Insulin Resistance as the Underlying Cause for the Metabolic Syndrome

https://doi.org/10.1016/j.mcna.2007.06.012Get rights and content

Classically, the metabolic syndrome is characterized as group of pathologies including visceral obesity, hypertension, dyslipidemia, and impaired glucose tolerance. It is now realized that insulin resistance plays a principal role in initiating and perpetuating the pathologic manifestations of the metabolic syndrome. A more in-depth understanding of the basic pathophysiologic mechanisms underlying insulin resistance may aid clinicians in treating and possibly delaying or even preventing the onset of the metabolic syndrome and its complications. This article outlines how abnormal insulin signaling and secretion, impaired glucose disposal, lipotoxicity, and proinflammatory cytokines exacerbate insulin resistance and result in the perturbations of the metabolic syndrome.

Section snippets

Defective insulin secretion and signaling

Normally, elevated glucose levels stimulate pancreatic β cells to secrete insulin and decrease glucagon production. This leads to suppression of hepatic glucose production and increased glucose uptake in muscle, liver, and adipose tissues. In the state of insulin resistance, β cell dysfunction occurs, manifesting as a loss of first phase insulin secretion or the lack of immediate release of insulin in response to a glucose load [3]. This deficiency of acute insulin secretion then leads to

Dysregulation of glucose disposal and production

Glucose transport into cells is mediated by numerous glucose transporters (GLUT) and sodium-glucose cotransporters [14]. One of the most important glucose transporters, GLUT4, is regulated by insulin. In response to insulin, GLUT4 is mobilized from intracellular storage vesicles and fuses to the cellular membrane to internalize glucose [15]. This process is mediated by PI3K and TC 10 pathways [16]. Clinical studies completed by Rothman and colleagues [17] and Cline and colleagues [18] reveal

Role of free fatty acids

Previous investigators have shown that obesity and elevated free fatty acids (FFA) levels play a major role in the development of insulin resistance. In 1963, Randle and colleagues [30] described the glucose-fatty acid cycle, also known as the Randle cycle, and showed that increased FFA levels inhibits glucose uptake and metabolism in rat muscle cells. These investigators postulated that elevated FFA oxidation increases the production of mitochondrial acetyl-CoA, which inhibits pyruvate

Impaired lipid metabolism

Hepatic insulin resistance also leads to up-regulated triglyceride (TG) synthesis and down-regulated FFA oxidation [37], [38]. The hypertriglyceridemia observed in the metabolic syndrome is manifested by elevated serum levels of triacylglycerols. The transport mechanisms for these particles are either by chylomicrons released from the gut or hepatically produced very low-density lipoproteins (VLDLs). Manifestations of the dyslipidemia observed in insulin resistance are elevated TG/VLDL levels

Adipose tissue, cytokines, and proinflammatory states

The metabolic syndrome and insulin resistance are strongly associated with excess adiposity and inflammatory states. Investigators have shown that depletion of intramyocellular fat stores in skeletal muscle improves insulin sensitivity [52]. Fat tissue can be considered an endocrine organ, as it secretes hormones and cytokines that affect insulin's actions [3].

Insulin resistant states are often associated with serine/threonine phosphorylation of IRS-1, one of the most proximal downstream

Hypertension

Multiple mechanisms have been proposed to explain the link between hypertension and insulin resistance. Hyperinsulinemia is associated with adrenergic overactivity, leading to increased cardiac output and urinary catecholamine excretion [67]. Insulin is also a potent antinatriuretic hormone, causing sodium retention and plasma volume expansion. Previous studies have shown that obesity leads to increased renal sympathetic activity, which results in retention of sodium and, in animal studies,

Endothelial dysfunction

Although not considered a classic function, insulin does exert physiologic effects on endothelial and vascular smooth muscle cells. Physiologic levels of insulin causes release of nitric oxide (NO) from endothelial cells, leading to vasodilation of peripheral vasculature, which results in the augmentation of blood flow and glucose disposal in skeletal muscle [78]. Insulin stimulates NO production from endothelial cells through the PI3K pathway and the secretion of endolethin-1 (ET-1), a potent

Identifying insulin resistance

Besides using guidelines such as ATP III or World Health Organization criteria for identifying patients with the metabolic syndrome, there are other surrogate markers of insulin resistance that can be employed in clinical practice. For instance, triglyceride level greater than 130 mg/dL, triglyceride-to-HDL ratio greater than 3, and serum insulin level greater than 15 μU/mL can be used to assess insulin resistance [84]. In the primary care setting, Reaven and colleagues suggest that the most

Summary

Classically, the metabolic syndrome is characterized as group of pathologies, including visceral obesity, hypertension, dyslipidemia, and impaired glucose tolerance. It is now realized that insulin resistance plays a principal role in initiating and perpetuating the pathologic manifestations of the metabolic syndrome. A more in-depth understanding of the basic pathophysiologic mechanisms underlying insulin resistance may aid clinicians in treating and possibly delaying or even preventing the

References (86)

  • M.J. Haas et al.

    Suppression of apoprotein A-I gene expression in HepG2 cells by TNF-α and IL-1β

    Biochim Biophys Acta

    (2003)
  • G.L. Vega et al.

    Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia

    Am J Cardiol

    (2005)
  • Y. Arita et al.

    Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity

    Biochem Biophys Res Commun

    (1999)
  • R.H. Eckel et al.

    The metabolic syndrome

    Lancet

    (2005)
  • B. Dahlof et al.

    Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol

    Lancet

    (2002)
  • Z.T. Bloomgarden

    Measures of insulin sensitivity

    Clin Lab Med

    (2006)
  • D.O. Smith et al.

    Insulin resistance, pre-diabetes, and the prevention of type 2 diabetes

    Clin Cornerstone

    (2004)
  • G. Setsi

    Pathophysiology of insulin resistance

    Best Pract Res Clin Endocrinol Metab

    (2006)
  • D. LeRoith

    Beta cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities

    Am J Med

    (2002)
  • I. Vauhkonen et al.

    Defects in insulin secretion and insulin action in non-insulin dependent diabetes mellitus are inherited: metabolic studies on offspring of diabetic probands

    J Clin Invest

    (1998)
  • S. Kashyap et al.

    A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to type 2 diabetes

    Diabetes

    (2003)
  • S. Del Prato et al.

    Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man

    Diabetologia

    (1994)
  • J. Roth et al.

    The obesity pandemic: where have we been and where are we going?

    Obes Res

    (2004)
  • S.L. Marban et al.

    Transgenic hyperinsulinemia: a mouse model of insulin resistance and glucose intolerance without obesity

  • S.B. Biddinger et al.

    From mice to men: insights into insulin resistance syndromes

    Annu Rev Physiol

    (2006)
  • S. George et al.

    A family with severe insulin resistance and diabetes due to a mutation in Akt2

    Science

    (2004)
  • R.A. Roth et al.

    Biochemical mechanisms of insulin resistance

    Horm Res

    (1994)
  • Y. Kido et al.

    Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2

    J Clin Invest

    (2000)
  • C. Bouche et al.

    The cellular fate of glucose and its relevance in type 2 diabetes

    Endocr Rev

    (2004)
  • R.T. Watson et al.

    Intracellular organization of insulin signaling and GLUT4 translocation

    Recent Prog Horm Res

    (2001)
  • D.L. Rothman et al.

    31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate: evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin dependent diabetes mellitus

    J Clin Invest

    (1992)
  • C.W. Cline et al.

    Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes

    N Engl J Med

    (1999)
  • A. Zisman et al.

    Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance

    Nat Med

    (2000)
  • K.F. Petersen et al.

    Mechanism of troglitazone action in type 2 diabetes

    Diabetes

    (2000)
  • M. Shintani et al.

    Troglitazone not only increases GLUT4 but also increases its translocation in rat adipocytes

    Diabetes

    (2001)
  • L. Al-Kahlili et al.

    Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1

    Diabetologia

    (2005)
  • J. Yang et al.

    Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase-dependent reduction in GLUT4 endocytosis

    Endocrinology

    (2006)
  • L.J. Goodyear et al.

    Exercise glucose transport, and insulin sensitivity

    Annu Rev Med

    (1998)
  • H.J. Kim et al.

    Effect of exercise training on muscle glucose transporter 4 protein and intramuscular lipid content in elderly men with impaired glucose tolerance

    Eur J Appl Physiol

    (2004)
  • A.D. Cherrington

    Banting lecture 1997. Control of glucose uptake and release by the liver in vivo

    Diabetes

    (1999)
  • P. Puigserver et al.

    Insulin-regulated hepatic gluconeogenesis through FoxO1-PCG-1alpha interaction

    Nature

    (2003)
  • G.I. Shulman

    Cellular mechanisms of insulin resistance

    J Clin Invest

    (2000)
  • P.A. Sarafidis et al.

    Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?

    J Hum Hypertens

    (2007)
  • Cited by (174)

    • Individual and combined relationship of serum uric acid and alanine aminotransferase on metabolic syndrome in adults in Qingdao, China

      2022, Nutrition, Metabolism and Cardiovascular Diseases
      Citation Excerpt :

      Excessive SUA accumulation led to impaired endothelial cell function, which could hinder the production of nitric oxide (NO) [48–50]. Deficiency of endothelial-formed NO was demonstrated to be related to IR, while IR was critical in the pathogenesis of MetS [51–53]. Up to now, only one study choosing individuals aged 60 years or more as subjects reported combined effects of ALT and SUA on MetS and its components.

    • The dietary and lifestyle indices of insulin resistance are associated with increased risk of cardiovascular diseases: A prospective study among an Iranian adult population

      2022, Nutrition, Metabolism and Cardiovascular Diseases
      Citation Excerpt :

      The findings of the present study are in agreement with the results of the Farhadnejad et al. study that has reported a diet and lifestyle with a higher score of EDIR and ELIR was related to increased risk of type 2 diabetes [28], however, contrary to our results, in the Lee et al. study no significant association was observed between the higher score of the higher insulinemic potential of diet, determined by the higher score of EDIR, with development of multiple myeloma risk [31]. As the Tabung et al. study reported, ELIR and EDIR indices are the empirical dietary indices for the prediction of insulin resistance, which are determined using the TG to HDL-C ratio in individuals; considering that IR can be the main starting point for the pathogenesis of chronic diseases such as cardiometabolic disorders [32,33], it was assumed that in our study a lifestyle and diet with a higher score of ELIS and ELIR increase the risk of CVDs and CHD incident via the increment risk of IR in participants. To prove this point, we have assessed the association of higher EDIR and ELIR scores with the risk of IR (determined based on two different biochemical markers ratios, including TGs to HDL-C and TGs to FPG ratios); our findings showed that individuals with a higher score of EDIR and ELIR are more prone to the risk of IR incident.

    View all citing articles on Scopus

    Dr. Derek LeRoith is presently a consultant and speaker, and receives an honorarium from Merck, Sanofi-Aventis, Pfizer, Takeda, and Novo Nordisk.

    View full text