Hyperinsulinemic diseases of civilization: more than just Syndrome X

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Abstract

Compensatory hyperinsulinemia stemming from peripheral insulin resistance is a well-recognized metabolic disturbance that is at the root cause of diseases and maladies of Syndrome X (hypertension, type 2 diabetes, dyslipidemia, coronary artery disease, obesity, abnormal glucose tolerance). Abnormalities of fibrinolysis and hyperuricemia also appear to be members of the cluster of illnesses comprising Syndrome X. Insulin is a well-established growth-promoting hormone, and recent evidence indicates that hyperinsulinemia causes a shift in a number of endocrine pathways that may favor unregulated tissue growth leading to additional illnesses. Specifically, hyperinsulinemia elevates serum concentrations of free insulin-like growth factor-1 (IGF-1) and androgens, while simultaneously reducing insulin-like growth factor-binding protein 3 (IGFBP-3) and sex hormone-binding globulin (SHBG). Since IGFBP-3 is a ligand for the nuclear retinoid X receptor α, insulin-mediated reductions in IGFBP-3 may also influence transcription of anti-proliferative genes normally activated by the body's endogenous retinoids. These endocrine shifts alter cellular proliferation and growth in a variety of tissues, the clinical course of which may promote acne, early menarche, certain epithelial cell carcinomas, increased stature, myopia, cutaneous papillomas (skin tags), acanthosis nigricans, polycystic ovary syndrome (PCOS) and male vertex balding. Consequently, these illnesses and conditions may, in part, have hyperinsulinemia at their root cause and therefore should be classified among the diseases of Syndrome X.

Introduction

Almost 60 years have passed since clinicians and researchers first suspected that tissue resistance to the actions of insulin may play a role in certain chronic disease states (Reaven, 1998). The recognition that insulin resistance and its metabolic sequel, compensatory hyperinsulinemia, represented a unifying link common to type 2 diabetes, coronary artery disease (CAD), hypertension, obesity and dyslipidemia (increased plasma triacylglycerols, decreased high density lipoproteins, and smaller, denser low-density lipoproteins) is a more recent phenomenon dating to the past decade or so (Reaven, 1988, Reaven, 1994, DeFronzo and Ferrannini, 1991). This cluster of maladies is frequently referred to as the metabolic syndrome or Syndrome X (Reaven, 1994). In addition, abnormalities of fibrinolysis and hyperuricemia also appear to be members of the collection of diseases comprising Syndrome X (Reaven, 1994).

A total of 63% of men and 55% of women over age 25 in the United States are either overweight or obese (Must et al., 1999) and the estimated number of deaths ascribable to obesity is 280 184 per year (Allison et al., 1999). More than 60 000 000 Americans have one or more types of cardiovascular disease, which represents the leading cause of mortality (40.6% of all deaths) in the US (American Heart Association, 2000). A total of 50 000 000 Americans are hypertensive, 10 000 000 have type 2 diabetes (American Heart Association, 2000), and 72 000 000 adults in the US maintain total cholesterol/high-density lipoprotein (HDL) cholesterol ratios of 4.5 or greater (Carroll et al., 1993). Accordingly, diseases of insulin resistance represent far and away the major health problem, not just in the US, but in virtually all of western civilization (Reaven, 1995, Seidell, 2000). Astonishingly, these maladies are either rare or virtually non-existent in hunter–gatherer and other, less westernized societies living and eating in their traditional manner (Schaeffer, 1971, Trowell, 1980, Eaton et al., 1988, Cordain et al., 2002). Hence, Syndrome X diseases have been dubbed, ‘Diseases of Civilization’ by numerous authors (Burkitt, 1973, Eaton et al., 1988, Reaven, 1995).

In the past 5 years, emerging evidence suggests that the web of diseases and abnormalities associated with hyperinsulinemia extend far beyond the common maladies (obesity, intra-abdominal obesity, type 2 diabetes, hypertension, dyslipidemia and CAD) that are frequently concurrently present in patients. Such diverse illnesses and conditions as acne, the secular trend for a reduced age of menarche, certain epithelial cell carcinomas (breast, colon and prostate), the secular trend for increased stature, myopia, cutaneous papillomas (skin tags), acanthosis nigricans, polycystic ovary syndrome (PCOS) and male vertex balding may all be linked to hyperinsulinemia by hormonal interaction.

Section snippets

Hyperinsulinemia

Upon digestion, dietary carbohydrates can be converted to glucose by enzymatic action in the gastrointestinal tract. In the first 2 h following carbohydrate consumption and digestion, glucose is rapidly absorbed and elevates plasma glucose concentrations. The subsequent hyperglycemia, along with increases in glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secreted from the gut, stimulate pancreatic insulin secretion, causing an acute rise in plasma insulin

High dietary glycemic loads and insulin resistance

Of the four major proximate dietary causes of peripheral insulin resistance (chronic and substantial elevations in plasma glucose, insulin, VLDL and free fatty acid concentrations), consumption of high-glycemic-load carbohydrates has the potential to promote all four. In the early (1–2 h) postprandial periods, blood glucose levels are significantly higher following consumption of high-glycemic-index meals (Ludwig, 2002). Plasma insulin concentrations are also higher in the early (1–2 h)

Secular changes in sucrose consumption

Although refined sugars and cereals are common elements of the modern urban diet, these high-glycemic-load carbohydrates were eaten sparingly or not at all by the average citizen in 17th and 18th century Europe and only started to become available to the masses in high quantities after the industrial revolution (Teuteberg, 1986). Fig. 1 shows that the per capita consumption of sucrose in England increased steadily from 6.8 kg in 1815 to 54.5 kg in 1970. Similar trends in sucrose consumption

Dietary fat and insulin resistance

Fig. 2 demonstrates that per capita dietary fat increased by 32% from 1909–1919 to 1990–1999, while total energy increased by 9%. Fig. 3 shows that the daily per capita increase in fat occurred primarily from increased consumption of monounsaturated and polyunsaturated fats, while saturated fat consumption remained nearly constant over the past 90 years. Hence, the increased consumption of dietary fat parallels that of dietary sugars; however, fat alone and under isocaloric conditions, unlike

Hyperinsulinemia and insulin-like growth factor (IGF) and IGF-binding proteins

The metabolic ramifications of chronic hyperinsulinemia are complex and diverse. It has been shown that the compensatory hyperinsulinemia that characterizes adolescent obesity chronically suppresses hepatic synthesis of insulin-like growth factor-binding protein-1 (IGFBP-1) which in turn serves to increase free insulin-like growth factor-1 (IGF-1), the biologically active part of circulating IGF-1 (Nam et al., 1997, Attia et al., 1998). The increase in circulating levels of insulin and IGFBP-1

Hyperinsulinemia, IGFBP-3 and retinoid receptors

Insulin-mediated reductions in IGFBP-3 may further promote unregulated tissue growth by its influence upon the nuclear retinoid signaling pathway. Retinoids are natural and synthetic analogues of vitamin A that inhibit cell proliferation and promote apoptosis (Evans and Kaye, 1999). The body's natural retinoids (trans- and 9-cis-retinoic acid) act by binding two families of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXR). Retinoid receptors, in turn, activate

Hyperinsulinemia, IGF-1 and sex steroids

Hyperinsulinemia may also influence the development of abnormalities involving unregulated tissue growth and/or other conditions via its well-established androgenic effects. Both insulin and IGF-1 stimulate the synthesis of androgens in ovarian (Barbieri et al., 1988, Cara, 1994) and testicular (De Mellow et al., 1987, Bebakar et al., 1990) tissues. Furthermore, insulin and IGF-1 inhibit the hepatic synthesis of sex hormone-binding globulin (SHBG) (Singh et al., 1990, Crave et al., 1995),

Hyperinsulinemia: more than Syndrome X diseases

Fig. 4 schematically demonstrates how diet-induced hyperinsulinemia may in part promote such diverse abnormalities as PCOS, acne, myopia, skin tags, acanthosis nigricans, certain epithelial cell cancers (breast, prostate and colon) and the secular trends for a reduced age of menarche and increased stature. Although these conditions and illnesses may appear to be seemingly unrelated, nearly all are characterized by enhanced or unregulated tissue growth that may be operative in part through

Summary

High-glycemic-load carbohydrates now comprise 36% or more of the daily energy in the typical US diet. Prior to the industrial revolution, refined sugars and cereal grains were rarely consumed by the average citizen. Accordingly, there has been a steady and continuous secular increase in the glycemic load of the typical western diet over the past 200–250 years. High-glycemic-load diets, coupled with susceptibility genes, initiate a hormonal cascade (Fig. 4) that facilitates unregulated or

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    This paper is part of a collection of inter-disciplinary, peer-reviewed articles under the Theme: “Origin and Diversity of Human Physiological Adaptability” invited by K.H. Myburgh and the late P.W. Hochachka.

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