Every day I see patients I talk about insulin resistance and how it leads to diabetes. I have based my conversations, on what I thought was the best data. Now that I read Insulin Resistance: A Vicious Circle Of Excess Fat, by Phil Wood DVM, MS, PhD I realize that I am going to have to change a few of my statements as there are some facts you won’t want to miss.
Phillip Wood DVM, MS, PhD
Insulin resistance is a common feature in patients who are obese or who have metabolic syndrome or type 2 diabetes. Insulin-resistant patients require higher than normal amounts of insulin to maintain normal blood glucose concentrations. The development of insulin resistance is complex, and many of its mechanisms are poorly understood. However, a common denominator in insulin-resistant patients is excess fatty acids (1), and insulin sensitivity is increased by any activity that reduces fatty acids in the tissues of the body. Such activities include increasing exercise with or without weight loss, reducing visceral adiposity with weight loss, or taking drugs that reduce fatty acids (thiazolidinediones, commonly known as “glitazones,” fibrates or metformin). The bottom line is that clearing the body of excess fat increases insulin sensitivity and, thus, decreases symptoms associated with insulin resistance.
Often, insulin resistance is thought of as a focal process restricting the uptake of glucose as accomplished by muscle and mediated by insulin. It is true that muscle is a major location for insulin-mediated glucose uptake; however, uptake of glucose by muscle is only one of many metabolic processes that are disrupted by insulin resistance. I want to focus on three of those processes to demonstrate the vicious circle of insulin resistance, as well as the tremendous benefits of breaking that circle.
Muscle tissues are clearly affected by insulin resistance because, after a meal, about 80% of insulin-mediated glucose uptake occurs in muscle. When this process is restricted, glucose builds up, and the pancreas puts out more insulin in an attempt to maintain normal blood glucose concentrations—a familiar condition, hyperinsulinemia. This condition is common among obese patients who are insulin resistant and have fasting blood glucose concentrations in the high range (100-126 mg/dl) but who have not been diagnosed as diabetic (i.e., >126 mg/dl) and may never develop diabetes. These patients demonstrate clearly that insulin resistance and diabetes are different conditions. Insulin resistance is common both in type 2 diabetes and in obesity, but while many obese patients are insulin resistant, most are not diabetic. In these patients, as in others, restricted glucose uptake by muscle tissue is a major indicator of insulin resistance.
In addition to muscle tissue, liver metabolism is also affected by insulin resistance (2). Normally, insulin sends two signals to the liver. One says stop making glucose (i.e., gluconeogenesis). The other says store the glucose available in the blood as glycogen. However, in insulin resistance, both of these processes respond poorly to the insulin signal, putting patients in a state of excessive glucose production. That state is the last thing insulin-resistant patients need because their glucose concentrations are already rising as a result of restricted insulin-mediated uptake of glucose in muscle tissues. In the liver, as opposed to muscle, insulin resistance is not equally restricted. Metabolically, insulin promotes synthesis of fat (fatty acids and triglycerides) and impairs mitochondrial beta-oxidation of fatty acids. Unfortunately for the patient with hyperinsulinemia, those metabolic processes continually respond to the extra insulin circulating in the body. Thus, the liver continues to synthesize and store fat, which results in the build-up of triglyceride in the liver, and at the same time it also exports triglyceride. Triglyceride export is often recognized clinically in insulin-resistant patients. Their elevated concentrations of blood triglyceride are the result of their livers trying to clear the excess fat by making and exporting excessive amounts of very low density lipoprotein (VLDL) particles (3), which are rich in triglycerides. Thus, insulin resistance affects the liver in several ways.
The next tissue to consider is body fat, also called adipose tissue, and especially visceral fat, also known as abdominal fat. Visceral fat is often excessive in insulin-resistant patients, and this is a problem because it too is affected by insulin resistance. Normally, when a person’s insulin level is high, such as after eating a meal, the insulin stops lipolysis, the process of fat breakdown. In conditions of insulin resistance, however, lipolysis is not turned off as it should be. As visceral fat increases, a highly beneficial protein known as adiponectin decreases. Among other things, adiponectin increases the oxidation of fatty acids, promotes the clearance of excess fat in tissues, and improves insulin sensitivity (4). Thus, visceral fat supplies a constant source of excess free fatty acids because lipolysis is not working properly. These additional fatty acids pass into the blood, which flows directly to the liver and, as I have described, the liver does not need any more fat to deal with.
What I have described here can be summed up as a vicious circle (5) in which excess fat promotes for increased insulin that, in turn, promotes for even more fat. There are examples of insulin resistance beyond those described here, and there are probably others we do not recognize yet. The good news is that reducing the body’s overall fat burden—by increasing physical activity, reducing calorie intake, and reducing visceral fat—markedly increases insulin sensitivity (5). That increased sensitivity to insulin improves control of blood glucose in both nondiabetic and diabetic people. Therefore, if the body can clear excess fat, regulation of glucose improves, and that is one big step toward breaking the vicious circle of insulin resistance.
1. Shulman GI. Unraveling the cellular mechanisms of insulin resistance in humans: New insights from magnetic resonance spectroscopy. Physiology 19:183-190, 2004
2. Samuel VT, Liu Z-X, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biolog Chem 279: 32345-32353, 2004.
3. Adiels M, Boren J, Caslake MJ, Stewart P, Soro A, Westerbacka J, Wennberg B, Olofsson S-O, Packard C, Taskinen M-R. Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arteioscler Thromb Vasc Biol 25:1697-1703, 2005).
4. Bajaj M, Suraamornkul S, Piper P, Hardies LJ, Glass L, Cersosimo E, Pratipanawatr T, Miyazaki Y, DeFronzo RA. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab 89:200-206, 2004.
5. Wood PA. How Fat Works, Chapters 5 and 16. Harvard University Press, Cambridge MA, 2006.