What is the pathophysiology of metabolic syndrome?

Updated: Jul 08, 2020
  • Author: Samuel T Olatunbosun, MD, FACP, FACE; Chief Editor: George T Griffing, MD  more...
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Answer

Insulin resistance plays a major pathogenic role in the development of the metabolic syndrome, which may include any or all of the following:

Inflammation and adipocytokines probably play some role in the etiopathogenesis of metabolic syndrome. [3, 17, 19, 20] Increased levels of the acute-phase inflammatory marker C-reactive protein (CRP) are related to insulin resistance and the metabolic syndrome, suggesting a role for chronic, low-grade inflammation. [4] In a number of prospective studies, increased levels of CRP predict the development of diabetes and cardiovascular disease. [16, 21, 22]  Indeed, insulin resistance is not only predictive for type 2 diabetes and associated with myriad metabolic derangements in fasting conditions, but nondiabetic insulin-resistant individuals are subjected to a similar adverse postprandial metabolic setting and cardiometabolic risk as those with type 2 diabetes. [1]

Reduced serum levels of adiponectin (a hormone made by fat tissue) and elevated leptin concentration are also features of conditions associated with the metabolic syndrome or cardiovascular disease. [23, 24, 25, 26]

Omentin, a novel adipokine, is a protein expressed and secreted from visceral but not subcutaneous adipose tissue that increases insulin sensitivity in adipocytes. Plasma levels of omentin-1, the major circulating isoform, are inversely correlated with body mass index (BMI), waist circumference, leptin levels, and insulin resistance syndrome and are positively correlated with adiponectin and high-density lipoprotein (HDL) levels. [27, 28, 29, 30]

Insulin resistance, the compensatory hyperinsulinemia, and other components are associated with increased risk of cardiovascular disease; endothelial dysfunction is a prominent feature of insulin resistance syndrome. [5] Type 2 diabetes is characterized by increased hepatic glucose output, increased peripheral resistance to insulin action (due to receptor and postreceptor defects), and impaired insulin secretion. [31]

In skeletal muscle, various abnormalities, including defective glucose transport, may cause insulin resistance. Glucose transporter 4 (GLUT-4) is the main insulin-responsive transporter. [32] Insulin and IGFs are important regulators of ovarian function. Insulin resistance and hyperinsulinemia are thought to be responsible for the hyperandrogenism that is characteristic of the polycystic ovary syndrome (PCOS). Other distinct manifestations of insulin resistance syndrome or related conditions involve various organs, as well as the skin.

Two major variants of insulin receptor abnormalities associated with acanthosis nigricans have been described—the classic type A insulin resistance syndrome, which is due to an absent or dysfunctional receptor, and type B insulin resistance syndrome, which results from autoantibodies to the insulin receptor. Both syndromes are associated with hyperinsulinemia.

Hypoglycemia may still occur in some individuals with insulin resistance syndrome because of an agonist effect of autoantibodies on the insulin receptor. In some patients with insulin-binding antibodies, hypoglycemia may occur when insulin dissociates from the antibodies several hours after a meal.

Insulin resistance may also develop in some type 1 diabetic patients. Uruska et al found that an independent relationship existed between insulin resistance and the risk of microangiopathy in 81 patients with diabetes type 1 who began receiving intensive insulin therapy right after their diagnosis. [33] The authors determined that insulin resistance indicators, including waist circumference, waist-to-hip ratio, and triglyceride levels, were greater in cohort members with microangiopathy than in those without it. In addition, the estimated glucose disposal rate was lower in the microangiopathy patients than in the others.


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