Q and A

July 2006

Richard A. Savage

Q: Several articles have stated that the triglyceride/HDL ratio can be used as a surrogate marker for fasting insulin levels and is clinically useful for monitoring the treatment of diabetics and assessing a patient’s cardiac risk. Can this information be validated?

A. The ratio of triglyceride to high-density lipoprotein cholesterol (Tg/ HDL-C ratio) is often related to a patient’s level of insulin resistance. Insulin-resistant patients commonly display elevated triglyceride levels and depressed HDL-C levels, increasing the Tg/ HDL-C ratio. The classic lipid findings in insulin-resistance syndrome—for example, the metabolic syndrome or dysmetabolic syndrome X (ICD-9:277.7)—include hypertriglyceridemia, low HDL-C, and an increased concentration of dense low-density lipoprotein particles that are depleted of cholesterol. Researchers have established that states of insulin resistance are associated with an increased risk for developing type 2 diabetes and cardiovascular disease.^1–4

The tissues most responsive to insulin are skeletal muscle, adipose tissue, and the liver. In nondiabetic, yet insulin-resistant, patients, insulin levels can be elevated as pancreatic beta cells attempt to compensate for decreased insulin action. Therefore, there is a positive correlation between the Tg/ HDL-C ratio and the fasting insulin concentration in nondiabetic individuals. However, because this correlation is modest at best and varies considerably throughout the general population, the calculation of Tg/ HDL-C ratio cannot be substituted for a measurement of the fasting insulin concentration should the physician want an assessment of insulin resistance.

The gold standard assessments of insulin resistance are dynamic tests carried out in research settings using the glucose or insulin clamp techniques or the frequently sampled intravenous glucose tolerance test.⁵ Whereas the fasting insulin concentration in nondiabetic individuals is positively correlated with the subject’s degree of insulin resistance, fasting insulin by itself is not the best static measurement of insulin resistance. Even dividing the insulin concentration into 40 improves the correlation of fasting insulin with insulin sensitivity.⁶

The more sophisticated, although controversial,⁷ static assessments of insulin resistance available to physicians include the homeostasis model assessment (Fig. 1),⁸ quantitative insulin sensitivity check index (Fig. 2),⁹ fasting glucose-to-insulin ratio (Fig. 3),¹⁰ and insulin sensitivity index, or ISI, corrected for fat-free mass divided by average insulin Mffm/I = exp[2.63 – 0.28 ln insulin – 0.31 ln (Tg)]; M = glucose disposal rate, ffm = fat-free mass; I= insulin.¹¹ Oral glucose tolerance tests have also been used to estimate insulin sensitivity.¹² For example, when insulin is expressed in microunits per milliliter and glucose is measured as milligrams per deciliter, a [glucose_fasting] / [insulin_fasting] ratio of less than 4.5 is considered abnormal.

Measurements of insulin resistance are not presently used to monitor the success of diabetes treatment. Glycemic monitoring is the providence of hemoglobin A1c measurements and self-monitoring of blood glucose.¹³ Lipid profile assessments are also a routine part of diabetes monitoring. However, the American Diabetes Association has no recommendations to calculate the Tg/HDL-C ratio or use such a ratio in assessing diabetic control. The lipid assessment of diabetic control is based on the absolute concentrations of LDL-C, triglycerides, and HDL-C. Similarly, in assessing any patient’s risk for cardiovascular disease, the National Cholesterol Education Program Adult Treatment Panel III, or NCEP ATP III, has no recommendations to calculate the Tg/HDL-C ratio or the total cholesterol-to-HDL-C ratio. This is because risk assessment and therapy are based on the absolute levels of LDL-C and because HDL-C, triglycerides, and the patient’s 10-year risk for cardiovascular disease are not based on ratios.^14-15

In short, the Tg/HDL-C ratio cannot be recommended as a routine tool for assessing diabetic control or risk for cardiovascular disease based on current recommendations from the ADA or NCEP ATP III.

References:

1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–1607.
2. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996;334(15):952–957.
3. Stolk RP, Pols HA, Lamberts SW, et al. Diabetes mellitus, impaired glucose tolerance, and hyperinsulinemia in an elderly population. The Rotterdam Study. Am J Epidemiol. 1997;145(1): 24–32.
4. Chien KL, Lee YT, Sung FC, et al. Hyperinsulinemia and related atherosclerotic risk factors in the population at cardiovascular risk: a community-based study. Clin Chem. 1999;45(6 Pt 1): 838–846.
5. Scheen AJ, Paquot N, Castillo MJ, et al. How to measure insulin action in vivo. Diabetes Metab Rev. 1994;10(2):151–188.
6. Raynaud E, Perez-Martin A, Brun JF, et al. Revised concept for the estimation of insulin sensitivity from a single sample. Diabetes Care. 1999;22(6): 1003–1004.
7. Yeni-Komshian H, Carantoni M, Abbasi F, et al. Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers. Diabetes Care. 2000;23(2):171–175.
8. Radziuk J. Insulin sensitivity and its measurement: structural commonalities among the methods. J Clin Endocrinol Metab. 2000;85(12):4426–4433.
9. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85(7): 2402–2410.
10. Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83(8):2694–2698.
11. McAuley KA, Williams SM, Mann JI, et al. Diagnosing insulin resistance in the general population. Diabetes Care. 2001;24(3):460–464.
12. Stumvoll M, Mitrakou A, Pimenta W, et al. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care. 2000;23(3): 295–301.
13. American Diabetes Association. Standards of Medical Care in Diabetes—2006. Diabetes Care. 2006;29:S4–42.
14. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497.
15. Grundy SM, Cleeman JI, Merz CN, et al. National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227–239.

William E. Winter, MD Department of Pathology
University of Florida
Gainesville
Member, CAP Special Chemistry Committee