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Insulin Resistance

Insulin Resistance

Insulin 101

The overall action of insulin is to increase energy storage in an organism in the form of transient glycogen and enduring fat. In addition to increasing glucose utilization form blood, insulin stimulates glucose conversion into stored glycogen in the skeletal muscle and liver, downregulates key gluconeogenic enzymes in the liver, and promotes accumulation of triglycerides by accelerating glucose degradation via glycolysis and synthesis of free fatty acids, as well as inhibiting lipolysis in the fat cells.

Insulin acts via cognate receptors on cells of the insulin-dependent tissues such as fat, liver, striated muscles, and endothelium. It also binds, with a one order of magnitude less affinity, to insulin-like growth factor receptors in many other cells. The signalling pathways activated by these receptors are similar, albeit not identical, which may account for differences in cell responses. The interplay between these hormones is physiologically important for the progression of T2DM and metabolic dysfunction. However, it seems rather marginal to the development of insulin resistance and for this reason will not be focused on here.

The insulin receptor is a heterotetrameric membrane glycoprotein consisting of two α- and two β-subunits. Insulin binds to the extracellular α-subunit and changes its conformation to promote ATP binding and autophosphorylation in the intracellular domain of the β-subunit, which is a tyrosine kinase. There are several autophosphorylation sites in the β-subunit. These sites form 3 groups according to their position either within active loop of the catalytic domain (Tyr-1158, Tyr-1160, and Tyr-1162), or juxtamembrane domain (Tyr-972), or distal C-terminal domain (Tyr-1328 and Tyr-1334). Phosphorylation of the active loop sites stimulates the kinase activity of insulin receptor, phosphorylation of juxtamembrane domain control receptor-substrate interactions, and stability of the receptor-substrate complex, whereas C-terminal phosphorylation mediates metabolic and mitogenic actions of insulin.

The insulin receptor substrate (IRS) proteins play a key role in insulin signalling. All of them are scaffolds that mediate further signalling by assembling and clustering specific signalling complexes via the Src homology (SH2) domain interactions. The activated insulin receptor recruits IRS and phosphorylates it on tyrosine residues thus creating the binding sites for other signalling molecules containing the SH2 domains. Thus, both the recruitment and binding of IRS to activated receptors and the subsequent binding of downstream effectors to IRS require tyrosine kinase activity of the receptor and phosphotyrosine-binding domains in the interacting proteins. Recruitment of IRS is further facilitated by its membrane localization mediated by the pleckstrin homology (PH) motif in IRS, which recognizes membrane-bound phosphoinositides. Thus, IRS proteins exert dual function by linking receptor-associated tyrosine kinase activity to cytoplasmic effectors and by bringing together the appropriate signalling molecules.[1]

Obesity and Insulin Resistance

Obesity is one of the most important public health problems in the world, reaching epidemic proportions in several industrialized countries and rising in many developing countries. Indeed, consequence of the obesity is the increased risk for various illnesses, such as diabetes mellitus, gallbladder disease, osteoarthritis, coronary artery disease and some forms of cancer.

In the last century, the disease that is increased the most in obese people, compared with lean ones, is type 2 diabetes mellitus (T2DM), a condition resulting from the metabolic changes associated with excess fat.

A pivotal role in T2DM development is played by insulin resistance (IR) that is the reduction of the response of peripheral target tissues to a physiological concentration of insulin. Skeletal muscle plays a central role in whole body IR, so that skeletal muscle IR is a predictor of the T2DM development and maintenance of adequate muscle glucose disposal may help to prevent diabetes.

The prevalent theory on impaired insulin signaling in obesity links IR to the increase of circulating FFA and excessive deposition of lipids in non-adipose tissues, including liver and skeletal muscle. However, two different mechanisms centered on mitochondria function have been proposed to explain the onset of IR in skeletal muscle following lipid storage. Indeed, either a decrease in mitochondrial fatty acid oxidation due to mitochondrial dysfunction or enhancement in mitochondrial oxidant production in response to excess fuel has been thought to contribute to IR development in skeletal muscle. Actually, the observation that increased production of radicals and other reactive oxygen species (ROS) is an early event in the development of IR suggests that mitochondrial dysfunction is a complication of the hyperlipidemia-induced ROS production, which might promote mitochondrial alterations, lipid accumulation and inhibition of insulin action.

Recently, due to the observation that IR and related disorders are growing dramatically all over the world, the efforts to identify and develop effective approaches for their treatment have been intensified. In addition to dietary regimes aimed at weight loss, two major non-pharmacological approaches to improve insulin sensitivity have included antioxidant supplementation and exercise training.[2]

Mechanisms of obesity-induced insulin resistance

One of the most harmful effects of obesity is the lipid deposition in non-adipose tissues that occurs when the capacity of adipose tissue to store lipids is overwhelmed and may lead to lipotoxicity and IR development.

The IR dependence on tissue lipid overload and the finding of mitochondrial dysfunction in obese and insulin-resistant patients suggested that a decrease in total mitochondrial oxidative capacity could contribute to IR reducing skeletal muscle capacity to manage increased FFA influx. In fact, mitochondrial dysfunction would decrease lipid utilization thereby contributing to fatty acid overload and muscle IR development. In particular, when faced with a chronic dietary overload with saturated fatty acids, muscle cells produce many lipid metabolites, including diacylglycerol (DAG), ceramide (CER) and derived gangliosides, which are considered maladaptive signals arising from disordered lipid metabolism. The accumulation of DAG and CER is tightly associated with the IR development since such molecules impair insulin signaling activating aPKC isoforms that inhibit IRS1 and Akt, respectively. CER also achieves Akt inhibition through activation of protein phosphatase 2A (PP2A) while GM3, a ceramide-derived ganglioside, inhibits the insulin receptor.[3]

Exercise Training and IR

In recent years, antioxidants have been used extensively to overcome the effects of excess of ROS in several pathologies. However, antioxidant supplementation, used in an attempt to protect against IR and related complications, has supplied contrasting results. The health-promoting effects of the physical activity have been known for a longer time. Already in ancient China the need to promote and prescribe exercise for health-related benefits was recognized.

Currently, physical inactivity is considered as a risk factor for cardiovascular disease and a widening variety of other chronic diseases, including diabetes, cancer (colon and breast), obesity, hypertension, bone and joint diseases (osteoporosis and osteoarthritis), and depression. Conversely, regular physical activity is considered to produce healthy effects, including increases in tissue metabolism, due to mitochondrial proliferation, insulin sensitivity and cardiorespiratory fitness, so that it is able to prevent diabetes and coronary heart disease.

The beneficial effects of exercise are evident, not only in healthy persons but also in patients, because, suitably graded, exercise is useful as an adjunctive therapy in the treatment of patients with several chronic diseases. The mechanisms underlying obesity-induced IR development have been recently reviewed, so that this review, after briefly examining the link among obesity, IR and ROS, focuses the attention on the potential role of exercise training in opposing metabolic dysfunction in patients with IR by describing possible cellular and molecular mechanisms.[4]

Figure 1. Schematic representation of the signaling pathways mediating insulin- and exercise-induced skeletal muscle glucose transport. In normal conditions, insulin binding to its receptor results in the phosphorylation of the insulin receptor substrate (IRS) on tyrosine residues allowing the activation of the phosphatidylinositol 3-kinase (PI3K), which leads to phosphorylation of phosphoinositide-dependent kinase (PDK). PDK, in turn, activates protein kinase B (Akt) and atypical protein kinase C (PKCζ). Akt inhibits a 160kDa protein (AS160), thus promoting the translocation of the glucose transporter type 4 (GLUT4) to the plasma membrane, in which PKCζ is also involved. PI3K also increases NADPH oxidase (NOX) activity, leading to increased production of O2 •− that is converted to H2O2 by superoxide dismutase (SOD). H2O2 enhances glucose uptake by inhibiting protein tyrosine phosphatases (PTPs) and promoting tyrosine phosphorylation of IRS. Muscle contraction activates an insulin-independent mechanism that stimulates glucose transport. The two pathways converge in their distal parts in which AS160 and aPKC are involved. A pivotal role is played by AMP-activated protein kinase (AMPK), and Ca2+- and calmodulin-dependent protein kinases. AMPK is activated by an increase in the AMP:ATP ratio, a serine threonine kinase (LKB1) and calcium/calmodulin-dependent protein kinase kinase (CaMKK). The Ca2+/calmodulin-dependent kinase II (CaMKII) also seems to be implicated in glucose transport.

The Inflammatory Input

It is well understood that excessive calorie diet is the major cause of obesity in the modern society. Facilitated by the low physical activity, excessive nutrients are converted into fat, which is the only long-term energy storage in an organism. Obesity promotes insulin resistance via ectopic lipid accumulation and PKC-related mechanism at least in the skeletal muscle. This mechanism is doubtful in adipocytes because they always store large amounts of lipids that are not ectopic. However, excessive lipid accumulation stimulates hypertrophy and hyperplasia of adipocytes, as well as increased adipogenesis and recruitment of new cells. In combination with a reduced blood supply, this creates hypoxic conditions and activates inflammatory signalling. In addition, recruitment of adipose tissue macrophages (ATM) and their polarization into the M1 proinflammatory phenotype maintains inflammatory response, resulting in latent inflammation if overnutrition persists. The inflammatory signals derived from the M1 macrophages promote insulin resistance, and inhibition of inflammatory signalling disturbs the link between obesity and insulin resistance.

The latent inflammation appears to be critical to insulin resistance, turning the plain abdominal obesity with relatively low morbidity risk into T2DM and metabolic syndrome (as an association of obesity with T2DM and cardiovascular disease). The cellular mechanisms of latent inflammation coupled to activation of the nuclear transcription factor (NF-κB) in adipose tissue have been extensively reviewed elsewhere. Here, we only briefly mention them and focus on the link between inflammation and insulin signalling. As discussed below, there are several pathways of how inflammation may be coupled to insulin signalling in adipocytes, resulting in reduced cell responsiveness to insulin. Conversely, the insulin pathway may also target the inflammatory one, creating an inhibitory feedback that becomes active under conditions of overnutrition. Whereas the dominating concept has been that inflammatory kinase IKKβ is critical to inflammatory link to insulin signalling, the studies over the recent years suggest that additional players are also involved and mediate reciprocal relationship between these phenomena.

Inflammation plays an important role in the development of obesity, diabetes, metabolic syndrome, and many other diseases. The development of metabolic diseases can be viewed as a system where obesity-associated molecular pathologies (i.e., cellular hypoxia, ER stress, oxidative stress, and releasing of damage-associated molecular patterns (DAMPs)) are at the entrance, a number of metabolic dysfunctions (i.e., metabolic syndrome, diabetes, atherosclerosis, and arterial hypertension) are the outputs, and inflammatory process is a narrow bottleneck in between.[5]

Figure 2. The inflammatory signalling with a focus on IKK and its interplay with insulin signalling. The red line symbolizes negative feedback. DAMPs: damage-associated molecular patterns; EPR stress: endoplasmic reticulum stress; HIF-1α: hypoxia inducible factor 1α; IRE-1α: inositol-requiring enzyme 1α; IκB: inhibitory subunit of nuclear factor κB; IKK: IκB kinase; IRS: insulin receptor substrate; mTORC2: mechanistic target of rapamycin; NF-κB: nuclear factor κB; PI-3K: phosphatidylinositol-3-kinase; PDK-1: phosphoinositide-dependent kinase; ROS: reactive oxygen species; TLRs: toll-like receptors.

 

The take home message

Insulin resistance is extremely common in adults in Western cultures. The key to treating this condition is a carbohydrate modified diet and exercise (especially fasted exercise). Detailed treatments have been discussed elsewhere.

Insulin resistance also severely affects many other organ systems throughout the body. It adversely affects cardiovascular health, hormonal levels, obesity, energy levels and possible worse than all of this, severely increases the risk of cancer. If this is you, do something about it. It is much easier to prevent disease and treat it after it occurs.

[1] I. S. Stafeev, 1 , 2 , * A. V. Vorotnikov, 1 , 3 E. I. Ratner, 1 , 4 M. Y. Menshikov, 1 and Ye. V. Parfyonova 1 , 2 Int J Endocrinol. 2017 Aug 17. Latent Inflammation and Insulin Resistance in Adipose Tissue

[2] Di Meo S1, Iossa S2, Venditti P2. J Endocrinol. 2017 Sep;234(3):R159-R181. Improvement of obesity-linked skeletal muscle insulin resistance by strength and endurance training.

[3] Di Meo S1, Iossa S2, Venditti P2. J Endocrinol. 2017 Sep;234(3):R159-R181. Improvement of obesity-linked skeletal muscle insulin resistance by strength and endurance training.

[4] Di Meo S1, Iossa S2, Venditti P2. J Endocrinol. 2017 Sep;234(3):R159-R181. Improvement of obesity-linked skeletal muscle insulin resistance by strength and endurance training.

[5] I. S. Stafeev, 1 , 2 , * A. V. Vorotnikov, 1 , 3 E. I. Ratner, 1 , 4 M. Y. Menshikov, 1 and Ye. V. Parfyonova 1 , 2 Int J Endocrinol. 2017 Aug 17. Latent Inflammation and Insulin Resistance in Adipose Tissue