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Great Diabetes Article from Quest Diagnostics

Insulin Resistance and the Evolution of Type 2 Diabetes


Type 2 diabetes mellitus (DM) generally evolves from a state of insulin resistance—cells become less sensitive to the effects of insulin and consequently cannot regulate blood glucose levels appropriately.1-3 Worsening insulin resistance eventually leads to prediabetes, and then to type 2 DM.1-3


This article reviews how insulin resistance contributes to the evolution of type 2 DM, a global health issue. Risk factors and laboratory testing that help identify individuals with insulin resistance are discussed, as well as lifestyle changes that can treat or prevent the development of DM and reduce the risk of other serious conditions associated with insulin resistance. Also reviewed are DM screening recommendations, diagnosis, management, complications, and comorbidities.

Type 2 DM: A Global Health Issue

The World Health Organization estimates that, worldwide, approximately 422 million people have diabetes.4 The Centers for Disease Control and Prevention estimates that 34 million people in the United States have diabetes, and 1 in 5 do not know they have it.5 Notably, more than 88 million adults in the United States have prediabetes, and 84% do not know they have it.5 Diabetes is the seventh leading cause of death in the United States; in the past 2 decades, the number of adults with diabetes has more than doubled owing to the aging population and the increase in the number of people who are overweight or obese.5

Insulin Resistance: A Metabolic Condition

Insulin resistance, rather than elevated fasting glucose or glycated hemoglobin (HbA1c), is the earliest laboratory indicator of progression to type 2 DM.1,2,6 Insulin regulates fasting blood glucose levels by regulating the formation and release of glucose by the liver and by stimulating glucose uptake by cells. In patients with insulin resistance, tissues do not respond fully to the effects of insulin. To compensate, pancreatic beta cells produce greater amounts of insulin to maintain a normal fasting blood glucose level. Eventually, insulin resistance may become so severe that the beta cells can no longer produce enough insulin to compensate.1,2,6 When this happens, fasting blood glucose rises from normal levels to levels defining prediabetes and ultimately type 2 DM.7 This progression from insulin resistance to onset of type 2 DM is believed to take 10 to 15 years.3 The combination of insulin resistance and compensatory hyperinsulinemia can result in the “metabolic syndrome,” which is defined by a cluster of abnormalities including obesity, hypertension, dyslipidemia, type 2 DM, and cardiovascular diseases (CVD) such as atherosclerotic heart disease.1


Identifying Insulin Resistance

Insulin resistance has no typical signs or symptoms, and at an early stage blood glucose and HbA1c may be normal (fasting glucose ≤99 mg/dL; HbA1c <5.7%).7 As such, it is difficult to diagnose. However, certain signs should raise the suspicion of insulin resistance3,8:

· Obesity, hypertension, or hyperlipidemia

· Increased waist circumference (for gender/race)

· Metabolic syndrome

· Prediabetes

· Microvascular disease (retinopathy, neuropathy, nephropathy)

· Macrovascular disease (stroke, coronary or peripheral artery disease)

· Polycystic ovary syndrome (PCOS)

· Characteristics of PCOS (menstrual irregularities, hirsutism, acne, and alopecia)

· Xanthelasma or xanthomas

· Acanthosis nigricans

· Findings consistent with type A or type B insulin resistance syndrome

Laboratory Testing

Methods to directly measure insulin resistance include the hyperinsulinemic-euglycemic glucose clamp technique and the insulin suppression test.9 These methods, however, have limited use in a routine clinical setting due to the technical requirements and time required to perform the tests. Other methods, using surrogate markers for insulin resistance have drawbacks such as not identifying insulin resistance at an early stage, and being cumbersome to perform.9 Consequently, measurement of insulin resistance using these methods is not currently recommended in guidelines for DM7,10 or PCOS.11


However, recent studies using surrogate markers of insulin resistance have shown promise for assessing the risk of developing diabetes. For example, the combination of HbA1c and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score, a surrogate marker that uses fasting insulin and glucose levels, improved risk assessment for type 2 DM as compared to HbA1c alone.12


A simpler surrogate marker based on simultaneous serum meas