Insulin Resistance versus B-Cell Dysfunction

When I wrote this blog about the possibilities of type 2 diabetes having sub classes, I had not expected another article this quickly. And this article says, “Identifying the profound differences in risk factors for diabetes in the subpopulations of this study is a step in the right direction.” Subpopulations is not sub-classes, but definitely raises the odds or may just a way of downplaying this.


At least adults older that 65 were the study subjects. Granted this was a multi-site cohort study and included about 4400 adults. The mean age of participants was 73 years, and 59% of them were women. The study followed 4384 participants who were free of diabetes at the start in 1992 through 2007 for the development of diabetes. Based on beginning data, the authors evaluated degrees of insulin resistance and beta-cell dysfunction, which was calculated from fasting glucose and insulin levels. This distinction is important.


In the median follow-up of 11.7 years, seven percent of the patients developed diabetes. And if you didn't guess, higher body mass index, hypertension, low HDL-C levels, elevated triglyceride levels, and elevated glucose levels were all independently associated with a higher risk for diabetes.


If insulin resistance (IR) was present (with or without beta-cell dysfunction), these same risk factors were similarly associated with incident diabetes. This was not the case when diabetes was preceded by only beta-call dysfunction. With these individuals, being overweight or obese were associated with a lower risk, and hypertension and low HDK-C also trended toward a lower risk. In comparing patients who had diabetes, those preceded predominately by IR differed significantly from those preceded by beta-cell dysfunction.


While it is known that hyperglycemia that characterizes type 2 diabetes is caused by both IR and beta-cell failure, it is generally assumed that both causes are present in a typical diabetes patient and the relative contribution of each could have important factors for both prevention and treatment. Prescribing weight loss in patients who are at the appropriate weight, but have little or no beta-cell function would not be an effective prevention measure.


This in turn creates the problem in selecting the most effective anti-hyperglycemic medication. We need to know precisely what is driving the hyperglycemia. Identifying the differences in risk factors for diabetes in the subpopulations of this study is a step in the right direction. This raises the interest that the differential contributions of beta-cell dysfunction and IR might help explain findings such as the apparent u-shaped relationship between glycated hemoglobin (A1c) and cardiovascular disease and mortality.


The important caveat is that the current study was conducted in older individuals who do not represent the vast majority of incident diabetes cases. Without further study with younger patients, this is an important open question. I feel that the concluding statement is worth quoting and bold is my emphasis. “In any case, as convenient as A1c is for diagnosing diabetes, one of its big detractions is that it tells us little about the underlying pathophysiologic abnormalities of diabetes.”