Thursday, May 13, 2010
Insulin Resistance and the Metabolic Syndrome
The metabolic syndrome is a symptom set that includes the following: increased truncal obesity, high blood pressure, high blood glucose, low HDL cholesterol and high triglycerides. As anyone who has observed adults and even children in Western countries can confirm, the metabolic syndrome is becoming more and more prevalent. In Good Calories Bad Calories, Gary Taubes uses several lines of argument to show that one unifying explanation for the development of the metabolic syndrome is the prior development of insulin resistance.
Interestingly, one of the arguments Taubes does not use for his hypothesis is something called the "knockout mouse." The knockout mouse is not a small pugilist with boxing gloves. Instead, it is a genetically engineered mouse in which one or more genes have been turned off (knocked out) through targeted deletions. If we want to know what the effect of insulin is on a particular tissue, one approach is to delete the expression of the insulin receptor in that tissue.
The first attempt at an insulin receptor knockout mouse was to remove insulin receptor expression from the entire mouse. These mice were smaller than normal but were born alive at term. Shortly after birth they developed diabetic ketoacidosis and died. This was not helpful to the investigation of the relationship of insulin receptor signaling to various metabolic conditions, and the investigators moved on.
Because muscle insulin resistance is thought to be important in the development of type 2 diabetes, the next group of knockout studies involved mice that lacked insulin receptors specifically on muscle tissue. These mice had normal levels of blood glucose and plasma insulin. However, they had a 74% decrease in insulin-stimulated glucose transport into their muscle tissue. This caused blood glucose to be preferentially taken up by adipose tissue. Although these mice did not develop overt symptoms of diabetes, they demonstrated two of the features of the metabolic syndrome: increased fat mass and high triglycerides.
Another tissue targeted for insulin receptor deletion was the liver. By two months of age, the mice lacking liver insulin receptors had high levels of serum insulin but were were hyperglycemic in the fed state. To a great extent this was found to be attributable to the fact that insulin was unable to suppress the production of glucose by the liver. This suggests that hepatic insulin resistance is necessary for the onset of overt diabetes.
Because insulin receptors are widely distributed in the brain, investigators also developed a neural insulin receptor knockout mouse. The brains of these mice were normally developed, but the mice showed increased food intake and moderate diet-dependent obesity. It is known that the brain is able to regulate hepatic glucose production. When these neural-knockout mice were given exogenous insulin, they were only about half as effective as normal mice at suppressing hepatic glucose output.
Finally, the insulin receptor was uniquely deleted in the pancreatic beta cells of another group of mice. The investigators were expecting the pancreas to sense glucose concentrations directly rather than to use insulin signaling as an intermediary. To their surprise, mice that lacked pancreatic beta cell insulin receptors showed both a decreased ability to sense glucose and an insufficient secretion of insulin in response to glucose. Some, but not all, of the mice developed diabetes.
For those who would like to read more about these experiments, additional information can be found here and here. The use of insulin receptor knockout mice is a rather blunt instrument to determine whether insulin resistance can be implicated as the cause of the development of the metabolic syndrome. And mice are not people. Nonetheless, it is interesting to note that the deletion of insulin signaling in various tissues can produce obesity, high triglycerides, poor suppression of glucose output by the liver and both impaired pancreatic production of insulin and insufficient release of insulin in response to glucose.