Role of Skeletal Muscle in Insulin Resistance and Glucose Uptake

by Benjamin Bunting BA(Hons) PGCert

Ben Bunting BA(Hons) PGCert Sports and Exercise Nutrition Level 2 Strength and Conditioning CoachWritten by Ben Bunting: BA(Hons), PGCert. Sport & Exercise Nutrition. British Army Physical Training Instructor (MFT).  


Several factors influence the role of skeletal muscle in insulin resistance and glucose uptake. These include oxidative stress, IL-6, and mitochondrial oxidative phosphorylation.

Skeletal Muscle Explained

Generally speaking, skeletal muscle is defined as a group of flexible muscles forming part of the vertebrate muscular system. They are involved in the different functions of the body, including moving the bones, protecting the internal organs, and maintaining the body's posture. They also help with defecation and maintain body temperature.

There are three types of muscle in the human body: striated, cardiac, and smooth. The strength of a muscle depends on the length, cross-sectional area, and pennation of the motor units. If a muscle is weak or inactive, it may be affected by an underlying pathology. A physiotherapist can help diagnose and treat any muscular disease.

Muscles are striated, meaning they are made up of bands of myosin and actin. These two proteins are connected at the cell membrane and form thick filaments. The myofibrils (the bundles of myofilaments) are separated into functional repeating segments called Sarcomeres.

The fibres of skeletal muscles are enclosed in layers of connective tissue. The outer layer is called fascia, and the inner layer is called endomysium. Both connective tissues are found throughout the body, and each contains several muscle fibres.

The fibres are composed of myofilaments, which are made of long protein molecules. There are two different kinds of myofilaments: thick and thin. The thick myofilaments are situated at the middle of the sarcomere. They are surrounded by six thinner myofilaments. Occasionally, thick myofilaments do not extend to the ends of the sarcomere.

Insulin Resistance Explained

Having a positive lifestyle change can help manage insulin resistance. This includes a healthy diet and regular exercise. It can also improve insulin sensitivity.

There are many different causes of insulin resistance. One of the most common is obesity.

Those who have a family history of diabetes are also at an increased risk of insulin resistance. There are also environmental factors and genetic syndromes that may play a role in developing it.

In addition to having a high risk of diabetes, people with insulin resistance may also be more likely to develop kidney damage or high blood pressure. In some cases, it may be necessary to take medication to control the condition.

The pancreas secretes more insulin when blood glucose levels are higher. However, the body cannot keep up with the demand. This can lead to a pre-diabetic state.

Symptoms of insulin resistance include tiredness, fatigue, thirst, and blurred vision. It can be difficult to tell whether you have the disease or not. If you think you have the disease, it is important to talk to your health care provider. He or she can prescribe medicine or exercise to treat the condition.

When the insulin is not working properly, the glucose from the blood is not absorbed by the cells. Instead, it builds up in the blood. This can cause problems in the heart, kidneys, and vascular system. Those with high insulin and high blood sugar are at a higher risk of developing type 2 diabetes.

Glucose Uptake Explained

Glucose uptake is a complex process, involving a number of regulatory steps. It is different depending on the tissue or organ. For example, glucose transport is dependent on the metabolism of the muscle. In adipocytes, the rate of glucose uptake is increased by insulin. In the kidney, glucose is cotransported with sodium from the lumen. In the liver, gluconeogenesis is regulated by the presence of glycogen.

In muscle, the uptake of glucose is controlled by GLUT4 and other non-GLUT4 transporters. Studies show that glucose uptake increases during exercise. However, there is a discrepancy in the uptake rate. The glucose uptake in skeletal muscle is regulated by the amount of glycogen available. When the level of glycogen in the muscles is low, the rate of muscle glucose uptake is low. On the other hand, when the muscle is loaded with glycogen, the uptake of glucose is high.

The glucose transporters are proteins that bind to glucose and enable the transport of glucose across the lipid bilayer. The transporters are categorized into two classes: basal and facilitative glucose transporters. The basal glucose transporters include GLUT1 and GLUT3. The basal glucose transporters are expressed in cells and in the plasma membrane of adipose tissue. The facilitator glucose transporters are expressed in cells and in renal proximal tubules.

GLUT4 is expressed in skeletal muscle, cardiac muscle, and adipose tissue. It is a key basal glucose transporter in VSMCs. It is also associated with insulin-stimulated glucose uptake in skeletal muscle. It is also found in the plasma membranes of hepatocytes and pancreatic beta cells.


Several factors contribute to insulin resistance and glucose uptake in skeletal muscle. These factors include fatty acids, increased phosphorylation and ROS production, decreased mitochondrial function, and inhibition of the insulin signaling pathway. The effects of these factors on glucose uptake and insulin resistance are not fully understood.

The cytokines IL-6, IL-8, and IL-15 are expressed in skeletal muscle. These cytokines are released by active muscles and have local as well as systemic effects. These cytokines have been associated with the development of insulin resistance and metabolic syndrome.

IL-6 increases fatty acid oxidation in vitro, and is also found to be a growth factor. Chronically elevated IL-6 is associated with hepatic and hematological insulin resistance in mice. However, it is unclear whether IL-6 has a direct effect on insulin.

Various a2A receptors are involved in the terminal sympathetic flow of muscle fibers. The a2A receptors are responsible for integrating peripheral actions of hypothalamic IL6. Inhibition of the a2A receptors may contribute to the development of muscle insulin resistance. The a2A receptors are found on adipose tissue, skeletal muscle, and liver.

IL-6 increased the protein expression of PPARa and UCP2 in skeletal muscle. It did not change the protein expression of PGC-1a or the lipid oxidation markers Uqcrc, Acadsb, or Mrpl41. IL-6 treatment did not affect the NFkB signaling cascade in skeletal muscle or the liver.

IL-6 treatment for 14 days increased the glucose tolerance of healthy rats and did not affect the hepatic insulin sensitivity of diabetic mice. The ability of IL6 to phosphorylate AMPK was reduced in mice after surgical denervation. The effect of IL-6 treatment did not vary with mode of delivery, i.e. intracerebroventricular microinjections or a minismotic pump.

The expression of SOCS3 was found in skeletal muscle. The BXD genetic reference population, a mouse genetic reference population geared towards multiscalar integration of traits, showed a positive interaction between the hypothalamic IL6 gene expression and the fatty acid oxidation gene sets in skeletal muscle. This relationship suggests that changes in genes involved in the inflammatory pathway contribute to the development of insulin resistance.

These findings indicate that IL-6 enhances fat oxidation in humans in vivo and skeletal muscle in vitro. This is compatible with the hypothesis that IL-6 activates the AMP-activated protein kinase.

Oxidative stress

During normal insulin-mediated glucose metabolism, skeletal muscle plays a central role. However, insulin resistance can lead to a decreased ability to process glucose, resulting in impaired glucose homeostasis. A number of mechanisms are involved in this phenomenon, including oxidative stress and muscle metabolic dysfunction. Understanding these mechanisms will help identify targets for therapeutic intervention.

Insulin resistance is a major contributor to cardiometabolic syndrome. This syndrome increases risk for cardiovascular disease, nonalcoholic fatty liver disease, and chronic kidney disease. In addition, insulin resistance may increase the risk of obesity. Despite advances in understanding the mechanisms behind insulin resistance, there is still much to learn.

Although oxidative stress and inflammatory cytokines play an important role in the development of insulin resistance, their impact on skeletal muscle remains elusive. The mechanisms are complex. These include increased production of mitochondrial ROS and low-grade inflammation, both of which play a critical role in insulin resistance. Interestingly, skeletal muscle also produces a number of myokines, including IL-6, IL-8, IL-10, and MCP-1. The effects of these molecules on skeletal muscle are modulated by exercise.

Another important molecule produced by skeletal muscle is myonectin, which has been shown to regulate glucose uptake by myocytes and is associated with the density of mitochondrial deoxyribonucleic acid (mtDNA). Myonectin is also involved in the autocrine effects of contraction on skeletal muscle.

In skeletal muscle, GLUT4 is an intracellular protein that facilitates the transport of glucose. GLUT4 is best known for its insulin-regulated function, but it also functions as a rate-limiting glucose transporter under unstimulated conditions. There are two pathways by which GLUT4 is translocated to the plasma membrane: a canonical pathway and a noncanonical pathway. In the canonical pathway, GLUT4 is recruited by insulin stimulation. In the noncanonical pathway, GLUT4 is integrated into PM. It is thought that this process is regulated by a number of signaling pathways that crosstalk with insulin metabolic signaling via the IRS-PI3K-Akt pathway.

Several circulating factors are also implicated in insulin resistance, including fatty acids. In the skeletal muscle, a higher concentration of plasma fatty acids inhibits glucose phosphorylation, leading to a decrease in intramuscular glucose 6-phosphate. This leads to a reduction in muscle glycogen synthesis.

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Mitochondrial oxidative phosphorylation

Several studies have shown that increased lipid accumulation in skeletal muscle is associated with reduced insulin sensitivity. This increased lipid content can be due to increased delivery of fatty acids to the liver, a defect in the oxidation of fatty acids in adipocytes or mitochondria, or a combination of these. Besides affecting insulin action, these changes may also contribute to impaired glucose uptake.

In addition, skeletal muscle has been shown to produce cytosolic ROS during moderate-intensity exercise. However, the source of this oxidative stress remains unknown. The resulting alterations in mitochondrial activity have not been studied in detail. Moreover, lipid peroxidation in skeletal muscle is largely regulated by the function of mitochondria. This means that the etiology of skeletal muscle insulin resistance is a complex multifactorial process.

It is also known that increased inflammatory cytokines are hallmarks of type 2 DM. Recent studies have also suggested that NF-kB plays a role in insulin resistance. This may be an important therapeutic target for combating DM. In addition, ROS are also a significant factor in hypertension and CVD. Therefore, understanding skeletal muscle insulin resistance may lead to the development of new therapeutic targets for treatment of these conditions.

The mitochondrial composition and activity are regulated carefully. Excess dietary lipids may alter these functions, but their effects on skeletal muscle have not been investigated in detail.

The mRNA levels of COX, CYC, PGC1a and PGC1b were decreased in HFHSD mice compared with SD mice after 4 weeks of diets. This decreased mRNA level is likely to be related to the reduced capacity of the muscle cells to oxidize FA. This may also be a consequence of the different composition of skeletal muscle fibers. The difference in the ratio of mitochondrial DNA to nuclear DNA was reduced in HFHSD mice compared with standard mice at 16 weeks of age.

Interestingly, the mRNA levels of cytochrome c oxidase were reduced in HFHSD mice at 16 weeks of age. This oxidase is a key enzyme in producing superoxide. The mRNA of CYC subunits 1 and 3 were also lower in HFHSD mice compared with the SD group.

Tissue recruitment

Among the many factors contributing to the development of insulin resistance, inflammation plays a significant role. In particular, low grade chronic inflammation is a key player in the development of both systemic and skeletal muscle insulin resistance. Inflammatory molecules can also contribute to insulin resistance by adversely regulating the metabolic function of myocytes. The inflammatory response of myocytes to insulin signaling may also contribute to muscle inflammation. However, the exact mechanisms are not fully understood.

Inflammatory cytokines are produced by various cells in skeletal muscle, including macrophages. Studies have shown that TNF-a is mainly produced by macrophages, but other cells are involved in the synthesis of TNF-a. TNF-a can induce mitochondrial dysfunction and contribute to insulin resistance. It is known that obesity-linked increases in TNF-a secretion are associated with incident of type 2 diabetes mellitus (T2DM). Several cellular responses are induced by TNF-a, such as increased secretion of IL-1b, IFN-g, and IL-6. Moreover, adipose-resident macrophages are characterized by a phenotypic switch from an alternatively activated M2 phenotype to a classically activated M1 phenotype. Although the mechanisms underlying this phenotypic switch are poorly understood, it is suggested that increased chemokine expression in adipose-resident macrophages triggers the phenotypic switch.

Inflammatory cytokines and oxidative stress are linked to skeletal muscle insulin resistance. In addition, the inflammasome pathway, which consists of a large number of cytosolic protein complexes, is implicated in the development of insulin resistance. It is believed that the inflammasome pathway regulates the infiltration of macrophages into adipose tissue, which is an important contributor to insulin resistance. In fact, in cultured myocytes, overexpression of perilipin 2, which is a cytoplasmic protein complex involved in the inflammasome pathway, significantly impaired insulin-stimulated glucose uptake. In contrast, knocking down NLRP3 in these myocytes reversed the effect of insulin-stimulated glucose uptake.

The insulin metabolic responsiveness of skeletal muscle is crucial for whole-body glucose homeostasis. The IRS-PI3K-Akt pathway is essential for normal insulin-mediated glucose metabolism in skeletal muscle. However, in skeletal muscle, dysregulation of this pathway may lead to increased inflammation, insulin resistance, and systemic inflammation. It is important to study the interaction of these signaling pathways in skeletal muscle insulin resistance.


Despite its vital role, the importance of skeletal muscle to metabolism has been overlooked. Metabolic derangements in skeletal muscle play a pivotal role in the development of type 2 diabetes (T2D). In addition, skeletal muscle is the main site for insulin-stimulated glucose uptake. Therefore, a detailed understanding of skeletal muscle function and function-related endocrine mechanisms is important for the development of effective therapeutic interventions.

Skeletal muscle is structurally complex and functionally diversified. It is composed of multinucleated and long postmitotic myofibers. These fibers respond to hormonal, neural, and energy substrate signals. As a result, they are capable of adapting to changes in their structure and function. This adaptation is important in the pathogenesis of metabolic disorders.

A variety of myokines are synthesized by myocytes in response to muscular contractions. These myokines are implicated in autocrine regulation of muscle and other organs. The myokines also act in paracrine hormone-like manner.

The main driver of T2D is skeletal muscle insulin resistance. Several myokines are implicated in the pathophysiology of the disease. They act in an autocrine fashion to promote fat oxidation and lipolysis, and enhance the activity of hepatic glucose production. The release of myokines is regulated by the availability of substrates during exercise.

Studies in mice have shown that the insulin receptor is crucial for postnatal fuel homeostasis. In addition, the IR is essential for embryonic muscle growth. In fact, the IR knockout (IR KO) mouse model has revealed that impaired insulin signaling leads to insulin resistance.

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