Most people are accustomed to thinking about insulin as a blood sugar regulating hormone. When blood glucose rises, insulin is secreted in order to help bring it down, partly via stimulation of insulin-sensitive glucose transporters. However, this is only one of insulin’s many roles completely unrelated to blood glucose. In fact, to many people’s surprise, insulin is not actually required for cellular glucose uptake. (The use of exogenous insulin in those with type 1 diabetes may be required more to suppress unopposed glucagon secretion than it is to facilitate glucose transport into cells. And even for insulin-sensitive glucose transporters, such as GLUT-4s, glucose uptake may occur in the absence of an insulin stimulus, such as via the non-insulin mediated glucose uptake induced by exercise.) The myopic focus on insulin as it relates to blood glucose has led us into a dark age wherein we have missed a host of health problems that occur in the presence of normal glucose but chronically elevated insulin.  

A previous article covered the work of Joseph Kraft, MD, who pioneered what is now sometimes referred to as the “Kraft test”—a modified oral glucose tolerance test (OGTT). It’s modified in that rather than the standard 2-hour test, the Kraft test is a 5-hour test, and instead of testing only glucose, insulin is also tested at each time point. These seemingly simple changes yielded extraordinary findings: a staggering number of people were identified as being hyperinsulinemic in the presence of normoglycemia. That is, high insulin levels were keeping the glucose from rising. But chronically elevated insulin, even in the absence of elevated glucose, is a major contributor to cardiometabolic disease. This is being missed because while fasting glucose is a routine part of a checkup or regular bloodwork, and even the HbA1c test is becoming more standard, insulin testing is still relatively uncommon.

Chronic hyperinsulinemia is the main causal factor in polycystic ovarian syndrome. To be clear, this is not a mere association. Hyperinsulinemia has been “causally linked to all features of the syndrome, such as hyperandrogenism, reproductive disorders, acne, hirsutism and metabolic disturbances.” (Emphasis added.) Looking at associations, chronically elevated insulin may be a factor in the etiology of conditions not typically thought of as having any connection to this “blood sugar hormone,” such as Parkinson’s disease, Alzheimer’s disease, benign prostate hyperplasia (BPH), erectile dysfunction, migraine, tinnitus, vertigo, Ménière’s disease, acne, and more. Obviously, not everyone living with these conditions has type 2 diabetes (T2D), which hammers home the point that it may be elevated insulin, rather than glucose, which may be conferring increased risk.

Indeed, a small study identified a high prevalence of undiagnosed insulin resistance among patients with Parkinson’s disease—and these individuals were not diabetic. (They were not classified as diabetic due to normal fasting glucose levels, but they were hyperinsulinemic.) It’s worth noting that insulin resistance (IR) was defined as HOMA-IR ≥ 2.0 or HbA1c ≥ 5.7, but HOMA-IR is based on fasting insulin and glucose levels. Using fasting levels, over half the subjects were identified as having undiagnosed IR. How many more might have been shown to have IR if insulin levels had been measured after a meal or a after a glucose load?

The same pattern was identified among patients with newly diagnosed multiple sclerosis (MS). A small study comparing newly diagnosed MS patients to healthy age-matched controls found that the two groups has similar fasting glucose levels and similar glycemic responses to an OGTT, but the MS patients showed an increased insulin response and decreased insulin sensitivity. This study and the Parkinson’s study both had very small sample sizes, but they raise interesting questions regarding a possible role for chronic hyperinsulinemia and IR in the etiology of neurodegenerative disorders. The authors of the MS paper noted, “The role of hyperinsulinemia in CNS function impairment should be further investigated.”

Chronically elevated insulin may be present long before rising blood glucose indicates any metabolic dysfunction. In one study, elevated insulin predicted progression to impaired glucose tolerance as far as twenty years in advance. It is imperative that physicians begin to understand the importance of measuring insulin levels when assessing patients and establishing the best course of treatment. In noting the numerous conditions that improve when insulin levels are reduced, one author even called lowering insulin “the sleeping giant in patient care.”

If someone is living with a condition known or highly suspected to be caused or exacerbated by chronic hyperinsulinemia, there are several interventions that may be effective for improving outcomes via lowering insulin levels. A previous article explored the powerful effects of very low-carbohydrate ketogenic diets for improving insulin and blood glucose dynamics. This dietary strategy is often used for weight loss, but it’s effective for reversing metabolic syndrome (i.e. “insulin resistance syndrome”) even in the absence of weight loss. Supplementation with inositol may be beneficial for those with IR. Metformin has been studied for numerous hyperinsulinemic conditions, and considering the overlapping effects of berberine and metformin, berberine may be a useful adjunct to diet and lifestyle changes.  

It’s time to awaken the sleeping giant and realize that even when blood sugar is normal, high insulin is an early indicator of metabolic dysfunction and may be a major contributor to the etiology and pathology of chronic cardiometabolic disease.