Julio Libman, Astrid Libman

In 1988, G. Reaven designated as “Syndrome X” the association of resistance to insulin-stimulated glucose uptake, glucose intolerance, hyperinsulinemia, increased triglyceride-rich very low-density lipoproteins (VLDL) (TGC). ) endogenous, decreased high-density lipoprotein (HDL) cholesterol and arterial hypertension.

The ability of insulin to stimulate glucose uptake varies between different individuals.

In the presence of insulin resistance (IR), the beta cells of the pancreas increase insulin secretion in order to maintain both fasting and postprandial normoglycemia. This compensatory hyperinsulinemia, although it prevents or delays for a time the development of type 2 diabetes, contributes together with IR to the appearance of a set of manifestations that predispose to atherosclerosis, endocrine disorders such as the androgenic ovary and perhaps certain neoplasms .

Pathophysiology and clinical manifestations

IR, defined according to its most evident physiological action, is manifested by a decrease in the capacity of insulin to stimulate the uptake, oxidation and deposition of glucose in the form of glycogen. IR is, however, a more general alteration, with, for example, a reduction in the insulin action of promoting increased blood flow through the activation of endothelial nitric oxide synthase (ecNOS), or of inhibiting the hydrolysis of TGCs via hormone-sensitive lipase (HLS).

IR is associated with certain non-communicable human diseases and fundamentally with the development of vascular disease (VE). In individuals with IR, multiple cardiovascular risk factors (dysglycemia, hyperinsulinemia, dyslipidaemia, hypertension, and obesity) are associated with a higher frequency than is attributable to chance. This association has received different names, such as syndrome X, metabolic syndrome or syndrome of insulin resistance (SRI).

Compensatory hyperinsulinemia as a consequence of the diminished effectiveness of insulin is associated with other effects, such as increased renal Na reabsorption and increased activity of the sympathetic nervous system (SNS). Genetic and environmental factors are involved in the development of SRI. Multiple genes, the effect of which is modulated by environmental factors, are believed to contribute to Rl in its most common forms (polygenic inheritance). A mutation has been identified in the gene that codes for the insulin receptor substrate 1 (IRS-1) (glycine-arginine substitution at codon 972) whose expression results in an alteration in the transmission of signals through this pathway. Homozygous carriers of a mutation in the phosphatidylinositol 3 kinase (PI3-K) gene have decreased glucose tolerance. A mutation in the gene coding for b3-adrenergic receptors has been described that is associated with characteristics of SRI and early onset of type 2 diabetes (DM2). Other candidate genes include lipoprotein lipase (LPL), LHS, peroxisome proliferator-activated receptors (PPARy), and glycogen synthase.

The hypothesis of fetal origin establishes a relationship between fetal malnutrition and the development of IR in adult life, through fetal adaptation to an adverse uterine environment that produces metabolic changes ("liver bias" towards higher production and lower utilization glucose) and neuroendocrine (increased permanent activity of the hypothalamic-pituitary-adrenal axis).

Environmental factors include obesity, smoking, and sedentary lifestyle, with an inverse relationship between insulin sensitivity and maximal aerobic capacity (VO2 max).

In recent years, the molecular basis for the actions of insulin has been partly elucidated. These are mediated by binding to its membrane receptor, with autophosphorylation of multiple tyrosine residues in the intramembrane portion of the  subunit thereof, which leads to a cascade of post-receptor events with phosphorylation of tyrosine residues of various proteins. Signaling. The 2 most important seem to be the IRS-1 and the Shc. The first leads to the activation of PI3-K and of several metabolic pathways dependent on it, which mediates, among other actions, glucose metabolism and ecNOS activity and expression. The second would lead to the activation of mitogen-activated protein kinases (MAPKs) and of the different metabolic pathways controlled by them.

Alterations in the IRS-1 / PI3-K pathway induce IR in glucose metabolism and a deficiency in ecNOS activity with the consequent vascular dysfunction, less vasodilation and increased platelet aggregation and the expression of molecules of accession. This pathway therefore plays an important role in preserving vascutar integrity, with the development of IR in it having a deleterious effect on vascular function.

IRS-1 activity is modulated positively by phosphorylation of tyrosine residues and negatively by phosphorylation of serine, as a consequence, for example, of exposure of the cell to tumor necrosis factor alpha (TNF -a) or hyperglycemia.

Hyperinsulinemia could promote atherogenesis through its stimulating action on cell proliferation, directly or by amplifying the proliferative response to various growth factors, such as angiotensin II and platelet-derived growth factor (PDGF). This action of insulin is mediated via Shc / MAPK. Activation of MAPK would mediate increased transcription of the endothelin A receptor, the ligand of which is endothelin 1, a vasoconstrictor agent that stimulates the proliferation of vascular smooth muscle cells (VSMCs).

Consequently, an imbalance between IRS-1 / PI3-K mediated processes that are decreased in IR, and those mediated via Shc / MAPK that preserve the insulin response even under IR conditions and can be overexpressed in compensatory hyperinsulinemia , could explain the IR-hyperinsulinemia-atherogenesis relationship.

Adipose tissue and fatty acids . A significant proportion of IR is attributable to visceral obesity. Visceral adipocytes have a more active lipolytic program, with a higher rate of catecholamine-induced lipolysis and higher expression of -adrenergic receptors. On the other hand, antilipolytic mechanisms are less active with a lower response to insulin due to lower affinity for its receptors and reduced expression of IRS-1. Free fatty acids (FFA) produce IR by inhibiting glucose transport, competition with it for oxidation (Randle cycle) and stimulation of hepatic and renal gluconeogenesis.

The adipose tissue acts as an endocrine organ, producing different cytokines and hormones (TNF-, IL-6, PAI-1, angiotensin II, resistin, adiponectin, leptin). With the exception of adiponectin, all increase in obesity and most have a deleterious effect on insulin sensitivity.

In patients with DM2, insulin sensitivity is inversely related to the hepatic TGC content and the sensitivity in skeletal muscle to that of intramyocellular fat.

Dyslipoproteinemia. Insulin normally suppresses VLDL production and increases its clearance, as well as that of chylomicrons by stimulation of lipoprotein lipase (LPL). IR determines an increase in TGC-rich lipoproteins due to the interference of both mechanisms. HDL levels decrease in individuals with elevated Rl and TGC. In the presence of hypertriglyceridemia, the exchange of TGC of VLDL for cholesterol esters (EC) of HDL increases, mediated by cholesterol ester transfer protein (CETP). HDL enriched in TGC constitute a good substrate for hepatic lipase (LH), with accelerated removal of these particles. Likewise, there is an accelerated exchange between TGC of VLDL by EC of LDL, originating LDL enriched in TGC that serve as a substrate for LH, producing small and dense LDL.

Hyperuricemia . In healthy people, insulin acutely decreases renal uric acid clearance. This action is maintained and increased in the presence of IR and compensatory hyperinsulinemia, explaining the association of gout with obesity, arterial hypertension, dyslipidemia and DM2. Hyperuricemia is one of the instances in which the manifestations of SRI occur due to the fact that in the same individual an organ, in this case the kidney, remains sensitive to the action of insulin, while other tissues, such as the muscle, are resistant to it.

Glucose metabolism . Most people with IR maintain normal glucose tolerance by secreting increased amounts of insulin. Those in whom compensatory hyperinsulinemia is not sufficient to preserve normogIukemia develop a picture of decreased glucose tolerance and eventually DM2.

Androgenic ovary . Polycystic ovary syndrome presents with hyperandrogenism, chronic anovulation, and IR. IR is found in both obese and lean women and is associated with excessive phosphorylation of the insulin receptor serine residues. The resulting hyperinsulinemia would play a fundamental role in the development of ovarian hyperandrogenism by a mechanism that has not been fully clarified.

Hypertension . IR is related to the development of hypertension through various mechanisms. Insulin itself has a direct vasodilator action mediated in part by the production of nitric oxide from the amino acid arginine by stimulation of ecNOS, an effect diminished in hypertensive and obese individuals.

IR in VSMC is associated with altered ion transport that results in an increase in Ca and Na and a decrease in cytosolic Mg, which causes greater vascular reactivity in response to different vasoconstrictor agents, such as angiotensin II, catecholamines and saline overload. On the other hand, IR in liver and muscle causes compensatory hyperinsulinemia that translates into increased sympathetic activity, angiotensin II-mediated aldosterone secretion, Na retention due to direct action on the distal convoluted tubule, and hyperplasia of the CMLVs.

Alterations of coagulation and platelet function . IR is associated with a hypercoagulable state, characterized by an increase in PAI-1, decreased fibrinolysis, and alterations in platelet function. Normally insulin inhibits platelet aggregation.

Oxidative stress (EO). The IR / hyperinsulinemia condition may be linked to an increase in EO, directly or through its complex relationships with other systems (angiotensinergic and kininergic) that regulate the balance between NO synthesis and the generation of superoxide anion and other reactive species. The recognition of ecNOS as an effector of insulin action suggests that IR has an important role in modulating the chronic inflammation reaction involved in atherogenesis through the loss of anti-inflammatory effects due to low concentrations of NOT.

Diagnostic criteria

The two most recognized definitions of metabolic syndrome are those established by the National Cholesterol Education Program (NCEP) and the modified World Health Organization (WHO)

The first is of greater clinical application and according to it, the metabolic syndrome can be diagnosed when three or more of the following alterations coexist:

- Abdominal obesity, with a waist circumference> 102 cm in men and> 88 cm in women;

Blood pressure> 130/85 mm Hg or medication;

Triglycerides> 150 mgs / dl;

HDL cholesterol <50 mgs / dl in women and <40 mgs / dl in men;

Fasting blood glucose> 110 mgs / dl. The American Diabetes Association recently established normal blood glucose levels as those below 100 mgs / dl in the fasting state.

The diagnosis of SRI is of clinical importance since it plays an important role in the development and predicts the appearance of T2DM and atherosclerotic disease.