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Microvasculature Insulin Resistance in Skeletal Muscle: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Jia Liu.

Insulin is a vascular hormone and regulates vascular tone and reactivity. Muscle is a major insulin target that is responsible for the majority of insulin-stimulated glucose use. Evidence confirms that muscle microvasculature is an important insulin action site and critically regulates insulin delivery to muscle and action on myocytes, thereby affecting insulin-mediated glucose disposal. Insulin via activation of its signaling cascade in the endothelial cells increases muscle microvascular perfusion, which leads to an expansion of the endothelial exchange surface area. Insulin’s microvascular actions closely couple with its metabolic actions in muscle and blockade of insulin-mediated microvascular perfusion reduces insulin-stimulated muscle glucose disposal.

  • insulin resistance
  • muscle
  • microvasculature
  • endothelial cells
  • inflammtion

1. Introduction

Diabetes prevalence continues to increase at an alarming rate and has become the most common and costly chronic disease worldwide. This pandemic currently affects over 400 million individuals, largely due to a rapid increase in the prevalence of type 2 diabetes mellitus (T2DM) [1]. Although the exact mechanisms underpinning the pathogenesis of T2DM remain to be elucidated, the disease is characterized by insulin resistance in multiple organs and systems. Insulin resistance is a complex metabolic abnormality that affects the ability of peripheral tissues to respond to insulin, leading to impaired peripheral tissue glucose utilization and resulting in the development of compensatory hyperinsulinemia and eventually hyperglycemia [2][3]. T2DM confers significant morbidity and mortality to patients by accelerating the development of atherosclerotic complications such as coronary artery disease, cerebrovascular disease and peripheral artery disease and predisposing patients to microvascular complications including retinopathy, nephropathy, and neuropathy [4][5]. Mounting evidence has confirmed that insulin, in addition to stimulating tissue glucose uptake and use [6], is also a vascular hormone that regulates vascular tone and tissue perfusion [7]. In healthy humans, insulin acts on all segments of the arterial tree, induces endothelium-dependent vasorelaxation and increases tissue perfusion [7]. Insulin’s actions in the muscle microvasculature has garnered much attention in the past decade as it is in the muscle microvasculature that the exchanges of nutrients, oxygen, and hormones such as insulin between the plasma compartment and muscle interstitium take place and we and others have convincingly demonstrated that insulin resistance in the muscle microvasculature closely couples with impaired insulin-stimulated glucose use in muscle [8][9][10].

2. Vasculature is a Target for Insulin Action

Insulin, in addition to exerting metabolic actions on traditional peripheral insulin response tissues such as liver, skeletal muscle and adipose tissue, actively regulates vascular tone and tissue perfusion and these actions have been linked to the pathogenesis of diabetes and its cardiovascular complications. Vascular endothelium, a single endothelial cell layer lining the inner surface of the vascular lumen, expresses abundant insulin receptors as well as the insulin-like growth factor I (IGF-1) receptors and the hybrid insulin/IGF-1 receptors [11][12][13][14]. At physiological concentrations, insulin binds and activates the insulin receptors exclusively but, at higher insulin concentrations, as seen in the insulin resistant states or in individuals receiving insulin injections, it also stimulates the IGF-1 receptors and the hybrid insulin/IGF-1 receptors, resulting in the phosphorylation of the endothelial NO synthase (eNOS) at Ser1177 through the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB or Akt) pathway and the production of NO [11][15][16]. NO is a potent vasodilator as well as an important vascular health keeper as it modulates vascular smooth muscle cell (VSMC) proliferation, reduces the production of adhesion molecules, diminishes endothelial adhesion of inflammatory cells and prevents platelet aggregation to the endothelium. On the other hand, insulin also acts through the mitogen-activated protein kinase (MAPK) pathway to increase the expression and secretion of endothelin-1 (ET-1) by endothelial cells, which binds to the ET-1 receptors to engender vasoconstriction, oxidative stress, and VSMC growth and mitogenesis [17][18][19]. Insulin fine-tunes vascular tone and health via balancing its signals through these two signaling pathways in the basal state but, at high physiological levels, as seen during euglycemic hyperinsulinemic clamp or in the postprandial state, insulin’s vasodilatory effect predominates. Ample evidence has confirmed that insulin exerts a vasoactive action at all levels of the arterial tree. It acts on large conduit arteries to increase compliance [20][21][22], the resistance arterioles to increase overall blood flow to tissue [23][24], the precapillary arterioles to enhance tissue perfusion and the capillaries to expand endothelial exchange surface area and promote substrate exchange between the plasma and tissue interstitium [8][9]. In the insulin resistant state, patients develop compensatory hyperinsulinemia but insulin’s vascular responses through the PI3-kinase/Akt/eNOS pathway are attenuated while its actions via the MAPK pathway remain intact or even enhanced (i.e., a pathway selective insulin resistance) [7][25][26]. As a result, the net (chronic) effects of insulin action on the vasculature are increased production of ET-1 and adhesion molecules and decreased production/bioavailability of NO, tilting the balance towards vasoconstriction and atherosclerosis predisposition [27][28]. Combined, this pathway selective insulin resistance and hyperinsulinemia-driven MAPK signaling likely contribute to the increased vascular tone and heightened predisposition to atherosclerosis and explain the high prevalence of hypertension, tissue hypoxia and macrovascular complications in patients with T2DM.

3. Metabolic Insulin Resistance Coexists with Microvascular Insulin Resistance

The close coupling between insulin’s microvascular actions and metabolic actions in muscle is further supported by the observation that metabolic insulin resistance coexists with microvascular insulin resistance in both clinical and animal studies. In humans or animals with either chronic or acute (experimental) insulin resistance microvascular responses to insulin are unequivocally reduced [29][30][31][32][33][34][35][36]. Insulin potently recruits muscle microvasculature in healthy humans [37] but fails to do so in obese humans or healthy humans receiving systemic infusion of lipid solution, which acutely raises plasma concentrations of free fatty acids (FFA) and causes metabolic insulin resistance [29][31][32]. Similarly, insulin’s muscle microvascular actions are blunted in animal models of obesity or diabetes [36][38], and the loss of muscle microvascular insulin responses is also apparent in healthy rodents with acute experimental insulin resistance conferred by systemic infusions of factors known to be elevated in the insulin resistant states, such as tumor necrosis factor α (TNF-α) [39] and FFAs [40]. As muscle microvascular endothelial exchange surface area is important in the delivery of insulin to muscle interstitium and thus insulin action in muscle, one would expect that expansion of the microvascular blood volume would result in increased delivery of insulin to the muscle and thus enhance insulin-mediated muscle disposal in the insulin resistant states. Indeed, studies from outhe researcher's and other laboratories have shown repeatedly that expansion of muscle microvascular blood volume with various agents can partially prevent or even reverse insulin resistance in rodents. Administration of losartan acutely expands muscle microvascular blood volume and this effect is associated with increased muscle use of glucose in the post-absorptive state and a full restoration of muscle insulin sensitivity in rats receiving systemic lipid infusion [41][42][43]. Systemic infusion of GLP-1 improves muscle insulin action by potently recruiting muscle microvasculature in rats with either acute (lipid infusion) or chronic (high-fat diet (HFD) feeding) insulin resistance [44][45]. Similarly, muscle contraction has been shown to recruit muscle microvasculature and increase muscle uptake of insulin during a systemic lipid infusion [46][47] and adiponectin, which induces microvascular recruitment via 5’ adenosine monophosphate-activated protein kinase (AMPK) activation and NO production, ameliorates metabolic insulin resistance in rats fed a HFD [30][48]. AMPK can functionally phosphorylate eNOS on multiple sites including Ser633 and Ser1177 to increase endothelial NO production [49][50] Activation of AMPK in addition to regulating NO production also regulates mitochondrial function and substrate metabolism as well as inhibits oxidative stress, ER stress and inflammation [51][52]. Together, these studies highlight an important link between microvascular and metabolic effects of insulin in muscle and indicate that a loss of microvascular insulin responses contributes to the development or worsening of metabolic insulin resistance and expansion of the muscle microvascular volume experimentally enhances metabolic insulin responses. As such, microvascular insulin resistance may play a pathogenesis role in the development of T2DM and a therapeutic target for the prevention and management of T2DM.

4. Metabolic Insulin Resistance is Associated with Inflammation in the Skeletal Muscle

Insulin resistance as seen in obesity and T2DM is associated with a chronic inflammatory state with increased tissue infiltration of immune cells in multiple organs and tissues such as adipose tissue, liver, skeletal muscle, pancreas, and brain, and people with or animal models of obesity and diabetes have elevated plasma levels of inflammatory mediators such as TNF-α, C-reactive protein, and FFAs [2][53][54]. While most studies have focused on inflammation in the adipose tissue, rising evidence suggests that inflammation occurs within skeletal muscle as well, with multiple factors contributing to the pathogenesis of inflammation in muscle, through endocrine, autocrine and paracrine actions. First, the circulating pro-inflammatory cytokines secreted and FFAs released from the adipose tissue, particularly the visceral fat depot, have been well studied and confirmed to cause insulin resistance in muscle [55][56][57]. They act through multiple signaling pathways including the NF-κB, JNK and p38 MAPK pathways [58]. In addition, adipose tissue actively secretes a variety of pro- and anti-inflammatory adipokines to modulate insulin action in muscle [59]. In patients with obesity and diabetes, plasma levels of leptin, resistin and visfatin are increased while plasma concentrations of adiponectin is reduced [59]. Second, skeletal muscle itself has been shown to be a secretory organ and myocytes are able to secrete many cytokines, known as myokines, such as interleukin (IL)-6, IL-18, IL-15, irisin, myostatin, and others, that can affect myocytes via autocrine actions and immune cells and microvasculature locally via paracrine actions [60]. The most studied myokine perhaps is IL-6 as its secretion from muscle is markedly increased after exercise and muscle contraction. The effects of IL-6 on insulin sensitivity vary depending on the exposure time. IL-6 acutely increases muscle glucose uptake and fat oxidation, hepatic glucose production, and lipolysis during exercise [61][62] to adapt to increased energy demand from muscle. While acute treatment of myocytes or intravenous infusion of IL-6 to healthy humans increases basal and insulin-stimulated glucose uptake by myocytes and improves whole body insulin sensitivity, chronic action of IL-6 induces insulin resistance [60]. Thus far, there is a clear lack of data on the impact of various myokines on muscle microvascular responses to insulin. Third, muscle infiltration of the immune cells such as macrophages and T lymphocytes, primarily located in the muscle adipose tissue between myocytes or surrounding the muscle (i.e., intermyocellular, intermuscular or perimuscular adipose tissue), that can upon activation secrete inflammatory cytokines [60][63][64]. They act on myocytes and local microvasculature through a paracrine fashion to induce insulin resistance. In addition, an increased influx of FFAs from these ectopic adipose depots to the myocytes and microvasculature within the muscle are certainly adding insults to the insulin signaling pathway and negatively regulate glucose metabolism.

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