Insulin Resistance

Article Author:
Andrew Freeman
Article Editor:
Nicholas Pennings
Updated:
6/26/2018 5:36:54 PM
PubMed Link:
Insulin Resistance

Introduction

Insulin resistance is identified as an impaired biologic response to insulin stimulation of target tissues, primarily 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 a 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.

Etiology

Insulin resistance etiology can be divided into acquired, hereditary, and mixed. The great majority of people with insulin resistance fall into the acquired categories.

Acquired

  • Excess dysfunctional adipose tissue
  • Aging 
  • Physical inactivity
  • Nutritional imbalance
  • Medications (glucocorticoids, anti-adrenergic, protease inhibitors, atypical antipsychotics, and some exogenous insulin)
  • Increased sodium diets
  • Glucose toxicity
  • Lipotoxicity from excess circulating free fatty acids

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.

Genetic

  • Myotonic Dystrophy
  • Ataxia-telangiectasia
  • Alstom syndrome
  • Rabson-Mendenhall syndrome
  • Werner syndrome
  • Lipodystrophy
  • PCOS
  • Type-A insulin resistance: Characterized by severe insulin resistance (abnormal glucose homeostasis, ovarian virialization, and acanthosis nigricans) in the absence of anti-insulin antibodies; typically occurs before middle age
  • Type-B insulin resistance: Characterized by the development of anti-insulin antibodies (typically in middle age) with resultant abnormal glucose homeostasis, ovarian hyperandrogenism, and acanthosis nigricans

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:

  • Pre-receptor
  • Receptor
  • Post-receptor 

Epidemiology

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 the older adults. From a demographic standpoint, insulin resistance effects all races with limited data on comparisons between different racial groups.

Pathophysiology

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

Adipose Tissue

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.

Muscle Tissue 

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.

Hepatic Tissue 

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.

History and Physical

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 asymptomatic patients with obesity, hypertension, or hyperlipidemia
  • Those with metabolic syndrome
  • Prediabetes or type 2 diabetes mellitus
  • Those with symptomatic microvascular disease (retinopathy, neuropathy, or nephropathy)
  • Those with macrovascular disease (stroke, PAD, and CAD)
  • Those with PCOS
  • Those with type A or type B insulin resistance
  • Elevated blood pressure
  • Gender and race-specific increased waist circumference
  • Those with xanthelasma or xanthomas
  • The stigmata of PCOS (menstrual irregularities, hirsutism, acne, and alopecia)
  • Acanthosis nigricans, a patchy velvety brown pigmentation around the neck axilla and groin regions.
  • The stigmata of one of several genetic syndromes that include insulin resistance

Evaluation

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:

  • A waist circumference of 32” to 40” based on gender and race
  • Elevated triglycerides greater than or equal to 150 mg/dL
  • Reduced HDL less than 40 mg/ dL in men, less than 50 mg/ dL in women
  • Elevated blood pressure greater than or equal to 130 mmHg systolic and/or greater than or equal to 85 mmHg diastolic
  • Elevated fasting glucose greater than or equal to 100 mg/ dL

The American College of Endocrinology identify specific physiologic abnormalities which increase the risk of Insulin Resistance Syndrome as follows:

  • Impaired glucose tolerance or impaired fasting glucose
  • Abnormal uric acid metabolism
  • Dyslipidemia (increased triglycerides, decreased HDL-C, or small, dense LDL)
  • Hemodynamic changes such as elevated blood pressure
  • Prothrombic factors (PAI-1, fibrinogen)
  • Markers of inflammation (CRP, WBC, etc.)
  • Endothelial dysfunction

Other factors include the following:

  • Body mass index (BMI) greater than or equal to 25 kg/m2
  • Diagnosis of CVD, PCOS, NAFLD, or acanthosis nigricans
  • A family history of T2DM, hypertension, or CVD
  • Sedentary lifestyle
  • Non-Caucasian ethnicity
  • Age greater than 40 years

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 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 for 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.

  • Dietary therapy with sodium reduction, fat reduction, calorie restriction, and attention to the glycemic index of foods
  • Education, support, and personalized programs
  • A 7% weight loss reduced the onset of T2DM by 58%
  • DPP included a metformin arm which reduced the onset of T2DM by 31%

Specific Pharmacological Interventions for Blood Glucose Management

While no medications are FDA approved for the treatment of insulin resistance, general approaches include the following:

  • Metformin: This is considered first-line therapy for medication treatment of T2DM and is approved for use in polycystic ovary syndrome. The DPP/DPPO study showed that the addition of metformin and lifestyle interventions combined were medically useful and cost-effective. Despite the concerns of use in mild to moderate renal dysfunction, several organizations including the American Geriatric Society and the KDIGO (Kidney Disease Improving Global Outcomes) guidelines endorse use as long as the GFR is greater than 30.
  • Glucagon-like peptide one inhibitors: The GLP-1 receptor agonists stimulate the GLP-1 receptors in the pancreas, thereby increasing insulin release and inhibiting glucagon secretion. Use of GLP-1 agonists is associated with weight loss, which may reduce IR. Liraglutide is FDA approved as and an anti-obesity agent.
  • Sodium-glucose cotransporter two inhibitors: The SGLT2 inhibitors increase the excretion of urinary glucose, thereby reducing plasma glucose levels and exogenous insulin requirements. Use of SGLT2 inhibitors has also been associated with weight loss, which may reduce insulin resistance.
  • Thiazolidinediones: TZDs improve insulin sensitivity by increasing insulin-dependent glucose disposal in muscle and adipose tissue as well as decreasing hepatic glucose output. Though effective, associated secondary weight gain and fluid retention, with associated cardiovascular concerns, limit their use.
  • Dipeptidyl peptidase-4 inhibitors: The DPP-4 inhibitors prolong the activity of endogenous GLP-1 and gastric inhibitory polypeptide(GIP) by preventing their breakdown.

For individuals on insulin therapy:

  • The use of concentrated insulin preparations when large doses (greater than 200 units per day) of insulin are required to improve tolerance and absorption. At this time U-500 and U-200 Lispro and U-300 Glargine 

Surgery

Surgical intervention in the form of gastric sleeves, 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.

Differential Diagnosis

  • Obesity: Excess body weight is categorized as overweight (BMI of 25 to 29.9), class I obesity (BMI of 30 to 34.9), class II obesity (BMI 35.0 to 39.9), and class III obesity (BMI greater than 40)
  • Hypertension: The most recent ACC/AHA guidelines for the diagnosis of hypertension include systolic BP greater than or equal to 130 mmHg or diastolic BP greater than or equal to 80 mmHg
  • Hypertriglyceridemia: Elevated triglyceride levels (greater than or equal to 150 mg/dL)
  • Type 1 diabetes
  • Type 2 diabetes
  • Glucose intolerance including impaired fasting glucose, impaired glucose tolerance, gestational diabetes, type 1 diabetes, and type 2 diabetes
  • Lipodystrophy (acquired, localized or generalized): Loss of adipose tissue that results from either genetic or acquired causation and can result in the ectopic deposition of fat in either hepatic or muscular tissue
  • Polycystic Ovary Syndrome (PCOS)

Prognosis

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 the 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 linked 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 the 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.

Complications

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.

Consultations

The consultations most indicated for the treatment of insulin resistance include:

  • Obesity medicine specialist: Medical management for weight loss and weight management
  • Bariatric surgeon: Bariatric surgery is effective for weight loss in individuals who satisfy criteria for surgery
  • Endocrinology: Early and aggressive management of both type I and type II diabetes, hyperlipidemia, and PCOS demonstrate merit.
  • Cardiology and cardiac surgery: Management of the vascular complications of insulin resistance.
  • Neurology: Management of the cerebrovascular and peripheral neurologic complications of insulin resistance
  • Vascular surgery: Surgical management of both carotid artery disease and PAD

Deterrence and Patient Education

Primary, secondary, and tertiary prevention all have distinct roles in the management of insulin resistance.

  • Primary prevention promotes public education regarding the importance of regular health monitoring. A healthy diet and increased activity level can prevent or ameliorate the onset of insulin resistance, metabolic syndrome, and diabetes along with the associated complications. The emphasis on behavior modification and a sustainable lifestyle are key items for long-term weight management
  • Secondary prevention in the form of lab screening for insulin resistance, diabetes, and further subspecialist referral to best manage the early intervention for insulin resistance.
  • Public acceptance of tertiary prevention (intensive medical intervention and bariatric surgery for weight reduction) can lead to decreased morbidity and mortality associated with the consequent complications of insulin resistance.

Pearls and Other Issues

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.