Syndrome X and the Baker’s Dozen
of Health Conditions

NOTE: Baker’s dozen refers to the custom of including an extra donut or cookie when a customer orders a dozen.

Introduction

In 1988, Dr. Gerald Reaven (Stanford University School of Medicine) announced the existence of a new health disorder he named “Syndrome X”, which, if left unidentified and untreated, results in significant increased risk for developing type 2 diabetes and cardiovascular disease. Since that time, he and other researchers around the world have enlarged the body of research on this disorder and have found evidence of a strong link between Syndrome X and insulin resistance on the one hand and numerous adverse health conditions on the other. As the body of research has grown, we have seen how much broader the role insulin plays in our lives than we had imagined.

Syndrome X is not a single-cause health problem. It’s not even a disease. Rather, it’s a cluster of metabolic abnormalities that over time can lead to one or more of the Baker’s Dozen (13) illnesses. It has no visible symptoms to warn you. You may not know the clock is ticking toward an illness or a heart attack until you land in the emergency room, or according to experts, you are fortunate enough to discover it in your doctor’s office during a routine visit with laboratory tests. This is why Syndrome X is known as the silent killer

In the early days of insulin research, medical investigators thought that the health risks associated with insulin occurred only when individuals didn’t have enough insulin, setting the stage for type 2 diabetes to develop. We now know that having too much insulin is just as dangerous as having too little.

In man’s ancient past, insulin functioned as a primary growth factor indispensable for the emergence of life. It told cells when to multiply and when to stop. In our modern, evolved form, insulin no longer needs to tell cells when to multiply and no longer does so, except possibly in the case of certain cancer cells.

Insulin’s primary role now is transporting glucose into cells to supply energy needs. Without glucose transport we would descend into a coma and life would end within a few days.

What Comprises Syndrome X?

When someone is insulin resistant and at risk to develop Syndrome X it means that the individual’s insulin is not efficient at shuttling glucose into insulin sensitive tissues (muscle, fat, and liver cells), leaving the cells with a lack of energy to supply ongoing physiological needs.

What can happen next to an insulin resistant individual is one of two things, and neither one is good. He or she can develop type 2 diabetes, or the individual can develop Syndrome X along with any of the adverse health conditions linked to Syndrome X.

Approximately 50 percent of the likelihood of developing type 2 diabetes or Syndrome X depends upon lifestyle. The other 50 percent depends largely on genetic differences leading to personal variations in the degree of insulin resistance and the number of insulin-secreting beta cells in the pancreas, which is an elongated organ that extends across the abdomen. If the degree of insulin resistance is high enough and the pancreas cannot secrete enough insulin to make up for the inefficiency, type 2 diabetes develops.

Who then, develops Syndrome X rather than type 2 diabetes? Some individuals have the capacity to secrete a level of insulin from the pancreas that is high enough to compensate for the inefficiency—up to two to three times a normal amount of insulin. In these people the pancreas secretes insulin until the concentration in the blood stream is high enough to force glucose into the cells. This adaptation is good in the sense that it keeps people alive, supplied with plenty of energy to go about daily life. On the other hand, this compensatory response also leaves leftover high insulin levels circulating in the blood stream.

These elevated insulin levels lead to the manifestations or expressions of Syndrome X. It is then only a matter of time before an individual may develop one or more of the age-related health consequences listed below. Thus, whether you can secrete a compensatory amount of insulin to make up for insulin that is not efficient in glucose transport or whether the pancreas cannot secrete enough to compensate, insulin resistance leads to problems. The good news is that the problems are avoidable or controllable if you know what to do. You can often even reverse damage already done.

Statistics and Prevalence

Approximately 85 million Americans, or 30% of the population-- one out of every 3 to 4 people you meet, are insulin resistant. Syndrome X is so common that such organizations as the American Diabetes Association have declared it a modern health disorder of epidemic proportion in economically developed countries. Moreover, according to the National Cholesterol Education Panel (NCEP), which has created criteria for diagnosing the “Metabolic Syndrome”, as it is sometimes called, Syndrome X poses a worldwide public health problem that affects all age groups, but primarily older adults.

Increased Risk with Age

In the late nineteenth century, a German pathologist named Paul Langerhans realized that there were concentrations of four different kinds of cells in the pancreas. We call those cells the islets of Langerhans.

Almost 90 percent of the cells in the islets of Langerhans are beta cells, which secrete the hormone insulin. Insulin regulates cell activity throughout your body.

Each one of us is born with a finite number of beta cells, with the number of cells differing from person to person. Day-by-day you use up your beta cells, one after the other as you secrete insulin to shuttle glucose into your cells. As you age, you will have fewer and fewer beta cells. If you run out, you develop type 2 diabetes.

What if you’re fortunate enough to have a plentiful enough supply of beta cells to last you throughout your life? Over the years, the high insulin levels present day-in and day-out produce layers of damage that can eventually lead to the health conditions linked with Syndrome X. Anyone with the risk factors for Syndrome X should consider being tested for insulin resistance and Syndrome X by age 40.

Risk in Children

Even our children are now at risk. There was a time when we didn’t worry much about determining whether children were insulin resistant because children were more physically active and used more calories, or they ate fewer. Their energy expenditure kept their energy intake in healthy balance.

With the dramatic rise in childhood obesity, type 2 diabetes is developing in epidemic proportions in insulin resistant children. Even if these children don’t develop type 2 diabetes, they unknowingly begin to accumulate damage from insulin resistance and Syndrome X, which can decrease length and quality of life as an adult.

According to the American Academy of Pediatrics, the number of overweight and obese children has doubled in the past twenty years. More than 15% of 6 to 19 year olds are obese or overweight. In California, for example, more than 25% of children ages 9 to 17 are overweight by 10 to 20 pounds, and some by 100 pounds or more. Moreover, the Surgeon General has declared childhood obesity a national epidemic in 2002.

Obesity itself doesn’t cause insulin resistance in children or adults, but it makes it far worse, which in turn increases the risk of developing type 2 diabetes or Syndrome X. On August 4, 2003, the American Academy of Pediatrics announced its recommendation for all children to have their body mass index evaluated every year to prevent obesity. Most of the time a doctor can just look at a child and see whether there is a problem. Any objective parent can do it. Every day our children are getting barraged with advertisements pitching all the wrong foods. We have parents working, unable to be home to make meals and sit down with their children to eat. Kids eat way too many carbs and the wrong kind of carbohydrate—foods full of sugar or saturated fat such as chips, ice cream, cookies, sodas, donuts, and white bread, instead of fruits, vegetables and whole wheat.

Part of the solution for overweight and obese children is for parents and physicians to monitor their eating habits and limit their foods to healthy choices 90% of the time. The other part of the solution is to encourage and actively support increased physical activity in children, which means limiting television and video time to no more than two hours each day. Research studies also demonstrate that mothers who breastfeed may reduce the risk for their children to become overweight or obese.

The Syndrome X Cluster of Metabolic Abnormalities

There is a long list, or cluster, of metabolic abnormalities characteristic of Syndrome X. They comprise the following:

• Compensatory high insulin levels circulating in the blood stream
• Impaired glucose transport into cells
• Elevated triglyceride levels (blood fat)
• Slow clearance of accumulated triglyceride (fat-rich) lipoproteins in the blood stream after eating
• Decreased (good) HDL cholesterol
• LDL particle diameter that is small, dense, and atherosclerotic
• Endothelial dysfunction leading to atherosclerosis and heart disease. (Endothelium consists of flat cells that line the blood and lymphatic vessels and the heart.)
• Increased endothelial cell adhesion
• Elevated plasma concentration of cellular adhesion molecules
• Increased plasma concentration of asymmetric dimethylarginine
• Decreased endothelial-dependent vasodilatation
• Excess fibrinogen, increasing likelihood of blood clots
• Excess plasminogen activator inhibitor-1 (PAI-1) diminishing capacity to dissolve blood clots
• Increased markers of inflammation, such as C-reactive protein
• Elevated uric acid concentration and clearance
• Insulin-stimulated sympathetic nervous system activity that increases risk of developing hypertension.
• Stimulation of the secretion of catecholamines within the body, such as noradrenalin and adrenalin, which constrict blood vessels.
• Renal sodium (salt) retention
• Ovarian testosterone secretion in women (masculinizing)

Who is at Risk of Developing Syndrome X?

An individual is at risk to develop Syndrome X and related illnesses if any of the following apply:

• Prior or current diagnosis of coronary vascular disease, hypertension, or polycystic ovary syndrome
• Family history of type 2 diabetes, hypertension, or cardiovascular disease
• Personal history of gestational diabetes or glucose intolerance
• Sedentary lifestyle
• Overweight with a body mass index greater than 25 (BMI > 25)
• Age greater than 40 years

What is the Baker’s Dozen List of Adverse Health Conditions that can Result from Insulin Resistance and Syndrome X?

To date, researchers have identified 13 adverse health conditions linked with insulin resistance:

1. Type 2 diabetes mellitus

2. Syndrome X with compensatory insulin levels that can lead to the following:

3. Heart attack

4. Stroke

5. Hypertension

6. Fatal non-alcoholic fatty liver disease (NAFLD)

7. Liver cancer

8. Colorectal cancer

9. Breast cancer

10. Prostate cancer

11. Polycystic ovary syndrome

12. Impaired cognitive function

13. Sleep disordered breathing

The consequences of insulin resistance lead in two directions: type 2 diabetes and its complications, or, Syndrome X and its consequences. Note that both type 2 diabetes and Syndrome X lead to cardiovascular disease.

Detecting Syndrome X

The greater the number of metabolic abnormalities individuals have, and the greater the degree of those abnormalities, the more likely people are to develop Syndrome X or health related problems, particularly as they age.

In addition to the risk criteria listed above, you can also obtain an initial assessment of the likelihood of developing the consequences of insulin resistance by reviewing the test values from your last fasting lipid panel. If your values are abnormal, there is more reason to pursue the fasting diagnostic tests described later in this article. Getting a fasting blood sample is easy to do. It only requires that you have not eaten food or caloric beverages for 12 hours prior to drawing your blood. Drinking water is encouraged. The chart below gives you the normal values to compare with your tests results.

TWO INDICATORS OF RISK TO DEVELOP CONSEQUENCES OF INSULIN RESISTANCE
YOUR TEST RESULTS HDL Cholesterol                               Triglycerides	COMPARATIVE HEALTHY RANGES Greater than 40 (>40) for men Greater than 50 (>50) for women Les than 150 (<150)

• Complete Diagnostic Tests

It’s quite easy to find out whether you have Syndrome X. There are no complicated or uncomfortable tests, and you don’t have to go to a hospital. The tests are simple, commonplace, and inexpensive. Below are five predictors of Syndrome X. Your doctor can test for them. You can find the evaluation of the test results described in the book, Syndrome X, The Silent Killer, by Reaven and Strom. (3)

• Glucose Tolerance Test. This is where you eat no food or drink caloric beverages (you may drink water) for 12 hours before you go in for the test. Then go to your doctor for a blood draw before you eat the next morning. You will have your fasting glucose measured, then again one and two hours after drinking 75 grams of glucose. The glucose beverage tastes like a cola drink.

• Triglyceride Levels. This is a fasting blood test taken to check your levels of blood fat. Ask for this test as part of the fasting Glucose Tolerance Test.

• HDL Cholesterol. This is a fasting blood test. Ask for this test as part of the fasting Glucose Tolerance Test.

• Blood Pressure. Ask your doctor to check whether your blood pressure is above 135/85.

• Weight Check. Ask your doctor if you are overweight, and if so, by how many pounds.

Treatment Options

There are two powerful lifelong methods of treating insulin resistance and Syndrome X. They both focus on improving insulin sensitivity and reducing the manifestations and degree of insulin resistance. In contrast to potential pharmaceutical approaches, which, to date, only treat the manifestations of Syndrome X once they have erupted, clinical studies show beyond any doubt that weight loss and aerobic exercise are very effective preventive treatments. They are also effective at improving the manifestations of Syndrome X if and when they do show up.

Diet is important as a third approach. Although changes in diet are unable to improve insulin sensitivity, the Syndrome X Diet® significantly decreases the need for insulin secretion, which will translate to lower levels of insulin that can trigger the list of adverse health conditions.

Improving Insulin Sensitivity

• Weight Loss: Weight loss of, for example, 5-10% body weight in overweight insulin resistant individuals will significantly enhance insulin sensitivity and decrease plasma insulin levels. For many people, that may be a realistic goal of 10-15 pounds. Even if someone is more substantially overweight, losing 15 pounds will significantly improve insulin sensitivity. The benefits are directional in that the closer we get to an ideal weight, the more health benefits we will experience. Maintaining a healthy weight also helps retain gains in insulin sensitivity.

• Physical Activity: Revving up aerobic physical activity levels and maintaining a regular exercise schedule can provide powerful improvement in insulin efficiency. Moreover, the benefits become more profound as you increase the amount and stick to your schedule. The healthiest approach is to engage in aerobic activity, where you accelerate your heart rate for a minimum of 30-40 minutes each session at least 4 days per week. Because the health benefits of physical activity disappear within 2-4 days after stopping, regularity of activity is a key component of success. According to the American Diabetes Association, there is strong clinical evidence showing that 30 minutes of aerobic exercise every day combined with a weight loss of 10-15 pounds reduces the risk of developing type 2 diabetes by a whopping 58%.

Maintaining regular physical activity has three benefits. It helps individuals lose weight, it helps keep it off, and it enhances insulin sensitivity. Recently completed prospective studies show that the combination of weight loss and increased physical activity significantly decrease the likelihood of developing Syndrome X and adverse health conditions stemming from insulin resistance.

• Pharmaceutical Intervention: Right now there is no approved pharmacological treatment for Syndrome X. Yet, there is a class of drug called thiazolidenedione (TZD) compounds that can improve insulin sensitivity. Unfortunately, the Food and Drug Administration (FDA) currently has only approved TZDs for treating hyperglycemia (elevated glucose levels) in patients with type 2 diabetes. Researchers are now conducting intensive investigations of the clinical utility of TZDs in people who have developed Syndrome X but who have not progressed to type 2 diabetes.

There is another drug, metformin, which may also prove beneficial. Physicians worldwide use metformin for treating type 2 diabetes and polycystic ovary syndrome (PCOS). Metformin has proven to have an outstanding record for both safety and efficacy. There is clinical evidence that metformin can lower circulating insulin levels and improve glucose and lipid metabolism in patients who have developed characteristics of Syndrome X. As good as this news is weight loss and increased physical activity are likely to be more effective than metformin in increasing insulin sensitivity and reducing the risk of the complications that can stem from insulin resistance and the Baker’s Dozen.

• Dietary Intervention: The macronutrient content of what we eat has no bearing on whether we are insulin resistant because insulin resistance is most likely preceded by multiple genetic factors. However, diet can have a sizable impact on the consequences of insulin resistance.

Clinical studies have shown that the most important dietary guideline, besides not eating too much, is to avoid diets high in carbohydrate and low in (good) fat. Unless you are losing weight, a high carbohydrate diet that is also low in fat will increase blood insulin levels. This is true because carbohydrate (and protein) stimulate insulin secretion from the pancreas, whereas fat does not. The more insulin resistant someone is the more insulin the body must secrete in response to carbohydrate, especially refined sugars, in order to maintain normal glucose levels. Studies have shown that the Syndrome X Diet of 15% protein, 45% carbohydrate, and 40% fat (with less than 10% saturated fat) is an effective dietary approach. (3)

• Fiber: Adding soluble fiber to our diet, while limiting the intake of refined carbohydrates, is also effective at maintaining more reasonable insulin levels.

Summary

In 1921, Dr. Frederick Banting, a young surgeon, and Charles Best, a young medical student, with the help of skilled chemist, J. B. Collip, succeeded in producing the first active insulin for treating diabetes in humans. It would be another sixty-five years before Gerald Reaven would describe Syndrome X and its cluster of abnormalities tied to insulin resistance and elevated insulin levels. Research has shown that combining changes in lifestyle, such as weight loss and physical activity, can prevent, control, and often reverse damage from insulin resistance—and help us avoid the adverse health conditions that can arise from these abnormalities.

Insulin still plays a crucial role as a protein hormone that directs the flow of energy throughout the body.

We just have to have the right amounts of it at the right times, day and night. Maintaining a balance is vital to good health and good aging. Syndrome X is still relatively unknown to the world and not everyone, including some of the many healthcare professionals, may have caught up with the latest research or risk criteria concerning this disorder. For those in the risk categories described above, checking for insulin resistance and Syndrome X should be at the top of their wellness list.

References

1. Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM. Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy, nondiabetic volunteers. Diabetes Care 23:171-175, 2000

2. Reaven, GM, Strom, TK, Type 2 Diabetes Questions and Answers, Merit Publishing International, 2003.

3. Reaven, Gerald M., Strom, Terry Kristen, Fox, Barry, Syndrome X: The Silent Killer, Simon & Schuster, 2000.

4. Reaven GM. Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988

5. Wingard DL, Barrett-Connor E. Heart disease in diabetes. Diabetes in America, 2nd Edition, 429-448, 1995.

6. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care (Supplement 1) 25:S5-S20, 2002.

7. Muller JF, Shipley MJ, Rose G, Jarrett RJ. Keen H. Coronary-heart disease and impaired glucose tolerance: the Whitehall Study. Lancet 1:13732-1376, 1980.

8. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin dependent diabetes mellitus N Engl J Med 329:1988-1992, 1993.

9. Facchini, F., Chen, Y.D.-I., Hollenbeck, C., Reaven, G.M. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 266:3008-3011, 1991.

10. Laws, A., Reaven, GM Evidence for an independent relationship between insulin resistance and fasting plasma HDLcholesterol, triglyceride and insulin concentrations. J. Int. Med. 231:25-30. 1992.

11. Castelli,WP, Garrison RJ, Wilson PWF. Abbott RO, Kalonsdian S, Kannel,W B. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA 256:2385-2387, 1986.

12. Austin MA, Hokanson JE, Edwards KI. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 81(4A):7B-12B, 1998.

13. 13.Reaven, G.M., Chen, Y. D.I., Jeppesen, J., Maheux, P., Krauss, R.M. Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles. J. Clin. Invest. 92:141-146, 1993.

14. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WS, Krauss, low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 260:1917-1921,1988.

15. Jeppesen, J., Hollenbeck, C.B., Zhou, M-Y, Coulston, A.M., Jones, C., Chen, Y-D.I., Reaven, G.M. Relation between insulin resistance, hyperinsulinemia,

16. postheparin plasma lipoprotein lipase activity, and postprandial lipemia. Arterioscler. Thromb. Vasc. Biol. 15:320-324l, 1995.

17. Patsch JR, Miesenbock T, HopferwieserT, et al. Relation of triglyceride metabolism and coronary artery disease :studies in the postprandial state. Arterioscler Thromb 12:1336-1345, 1992.

18. 17.Facchini FS, Riccardo A, Stoohs A. Reaven GM. Enhanced sympathetic

19. nervous system activity-The linchpin between insulin resistance, hyperinsulinemia, and heart rate. Am. J. Hypertens. 9:1013-1017,1996.

20. 18. DeFronzo RA, Cooke C, Andres R, Faloona GR, David PJ. The effect of insulin in renal handling of sodium, potassium, calcium and phosphate in man. J Clin Invest 55:845-855, 1975.

21. 19. Zavaroni I. Mazza S, Dall’Aglio E. Gasparini P, Passeri M, Reaven GM. Prevalence of hyperinsulinaemia in patients with high blood pressure. J Int Med 231:1128-1130, 1992.

22. 20. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. High triglycerides and low HDL cholesterol and blood pressure and risk of ischemic heart disease. Hypertension 36:226-232, 2000

21. Juhan-Vague I, Thompson SG, Jeppesen J, on behalf of the ECAT Angina Pectoris Study Group. Involvement of the hemostatic system in the insulin resistance syndrome. Arteriioscler Thromb 13:1865-1873, 1993.

22. Meigs JB, Mittelmann MA, Nathan DM, et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis. The Framingham Offspring Study. JAMA 283:221-228, 2000.

23. Chen, N.-G., Abbasi, F., Lamendola, C., McLaughlin, T., Cooke, J.P., Tsao

23. P.S., Reaven, G.M. Mononuclear cell adherence to cultured endothelium is enhanced by hypertension and insulin resistance in healthy nondiabetic volunteers. Circulation 100:940-943,1999.

24. Chen, N.-G., Holmes, M., Reaven, G.M. Relationship between insulin resistance, soluble adhesion molecules, and mononuclear cell binding in healthy volunteers. J Clin Endocrinol Metab 84:3485-3489, 1999.

25. Stuhlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP, Reaven GM, Tsao PS. Relationship between insulin resistance and an endogenous nitiric oxide synthase inhibitor. JAMA 2002; 287:1420-1426.

26. Baron A. Vascular reactivity. Am J Cardiol 84:25J-27J, 1999.

27. Dunaiff A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18:774-800, 1997.

28. Sanyal AJ, Campbell-Sargent C, Mirashi f, et al. Nonalcoholic steatohepatitis ;Association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183-1192, 2001.

29. Argiles JM, Lopez-Soriano. Insulin and cancer. Int J Oncol 18:683-687, 2001.

30. Jeppesen, J, Hein HO, Dsuadicani P, et al. Low triglycerides-high high density lipoprotein cholesterol and risk of ischemic heart disease. Arch Int Med

31. 161:361-366, 2001.

32. Warram JH, Martin BC, Krowlewski As, et al. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of the diabetic parents. Ann Intern Med 113:909,1990.

33. Facchini, F., Chen, Y.-D.I., Clinkingbeard, C., Jeppesen, J., Reaven, G.M. Insulin resistance, hyperinsulinemia, and dyslipidemia in nonobese individuals with a family history of hypertension. Am. J. Hypertens. 5:694-699, 1992. .

34. Lillioja S, Mott DM, Zawadzki JK, et al. In vivo insulin action is a familial characteristic in nondiabetic Pima Indians. Diabetes 36:1329-1335, 1987.I

35. O”Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 13, 278,1964.

36. McKeigue PM. Ethnic variations in insulin resistance and glucose tolerance, in Insulin Resistance: The Metabolic Syndrome X. 19-34, 1999.

37. Bogardus, C., Lillioja, S., Mott, D.M., Hollenbeck, C., and Reaven, G.M. Relationship between degree of obesity and in vivo insulin action in man. Am. J. Physiol. 248 (Endocrinol. Metab.11):E286-E291, 1985.

38. Ferrannini E, Natali A, Bell P, Cavallo-Perin, Lalic N, Mingrone G, on behalf of the European Group for the Study of Insulin Resistance. Insulin resistance and hypersecretion in Obesity. J Clin Invest 100:1166-1173, 1997.

39. Executive summary of the third report of he national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 285:2846-2497,2002.

40. The DECODE Study Group, on behalf of the European Diabetes Epidemiology Group. Glucose Tolerance and Cardiovascular Mortality. Comparison of fasting and 2-hour diagnostic criteria. Arch Int Med 161;397-404, 2001.

41. Yip, J., Facchini, F.S., Reaven, G.M. Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease. J Clin Endocrinol & Metab 83:2773-2776, 1998.

42. Facchini, FS, Hua, N, Abbasi, F, Reaven, GM. (2001) Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab, 86:3574-3578, 2001.

43. McLaughlin T, Abbasi F, Kim H-S, Lamendola C, Schaaf P, Reaven g. Relationship between insulin resistance, weight loss, and coronary heart disease in healthy, obese women. Metabolism 7:795-800, 2001.

44. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343-1350, 2001.

45. Knowler WC, Barrett-Connor E, Fowler SE, et al for The Diabetes Prevention Program Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393-403, 2002.

46. Golay, A., Allaz, A-F., Morel, Y., de Tonnac, N., Tankova, S., Reaven, G.M. Similar weight loss with low- or high carbohydrate diets. Am J. Clin. Nutr. 63:174-178, 1996.

47. Nestler JE, Jakuboficz J, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Eng J med 338:1876-1880, 1998.

48. Hollenbeck, C.B., Johnston, P., Varasteh, B.B., Chen, Y-.D.I., Reaven, G.M. Effects of metformin on glucose insulin and lipid metabolism in patients with mild hypertriglyceridemia and non-insulin dependent diabetes by glucose tolerance test criteria. Diabete & Metabolisme 17:483-45, 1991.

49. 48. Reaven GM, Segal K, Hauptman J, Boldrin M, Lucas C. Effect of orlistat- v assisted weight loss in decreasing coronary heart disease risk in patients with syndrome x. Am J Cardiol 87:827-831, 2001

50. Reaven GM. Do high carbohydrate diets prevent the development or attenuate the manifestations (or both) of syndrome X? A viewpoint strongly against. Cur Opin in Lipidology 8:23-27, 1997.

51. Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids and lipoproteins. Arterioscler Thromb 12:911-919, 1992.

52. Gardner CD, Kraemer HC. Monounsaturated versus polyunsaturated dietary fat and serum lipids-meta analysis. Arterioscler Thromb Vasc Biol 15:1917-1927, 1995.

53. Standards of medical care for patients with diabetes mellitus. Diabetes Care (Supplement 1) 25: S33-49, 2002.