How the Term "Insulin Resistance" is Often Misused

Author: Jeffrey Wacks, MD

TL;DR: Insulin resistance is an important scientific principle that refers to a lack of response to the binding of insulin with its receptor. This idea helps to explain "engine malfunction," or failure to burn carbohydrates effectively in the mitochondria. What has created some confusion, however, is extrapolation of the idea that the serum insulin level is essentially analogous to insulin resistance. As we will discuss, we believe that these ideas are not the same the thing. If one believes that metabolic dysfunction = insulin resistance = elevated serum insulin and thus the goal of health becomes to lower the serum insulin, then this will drive people to consume a long-term low-carbohydrate diet, a strategy with which we would disagree.

Background Information and Definition of Terms

In order for glucose to enter the cell (and ultimately the mitochondria) from the blood, insulin must bind to its receptor and trigger the cellular uptake of the glucose molecule. Insulin is a hormone that comes from the pancreas, and its release is triggered by sugar itself. The function of insulin is essential for carbohydrate-driven metabolism. The condition Type 1 Diabetes Mellitus is a failure of the pancreas to secrete insulin, causing insulin deficiency and resulting in significant hyperglycemia and failure to burn sugar effectively.

In nutritional biochemistry, "resistance" of any receptor refers to the situation where  the receptor fails to respond properly to the presence of its ligand. Thus in the case of insulin resistance, this means that even though there is plenty of insulin in the blood, it is not acting effectively at the cellular level, causing failure of glucose uptake. Because the system continues to sense hyperglycemia, the pancreas continues to secrete insulin and the serum level will tend to rise to higher than normal levels. Thus it is true that insulin resistance causes elevated serum insulin levels.

Applying These Concepts to the Bioenergetic Model

Figure 1 below illustrates how we would apply the concept of insulin to our bioenergetic model. We consume dietary carbohydrates which are broken down and absorbed by the gastrointestinal system. Once the carbohydrates are in the blood, we would describe them as fuel. Fuel is potential energy that is available to be burned into cellular energy. The blood sugar itself triggers the pancreas to secrete insulin, which then allows for the uptake and subsequent burning of those carbohydrates into cellular energy by the mitochondria (i.e., the engine of the system). 

Figure 1. Application of basic principles of insulin to carbohydrate-driven metabolism.

In Volume 1 of the training manual, we define the term "engine malfunction" as failure of the mitochondria to perform optimal fuel oxidation. Thus, from our perspective, the idea of insulin resistance is incorporated within the idea of engine malfunction. To this point, it is likely that "insulin resistance" is a downstream consequence of dysfunction of the mitochondrial machinery itself.^1,2 Thus we will graphically demonstrate the idea of insulin resistance by Figure 2 below.

Figure 2. Illustration of insulin resistance (i.e., engine malfunction) and its impact on insulin and blood sugar levels.

Note that we can state that similarly to the blood sugar level, the serum insulin level is essentially a fuel marker. The serum insulin level will go up when there is engine malfunction and the fuel backs up. It is also critically important to note that fuel markers will go down when the intake goes down. As stated above, the pancreas secretes insulin in response to carbohydrates. So reduction of the carbohydrate intake will generally lower the fasting insulin level via a mechanism that is independent of the actual mitochondrial function or more specifically the sensitivity of the insulin receptor.

Figure 3. Illustration of the effect of low-carbohydrate intake on insulin levels, blood sugar levels, and energy supply. 

Because of this relationship, it is not accurate to say that "insulin resistance" and the fasting serum insulin level are the same thing. In other words, it is possible to push fuel markers in the right direction for the wrong reason. This is what is happening in Figure 3, the decrease in the fasting insulin level is occurring at the expense of the energy supply. 

The Idea that an Elevated Fasting Serum Insulin Level Defines Insulin Resistance is True Only If the Carbohydrate Intake is Normal

Consider the case of a 60-year-old female who maintains a long-term low-carbohydrate, ketogenic diet. On laboratory analysis, she has a fasting insulin level of 6.0 mIU/mL, fasting glucose of 84 mg/dL, and a Hemoglobin A1c of 5.4%, all of which we would consider optimal. However, she states that when she consumes a carbohydrate (e.g., fruit, potatoes, etc.) her blood sugar goes up dramatically to as high as 180 mg/dL. Thus, despite her impressive looking baseline labs, in our opinion, her insulin sensitivity is actually very poor. She would likely fail an oral glucose tolerance test (OGTT), which is a better indicator of the insulin sensitivity. Remember, the insulin sensitivity is the degree to which insulin is able to interact with its receptor and pull the sugar from the blood into the cell. Thus to equate insulin resistance with the fasting insulin level is simply a misuse of the term. 

The misuse of the term "insulin resistance" is common among physicians, healthcare professionals, and health-related social media influencers. For example, there are many scientific articles that discuss a concept called the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), which is thought to estimate the degree of insulin resistance, but in context, is often used to define it. The equation for HOMA-IR is given below:

HOMA-IR = (Fasting plasma glucose [mg/dL] x Fasting serum insulin [mIU/mL]) / 405

Thus, we can see that we are simply using the elevated fuel markers to define "insulin resistance." Again, we agree that this is reasonable for patients consuming a "normal" diet with a normal carbohydrate intake, but the goal of health should not be to lower fasting insulin by whatever means possible.

Why This Matters

Because the term insulin resistance has been misused and equated with elevated fasting insulin level, many people believe that it is the insulin molecule itself that actually causes chronic disease. This is simply not true. Correlation does not mean causation. Insulin is an important hormone that is required for the utilization of carbohydrates (the primary fuel of the system). The evidence that insulin in its normal functional state causes systemic inflammation or metabolic dysfunction is extremely weak. However, if one believes that the goal of health is to minimize the fasting insulin level, it will push them into a low-carbohydrate diet in order to achieve this. We discuss in detail in Volume 1 of the training manual that low carbohydrate diets promote secondary hypothyroidism, stress activation, and oxidative stress and are therefore anti-metabolic in the long-term. We believe the goal of health should be to optimize the long-term metabolic function and energy supply. Thus the whole issue becomes a slight-of-hand. By saying that a low-carbohydrate diet reduces the fasting insulin and that this means the insulin resistance has been improved, low-carb advocates are essentially saying that by definition, low-carb diets are pro-metabolic. But in conclusion, it is a logical error. The fasting insulin level does not define the scientific principle of "insulin resistance." It is for this reason that we recommend that the use of this term be decreased in general. Instead, we recommend that we use the term "mitochondrial dysfunction" (or colloquially "engine malfunction") to describe the suboptimal burning of fuel into biochemical energy.

References

1. Sergi D, Naumovski N, Heilbronn LK, et al. Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet. Front Physiol. 2019;10:532. Published 2019 May 3. doi:10.3389/fphys.2019.00532
2. Kim JA, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res. 2008;102(4):401-414. doi:10.1161/CIRCRESAHA.107.165472