What is insulin resistance?
Broadly, insulin resistance can be defined as an abnormal biologic response to insulin; insulin, whether endogenous or exogenous in origin, has limited ability to reverse a hyperglycemic metabolic state.Thus a person with insulin resistance is, almost inevitably, progressing towards developing frank type 2 diabetes (T2DM) if an intervention (usually lifestyle) is not implemented. Due to the very close link between diabetes and insulin resistance, no formal clinical definition of insulin resistance has emerged.We will discuss the potential clinical use of the insulin resistance syndrome and the metabolic syndrome later in the chapter. For now, we focus on investigation of insulin resistance as a useful entity for research concepts, and in particular discuss its biologic consequences by describing its associated risk factor perturbations.
Multiple roles of insulin
To understand the link between many novel parameters and insulin resistance, and thereby their association with T2DM, it is important to appreciate that insulin imparts its effects not only on skeletal muscle but also on many tissues including adipose, liver, endothelium, and immune cells. Thus, insulin is relevant not simply for glucose uptake and metabolism, but also for (i) suppression of free fatty acid (FFA) release from adipose tissue, (ii) limiting hepatic triglyceride synthesis, (iii) helping to maintain endothelial homeostasis, (iv) regulating thrombotic cascades, and (v) potentially playing a role in regulating inflammatory cascades (Figure 23.1). With increasing adiposity, fat cells become enlarged and less responsive to insulin, that is, they become insulin resistant. The subsequent excessive release of FFAs into the portal circulation in part drives excess hepatic fat accumulation and triglyceride synthesis (leading to elevated circulating triglyceride levels and associated changes in circulating lipids) and muscle fat accumulation. Excess fat in the latter two organs is considered to enhance their insulin resistance; specifically, excess fat in the liver limits glucose storage (in the form of glycogen) but enhances glucose synthesis via gluconeogenesis, whereas excess fat in muscle lessens glucose uptake. The combined effects thus promote hyperglycemia.This hyperglycemia can be offset for many years by an increase in pancreatic insulin secretion, and hence hyperinsulinemia accompanies insulin resistance. In persons who develop T2DM, the pancreas has eventually become “exhausted”—it can no longer produce sufficient insulin to counteract the hyperglycemic drive—and glucose concentrations rise into the diabetic range.
How do we measure insulin resistance?
The gold standard method for measuring insulin resistance focuses on maintaining a normal blood glucose level in a hyperinsulinemic state—the so-called euglycemic hyperinsulinemic clamp. This technique involves infusing insulin at supraphysiologic rates based on body size, while also infusing glucose at the necessary rate to maintain euglycemia. The use of stable isotopes provides further information on the relevant roles of the liver and peripheral tissue (muscle and adipose tissue). When a steady state is achieved, the glucose infusion rate is essentially a measure of the ability of all tissues to respond to insulin and take up glucose for a standard insulin dose . Thus, the global sensitivity to insulin is comparable between patients or participants. There are several different specific methodological variations of this approach to measure insulin resistance, each with strengths and weaknesses, although the aim is always similar.The major drawback of this gold-standard approach is its labor-intensive and time-consuming nature. Thus, it is not a practical test for routine screening or for large epidemiologic studies. Other dynamic tests to measure sensitivity to insulin are available but are infrequently used in clinical settings (Table 23.1).
Simple characteristics associated with insulin resistance
If one looks at any reputable risk score for the prediction of T2DM, certain parameters always appear—age, gender, adiposity measures, family history of T2DM, and ethnicity. Of all of these, rising obesity levels are strongly associated with insulin resistance whatever the other characteristics of an individual and, as such, fat accumulation is the primary risk factor that drives increasing insulin resistance at a population level. That noted, the other risk factors are also of importance in considering an individual’s risk. For example, an older Asian male with a family history of T2DM will have greater insulin resistance for a given weight than younger white females without a family history of diabetes. In other words, nonmodifiable characteristics (age, sex, ethnicity, family history) interact with adiposity to determine degree of insulin resistance and T2DM risk. Interestingly, as recently reviewed , these simple characteristics give good prediction of T2DM risk (area under receiver operator curve around 80%) and thus the benchmark for biomarkers to meaningfully improve prediction beyond simple measures is high.