Insulin Resistance as the Underlying Cause for 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)
- et al.
A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation
J Bio Chem
(1997) - et al.
Insulin signaling pathways in time and space
Trends Cell Biol
(2002) - et al.
Divergent regulation of hepatic glucose and lipid metabolism by phophoinositide 3-kinse via Akt and PKCλ/ζ
Cell Metab
(2006) - et al.
FoxOs at the crossroads of cellular metabolism, differentiation, and transformation
Cell
(2004) - et al.
The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus
Lancet
(1963) - et al.
Lipoprotein lipase: genetics, lipid uptake, and regulation
J Lipid Res
(2002) - et al.
Accumulation of large very low density lipoprotein in plasma during intravenous infusion of a chylomicron-like triglyceride emulsion reflects competition for a common lipolytic pathway
J Lipid Res
(1996) - et al.
Diabetic dyslipidemia
Endocrinol Metab Clin North Am
(2006) - et al.
Activation of apoprotein AI gene expression by protein kinase A and C through transcription factor, Sp1
J Biol Chem
(2000) - et al.
Induction of the apolipoprotein AI promoter by Sp1 is repressed by saturated fatty acids
Metabolism
(2004)
Suppression of apoprotein A-I gene expression in HepG2 cells by TNF-α and IL-1β
Biochim Biophys Acta
Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia
Am J Cardiol
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
Biochem Biophys Res Commun
The metabolic syndrome
Lancet
Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol
Lancet
Measures of insulin sensitivity
Clin Lab Med
Insulin resistance, pre-diabetes, and the prevention of type 2 diabetes
Clin Cornerstone
Pathophysiology of insulin resistance
Best Pract Res Clin Endocrinol Metab
Beta cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities
Am J Med
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
A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to type 2 diabetes
Diabetes
Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man
Diabetologia
The obesity pandemic: where have we been and where are we going?
Obes Res
Transgenic hyperinsulinemia: a mouse model of insulin resistance and glucose intolerance without obesity
From mice to men: insights into insulin resistance syndromes
Annu Rev Physiol
A family with severe insulin resistance and diabetes due to a mutation in Akt2
Science
Biochemical mechanisms of insulin resistance
Horm Res
Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2
J Clin Invest
The cellular fate of glucose and its relevance in type 2 diabetes
Endocr Rev
Intracellular organization of insulin signaling and GLUT4 translocation
Recent Prog Horm Res
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
Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes
N Engl J Med
Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance
Nat Med
Mechanism of troglitazone action in type 2 diabetes
Diabetes
Troglitazone not only increases GLUT4 but also increases its translocation in rat adipocytes
Diabetes
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
Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase-dependent reduction in GLUT4 endocytosis
Endocrinology
Exercise glucose transport, and insulin sensitivity
Annu Rev Med
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
Banting lecture 1997. Control of glucose uptake and release by the liver in vivo
Diabetes
Insulin-regulated hepatic gluconeogenesis through FoxO1-PCG-1alpha interaction
Nature
Cellular mechanisms of insulin resistance
J Clin Invest
Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?
J Hum Hypertens
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 DiseasesCitation 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 DiseasesCitation 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.
Dr. Derek LeRoith is presently a consultant and speaker, and receives an honorarium from Merck, Sanofi-Aventis, Pfizer, Takeda, and Novo Nordisk.