Insulin Resistance

Link to article at PubMed

2023 Aug 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.


Insulin resistance is identified as the impaired biologic response of target tissues to insulin stimulation. All tissues with insulin receptors can become insulin resistant, but the tissues that primarily drive insulin resistance are the liver, skeletal muscle, and adipose tissue. Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia. Recent studies have debated whether hyperinsulinemia precedes insulin resistance, as hyperinsulinemia itself is a driver of insulin resistance. This concept may be clinically valuable, suggesting that hyperinsulinemia associated with excess caloric intake may drive the metabolic dysfunction associated with insulin resistance. The metabolic consequences of insulin resistance include hyperglycemia, hypertension, dyslipidemia, hyperuricemia, elevated inflammatory markers, endothelial dysfunction, and a prothrombotic state. Progression of insulin resistance can lead to metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes.

Insulin resistance is primarily an acquired condition related to excess body fat, though genetic causes are also identified. The clinical definition of insulin resistance remains elusive, as there is no 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 research technique has limited clinical applicability; however, several clinically useful surrogate measures of insulin resistance include HOMA-IR, HOMA2, QUICKI, serum triglyceride, and triglyceride/HDL ratio. In addition, several measures assess insulin resistance based on serum glucose or insulin response to a glucose challenge.

The predominant consequence of insulin resistance is type 2 diabetes (T2D). Insulin resistance is thought to precede the development of T2D by 10 to 15 years. The development of insulin resistance typically results in impaired glucose disposal into insulin-resistant tissues, especially skeletal muscle. Consequently, in the presence of excess calorie consumption, more insulin is required to traffic glucose into these tissues. The resultant hyperinsulinemia further contributes to 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 a continued mismatch between insulin demand and insulin production, glycemic levels rise to those consistent with T2D. Weight gain usually occurs alongside hyperinsulinemia but may be related more to a chronic caloric excess than hyperinsulinemia. The anabolic effect of insulin decreases as tissues become more insulin-resistant, and weight gain eventually slows.

Resistance to exogenous insulin has also been described. An arbitrary but clinically useful benchmark considers patients insulin-resistant when requiring more than 1 unit/kilogram/day of exogenous insulin to maintain glycemic control. Patients requiring greater than 200 units of exogenous insulin per day are considered severely insulin-resistant.

In addition to T2D, the disease spectrum associated with insulin resistance includes obesity, cardiovascular disease, NAFLD, metabolic syndrome, and polycystic ovary syndrome (PCOS). These are all of great consequence in the United States, with a tremendous burden on the healthcare system to treat the direct and indirect conditions associated with insulin resistance. The microvascular complications of diabetes, such as neuropathy, retinopathy, and nephropathy, as well as the associated macrovascular complications of coronary artery disease [CAD], cerebral-vascular disease, and peripheral artery disease (PAD), will eventually consume the lion's share of the healthcare dollar as the disease progresses in severity.

Lifestyle modifications should be the primary focus when treating insulin resistance. Nutritional intervention with calorie reduction and avoidance of carbohydrates that stimulate excessive insulin demand is a cornerstone of treatment. Physical activity helps to increase energy expenditure and improve skeletal muscle insulin sensitivity. Medications also can improve insulin response and reduce insulin demand.

PMID:29939616 | Bookshelf:NBK507839

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