Insulin resistance syndrome (IRS) is a cluster of abnormalities that is also known as the metabolic syndrome or Syndrome X. IRS refers to the occurrence, in the same person, of obesity, high blood pressure, and abnormalities in glucose and lipid metabolism. All 3 of these features are connected by insulin resistance-that is, reduced sensitivity of the tissues to the action of insulin. Insulin resistance is the core metabolic substrate of Type 2 diabetes.
How is insulin resistance diagnosed?
The clinical likelihood of insulin resistance closely follows the diagnostic criteria for the metabolic syndrome.
a. The first step in diagnosing insulin resistance is to examine the patient for obvious risk factors, such as abdominal obesity, which is measured as waist circumference: > 40 inches in a male, > 35 inches in a female.
b. The next step in the diagnosis insulin resistance syndrome is a careful taking of the patient's medical history-including, in women, a history of gestational diabetes. The likelihood of developing Type 2 diabetes is increased by medical events where the patient has demonstrated insufficient beta cell insulin secretion in the setting of insulin resistance (ie, pregnancy).
c. A family history of diabetes should be noted, as should the patient's ethnic background. It is true that persons are at increased risk of having insulin resistance syndrome if they have a close relative with insulin resistance, perhaps in the setting of obesity or actual family history of diabetes Certain ethnic groups are at greater than normal risk for Type 2 diabetes and insulin resistance: African Americans, Native Americans, Hispanics, and Pacific Islanders.
d. Other commonly measured clinical variables make it more likely that a patient has insulin resistance, including the patient's blood pressure and lipid profile. Common manifestations of insulin resistance include: blood pressure ≥ 130/85 mm Hg, a low level of high-density-lipoprotein (HDL) cholesterol (<40 mg/dL in men and < 50 mg/dL in women); and triglycerides ≥150 mg/dL.
e. Abnormal blood glucose levels also frequently indicate the likelihood of underlying insulin resistance-eg, fasting plasma glucose ≥ 110 mg/dL or impaired glucose tolerance (2 hours postÐoral glucose challenge levels between 140 and 200 mg/dL-or even overt diabetes, with fasting plasma glucose (FPG) ≥ 126 or random glucoses of ≥ 200 mg/dL. Note that the glucose level per se does not indicate the severity of the underlying insulin resistance, as it depends on the level of secretion of insulin from the pancreatic beta cells.
f. A diagnosis of insulin resistance is not based on a measurement of insulin levels; this is because plasma insulin determinations done in commercial laboratories tend to be poorly standardized. Nor is the diagnosis made by measuring levels of C-peptide (a by-product of insulin secretion). Although C-peptide may be elevated in insulin-resistant subjects, these levels are quite variable and do not offer a specific diagnostic advantage in the recognition of insulin resistance. A diagnosis of insulin resistance is typically made on purely clinical grounds, as noted above.
How is clinical Type 2 diabetes diagnosed?
The fasting plasma glucose (FPG) test is the preferred test for diabetes, according to the American diabetes Association. With the fasting plasma glucose test, the person's blood glucose is measured after an 8- to 12-hour fast. The test results are interpreted as follows: Normal blood glucose is indicated by a blood glucose level below 110 mg/dL. Impaired fasting glucose is indicated by a blood glucose level between 110 and 125 mg/dL. Diabetes is indicated if the fasting blood glucose level rises to 126 mg/dL or above; this diagnosis is confirmed by a level of ≥ 126 mg/dL on 2 FPG tests given on 2 different days.
A measurement known as impaired glucose tolerance (IGT) is also now used to diagnose Type 2 diabetes. IGT is diagnosed using the oral glucose tolerance test (OGTT), which measures blood glucose levels after a fast and after a glucose challenge. After an 8- to 12-hour fast, the person drinks a glucose-containing solution. The person's blood glucose is measured just before and 2 hours after drinking the solution. If glucose tolerance is normal, the 2-hour blood glucose will rise no higher than 140 mg/dL. If glucose tolerance is impaired, the 2-hour blood glucose will be between 140 and 199 mg/dl. If the person has diabetes, the 2-hour blood glucose will rise to 200mg/dL or above.
How does insulin resistance differ from clinical Type 2 diabetes?
Type 2 diabetes-according to diagnostic and classification criteria issued by the American Diabetes Association (ADA) in 1997-"results from a progressive insulin secretory defect on the background of insulin resistance." Hyperglycemia that is not sufficient to meet the diagnostic criteria for diabetes is categorized by the ADA as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Both of these categories are risk factors for the future development of diabetes.
Does insulin resistance adversely affect the cardiovascular system?
Insulin resistance causes a constellation of abnormalities that affect both glucose metabolism and the tendency to develop Type 2 diabetes, as well as abnormalities in endothelial function and other factors that contribute to the development of cardiovascular disease. In fact, CVD is the leading cause of death in persons with diabetes, most of whom have insulin resistance.
Insulin resistance is driven to a large extent by visceral obesity, which affects insulin action in its metabolic tissues as well as vascular endothelial function. Changes in several circulating factors secreted from adipose tissue contribute to vascular dysfunction, including increases in free fatty acids (FFA); increases in cytokines, such as tumor necrosis factor (TNF)-_, interleukin (IL)-6, and plasminogen activator inhibitor-1 (PAI-I); and decreases in other proteins, such as adiponectin. These changes render the endothelial cells less capable of secreting nitric oxide (NO); this result in vascular "stiffness," contributing to hypertension. Other atherogenic changes also result from the endothelial dysfunction, including the elaboration of cell adhesion molecules, which leads to leukocyte migration into the vessel wall and the initiation of atherosclerotic plaque.
Vascular changes are also elicited by the dyslipidemia that is characteristic of the insulin-resistant state-especially the formation of small, dense low-density lipoprotein (LDL) particles that are more susceptible to oxidation and more likely to penetrate the vessel wall and contribute to inflammatory responses and plaque formation.
Hypertension is also characteristic of the insulin-resistant state, as a result of endothelial dysfunction and responses in the body to the high circulating insulin levels; these responses are thought to include activation of the sympathetic nervous system and retention of salt and water from the kidney.
The aforementioned are some of the most commonly cited factors that increase CV risk in the insulin-resistant state.
What is atherogenesis and how is it influenced by insulin resistance?
Atherogenesis is the formation of atheroma-lipid deposits in the intima of the arteries. Atheroma produce a swelling on the endothelial surface, which is a characteristic of atherosclerosis. In the prediabetic patient, the macrovascular system tends to be in a highly atherogenic state. The results of several recent studies of diabetes and CV disease implicate increased insulin resistance as the culprit in the enhanced risk of the prediabetic state.
Is there a correlation between hypertension and insulin resistance?
Hypertension is a common manifestation of insulin resistance. In fact, it is estimated that 20% to 60% of persons who have diabetes also have hypertension (defined as blood pressure ≥ 140/90 mm Hg). Hypertension is also a major factor for the microvascular complications linked to diabetes, including diabetic retinopathy and nephropathy.
How does insulin resistance affect the development of dyslipidemia?
Persons with insulin resistance often have decreased levels of HDL (a significant risk factor for CV disease). Such persons also tend to have increased levels of very-low-density lipoprotein (VLDL) cholesterol and triglycerides, and, sometimes, an increased level of low-density-lipoprotein (LDL) cholesterol.
How do diet and exercise improve insulin resistance?
Lifestyle changes-including a healthy diet and regular exercise-contribute to weight loss, improve blood glucose control, and reduce hypertension and other cardiovascular risk factors. Regular exercise may even prevent the development of Type 2 diabetes in persons at high risk for the disease.
What therapeutic options are available for the treatment of insulin resistance?
Insulin resistance can be improved by lifestyle modifications, including a healthy diet and regular exercise. When these measures are not sufficient, pharmacotherapy with an oral hypoglycemic agent (OHA) should be added. Among the OHAs, only the thiazolidinediones (TZDs) have an FDA-approved indication specifically for the treatment of insulin resistance.
What are the thiazolidinediones (TZDs) and how do they differ from other pharmacotherapies?
The thiazolidinediones (known commercially as the glitazones) are the newest class of OHAs. The TZDs are insulin sensitizers; they reduce insulin resistance and increase glucose uptake into peripheral tissues, which results in decreased insulin levels.
The TZDs are different from all other OHAs, most of which increase insulin by directly affecting the beta cells of the pancreas. The sulfonylureas work by stimulating the beta cells of the pancreas to make more insulin. Metformin, the only biguanide, inhibits glucose production in the liver and sensitizes organs to the presence of an endogenous, direct effect on the beta cells of the pancreas to increase insulin production. The prandial glucose regulators, repaglinide and nateglinide, work by stimulating insulin release from the beta cells.
What are the benefits of the TZDs' mechanism of action on insulin resistance compared with other therapies?
The TZDs are true insulin sensitizers-ie, their ability to enhance the action of insulin in the body is central to their clinical action. None of the other modalities used to treat diabetes are as effective at reducing insulin resistance as the TZDs. Metformin is sometimes considered to act as a "sensitizer," but it has not shown that ability in all studies. Metformin reduces the production of glucose by the liver and effectively reduces insulin levels secondary to the reduction in plasma glucose; thus, it is more correctly referred to as an insulin-"sparing" drug. The clinical effects of metformin on some of the risk variables associated with the insulin-resistant state are in the same direction as that caused by the TZDs; however, they are generally less robust, including anti-inflammatory effects, reduction in free fatty acid (FFA) levels, and reduction in high-sensitivity C-reactive protein (hs-CRP). The other oral medications for Type 2 diabetes-and even insulin insulin itself--have no effect on insulin sensitivity, nor on any of these underlying CVD risk factors.
Therapy with TZDs also has been shown in preclinical and clinical studies to enhance the insulin secretory capacity of the pancreatic beta cells. The mechanism of this effect appears to be coupled with improvement in lipotoxicity, by reducing circulating FFA levels and removing tissue triglyceride and FFA derivatives, as well as an improvement in glucotoxicity, by reducing circulating glucose levels. Since a decline in beta cell insulin secretion is a fundamental defect in the progression of Type 2 diabetes, this is one of the major beneficial effects of the TZDs in their ability to maintain durable glycemic control. None of the other oral therapies for the treatment of Type 2 diabetes (metformin, SU) or insulin itself has demonstrated the durable control of glycemia, and have no known effect on beta cell preservation or functional rejuvenation.
What are the clinical considerations in patient selection and treatment initiation with the TZDs?
Before therapy with a TZD is initiatied, liver function tests (LFTs) should be performed. LFTs should be performed every 2 months during the first year of TZD therapy and periodically thereafter. Therapy with a TZD should be discontinued if ALT levels increase to 3 times the upper limit of normal and stay at that level.
All of the TZDs can cause fluid retention, which can exacerbate or lead to congestive heart failure. The TZDs should be used with caution in patients who are at risk for heart failure, and patients should be monitored for signs or symptoms of heart failure.
That was a great article, thank you for posting it! I really like (F) because it explained that really well where as I never understood why in the past.
Insulin Resistance Syndrome 
