, as well as glucocorticoid receptor (GR) activity, can have adverse effects on peripheral insulin sensitivity. Reynolds et al., found increased GR mRNA levels and increased expression of glucocorticoid receptors in SM of men with IR and hypertension, implicating the dysregulation of glucocorticoid receptor expression and/or function as a possible underlying pathogenetic mechanism for IR in SM [
Insulin-mediated increased blood flow seems to be an important step for insulin delivery and glucose metabolism in peripheral tissues, including SM [
Insulin regulates blood flow in peripheral tissues through a variety of mechanisms. Insulin induces dilatation of terminal arterioles and provides a constant rate of vasodilatation or vasoconstriction, in order to maximally extend the period of peripheral tissue perfusion. In this way, insulin enhances nutrient delivery and expands the surface area available for exchange of insulin, glucose, and other nutrients in peripheral tissues, including SM. Furthermore, after its binding to the receptor, insulin seems to promote its own translocation across the endothelial cell barrier [
Although generalized and muscle IR remains a hot topic for the investigation of metabolic disease, it would be quite interesting to expand this research to a number of common and clinically relevant endocrine diseases, including PCOS, adrenal dysfunction, and thyroid disorders.
PCOS is a common endocrine disorder with a worldwide prevalence of 6%-7% among premenopausal women [
Women with PCOS exhibit basal hyperinsulinemia, decreased glucose-stimulated insulin release and IMGU, due to reduced hepatic insulin clearance and pancreatic
IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling due to a complex interaction between intrinsic (genetically determined) and environmental factors [
In vitro studies have shown that cultured SM cells from women with PCOS display normal insulin sensitivity, while SM cells from in vivo studies in PCOS exhibit resistance to insulin, suggesting the important role of extrinsic factors in producing muscle IR in PCOS [
The existing data indicate that adipose tissue, which is also an insulin resistant site in PCOS, and especially when it is centrally accumulated, secretes increased levels of adipokines, FFA, and inflammatory mediators (TNF-
Multiple studies suggest the association between androgen excess and IR in women with PCOS, but their cross-sectional nature does not allow safe conclusions about causality [
On one hand, hyperandrogenemia in women with PCOS appears to be an effect of the augmented steroidogenesis by hyperinsulinemia secondary to IR [
Summarizing the existing data, androgens promote IR at the tissue level of SM by reducing capillary network formation for adequate delivery of insulin to SM, switching muscle fiber isoforms, reducing glycogen synthase activity and impairing insulin-mediated GLUT4 plasma membrane translocation [
However, the finding of hyperinsulinemia in PCOS patients raises the questions what the cause is and what the effect is. Most of the existing clinical data suggest, without providing definitive confirmation, that hyperinsulinemia causes hyperandrogenism, more than the other way around [
Current evidence suggests that excessive serine phosphorylation of the insulin receptor or downstream signaling molecules plays a pivotal role for the pathogenesis of muscle IR in PCOS [
Corbould et al. who studied cultured SM cells of obese nondiabetic women with PCOS and of age- and BMI-matched control women, did not observe a decrease in IMGU and basal autophosphorylation in vitro, while insulin-stimulated tyrosine phosphorylation of the insulin receptor was found to be normal [
A putative serine kinase, extrinsic to the insulin receptor, has been implicated in the abnormal pattern of phosphorylation in PCOS but has not been identified yet. Although there are at least 50 known potential serine/threonine phosphorylation sites on IRS-1, phosphorylation at both serine 312 and serine 636/639 has been frequently reported in several studies associating IRS-1 serine phosphorylation with IR [
The defective activation of aPKC (atypical protein kinase C), a downstream effector of PI3K, in SM of PCOS obese patients has been also involved in the pathogenesis of muscle IR in this syndrome. In humans, marked defects in aPKC activation in SM have been reported in T2DM, obesity, obesity-associated PCOS, and impaired glucose tolerance [
Despite the well established identification of several molecular abnormalities in PCOS, it remained initially unclear whether the observed defects in insulin-signaling are actually intrinsic, genetically determined to SM, or rather acquired secondary to exposure to in vivo environmental factors such as hyperinsulinemia, hyperandrogenemia, increased circulating FFAs, or sustained hyperglycemia. According to Corbould et al. muscle IR is not an intrinsic feature in PCOS but appears rather to be significantly influenced by endogenous environmental factors [
Indeed, exposure to a number of molecules, including FFA, TNF-
In vivo studies of PCOS patients, where serial SM biopsies were performed during hyperinsulinemic-euglycemic clamps, have revealed a significant impairment in IMGU, an increased expression of IRS-2, and normal expression of insulin receptor, IRS-1, and PI3K. These data suggest that the increased expression of IRS-2 might represent a compensatory adaptation for the decreased insulin-mediated IRS-1-associated PI3K activity, which is not, however, completely effective, since IMGU was not restored to normal [
Recently, another candidate pathogenetic mechanism for muscle IR in women with PCOS has been proposed, consisting in a defective insulin regulation of ERK 1/2 (extracellular signal-regulated kinases 1/2). Rajkhowa et al. compared the relative contribution of two distinct insulin-signaling pathways to muscle IR in nine women, diagnosed with PCOS. The study involved the Ras-ERK and the IRS-PKB pathways, mediating the mitogenic and metabolic effects of insulin, respectively, and found no significant difference in the expression, basal activity, or insulin activation of IRS-1 and PKB between PCOS subjects and controls [
Based on the few existing human in vivo studies, it seems that in PCOS there is a severe functional defect in the insulin-signaling cascade within SM, consisting in an abnormal phosphorylation pattern of the insulin receptor or downstream key signaling proteins.
It has been recently demonstrated that PCOS is associated with impaired mitochondrial structural integrity and oxidative metabolism. Skov et al. studying insulin resistant women with PCOS, demonstrated a significant downregulation of the expression of nuclear-encoded genes representing mitochondrial oxidative phosphorylation, ribosomal proteins, mRNA processing reactome, translation factors, and proteasome degradation (OXPHOS), compared to control women. This effect was mainly mediated by a decrease in PGC-1a expression (PPAR-
Calcium transporter activity was also significantly downregulated in PCOS patients. Increasing evidence supports a modulating role for calcium influx, calmodulin and
Future studies, unraveling the exact molecular mechanisms of IR in general or in SM in particular in PCOS, may help develop effective gene-based strategies in order to prevent the increased risk of early onset type 2 diabetes in women suffering from this condition.
Adrenal disorders characterized by increased secretion of adrenocortical or adrenomedullary hormones such as hyperaldosteronism, Cushing’s syndrome, hyperandrogenism, and pheochromocytoma have been associated with various metabolic disorders, including impaired glucose tolerance, IR, and overt diabetes [
Adrenal hormone excess is associated with decreased insulin secretion by the pancreatic
Aldosterone is the final mediator of the renin-angiotensin-aldosterone system (RAS), which mediates blood pressure control and electrolytic balance in the kidney. However, a significant body of evidence indicates that aldosterone—in concert with other independently acting mediators of RAS axis (renin and angiotensin)—impairs insulin secretion and metabolic signaling, resulting in impaired glucose tolerance and overt diabetes. Focusing on aldosterone, which can be significantly elevated in some patients with hypersecreting adrenal lesions, it promotes IR, inflammation, fibrosis, oxidative stress, and sodium retention, with detrimental cardiometabolic effects [
Mounting evidence supports that aldosterone exerts its diabetogenic actions by a direct effect on insulin receptor function and metabolic signaling cascade in several peripheral tissues, including cardiovascular and renal tissue, fat, liver and SM [
However, the underlying molecular and cellular mechanisms linking aldosterone excess with changes in the glucose and insulin metabolism remain still elusive, especially regarding the contribution of SM.
In addition to its classic effects, aldosterone induces rapid (nongenomic) adverse responses in both vascular smooth muscle cells and SM. This effect is mediated by NADPH oxidase (nicotinamide adenine dinucleotide phosphate), which generates excess reactive oxygen species (ROS), redox imbalance, and oxidative stress [
Chronic exposure to glucocorticoid excess, a typical feature of Cushing’s syndrome, is associated with various metabolic disorders, including glucose intolerance, IR, or overt diabetes [
Since studies into the effects of GCs on the expression of insulin receptor in SM have yielded contradictory results, the markedly reduced IMGU under conditions of GC excess has been proposed as a postreceptor defect. In vitro studies using isolated SM cells treated with dexamethasone showed a decreased expression and phosphorylation of IRS-1, PI3K, and PKB/Akt as well as reduced GLUT4 migration to the cell surface [
Some data support an indirect effect of GS on SM insulin-signaling, which is mediated through enhanced proteolysis, and thus increased circulating amino acid levels. Elevated circulating amino acids seem to inhibit insulin-stimulated IRS tyrosine phosphorylation and activation of PI3K in vitro [
Another indirect negative effect of GCs on SM insulin sensitivity appears to be mediated through the GC-induced dyslipidemia. GCs promote whole body lipolysis, resulting in increased plasma levels of FFAs, which enhance in turn the accumulation of intramyocellular lipids (IMCLs), such as fatty acyl CoA, diacylglycerol, and ceramide, affecting negatively glucose uptake and disposal [
In summary, GCs reduce insulin sensitivity and consequently IMGU in SM, not only by directly perturbing insulin-signaling and glycogen synthesis, but also secondarily to unfavorable changes in protein and lipid metabolism, which further affect negatively the insulin-signaling cascade, in peripheral tissues, including SM.
The exact relationship between increased adrenal androgens and IR remains to be elucidated. It has been shown that experimentally induced hyperinsulinemia elicited an acute decline in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S). However, the regulatory role of insulin on adrenal androgen production and metabolism in normal physiology or disease remains still speculative [
Pheochromocytoma, typically characterized by endogenous catecholamine excess, is associated with several glucometabolic abnormalities, ranging from impaired glucose tolerance (25%–75%) to overt diabetes [
In summary, excessive catecholamines in patients with pheochromocytoma can induce or aggravate IR in peripheral tissues including SM, while the surgical treatment of pheochromocytoma can reverse the hyperinsulinemia and cardiometabolic abnormalities observed in these patients [
Adrenal incidentalomas (AIs) are defined as randomly discovered adrenal masses, which are diagnosed by abdominal ultrasound or computed tomography scan, performed for unrelated causes. Recent literature suggests that 10%–20% of solid AIs demonstrate a subclinical hormonal dysfunction, which may place patients at a higher risk for metabolic derangements such as IR [
In a study from Japan, all 12 patients with AIs exhibited IR, based on the steady state of plasma glucose [
Trying to provide an explanation for the increased risk of developing IR in patients with nonfunctioning AIs (NFAIs), Ermetici et al. have recently formulated the hypothesis of adipokine involvement [
In a recent study by our research team [
Thyroid hormones (THs) constitute important mediators of body metabolism and affect various metabolic aspects involving glucose and insulin metabolism, through a variety of mechanisms. Data from animal studies have shown that THs play a key role in the regulation and activation of insulin receptor and glucose transporter proteins, in signaling pathways and in the expression of different isoforms of SM myosin heavy chains [
Hypothyroidism (HP) has been associated with disorders of glucose and insulin metabolism, involving defective insulin secretion in response to glucose, hyperinsulinemia, altered peripheral glucose disposal, and IR.
According to in vivo data, HP is associated with a decreased glucose-induced insulin secretion by the
In addition, it is suggested that HP is an insulin resistant state. Interestingly, even subtle decreases in the levels of TH within the normal range have been shown to correlate inversely with markers of IR [
The mechanisms linking HP with IR in general and in SM in particular are still under investigation. IR in HP is associated with a negative regulation of one or more intracellular enzymes involved in glucose catabolism [
It is obvious that, although HP constitutes an insulin resistant state, more studies need to be done in order to clarify the underlying pathogenetic mechanisms. However, it has to be mentioned that IR appears to be similar in patients with overt clinical and subclinical HP [
Hyperthyroidism (HPR) is also associated with metabolic abnormalities, including disorders of the glucose and insulin metabolism [
Insulin secretory capacity seems to be disrupted in HPR, but the existing data are rather heterogeneous, suggesting increased, normal, or decreased insulin secretion. This estimation has been based on the measurement of circulating C-peptide levels. However, when individually derived C-peptide kinetic parameters were measured, the insulin secretory rate was significantly increased, possibly reflecting an increased response of
HPR has been also associated with hyperinsulinemia, which is considered to be compensatory for the increased insulin clearance [
However, there are only few data regarding the underlying pathogenetic mechanisms of IR in HPR. The existing data regarding the number of high and low affinity insulin receptors are conflicting, suggesting either an increased or unaltered expression in HPR [
A decreased insulin-mediated stimulation of major intracellular pathways of glucose metabolism has been also reported [
HPR is generally thought to be an insulin-resistant state, but further studies are definitely needed in order to prove this association and reveal the underlying pathogenetic mechanisms. It has been generally suggested that THs are not the only factors involved in the initiation of the IR cascade, but they most commonly interact with various tissues and molecules, in order to regulate glucose metabolism and insulin action.
SM constitutes an insulin-responsive peripheral tissue with a major role in maintaining systemic glucose metabolism. In a general overview of insulin-resistant states, including PCOS as well as adrenal and thyroid disorders, IR in SM appears to be a clinically important manifestation. Specific alterations at the insulin receptor level or the signal transduction pathway have been suggested as the main underlying pathogenetic mechanisms which lead to impaired IMGU and defective glycogen synthesis.
In PCOS, muscle IR has been associated with abnormal phosphorylation of insulin-signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.
The metabolic abnormalities associated with hypersecreting adrenal disorders constitute the end result of the adverse effects of adrenal hormones on various components of insulin action and glucose metabolism. Aldosterone is associated with IR in SM either directly through its effects on the insulin receptor function and metabolic signaling cascade, or indirectly through oxidative stress induction. GCs reduce IMGU in SM, either directly by perturbing insulin-signaling and glycogen synthesis, or indirectly through unfavorable changes in protein and lipid metabolism. Catecholamine excess can induce or aggravate IR in SM. Furthermore, AIs—including NFAIs—are characterized by an increased prevalence of generalized and muscle IR, possibly due to the subclinical proinflammatory milieu and the biochemically silent endocrine abnormalities.
Thyroid disorders, including both hypo- and hyperthyroidism, have been associated with IR in SM and altered peripheral glucose disposal, due to impaired GLUT4 translocation, decreased glycogen synthesis, downregulated intracellular glucose catabolism, altered blood flow, and decreased muscle oxidative capacity.
Based on the data presented herein, it is strongly emphasized that all patients with common endocrine disorders such as PCOS as well as adrenal and thyroid disorders, should undergo a thorough metabolic evaluation, since IR—particularly at the level of SM—appears to be a prominent feature in these states. Far more clinical and experimental studies are required in order to fully clarify the underlying pathophysiology of the clinically meaningful relationship between endocrine disease and impaired SM insulin sensitivity.
Polycystic Ovary Syndrome
Insulin Resistance
Hypothyroidism
Hyperthyroidism
Adrenal Incidentalomas
Nonfunctioning Adrenal Incidentalomas
Skeletal Muscle
Adipose Tissue
Insulin-mediated glucose uptake
Glucose Transporter 4
Insulin receptor substrate-1
Phosphatidylinositol 3-kinase
Akt/Protein kinase B
Atypical protein kinase C
Glycogen synthase kinase-3
Extracellular signal-regulated kinases 1/2
Akt substrate of 160 kDa
mammalian Target Of Rapamycin
Mitogen-activated Protein Kinases
Inositol Triphosphate
AMP-dependent kinase
Protein kinase A
Hormone-Sensitive Lipase
Tumor necrosis factor-a
Free Fatty Acid
Interleukin-6
Nuclear Factor
Peroxisome-Proliferator Activated Receptor
PPAR
Endothelial Nitric Oxide Synthase
Nicotinamide Adenine Dinucleotide Phosphate
Reactive Oxygen Species
Renin-angiotensin-aldosterone system
Oxidative Phosphorylation
Glucocorticoids
Glucocorticoid Receptors
Thyroid Hormones
Thyroid hormone Receptors
Thyroid hormone response elements
Dehydroepiandrosterone
Intramyocellular Lipids
High-Affinity Insulin Receptors.