Insulin resistance is identified as an impaired biologic response to insulin stimulation of target tissues, primarily the liver, muscle, and adipose tissue. Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia. The metabolic consequences of insulin resistance can result in hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperuricemia, elevated inflammatory markers, endothelial dysfunction, and a prothrombic state. Progression of insulin resistance can lead to metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus.
Insulin resistance is primarily an acquired condition related to excess body fat, though genetic causes are identified as well. The clinical definition of insulin resistance remains elusive as there is not a generally accepted test for insulin resistance. Clinically, insulin resistance is recognized via the metabolic consequences associated with insulin resistance as described in metabolic syndrome and insulin resistance syndrome.
The gold standard for measurement of insulin resistance is the hyperinsulinemic-euglycemic glucose clamp technique. This is a research technique with limited clinical applicability; however, there are a number of clinically useful surrogate measures of insulin resistance, including HOMA-IR, HOMA2, QUICKI, serum triglyceride, and triglyceride/HDL ratio. In addition, several measures assess insulin resistance based on serum glucose and/or insulin response to a glucose challenge.
The predominate consequence of insulin resistance is type 2 diabetes (T2DM). Insulin resistance is thought to precede the development of T2DM by 10 to 15 years. The development of insulin resistance typically results in a compensatory increase in endogenous insulin production. Elevated levels of endogenous insulin, an anabolic hormone, is associated with insulin resistance and results in weight gain which, in turn, exacerbates insulin resistance. This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia. With continued mismatch between insulin demand and insulin production, glycemic levels rise to levels consistent with T2DM.
Resistance to exogenous insulin has also been described. An arbitrary but clinically useful benchmark considers patients requiring greater than 1 unit/kilogram/day of exogenous insulin to maintain glycemic control insulin resistant. Patients requiring greater than 200 units of exogenous insulin per day are considered severely insulin resistant.
In addition to T2DM, the spectrum of disease associated with insulin resistance includes obesity, cardiovascular disease, nonalcoholic fatty liver disease, metabolic syndrome, and polycystic ovary syndrome(PCOS). These are all of great consequence in the United States with a tremendous burden being placed on the healthcare system to treat the direct and indirect conditions associated with insulin resistance. The microvascular complications of diabetes (neuropathy, retinopathy, and nephropathy), as well as the associated macrovascular complications (coronary artery disease [CAD], cerebral-vascular disease, and peripheral artery disease [PAD]), consume the lion's share of the healthcare dollar.
Lifestyle modification should be the primary focus for the treatment of insulin resistance. Nutritional intervention with calorie reduction and avoidance of carbohydrates that stimulate excessive insulin demand are a cornerstone to treatment. Physical activity helps to increase energy expenditure and improve muscle insulin sensitivity. Medications also can improve insulin response and reduce insulin demand.
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