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Insulin resistance (IR) is thought to underlie the development of a number of clinically important disorders, including type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), hypertension, polycystic ovary syndrome (PCOS), and non-alcoholic fatty liver disease (NAFLD). The identification of individuals with IR is, however, problematic and appropriate, cost- effective management remains controversial. Various aspects of this important subject are addressed in the current issue of JEMDSA. Crowther cautions against the inappropriate use of fasting serum insulin levels in clinical practice. Maritz reviews the complex patho- genesis of insulin resistance-mediated macrovascular disease, emphasising the importance of early detection, while Till and Buys provide insights into the lifestyle and dietary management of the syndrome.
How do we identify individuals with insulin resistance?
A number of metabolic markers have been employed over the past 15 years, with varying success. The terms ‘syndrome X’ or the ‘metabolic syndrome’ were originally coined to describe the apparent clustering of individuals with an increased waist circumference, blood pressure, fasting glucose, serum triglycerides (TG) and decreased levels of HDL cholesterol.1 Accumulating evidence indicates that IR is the common pathogenic factor for the individual components of the metabolic syndrome and explains the trait cluster.1-4 In 2001 the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Education and Treatment of High Blood Cholesterol in Adults (ATPIII) established criteria for diagnosing the syndrome.5 Individuals with 3 or more of the following 5 abnormalities were considered to have the insulin resistance syndrome (IRS): abdominal obesity (waist circumference > 102 cm in men and > 88 cm in women), elevated blood pressure (systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥ 85 mmHg), hypertriglyceridaemia (≥1.7 mmol/l), low high-density lipoprotein (HDL) cholesterol (< 1.04 mmol/l in men and < 1.29 mmol/l in women) and high fasting blood glucose (≥6.1 mmol/l).
Recent reports have, however, questioned the sensitivity and specificity of the ATPIII criteria to identify non-diabetic individuals with IR. Employing the euglycaemic-hyperinsulinaemic clamp technique to confirm IR, sensitivity of the ATPIII criteria ranged from 20% to 50%.6-8 This detracts from the value of the ATPIII criteria as a screening paradigm where high sensitivity is essential. A major objection to the ATPIII
criteria involves the use of the fasting blood glucose.
Instead, the 2-hour post-challenge glucose is recommended by the American College of Endocri- nology7to increase sensitivity for identification of IR.
This College also recommended the addition of body mass index (BMI) as a measure of obesity (yet ignoring the waist-hip ratio which correlates better with visceral obesity), the classification of obesity as a risk factor rather than a diagnostic criterion, and expanding the list of associated disorders and individuals considered at risk (e.g. including those with a family history of diabetes or a history of gestational diabetes, acanthosis nigricans, PCOS, NAFLD). Others6regard the con- ventional lipid profile employed by the ATPIII (TG, HDL) as too insensitive and emphasise the use of qualitative lipid changes. Clearly important in South Africa, with its heterogeneous populations, is the need to adjust the ATP criteria for race or ethnicity. African Americans have, for example, been shown to be more insulin resistant than Caucasians yet exhibit paradoxically lower TG and higher HDL cholesterol levels,9whereas use of the ATPIII obesity criteria for Asians significantly underestimates the population at risk.10
Whereas the ATPIII criteria are thought to lack sensitivity, specificity is generally regarded as high.6-8 While the IRAS data11regard an increased waist circumference, locally referred to as the ‘braaivleis physique’ by Maritz (this issue of JEMDSA), as the optimal predictor of the incident metabolic syndrome in adults, we do need to take cognisance of the fact that not all overweight (BMI > 25 kg/m2) or obese (BMI > 30 kg/m2) persons are insulin resistant.8,12In fact, IR is thought to be present in only about half of all overweight individuals. Furthermore, it is this subgroup of insulin-resistant overweight individuals who are largely at risk of CAD and would benefit from weight loss.8,12 Given the pandemic of obesity in westernised as well as many developing countries, including our own,13it would seem prudent to preferentially target these individuals, at highest risk, for therapeutic intervention. Reaven and co-workers8 recently examined 258 non-diabetic, normotensive overweight volunteers to assess which metabolic markers could identify IR. They concluded that the plasma TG concentration, TG/HDL cholesterol ratio, and fasting plasma insulin were the most useful, with sensitivity and specificity values of 60 - 65% and 70 - 85%, respectively.
A number of epidemiological studies have documented
The insulin resistance syndrome — diagnosis and management
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a strong association between hyperinsulinaemia and an increased risk of T2DM and CAD. In a case-controlled study involving more then 27 000 participants from the Women’s Health Initiative (WHI), Pradham and colleagues14have shown that fasting levels of plasma insulin (and proinsulin) were associated with a 5.6 - 16.4-fold increase in the risk of T2DM. In the Kuopio Ischaemic Heart Disease Risk Factor Study15hyper- insulinaemia was associated with a 3-fold increased risk of cardiovascular disease mortality. A nested, case-control study within the Quebec Cardiovascular Study cohort documented significantly (p < 0.001) higher fasting plasma insulin levels in those who developed a first ischaemic event — an association that persisted after adjustment for BMI and plasma lipid levels.16
Should fasting plasma insulin not therefore be added to the diagnostic criteria for the IRS, as originally recom- mended by George Alberti and Paul Zimmet in com- piling the WHO criteria for the syndrome?17The primary means for measuring insulin sensitivity is the eugly- caemic-hyperinsulinaemic clamp technique.18 This test is, however, not suitable for routine clinical practice.
The homeostasis model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI) employ simple fasting plasma glucose and insulin levels to assess IR, and have been shown to correlate well with data obtained from the clamp technique.19,20 However, whereas plasma insulin levels have been employed in epidemiological studies to confirm an association between hyperinsulinaemia and an increased risk of T2DM and CAD,8,12-16interpretation of insulin levels in individualsubjects is fraught with problems. Commercially available insulin assays vary and are not standardised. Resistance to insulin- mediated glucose disposal is distributed continuously throughout the general population, and whereas it is readily feasible to separate study populations into upper/lower tertiles or quartiles, no absolute cut-off values exist to classify an individual as being insulin resistant or insulin sensitive. Furthermore, the HOMA and QUICKI techniques employ basal, fasting glucose and insulin levels whereas the IR in, for example, obesity is primarily due to an impairment of stimulated insulin concentrations to increase peripheral glucose uptake.21 Day-to-day and diurnal variations in plasma insulin levels further compound interpretation. Finally, plasma insulin concentrations are of course dependent on the ability of the pancreas to secrete insulin and on ambient glycaemia and insulin clearance — fasting insulin is, therefore, less useful as a marker of IR in patients with impaired glucose tolerance or disorders of insulin clearance (e.g. cirrhosis).
Should fasting insulin levels be routinelyemployed to help identify individuals with the IRS? Most autho- rities would agree that, whereas the selective use of insulin levels by knowledgeable clinicians is accep- table, routine measurement is not recommended —
certainly not as a shopping mall diagnostic modality, akin to the measurement of plasma glucose or cholesterol. We do, however, need to understand that this recommendation is not based on the fact that such a measurement is clinically irrelevant, or because existing metabolic markers are sufficiently sensitive and specific to identify those at risk. Logistical considerations, in particular the lack of a standardised insulin assay and the absence of absolute cut-off values to identify individuals with IR, are the major obstacles which hamper the clinical utility of a potentially invaluable diagnostic test. This is not an
insurmountable problem, since most tests that assess quantitative risk factors (blood pressure, glucose, cholesterol, bone mass, etc.) suffer a similar fate.
Objections to the utilisation of basal, fasting insulin levels may ultimately have to be circumvented by employing insulin sensitivity indices derived from stimulated (e.g. OGTT) parameters.21 To quote the man who described the insulin resistance syndrome for the first time, Gerry Reaven: ‘... it seems evident that a standardized insulin assay would be significantly clinically useful, and there is no intellectual reason why this cannot be accomplished in the future’.8 In the meantime, surrogate markers of IR, both conventional and novel (e.g. the triglyceride/HDL ratio), should be employed and validated in local populations.
Any discussion of treatment considerations for patients with IRS must begin by differentiating those efforts aimed at improving insulin sensitivity per seand those addressing management of the individual components of the syndrome. Evidence-based guidelines exist for the pharmacological treatment of the latter and these are eloquently summarised by Maritz in this issue of the Journal. There is general consensus that indivi- dualised lifestyle modification (diet and physical exer- cise) is appropriate and effective to improve insulin sensitivity. The Diabetes Prevention Program22as well as the Diabetes Prevention Study23showed an impres- sive 58% risk reduction for developing T2DM with life- style changes alone. Till and Buys provide a practical approach to the lifestyle and dietary management of IRS in this issue of JEMDSA, but caution that such intervention is extremely difficult and requires inten- sive behavioural modification, cognitive restructuring, stress management and social support.
Other than the development of a better diagnostic test for insulin resistance, the American College of Endo- crinology Task Force on the IRS7regards research into pharmacological therapies to improve insulin sensitivity as the top priority for the future. The Diabetes Preven- tion Program22showed a 31% reduction for developing T2DM in non-diabetic patients with IRS treated with metformin, and the thiazolidenediones, antigiotensin- converting enzyme inhibitors, statins and others hold much promise.
Since Reaven1first introduced this syndrome in 1988,
new clinical and metabolic features have been added and insights into its pathophysiology and management have improved. This evolution invites an ongoing re- examination of diagnostic criteria and therapeutic modalities — none more so than in our own country, with its heterogeneous populations, good infrastructure and more than adequate stock of ‘braaivleis physiques’.
Stephen Hough
Endocrine Unit
Department of Medicine University of Stellenbosch
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