Last week I had the great opportunity to meet Dr. Phil Wood at the ADA conference in Chicago, we chatted about fat and other things and he prepared this week’s article based on his review of the abstracts. Be sure to read Dyslipidemia In Insulin Resistance: Hypertriglyceridemia And Low HDL Cholesterol
Dyslipidemia In Insulin Resistance:
Hypertriglyceridemia And Low HDL Cholesterol
Philip A. Wood
People who are obese and insulin resistant often have a dyslipidemia that is characterized by elevated blood triglyceride (TG) concentrations and low high-density lipoprotein cholesterol (HDL-C). These two characteristics are also considered important cardio-metabolic risk factors for the development of diabetes, cardiovascular disease, or both. This duet of factors often appears together, but lifestyle changes and drug therapy can improve both of them.
One common underlying problem in development of insulin resistance is the body’s excessive burden of fatty acids (1, 2), many of which build up in the liver as TG. The liver has at least three options for handling excess TG: (a) store it, (b) burn it through β-oxidation in mitochondria, or (c) export it by synthesizing very low-density lipoprotein (VLDL) particles, which are TG rich. Chylomicrons, also abounded with TG, are formed by the intestine after eating; however, these should clear within a few hours after eating and should not be found in a fasting blood sample. Together, these TG-rich lipoproteins (i.e., VLDL particles and chylomicrons) deliver fatty acids to tissues such as adipose tissue and muscle. Thus, excess fat in muscle, liver, and visceral adipose tissues usually indicates insulin resistance. Therefore, the abnormal blood lipid component most often associated with obesity and insulin resistance is hypertriglyceridemia caused by the liver producing excess VLDL particles, their slow clearance from the circulation, or both. If chylomicrons are not effectively cleared from the blood after a meal, they also contribute to hypertriglyceridemia.
Another common feature in these same patients is low HDL-C. The metabolism of HDL-C is complex, incompletely understood, and therefore controversial. Despite that controversy, I will review two major concepts here regarding how low HDL-C often accompanies hypertriglyceridemia. First, although HDL particles are produced by the liver, a significant portion of them are formed from remnant particles of TG-rich lipoproteins as they are metabolized. This metabolism is often defective in diabetes, reducing the production of HDL-C from this source (3). Second, a protein called cholesterol ester transport protein (CETP) transports cholesterol ester away from HDL particles in exchange for TG from VLDL particles. This transport lowers HDL-C in the blood, which also promotes for small, dense LDL particles. Together, these shifts steer the body in an undesirable direction: increased VLDL with its TG leads to decreased HDL-C, which leads to small, dense LDL particle formation. Overall, this results in a proatherogenic lipid profile. That is, HDL particles function in reverse cholesterol transport and may be anti-inflammatory and anti-oxidant. Many studies have shown that the risk of cardiovascular disease is lower when HDL-C is above 40 mg/dl in men and above 50 mg/dl in women.
Of course our goal should be to reverse the trend—to decrease VLDL and its TG and to increase HDL-C. Lifestyle changes can be a big help. Increasing physical activity, with or without weight loss, often helps reduce TG and raise HDL-C concentrations. Regarding the diet, decreased calorie intake is beneficial, particularly by reducing excess sugars and starches and replacing some of those calories with some omega-3 (fish oil) and monounsaturated fats (4). Certain drugs can also help. For example, fibrates can lower TG by increasing β-oxidation and fat clearance from the liver, as well as increasing clearance of TG-rich lipoproteins (VLDL, chylomicrons) from the bloodstream with marginal increases in HDL-C. Niacin in high doses can have potent effects on lowering TG while raising HDL-C, although its side effects of flushing and itching can lead to poor patient compliance. Another caveat of using high dose niacin is the potential for it to aggravate insulin resistance in some individuals. Pharmaceutical companies are very interested in developing drugs that raise HDL-C. Recently reported in the lay news (e.g., Wall Street Journal December 4, 2006) was the termination of a large clinical trial of the new drug torcetrapib. It was designed to inhibit CETP and prevent the loss of cholesterol ester from HDL, thus raising HDL-C concentrations. Although it did raise HDL-C, unfortunately it did not prevent development of atherosclerotic lesions, was associated with side effects such as raising blood pressure and an increased death rate (5). It remains to be seen whether other compounds that inhibit CETP will safely and effectively raise levels of HDL-C while reducing atherosclerosis and cardiovascular disease.
In summary, beware of hypertriglyceridemia and low HDL-C, the duo of dyslipidemia commonly found in insulin resistance. These two characteristics often accompany obesity, physical inactivity, and high dietary intake of simple carbohydrates. Alone or together, they can increase the risk of cardiovascular disease and, if found, reversed as much as possible. They can be changed by improving the diet—reducing total caloric intake, especially cutting back on sugars, starches and other carbs—and by increasing physical activity. Drugs that may help include fibrates, high-dose niacin, as well as fish oil supplements containing long-chain omega-3 fatty acids. Overall, the general concept is that clearing the body of excess fatty acids decreases dyslipidemia, increases insulin sensitivity, and reduces risk factors for diabetes and cardiovascular disease.
1. Wood, PA. How Fat Works, Chapters 5, 15, 16. Harvard University Press, Cambridge, Massachusetts, 2006.
2. Savage DB, Petersen KF, Shulman GI. Disoredered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 87:507-520, 2007.
3. Taskinen MR. Lipoprotein lipase in diabetes. Diabetes Metab Rev 3:551-570, 1987.
4. Hu FB, Willett WC. Optimal diets for prevention of coronary heart disease. JAMA 288:2569-2578, 2002.
5. Tall AR. CETP inhibitors to increase HDL cholesterol levels. N Engl J Med 356:1364-1366, 2007.