This comprehensive review reveals that high insulin levels caused by modern diets may be responsible for far more health problems than just diabetes and heart disease. The authors show how insulin resistance drives a hormonal cascade that can promote acne, early puberty, certain cancers, vision problems, and other conditions through effects on growth factors and sex hormones. These findings suggest that many "diseases of civilization" share a common root in our high-sugar, refined carbohydrate diet patterns.

Beyond Metabolic Syndrome: How High Insulin Levels Drive Modern Health Problems

Table of Contents

• Introduction: The Expanding Web of Insulin-Related Diseases
• Understanding Hyperinsulinemia and Insulin Resistance
• The Dietary Connection: How Modern Foods Drive Insulin Problems
• Historical Changes in Our Diet
• How Insulin Affects Growth Hormones and Sex Hormones
• Specific Health Conditions Linked to Hyperinsulinemia
• What This Means for Patients
• Study Limitations
• Practical Recommendations
• Source Information

Introduction: The Expanding Web of Insulin-Related Diseases

For nearly 60 years, doctors and researchers have suspected that insulin resistance—where your body's cells don't respond properly to insulin—plays a key role in many chronic diseases. The recognition that insulin resistance and its metabolic consequence, compensatory hyperinsulinemia (chronically high insulin levels), represent a unifying link common to type 2 diabetes, coronary artery disease, hypertension, obesity, and dyslipidemia (abnormal blood fats) is a more recent discovery from the past few decades.

This cluster of health problems is frequently called metabolic syndrome or Syndrome X. Additionally, abnormalities in fibrinolysis (how your body breaks down blood clots) and hyperuricemia (high uric acid levels) also appear to be part of this disease collection. The scale of these problems is staggering: 63% of men and 55% of women over age 25 in the United States are either overweight or obese, with an estimated 280,184 deaths per year attributable to obesity.

More than 60 million Americans have cardiovascular disease (the leading cause of mortality at 40.6% of all deaths), 50 million have hypertension, 10 million have type 2 diabetes, and 72 million adults maintain unhealthy cholesterol ratios. These diseases of insulin resistance represent the major health problem not just in the US, but throughout Western civilization.

Astonishingly, these conditions are either rare or virtually non-existent in hunter-gatherer and less Westernized societies eating their traditional diets. In the past 5 years, emerging evidence suggests that the web of diseases associated with high insulin levels extends far beyond the common metabolic problems. Such diverse conditions as acne, early puberty, certain cancers, increased height, nearsightedness, skin tags, acanthosis nigricans (darkened skin patches), polycystic ovary syndrome (PCOS), and male pattern baldness may all be linked to hyperinsulinemia through hormonal interactions.

Understanding Hyperinsulinemia and Insulin Resistance

When we eat carbohydrates, our digestive system breaks them down into glucose, which enters our bloodstream. In the first 2 hours after eating, glucose is rapidly absorbed and raises blood sugar levels. This increase, along with other digestive hormones, stimulates the pancreas to secrete insulin, causing a rapid rise in insulin levels.

The degree of blood sugar and insulin response depends primarily on the glycemic index (how quickly a food raises blood sugar) and glycemic load (glycemic index multiplied by carbohydrate content) of the food eaten. While mixed meals containing protein and fat alongside carbohydrates may lower the total response, repeated consumption of high-glycemic-index meals results in higher average 24-hour blood glucose and insulin concentrations compared to low-glycemic-index meals of identical calorie content.

Insulin resistance occurs when skeletal muscle resists insulin's signal to take up glucose. Although muscle is the main site of insulin-stimulated glucose uptake, fat tissue, liver, and endothelial cells also develop insulin resistance. The molecular basis is complex, but we know it results from four dietary-related elements working together: (1) chronic high blood glucose levels; (2) high insulin levels; (3) elevated VLDL cholesterol particles; and (4) high free fatty acids, along with genetic susceptibility.

When tissues become resistant to insulin's blood sugar-lowering effects, blood sugar doesn't necessarily rise pathologically at first because the pancreas secretes additional insulin. This maintenance of normal blood sugar through elevated insulin levels is called compensatory hyperinsulinemia—the fundamental metabolic disturbance underlying Syndrome X diseases.

The Dietary Connection: How Modern Foods Drive Insulin Problems

Of the four major dietary causes of insulin resistance (chronic elevations in blood glucose, insulin, VLDL, and free fatty acids), consumption of high-glycemic-load carbohydrates has the potential to promote all four. In the early (1-2 hour) period after eating, blood glucose levels are significantly higher following high-glycemic-index meals. Plasma insulin concentrations are also higher during this early post-meal period.

Compared to low-glycemic-load meals, high-glycemic-load meals acutely elevate plasma non-esterified free fatty acid (FFA) concentrations in the late (4-6 hour) post-meal period by enhancing fat breakdown from fat cells. These meals also increase liver secretion of VLDL particles during fasting and after absorption. Furthermore, insulin becomes stimulatory for VLDL secretion when the time between meals is short and insulin levels can't fall to baseline.

Taken together, the hormonal changes caused by habitual consumption of high-glycemic-load carbohydrates over a 24-hour period, particularly when consuming more calories than needed, promote the development of insulin resistance and compensatory hyperinsulinemia.

Paradoxically, while dietary fructose has a low glycemic index and load, it's routinely used to induce insulin resistance in animal studies at high dietary concentrations (35-65% of energy). Human studies show that high fructose feeding (usual diet plus 1000 extra calories of fructose daily) in healthy people also impairs insulin sensitivity. Even at concentrations achievable in a normal diet (17% of energy), fructose elevated blood triglyceride levels in healthy subjects.

Dietary fructose may contribute to insulin resistance through its unique ability among sugars to cause a shift in how the body handles free fatty acids. Although pure fructose elicits minimal insulin response, the most common forms in our diet—high-fructose corn syrup (HFCS) 42 and HFCS 55—are mixtures of fructose and glucose (42% fructose/53% glucose and 55% fructose/42% glucose, respectively) that do provoke significant insulin responses.

Historical Changes in Our Diet

Although refined sugars and cereals are common in modern diets, these high-glycemic-load carbohydrates were eaten sparingly or not at all by average people in 17th and 18th century Europe. They only became widely available in large quantities after the Industrial Revolution.

Data shows that per capita sucrose consumption in England increased steadily from 6.8 kg in 1815 to 54.5 kg in 1970. Similar trends occurred in the US and most European countries during this period. Since sucrose is digested into equal parts glucose and fructose, this increase meant a dramatic rise in both fructose and glucose consumption.

The changes in fructose consumption are particularly striking. With the advent of chromatographic fructose enrichment technology in the late 1970s, mass production of high-fructose corn syrup became economically feasible. The data shows rapid increases in HFCS 42 and HFCS 55 in the US food supply since their introduction.

The total amount of unbound fructose as a monosaccharide has increased by an astonishing 4800% in the past 30 years, from 0.3 kg in 1970 to 14.7 kg in 2000. Total dietary fructose (unbound plus fructose from sucrose) has increased by 26%, from 23.4 kg in 1970 to 29.5 kg in 2000. Total sugar intake has increased from 55.5 kg in 1970 to 69.1 kg in 2000.

Per capita sugar consumption in the US increased by 64% from 1909 to 1999, while fiber intake declined by 17.9% during this period. There have been important qualitative changes in carbohydrate consumption beyond increased sugar. High-glycemic-load refined cereal products now comprise 85.3% of all grain products consumed in the US, supplying 20% of energy in the typical US diet.

In the typical US diet, high-glycemic-load sugars now supply 16.1% of total energy and refined grains supply 20% of energy. This means at least 36% of total energy comes from foods known to promote the four causes of insulin resistance. These foods were rarely or never consumed as recently as 200 years ago.

While dietary fat consumption has also increased (up 32% from 1909-1919 to 1990-1999), fat alone under equal-calorie conditions doesn't cause insulin resistance in humans. Research shows that a range of equal-calorie diets containing up to 83% fat did not directly cause insulin resistance. Only when increased dietary fat leads to obesity does insulin resistance result.

However, high-glycemic-index foods are often high-fat foods as well (as shown in Table 3 of the original research). These foods frequently initiate a cycle of insulin-induced low blood sugar followed by overeating, where high-glycemic-index carbohydrates are preferentially consumed. The energy-dense fat component of these foods is often consumed simultaneously with the high-glycemic elements that promote insulin resistance.

How Insulin Affects Growth Hormones and Sex Hormones

The metabolic effects of chronic high insulin levels are complex and diverse. Research shows that the compensatory hyperinsulinemia that characterizes adolescent obesity chronically suppresses liver production of insulin-like growth factor-binding protein-1 (IGFBP-1), which in turn increases free insulin-like growth factor-1 (IGF-1), the biologically active part of circulating IGF-1.

Insulin and IGFBP-1 levels vary inversely throughout the day, and the suppression of IGFBP-1 by insulin (and consequent elevation of free IGF-1) may be maximal when insulin levels exceed 70-90 pmol/l. Additionally, growth hormone (GH) levels fall through negative feedback of free IGF-1 on GH secretion, resulting in reductions in IGFBP-3.

These studies demonstrate that both acute and chronic elevations of insulin result in increased circulating levels of free IGF-1 and reductions in IGFBP-3. Free IGF-1 is a potent growth promoter for virtually all of the body's tissues.

The reductions in IGFBP-3 stimulated by elevated serum insulin levels or by acute ingestion of high-glycemic carbohydrates may also contribute to uncontrolled cell proliferation. IGFBP-3 acts as a growth inhibitory factor in cells lacking the IGF receptor. In this capacity, IGFBP-3 inhibits growth by preventing IGF-1 from binding to its receptor.

Because consumption of refined sugars and starches promotes both acute and chronic high insulin levels, these common Western foods have the potential to elevate free IGF-1 and lower IGFBP-3 concentrations in the blood, thereby stimulating growth in many tissues throughout the body.

Insulin-mediated reductions in IGFBP-3 may further promote unregulated tissue growth through effects on the nuclear retinoid signaling pathway. Retinoids are natural and synthetic vitamin A analogues that inhibit cell proliferation and promote programmed cell death (apoptosis). The body's natural retinoids work by binding to nuclear receptors that activate genes whose function is to limit growth in many cell types.

IGFBP-3 is a ligand for the RXR alpha nuclear receptor and enhances its signaling. Studies show that both RXR alpha agonists and IGFBP-3 inhibit growth in many cell lines. Since RXR alpha is the major RXR receptor in epithelial tissue, low plasma levels of IGFBP-3 induced by high insulin may reduce growth-limiting signals in these tissues.

High insulin levels also reduce serum concentrations of sex hormone-binding globulin (SHBG), which carries testosterone and estrogen in the blood. Low SHBG increases free (biologically active) testosterone concentrations. SHBG levels are inversely related to both insulin and IGF-1 levels. Therefore, high-glycemic-load carbohydrates that promote hyperinsulinemia may simultaneously elevate serum androgen (male hormone) concentrations.

Specific Health Conditions Linked to Hyperinsulinemia

The authors identify multiple health conditions that may be connected to the hormonal changes caused by hyperinsulinemia:

• Acne: The hormonal environment created by high insulin levels (increased free IGF-1 and androgens, decreased IGFBP-3) promotes the development of acne
• Early menarche (puberty): The growth-promoting effects of this hormonal environment may accelerate the onset of puberty
• Certain cancers: Epithelial cell carcinomas (breast, colon, prostate) may be influenced by the growth-promoting environment
• Increased stature: The secular trend toward greater height in Western populations may be partially explained by these hormonal effects
• Myopia (nearsightedness): Unregulated growth effects may extend to eye development
• Cutaneous papillomas (skin tags): These common skin growths may result from the growth-promoting environment
• Acanthosis nigricans: Darkened, thickened skin patches often associated with insulin resistance
• Polycystic ovary syndrome (PCOS): The elevated androgens and metabolic disturbances directly contribute to this condition
• Male vertex balding: Pattern hair loss in men may be influenced by these hormonal changes

What This Means for Patients

This research suggests that many common health problems that we often consider separate conditions may actually share a common root cause in insulin resistance and compensatory hyperinsulinemia. The hormonal cascade triggered by high insulin levels—elevated free IGF-1 and androgens, reduced IGFBP-3 and SHBG—creates an environment throughout the body that promotes unregulated tissue growth and various abnormalities.

The implications are significant because they suggest that dietary interventions aimed at reducing insulin levels might help prevent or improve a wide range of conditions beyond diabetes and heart disease. This unified understanding of these "diseases of civilization" provides a framework for addressing multiple health issues through common lifestyle approaches.

For patients struggling with any of these conditions, this research offers hope that addressing the underlying insulin resistance through dietary changes may provide benefits across multiple health domains simultaneously.

Study Limitations

This research presents a theoretical framework based on existing evidence, but it's important to note that not all the proposed connections have been definitively proven through clinical trials. The article synthesizes evidence from multiple domains to build a compelling case, but more research is needed to confirm some of the specific mechanisms and relationships proposed.

The authors acknowledge that the molecular basis for peripheral insulin resistance is complex and incompletely understood. While the proposed mechanisms are biologically plausible and supported by various lines of evidence, human studies specifically testing these connections across all the mentioned conditions are limited.

Additionally, while the historical dietary data shows correlation between changes in food consumption patterns and health outcomes, causation cannot be definitively established from this evidence alone. Many other lifestyle factors have also changed during the period examined.

Practical Recommendations

Based on this research, patients concerned about insulin-related health issues might consider:

1. Reduce high-glycemic-load carbohydrates: Limit foods with high glycemic indexes such as refined sugars, white bread, white rice, and processed cereals
2. Choose whole food carbohydrates: Select fruits, vegetables, legumes, and whole grains that have lower glycemic impacts
3. Be mindful of fructose consumption: Limit foods with added fructose, particularly in the form of high-fructose corn syrup
4. Combine macronutrients: Eating proteins and healthy fats along with carbohydrates can help moderate blood sugar and insulin responses
5. Maintain healthy weight: Since obesity exacerbates insulin resistance, weight management is crucial
6. Regular physical activity: Exercise improves insulin sensitivity independently of dietary changes

It's important to note that dietary changes should be undertaken with professional guidance, especially for individuals with existing health conditions or those taking medications that affect blood sugar.

Source Information

Original Article Title: Hyperinsulinemic diseases of civilization: more than just Syndrome X

Authors: Loren Cordain, Michael R. Eades, Mary D. Eades

Publication: Comparative Biochemistry and Physiology Part A, Volume 136, Issue 1, September 2003, Pages 95-112

Affiliation: Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523, USA

This patient-friendly article is based on peer-reviewed research and aims to faithfully represent the original scientific content while making it accessible to educated patients. All numerical data, statistics, and findings have been preserved from the original publication.