In the last post, I reviewed a study by Gerald Reaven's group showing that insulin resistance strongly predicts the risk of cardiovascular disease over a 5-year period. In 2001, Reaven's group published an even more striking follow-up result from the same cohort (1). This study shows that not only does insulin resistance predict cardiovascular disease risk, it also predicts a variety of age-related diseases, including hypertension, coronary heart disease, stroke, cancer, type 2 diabetes, and even overall mortality risk.
The study was very similar to the previous one: first, they recruited 147 lean and overweight middle-aged volunteers without diabetes or diagnosed cardiovascular disease. Then, they measured the volunteers' insulin sensitivity. While most studies of this nature indirectly estimate insulin sensitivity simply by using a formula based on fasting insulin and glucose measurements (HOMA-IR), which can be inaccurate, Reaven's group directly measured insulin sensitivity using a gold standard method*.
Next, they waited 6 years and watched who developed a variety of diseases over that period.
As in the previous study, they divided the volunteers into three equal-sized groups based on their degree of insulin resistance. Group I had the lowest level of insulin resistance, group II had an intermediate level, and group III had the highest level. The following graph illustrates the number of people who were diagnosed with disease (and/or died) in each group over the course of the study:
As you can see, over the 6-year period, none of the people in the least insulin-resistant group developed disease or died. In contrast, 36 percent of the people in the most insulin-resistant group developed disease and/or died, from a variety of causes including hypertension, coronary heart disease, stroke, type 2 diabetes, and cancer. People in the middle group had an intermediate rate of disease.
This is an incredibly striking result.
Again, people who were most insulin-sensitive also had a variety of other healthy signs, including less body fatness, higher physical activity, lower blood pressure, lower levels of LDL ("bad") cholesterol, and the higher levels of HDL ("good") cholesterol. And again, after mathematically adjusting for all of these other factors, "only insulin resistance was an independent predictor of the 40 age-related clinical events."
Many researchers, including myself, believe that insulin resistance is a central feature of a metabolic dysfunction syndrome that drives much of the chronic disease of the modern affluent world. Reaven's results strongly support this contention, since they show that insulin resistance clusters not only with a variety of other metabolic disturbances, but also with the risk of a variety of common chronic diseases.
These results don't allow us to know whether insulin resistance caused the other metabolic disturbances and/or diseases, rather than simply being associated with them, but other research gives us good reason to suspect that it does play at least somewhat of a causal role. Insulin resistance is intimately involved in the development of type 2 diabetes, which is itself damaging to the cardiovascular system. Insulin resistance also contributes to disturbed blood lipid levels, including elevated LDL particle number and reduced HDL-cholesterol, which further damage cardiovascular health. The relationship of insulin resistance with cancer is less straightforward, but the elevated insulin levels that accompany insulin resistance are thought to drive the progression of certain cancers. Also, insulin resistance is typically associated with chronic, low-grade inflammation, another factor that can promote the development of cancer.
Even though insulin resistance and elevated insulin levels don't reliably predict weight gain over time (2, 3), insulin resistance does predict chronic disease risk. This suggests that even though insulin resistance probably doesn't play a major role in body fatness, it's still a metabolic characteristic we should care quite a bit about.
* Insulin suppression test, which is a direct measure of insulin sensitivity that is highly correlated with euglycemic-hyperinsulinemic clamp (4). The output is "SSPG" or Steady-State Plasma Glucose, which is the level of blood glucose that results from "clamping" circulating insulin at a standardized level. The higher your blood glucose (SSPG) is at a given level of circulating insulin, the more insulin-resistant you are.