Today, I review, link to, and excerpt from StatPearls‘ Insulin Resistance. Andrew M. Freeman1; Luis A. Acevedo2; Nicholas Pennings3. Last Update: August 17, 2023.
All that follows is from the above resource.
Introduction
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.
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.[1][2][3][4][5]
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.[6][7]
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.[8][9][10][11]
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.[12][13][14][15]
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.[16]
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.[17][18][19][20][21][22][23]
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.[24][25][26]
Etiology
The etiologies of insulin resistance may be acquired, hereditary, or mixed. The great majority of people with insulin resistance fall have an acquired etiology.[25] [obesity]
Pathophysiology
The 3 primary sites of insulin resistance are the skeletal muscle, liver, and adipose tissue. In a state of chronic caloric surplus, the tissues in the body become resistant to insulin signaling. Skeletal muscle is a large reservoir for circulating glucose, accounting for up to 70% of glucose disposal as measured by the hyperinsulinemic-euglycemic clamp. The direct result of muscle insulin resistance is decreased glucose uptake by muscle tissue. Glucose is shunted from muscle to the liver, where de novo lipogenesis (DNL) occurs. With increased glucose substrate, the liver develops insulin resistance as well. Higher rates of DNL increase plasma triglyceride content and create an environment of excess energy substrate, which increases insulin resistance throughout the body, contributing to ectopic lipid deposition in and around visceral organs. [25]
History and Physical
The clinical presentation of insulin resistance is variable concerning both history and physical examination findings. It depends on the subset of insulin resistance present, the duration of the condition, the level of beta-cell function, and the individual’s propensity for secondary illnesses due to insulin resistance. Common presentations include:
Associated Diseases
Associated Symptoms
Evaluation
The gold standard for measuring insulin resistance is the hyperinsulinemic-euglycemic glucose clamp technique. This is a research technique in which a fasting, non-diabetic patient is placed on a high-rate constant infusion of insulin to suppress hepatic glucose production; the blood glucose is frequently monitored while a concomitant 20% dextrose solution is given at varying rates to regulate the blood glucose in the euglycemic range. The amount of glucose required to reach a steady state reflects the exogenous glucose disposal needed to compensate for hyperinsulinemia. Insulin resistance calculation is based on whole-body glucose disposal and body size.[31]
The associated risks and complexity of the glucose clamp method limit its clinical usefulness. As a result, multiple surrogate markers for insulin resistance have been developed and tested. The homeostatic model assessment for insulin resistance (HOMA-IR), based on fasting glucose and fasting insulin levels, is a widely utilized measure of insulin resistance in clinical research. Other measures based on fasting insulin include HOMA2, the Glucose to Insulin Ratio (GIR), and the Quantitative Insulin Sensitivity Index (QUICKI). The McAuley Index utilizes fasting insulin and triglycerides. Post-glucose challenge tests, done after an overnight fast, measure insulin and glucose response to a 75-gram glucose load. Methods include the Matsuda Index and Insulin Sensitivity Index (ISI).[8][9][10][32][33][34][35][36]
Other surrogate markers involve triglycerides alone or in relation to HDL cholesterol. Patients with prediabetes and triglycerides greater than or equal to 150 g/dL were more likely to have insulin resistance. The triglyceride/HDL ratio is correlated with insulin resistance in individuals who identify as White. In general, a ratio greater than 3.0 is associated with insulin resistance. More specifically, a ratio greater than or equal to 3.5 in males and greater than or equal to 2.5 in females indicates insulin resistance. These correlations do not hold up in individuals who identify as Black.[11][37]
Measures of insulin resistance have not been integrated into clinical guidelines. As a result, the presence of insulin resistance is generally inferred from the clinical presentation. Metabolic syndrome (MetS) and insulin resistance syndrome (IRS) are considered to be clinical indicators of insulin resistance.
Multiple criteria for metabolic syndrome (MetS) exist. In 2009, a joint scientific statement harmonizing criteria for MetS was released.[38] MetS is identified by the presence of 3 or more of the following diagnostic cut points:
The American College of Endocrinology identifies specific physiologic abnormalities that increase IRS risk.[39] These abnormalities include:
Other factors include the following:
Treatment / Management
Intensive Lifestyle Intervention
Lifestyle intervention represents the cornerstone of treatment for insulin resistance. Dietary intervention should include a combination of calorie restriction and high glycemic index carbohydrate reduction. Physical activity improves both calorie expenditure and insulin sensitivity in muscle tissue.[40][41][42]
Individuals with insulin resistance are at high risk of developing T2D. The Diabetes Prevention Program and its Outcomes Study (DPP & DPPOS) demonstrated that lifestyle intervention was a significant and cost-effective intervention for diabetes prevention in high-risk adults.[24][26] These interventions include:
See the article for Specific Pharmacological Interventions for Blood Glucose Management.
Complications
Most of the complications from insulin resistance are related to the development of vascular complications.
The microvascular disease manifests as retinopathy, nephropathy, and peripheral neuropathy. In the central nervous system, dementia, stroke, mood disturbance, and gait instability may occur. Cardiac microvascular disease can manifest as angina, coronary artery spasm, and cardiomyopathy. Renal microvascular disease is a significant cause of chronic kidney disease, renal failure, and dialysis. Ophthalmological small vessel disease is a leading cause of retinopathy and visual impairment. Macrovascular disease, secondary to insulin resistance, causes PAD, CAD, and CVA.
Non-alcoholic fatty liver disease (NAFLD) is intricately related to insulin resistance and T2D. Patients with T2D have a 2-fold increased risk for NAFLD. With an increasing worldwide prevalence and incidence in children, NAFLD should be of great concern to clinicians treating patients with insulin resistance.[19][20]
Pearls and Other Issues
Intensive lifestyle intervention should be the first line of therapy for patients with metabolic syndrome or insulin resistance syndrome. The benefits of exercise cannot be understated in treating patients with insulin resistance. Barriers to exercise should be discussed, and a well-formulated plan, including moderate-intensity cardiovascular exercise like walking, should be provided in accordance with the physical activity guidelines. Discussion of dietary modification following the dietary guidelines should also be provided with individualization to the patient’s preferences, with particular attention to reducing sugar, refined grain products, and high glycemic index carbohydrates.
For patients with T2D, insulin resistance, and hyperinsulinemia, consider treatment with agents to improve insulin sensitivity or contribute to weight loss, like metformin, GLP-1 receptor agonists, GLP-1/GIP receptor agonists, and SGLT2 inhibitors. [60][61][62]
Enhancing Healthcare Team Outcomes
Over the past few decades, the incidence of insulin resistance has skyrocketed primarily due to our lifestyle and the rising incidence of obesity. Without treatment, the condition is associated with numerous complications, including fatal cardiac events.
