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.
Insulin resistance etiology can be divided into acquired, hereditary, and mixed. The great majority of people with insulin resistance fall into the acquired categories.
In addition to the heritable components of the above etiologies of insulin resistance, there are a number of unrelated genetic syndromes with associated insulin resistance.
Of note, an alternative classification of insulin resistance is the division for the site of dysfunction concerning the insulin receptor itself as opposed to etiology. The categories include the following:
Epidemiologic assessment of insulin resistance is typically measured in relation to the prevalence of metabolic syndrome or insulin resistance syndrome. Criteria proposed by the National Cholesterol Education Program Adult Treatment Panel III national survey data suggest insulin resistance syndrome is very common, affecting about 24% of United States (US) adults older than 20 years. While there has been a rapid rise in pediatric obesity and type 2 diabetes, no consensus has been reached on diagnostic criteria for insulin resistance in the pediatric population at this time. The type-A syndrome is predominantly found in younger adults while the type-B syndrome is found in older adults. From a demographic standpoint, insulin resistance affects all races with limited data on comparisons between different racial groups.
The three primary sites of insulin resistance are the muscle, liver, and adipose tissue. Insulin resistance is postulated to begin in muscle tissue with immune-mediated inflammatory change and excess free fatty acids, causing ectopic lipid deposition. Muscle accounts for up to 70% of glucose disposal. With impaired muscle uptake, excess glucose returns to the liver increasing de novo lipogenesis (DNL) and circulating free fatty acids, further contributing to ectopic fat deposition and insulin resistance
By use of the hyperinsulinemic-euglycemic clamp technique, researchers determined that lipolysis is most sensitive to insulin. Failure of insulin to suppress lipolysis in insulin-resistant adipose tissue, especially visceral adipose tissue, increases circulating free fatty acids. Higher levels of circulating FFAs directly affect both liver and muscle metabolism, further exacerbating insulin resistance.
After intake of a caloric load and conversion to glucose, muscle is the primary site for glucose disposal, accounting for up to 70% of tissue glucose uptake. With excess calorie loads, glucose uptake by muscle exceeds capacity, and excess glucose returns to the liver where it triggers DNL. Increased DNL increases triglyceride and FFA production, causing ectopic fat deposition into the liver, muscle, and adipose tissue. As a result, insulin resistance increases as well as the production of inflammatory markers. Additional factors influencing insulin resistance in muscle tissue include physical inactivity and genetic risk.
Insulin resistance in muscle results in increased delivery of glucose substrate to the liver, which triggers DNL, with associated inflammation, and ectopic lipid deposition. Insulin resistance in adipose tissue results in increased lipolysis in adipocytes, resulting in increased circulating FFA and further exacerbating steatosis and insulin resistance in muscle tissue. In the presence of caloric intake, insulin reduces hepatic glucose production via inhibition of glycogenolysis, limiting the postprandial rise in glucose. With insulin resistance, this feedback mechanism is impaired, and hepatic glucose production continues to rise, even as postprandial glucose rises. Glucotoxicity, associated with elevated glucose levels, further contributes to insulin resistance.
The clinical presentation of insulin resistance is variable with respect to both history and physical exam findings. It is dependent on the subset of insulin resistance present, duration of the condition, level of beta-cell function, and the individual’s propensity for the secondary illnesses due to insulin resistance. Common presentations include:
The gold standard for measurement of insulin resistance is the hyperinsulinemic-euglycemic glucose clamp technique. This is a research technique in which a fasted, 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 clamp the blood glucose in the euglycemic range. The amount of glucose required to reach a steady state reflects exogenous glucose disposal required to compensate for the hyperinsulinemia. Insulin resistance calculation is based on whole-body glucose disposal and body size.
The complexity of the glucose clamp method limits its clinical usefulness. As a result, multiple surrogate markers for insulin resistance have been developed and tested. HOMA-IR and HOMA2, based on fasting glucose and fasting insulin levels, are widely utilized measures of insulin resistance in clinical research. Other measures based on fasting insulin include 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 g glucose load. Methods include the Matsuda Index and Insulin Sensitivity Index (ISI).
Other surrogate markers involve triglycerides alone or in relation to HDL cholesterol. Patients with prediabetes and triglyceride 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 Caucasian individuals. In general, a ratio greater than 3.0 is associated with IR. More specifically, a ratio greater than or equal to 3.5 in men and greater than or equal to 2.5 in women indicates insulin resistance. These correlations do not hold up in African American individuals.
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. The Metabolic Syndrome (MetS) and Insulin Resistance Syndrome (IRS) are considered clinical indicators of insulin resistance.
Multiple criteria for metabolic syndrome exist. In 2009, a joint scientific statement harmonizing criteria for MetS was released. MetS is identified by the presence of 3 or more of the following diagnostic cut points:
The American College of Endocrinology identify specific physiologic abnormalities which increase the risk of Insulin Resistance Syndrome as follows:
Other factors include the following:
Intensive Lifestyle Intervention
Lifestyle intervention represents the cornerstone of treatment for insulin resistance. Dietary intervention should include a combination of calorie restriction and reduction of high glycemic index carbohydrates. Physical activity improves both calorie expenditure and insulin sensitivity in muscle tissue.
Individuals with insulin resistance are at high risk of developing T2DM. The Diabetes Prevention Program and its Outcomes Study (DPP & DPPOS) demonstrated that lifestyle intervention was both a significant and cost-effective intervention for diabetes prevention in high-risk adults.
Specific Pharmacological Interventions for Blood Glucose Management
While no medications are FDA approved for the treatment of insulin resistance, general approaches include the following:
For individuals on insulin therapy:
Surgical intervention in the form of gastric sleeve, banding, and bypass is available for qualified individuals with obesity. The excess fat loss associated with bariatric surgery improves insulin sensitivity. The STAMPEDE trial has shown good evidence of the benefit of bariatric surgery on type 2 diabetes.
The prognosis of insulin resistance is dependent on the subset of the disease, the severity of the disease, pancreatic beta-cell function, the heritable susceptibility of the patient to the secondary complications from insulin resistance, and individual response to appropriate therapy. The spectrum of outcome ranges from the mildly insulin resistant, asymptomatic individuals to individuals with catastrophic cardiovascular or cerebrovascular events and their resultant morbidity and mortality.
Statistically, coronary artery disease is the leading cause of mortality in the United States, with diabetes as the seventh. The common basis for diabetes and much of the resultant vascular disease (CAD, cerebrovascular disease, and PAD) is insulin resistance. Additional mortality from insulin resistance occurs in the less common manifestations of the disease, including the genetic syndromes and the fatty deposition diseases. Finally, substantial morbidity manifests with the loss of reproductive function and associated stigmata of PCOS.
Mitigation for the disease exists. Increased clinical awareness enables early diagnosis and treatment. Improved understanding of the disease process has resulted in more targeted, multi-faceted treatments. Sustained efforts to attain and maintain a healthy weight through improved dietary intake and increased physical activity can reduce insulin resistance and prevent associated complications. More generalized lay recognition can increase the efficacy of preventative care, with the hope of an eventual downturn in epidemic obesity and resultant insulin resistance.
The majority of the complications from insulin resistance is 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 renal failure and dialysis. Ophthalmological small vessel disease is a leading cause of loss of visual acuity. Macrovascular disease, secondary to insulin resistance, causes PAD, CAD, and CVA.
Primary, secondary, and tertiary prevention all have distinct roles in the management of insulin resistance.
Intensive lifestyle intervention should be the first line of therapy for patients with metabolic syndrome or insulin resistance syndrome.
In patients with type 2 diabetes, insulin resistance, and hyperinsulinemia consider treating with agents to improve insulin sensitivity and/or contribute to weight loss like metformin, GLP-1 agonists, and SGLT2 inhibitors.
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. The management of insulin resistance is best done with an interprofessional team. The consultations most indicated for the treatment of insulin resistance include:
The key is encouraging lifestyle changes in these patients. Dietary intervention should include a combination of calorie restriction and reduction of high glycemic index carbohydrates. Physical activity improves both calorie expenditure and insulin sensitivity in muscle tissue.
For those who remain compliant with therapy, the outcomes are good but unfortunately, many patients remain non-compliant and suffer adverse cardiac or CNS events. This is why an interprofessional team approach is needed in the management of these patients. [Level 5]
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