• myopia;
  • form deprivation;
  • insulin resistance;
  • retinoic acid (RA);
  • retinoic acid receptors (RAR);
  • retinoid X receptors (RXR);
  • hunter gatherers;
  • insulin like growth factor 1 (IGF-1);
  • insulin like growth factor binding protein 3 (IGFBP-3)


  1. Top of page
  3. The evolutionary perspective
  4. Dietary induced hyperinsulinaemia and myopia
  5. References

The available evidence suggests that both genes and environment play a crucial role in the development of juvenile-onset myopia. When the human visual system is examined from an evolutionary perspective, it becomes apparent that humans, living in the original environmental niche for which our species is genetically adapted (as hunter-gatherers), are either slightly hypermetropic or emmetropic and rarely develop myopia. Myopia occurs when novel environmental conditions associated with modern civilization are introduced into the hunter-gatherer lifestyle. The excessive near work of reading is most frequently cited as the main environmental stressor underlying the development of myopia. In this review we point out how a previously unrecognized diet-related malady (chronic hyperinsulinaemia) may play a key role in the pathogenesis of juvenile-onset myopia because of its interaction with hormonal regulation of vitreal chamber growth.

Within the visual science community there is emerging consensus that the aetiology of juvenile-onset myopia involves both genetic and environmental elements (Wallman 1994; Mutti et al. 1996). However, the exact manner by which these two components interact to cause refractive errors remains elusive. Numerous studies have demonstrated that near work is related to myopia (Goldschmidt 1968; Angle & Wissmann 1980; Adams & McBrien 1992; Zylbermann et al. 1993), and a prospective study of microscopists, whose occupation requires excessive near work, has demonstrated that former emmetropes develop a progressive myopic shift during the course of their work (McBrien & Adams 1997). Further, animal studies verify that refractive errors can be induced through form deprivation and lens-induced defocus (Raviola & Wiesel 1985; Troilo & Wallman 1991; Norton & Siegwart 1995). Hence, excessive near work represents the single most frequently cited environmental factor associated with the development of juvenile-onset myopia.

Virtually all literate people in industrialized countries must do regular near work during childhood education, yet only a certain percentage (∼25–35% of the US population) ultimately develop myopia (Angle & Wissmann 1980; Sperduto et al. 1983; Wingert 1995). Therefore, the development of juvenile-onset myopia must also involve genetic susceptibility to excessive near work, and/or another unrecognized environmental stressor or stressors must operate either synergistically with, or independently of, excessive near work to elicit the phenotypic expression of juvenile-onset myopia.

Previous aetiologic analyses of myopia have almost always evaluated proximate mechanisms and have not considered evolutionary or ultimate explanations for this refractive malady. The intent of the present analysis is to review the available literature on the aetiology and pathogenesis of myopia from an evolutionary perspective in order to facilitate an understanding of how environmental factors may interact with genetic factors to cause refractive errors. Furthermore, we point out how a previously unrecognized dietary factor may play a key role in the pathogenesis of juvenile-onset myopia via interaction with hormonally mediated regulation of vitreal chamber growth.

The evolutionary perspective

  1. Top of page
  3. The evolutionary perspective
  4. Dietary induced hyperinsulinaemia and myopia
  5. References

There is little doubt that the development of myopia, in virtually all free-living wild vertebrates, represents a severe defect that in most cases would result in an early death. Except for certain species of non-visually dependent wild animals or domesticated animals, clear distance vision is required for escape from predators, location of food, recognition of other species members and awareness of environmental dangers and benefits. Consequently, any gene or genes that would elicit myopia would be lethal and rapidly eliminated by natural selection. Virtually all mammalian and bird eyes are usually slightly hyperopic at birth and move towards emmetropization during growth and development (Wallman 1990). The failure to appropriately match the focal length of the eye's optics with its axial length during growth and development produces myopia and, except for recent evidence with domesticated dogs (Mutti et al. 1999), appears to be unique to the human species.

The first members of the human genus (Homo) appeared in East Africa approximately 2.33 million years ago, and for all but the past 10,000 years (500 generations) since the advent of the agricultural revolution, all human ancestors have occupied the hunter-gatherer niche (Eaton & Konner 1984), a niche in which accurate distance vision was essential for survival (Nesse & Williams 1994). Despite the enormous selective pressures that would tend to eliminate myopic genes in humans living in a preagricultural, pretechnological society, myopia is extremely prevalent, affecting 25–35% of European descent populations (Angle & Wissmann 1980; Sperduto et al. 1983; Wingert 1995) and up to 50% or more of Asian descent populations (Au Eong et al. 1993). It has been suggested that, as primitive human societies acculturate, a relaxation of the selective pressures which would normally eliminate the gene or genes that evoke myopia has been responsible for its increased prevalence (Post 1962). It is certainly plausible that the natural selection pressures that had previously strongly selected against myopia in hunter-gatherers may have been slightly reduced with the advent of organized society. Moreover, these selective pressures would have been almost completely eliminated with the wide-scale availability of spectacle lenses in the 200 years since the industrial revolution. However, a number of lines of evidence strongly reject the notion that this recent (in evolutionary terms) relaxation of natural selection pressures could be responsible for the high incidence of myopia in modern, technological societies.

Visual acuity in hunter-gatherers

Most human populations worldwide abandoned the hunter-gatherer mode of subsistence long before the advent of modern visual refractive procedures. However, a few isolated hunter-gatherer societies persisted into the early 20th century and, fortunately, were refracted by frontier physicians, optometrists and ophthalmologists. These data provide important glimpses into the natural status of the primordial human visual system before our species' recent departure from the environmental niche to which we are genetically adapted.

Using a retinoscope and cycloplegia, Holm (1937) refracted 2364 members (aged 20–65 years) of several hunter-gatherer tribes in Gabon (formerly French Equatorial Africa) in 1936. Of the 3624 eyes examined, only 14 were classified as myopic (nine eyes from − 0.50 to 1.00 D; five eyes from − 3.00 to − 9.00 D), thereby yielding a myopia incidence rate of 0.4%. Similar low rates for myopia were reported by Skeller (1954), who refracted the eyes of 775 Angmagssalik Eskimos as part of a comprehensive anthropological study carried out in 1954. Retinoscopy in conjunction with cycloplegia demonstrated that of the 1123 eyes examined, only 13 (1.2%) were classified as myopic (nine eyes =− 1.00 D; four eyes =− 1.25 D). The now classic and often cited work by Young et al. (1969) demonstrated that the rate of myopia in 508 recently acculturated Eskimos in Barrow, Alaska was largely a function of age. The right eyes of 131 subjects over 41 years of age yielded only two myopic eyes (1.5%), whereas examination of the right eyes of 284 subjects aged between 11 and 40 years indicated a 51.4% rate of myopia of at least − 0.25 D. It was suggested that this astounding difference in incidence rates of myopia between younger and older subjects may have resulted from the influence of increasing acculturation. Most of the older adults had grown up and lived most of their early lives in isolated communities in the traditional aboriginal Eskimo mode and consequently had little or no schooling, whereas many of their children and grandchildren grew up in Barrow and had compulsory American style schooling. Young et al. (1969) concluded that the aetiology of myopia was largely due to environmental factors, specifically the excessive near work of reading that had only recently (within 2–3 generations) been introduced into this formerly traditional society of hunters and fishermen.

In a comparable study of 3677 recently acculturated Eskimos and Indians living in the Yukon and NorthWest territories, Morgan & Munro (1973) demonstrated a similar age-dependent reduction in myopia to that of the Alaskan Eskimos. Figure 1 shows that the prevalence of myopia (∼25–35%) in the younger subjects (aged 10–20 years) is similar to rates found in fully westernized countries, whereas the incidence of myopia (2–7%) in the older subjects (aged 30–60 years) more closely resembles rates of myopia among hunter-gatherers. This dramatic and rapid increase in the prevalence of myopia in a single generation (> 30 years versus < 20 years) occurred much too rapidly to reflect a sudden reduction in natural selection pressures. These data and that supplied by Young et al. (1969) fully support the notion that recently introduced, novel environmental stressors, perhaps interacting with previously latent myopia susceptibility genes, induce the phenotypic expression of refractive errors in distance vision. Morgan & Munro (1973), like Young et al. (1969) before them, suggested that increased schooling and hence increased near work in the younger subjects represented a novel environmental stressor that may have produced the dramatically higher rates of myopia in the younger subjects relative to their elders. Morgan & Munro 1973) hypothesized that dietary changes, especially increases in carbohydrate intake, might affect the structure of a growing eye. Cass (1966, 1973) has likewise reported low incidence rates of myopia in Eskimo adults when compared to those in children and suggested that increasing westernization, particularly the availability of store-bought food that is high in sugars and carbohydrate, may have been associated with the rapid increase of myopia noted in these aboriginal people.


Figure 1. Moderate myopia (1.00–5.00 D) by age in Indians and Eskimos of the Yukon and NorthWest territories. Adapted from Morgan et al. (1973).

Download figure to PowerPoint

Taken together, the few studies carried out in existing hunter-gatherer societies and in recently westernized hunter-gatherer groups indicate that the prevalence of myopia normally occurs in 0–2% of the population, and most refractive errors are less than − 1.00 D. Moderate to high myopia (− 3.00 to − 9.00 D) is either non-existent or occurs in about one person out of a thousand. The available literature suggests that either emmetropia or a slight hypermetropia represent the normal human refractive state under the environmental conditions for which our current genes were selected. When the novel environmental conditions associated with modern civilizations are introduced into the hunter-gatherer lifestyle, these people rapidly develop (within a single generation) incidence rates for myopia that equal or exceed those in western societies. There is substantial evidence to show that increased near work brought on by civilization's requirement for literacy, perhaps interacting with latent myopia susceptibility genes, may sometimes induce myopia. However, modern civilization brings with it not only literacy, reading and increased near work, but other environmental factors that may have the potential to disrupt the emmetropization process during growth and development.

Refractive status in partially westernizedpopulations

When the remnant hunter-gatherer societies of the far Northern Arctic westernized in the 20th century, the process was immediate, rapid and virtually all-inclusive. Many groups literally progressed from a Stone Age to a Space Age way of life in one or two generations. They rapidly adopted most of the trappings of fully modern societies with few or no intermediate steps (Schaefer 1977). In contrast, many of the less industrialized and less westernized societies that are still present on the earth maintain traditional ways of life that are intermediate between fully modern western societies and hunter-gatherer societies. Quite often these less westernized societies have schools and formalized educational systems, and a majority of their populations are literate. Near work and reading are therefore requirements, yet the prevalence of myopia is frequently lower than in more industrialized countries and similar to rates found in hunter-gatherer societies. These studies suggest that other environmental factors in addition to near work may induce refractive errors in distance vision.

Garner et al. (1999) measured visual acuity in two groups of children of similar genetic background but with varying degrees of acculturation living in Nepal. Children (n = 555) residing in the urban environment of Kathmandu had a 21.7% prevalence of myopia, whereas Sherpa children (n = 270) living in the rural region of Solu Khumbu maintained a 2.9% rate of myopia. In the Sherpa children, the highest negative refractive error was − 1.00 D, while it was − 6.50 D in the Kathmandu population. Both groups of children had compulsory schooling. However, those in Kathmandu were thought, by the authors, to attend a more rigorous programme than those in Solu Khumbu and hence more demands may have been placed upon their near vision. It should be noted that Kathmandu is a large city in which all western-type goods, including modern, processed foodstuffs are available, whereas Khumjung is an isolated village without electric power, television and other urban trappings. Consequently, Garner et al. (1999) suggested that other environmental factors besides excessive near work may have contributed towards the differences in the rates of myopia they observed. In an earlier study of 977 school children (6–17 years of age) on the remote South Pacific island of Vanuatu, Garner et al. (1985) found that only 1.3% of subjects had myopia greater than − 0.25 D, despite engaging in about 8 hrs of school work per day. These researchers concluded that genetic factors might have been responsible for the extremely low myopic rates in this group; however, they did not rule out environmental factors other than near work.

Lewallen et al. (1995) studied the prevalence of refractive errors in students (n = 352) attending a teacher's college in Malawi in sub-Saharan Africa. The students had originally come from rural areas where they had completed primary school and at least 2 years of secondary school, and all had engaged in regular reading. The prevalence of myopia was quite low, with only 4.1% of the population exhibiting mean spherical equivalents more negative or equal to − 0.50 D. Collectively, these studies indicate that, in rural populations, the near work of schooling does not elicit myopia incidence rates much beyond rates found in hunter-gatherer societies. It may be that the quantity and intensity of near work brought on by rural schooling is less than with urban schooling and hence produces lower rates of myopia. It could also be argued that additional environmental factors in urban areas, which are not present in rural areas, may influence the development of myopia.

In contrast to literate populations raised or living in rural areas, a number of studies have reported the incidence of myopia in illiterate populations living in both urban and rural areas. The percentage of myopes among urban illiterates in Cairo, Egypt has been reported as ranging from 11 to 39% in four groups totaling 1173 subjects (Post 1962). More recently, Wong et al. (1993) demonstrated an 18.4% rate of myopia among urban Hong Kong fishermen (n = 152) who had never attended school. In contrast to illiterate urban populations, the rate of myopia (2.4%) in illiterate rural groups (Lewallen et al. 1995) is similar to the rates found in hunter-gatherer societies (Holm 1937; Skeller 1954; Cass 1966; Young et al. 1969; Cass 1973; Morgan & Munro 1973). It is certainly possible that illiterate urban workers may engage in other near work besides reading that could potentially evoke myopia. However, anthropological studies of hunter-gatherers, particularly Eskimos, have shown that while both women and men may engage in near work (sewing, tool making, artwork) for hours on end in dimly lit snow houses during the long arctic winter (Stefansson 1919), they do not develop myopia (Skeller 1954; Cass 1966; Young et al. 1969; Cass 1973; Morgan & Munro 1973). Furthermore, because three peculiarities of the printed page (a narrow range of luminance, achromaticity of text, and high spatial frequency of text) reduce the activity of non-foveal retinal neurons during reading, it has been argued that the near work of reading is a more potent inducer of form deprivation and hence the development of myopia than other types of near work (Chew & Balakrishnan 1992). These studies of the incidence rates of myopia among illiterate groups again suggest that environmental factors as well as excessive near work play a part in the aetiology of myopia.

Dietary induced hyperinsulinaemia and myopia

  1. Top of page
  3. The evolutionary perspective
  4. Dietary induced hyperinsulinaemia and myopia
  5. References

Dietary carbohydrates in hunter-gatherers

When hunter-gatherer societies of the 20th century left their Stone Age existence behind, they not only became literate and began reading within one or two generations, but they characteristically altered the type of food they had previously consumed (Schaefer 1971; Schaefer 1977). In their study of 229 hunter-gatherer societies, Cordain et al. (2000) found that although refined cereals and sugars were rarely if ever consumed by groups living in their traditional manner, these foods quickly became dietary staples following western contact. Schaefer (1971; 1977) has shown that, in two Eskimo groups undergoing western acculturation, the per capita consumption of sugar in all forms increased from 11.8 kg in 1959 to 47.4 kg in 1967. The same groups' per capita consumption of cereals and flour products increased from 71.0 kg in 1959 to 80.0 kg in 1967. Prior to western contact, neither of these carbohydrates was ever consumed (Stefansson 1919).

Hunter-gatherer diets are typically characterized by high levels of protein, moderate levels of fat and low levels of carbohydrate when compared to modern western diets (Cordain et al. 1999). The carbohydrates present in hunter-gatherer diets are of a low glycaemic index: they are slowly absorbed and produce a gradual and minimal rise in plasma glucose and insulin levels when compared to the sugars and refined starches in western diets (Thorburn et al. 1987a; Thorburn et al. 1987b). The glycaemic index is influenced by the particle size, processing technique, and relative fibre, protein and fat content of the carbohydrate food. The glycaemic index of mixed meals is determined by multiplying the percentage of total meal carbohydrate by its glycaemic index and summing these values for all foods (Wolever et al. 1991). The total glycaemic load is the (glycaemic index × carbohydrate content) of each food.

The addition of high glycaemic load carbohydrates to the diet represented a near universal change in the nutritional patterns of hunter-gatherer populations as they made the transition from forager to modern consumer in the 20th century (Brand & Colagiuri 1994; Eaton et al. 1997). Studies of recently acculturated hunter-gatherer populations that have adopted western dietary patterns frequently show high levels of hyperglycaemia, insulin resistance, hyperinsulinaemia and type II diabetes (Ebbesson et al. 1998; Daniel et al. 1999). Conversely, hunter-gatherer populations in their native environments rarely exhibit these symptoms (Schaefer 1969; Merimee et al. 1972; Spielman et al. 1982; O'Dea 1984).

The secular increase in high glycaemicload foods in industrialized countries

Hunter-gatherer populations that adopted modern foods in the 20th century were subjected to an immediate change from low glycaemic to high glycaemic load carbohydrates that occurred shortly after western contact began. In industrialized countries, this dietary shift occurred more slowly over the 200 or so years since the advent of the industrial revolution as more and more refined sugars were gradually included in the diet along with increasingly greater levels of refined cereals. Although highly refined sugars and cereals are common elements of the modern urban diet, these 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 after the industrial revolution (Teuteberg 1986). In England, the per capita consumption of sucrose has risen steadily risen from 6.8 kg in 1815 to 54.5 kg in 1970 (Cleave 1974). Although refined cereals represent the highest percentage of carbohydrate in the western diet, this has not always been the case (Cordain et al. 1999). Only with the widespread introduction of steel roller mills in the late 19th century (∼ 1880) did fibre-depleted wheat flour of a low extraction (≤ 70%) become widely available (Cleave 1974). Hence, over the last 200–250 years the average glycaemic load of foods in urban areas of industrialized countries has risen steadily, primarily because of increasing consumption of refined cereals and sugars (Cleave 1974). Populations living in more rural areas of both industrialized and non-industrialized countries typically have limited access to processed foods, sugars and refined cereal products (Trowell 1985). Accordingly, their diets are usually comprised of locally grown, minimally processed foods, and hence the glycaemic load of these traditional foods is generally lower than highly processed and packaged foods typically available in urban markets (Foster-Powell & Brand Miller 1995). Table 1 shows the glycaemic index and glycaemic load of both traditional and processed foods.

Table 1.  Glycaemic indices and loads (glycaemic index × carbohydrate content in 10 g portions) of refined western foods and unrefined traditional foods (glucose as reference standard = 100), adapted from Foster-Powell & Brand Miller (1995).
FoodWestern refined foodsFoodUnrefined traditional foods
Glycaemic indexGlycaemic loadGlycaemic indexGlycaemic load
Rice crispie cereal8877.3Parsnips9719.5
Jelly beans8074.5Baked potato8518.4
Cornflakes8472.7Boiled millet7116.8
Lifesavers7067.9Boiled broad beans7915.5
Rice cakes8266.9Boiled couscous6515.1
Table sugar (sucrose)6564.9Boiled sweet potato5413.1
Shredded wheat cereal6957.0Boiled brown rice5512.6
Graham crackers7456.8Banana5312.1
Grapenuts cereal6754.3Boiled yam5111.5
Cheerio cereal7454.2Boiled garbanzo beans339.0
Rye crispbread6553.4Pineapple668.2
Vanilla wafers7749.7Grapes437.7
Corn chips7346.3Kiwi fruit527.4
Mars bar6842.2Carrots717.2
Stone wheat thins6741.9Boiled peas486.8
Shortbread cookies6441.9Boiled beets646.3
Granola bar6139.3Boiled kidney beans276.2
Angel food cake6738.7Apple396.0
Bagel7238.4Boiled lentils295.8
White bread7034.7Watermelon725.2
All bran cereal4232.5Cherries223.7
Whole wheat bread6931.8Peach283.1

Hyperinsulinaemia and the consumptionof high glycaemic load foods

Over the past 20 years, accumulating evidence has shown that the consumption of foods with a high glycaemic load, such as processed foods containing refined starches and sugars, promotes the development of both acute and chronic hyperinsulinaemia. Numerous studies have demonstrated that the addition of sucrose to the diet of both normal (Reiser et al. 1979; Coulston et al. 1983) and hyperinsulinaemic subjects (Reiser et al. 1981) causes an increase in postprandial insulin levels. Larger intakes of sucrose (35% total energy) have been shown to decrease insulin sensitivity (Beck-Nielsen et al. 1978), and impaired insulin binding also occurs from high fructose feedings (Beck-Nielsen et al. 1980; Dirlewanger et al. 2000). Further, dietary intervention studies using low glycaemic loads are known to improve insulin sensitivity (Frost et al. 1998), and low glycaemic loads reduce the risk of type II diabetes (Salmeron et al. 1997). In contrast, intervention studies manipulating dietary fatty acids have shown no beneficial effects upon insulin metabolism (Vessby 2000), nor have dietary interventions been able to show deleterious effects upon insulin sensitivity when total fat was increased from 20 to 40% energy (Riccardi & Rivellese 2000). When dietary manipulations lead to weight loss, insulin sensitivity is generally improved (Klein 2001). Collectively, these studies show that increasing consumption of high levels of refined carbohydrates, particularly under hyper caloric conditions, is partially responsible for the worsening of glycaemic control, which may in turn promote insulin resistance and compensatory hyperinsulinaemia (Reaven 1994).

Hyperinsulinaemia and insulin likegrowth factor (IGF) and IGF bindingproteins

The metabolic ramifications of dietary induced perturbations of insulin action are diverse and complex. It has recently been demonstrated that the compensatory hyperinsulinaemia 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). Circulating levels of insulin and IGFBP-1 vary inversely throughout the day, and the suppression of IGFBP-1 by insulin (Brismar et al. 1994), and hence elevation of free IGF-1, may be maximal when insulin levels exceed 70–90 pmol/L (Holly 1991). Additionally, growth hormone (GH) levels fall via negative feedback of free IGF-1 on GH secretion, resulting in reductions in IGFBP-3 (Attia et al. 1998). These experiments show that both acute (Attia et al. 1998) and chronic (Nam et al. 1997; Attia et al. 1998; Wong et al. 1999) elevations of insulin result in increased circulating levels of free IGF-1, a potent stimulator of growth in all tissues. Because consumption of refined sugars and starches promotes both acute and chronic hyperinsulinaemia, these common foods in the western diet have the potential to elevate free IGF-1 and lower IGFBP-3 in all peripheral tissues, including scleral chondrocytes and fibroblasts.

The reductions in IGFBP-3 stimulated by elevated serum insulin levels (Nam et al. 1997; Attia et al. 1998) or by acute ingestion of high glycaemic carbohydrates (Liu 2000) may also contribute to unregulated cell proliferation in scleral tissue. Insulin like growth factor binding protein-3 has been shown to act as a growth inhibitory factor in murine knockout cells lacking the IGF receptor (Valentinis et al. 1995). Accordingly, in this capacity IGFBP-3 is inhibitory to growth by preventing IGF-1 binding to its receptor. Consequently, enhanced scleral growth may result synergistically from both elevations in free IGF-1 and reductions in IGFBP-3.

Hyperinsulinaemia and retinoid receptors

Retinoids are natural and synthetic analogues of vitamin A that inhibit cell proliferation and promote apoptosis (programmed cell death) (Evans & Kay 1999). The body's natural retinoids (trans retinoic acid and 9 cis retinoic acid) act by binding two families of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Retinoid receptors, in turn, activate gene transcription by binding as RAR/RXR heterodimers or RXR homodimers to retinoic acid response elements located in the promoter regions of target genes whose function is to limit growth in many cell types (Yang et al. 2001). It has recently been established that IGFBP-3 is a ligand for the RXR alpha nuclear receptor and that IGFBP-3 enhances RXR-RXR homodimer mediated signaling (Liu et al. 2000). Studies in knockout rodents show that the RXR alpha gene is required for actions of the two endogenous retinoic acid ligands (trans retinoic acid and cis 9 retinoic acid) (Chiba et al. 1997; Wendling et al. 1999), and both RXR alpha agonists and IGFBP-3 are growth inhibitory in many cell lines (Grimberg & Cohen 2000).

Additionally, RXR alpha receptors are preferentially found in periocular mesenchyme (Mori et al. 2001) and scleral chondrocytes (Fischer et al. 1999). Consequently, low plasma levels of IGFBP-3 induced by hyperinsulinaemia may reduce the effectiveness of the body's natural retinoids in activating genes that would normally limit scleral cell proliferation.

Proposed model of juvenile-onset myopia

Numerous studies have conclusively demonstrated that, in juvenile-onset myopia, abnormal axial elongation of the eyeball is the major structural change that causes refractive errors in distance vision (Zadnik et al. 1993; Lin et al. 1996; Lam et al. 1999). Both animal (Raviola & Wiesel 1985; Troilo & Wallman 1991; Norton & Siegwart 1995) and human (Meyer et al. 1999) studies suggest that the absence of a clear retinal image during critical periods of postnatal development triggers an axial elongation of the vitreal chamber producing a so-called form deprivation myopia. Furthermore, in animal models of form deprivation myopia, there is a characteristic active remodelling and differentiation of scleral cartilage brought about by proliferation of both scleral chondrocytes and fibroblasts that causes the axial elongation of experimental myopia (Seko et al. 1995; Kusakari et al. 1997; Gentle and McBrien 1999).

The chemical messenger linking retinal image clarity to appropriate growth rates in scleral tissue has recently been shown to be retinoic acid synthesized by both the retina and choroid (Bitzer et al. 2000; Mertz & Wallman 2000). Reduced choroidal synthesis of retinoic acid increases scleral growth, whereas increased synthesis of retinoic acid slows growth (Mertz & Wallman 2000). Consequently, excessive near work may induce myopia because form deprivation causes the choroid to produce too little retinoic acid.

Compensatory hyperinsulinaemia, via its lowering of plasma IGFBP-3 and subsequent reduction in RXR homodimer signaling, may augment scleral tissue growth by attenuating the ability of endogenous retinoids to activate genes that would normally limit scleral cell proliferation. Additionally, diet-induced hyperinsulinaemia chronically elevates IGF-1, which may operate synergistically with plasma reductions in IGFBP-3 to accelerate scleral tissue growth. Figure 2 schematically represents our model of juvenile-onset myopia.


Figure 2. Schematic diagram depicting how compensatory hyperinsulinaemia facilitates unregulated scleral tissue growth via increases in IGF-1 and attenuation of the retinoic acid signal.

Download figure to PowerPoint

Corroborative evidence

The recent realised fact that hyperinsulinaemia elicits an abnormal increase in circulating levels of free IGF-1 has ramifications that extend beyond the accelerated growth of scleral tissue and the development of myopia. Free IGF-1 is a potent mitogen for virtually all of the body's tissues (Ferry et al. 1999), as well as a stimulant for increased growth velocity during puberty (Juul et al. 1995). Numerous studies have confirmed that low levels of IGF-1 are associated with reduced stature (Blum et al. 1993; Lindgren et al. 1996) and conversely high levels are known to result in increased stature (Gourmelen et al. 1984; Binoux & Gourmelen 1987; Blum et al. 1993). Human recombinant IGF-1 therapy has also been shown to improve linear growth (Camacho-Hubner et al. 1999). Further, hyperinsulinaemic subjects with elevated levels of free IGF-1 are more sexually mature than subjects with superior insulin sensitivity (Travers et al. 1998; Wong et al. 1999), and recombinant IGF-1 therapy has been shown to accelerate the tempo of puberty in a primate model (Wilson 1998). Recently, Wong et al. (1999) provided metabolic evidence showing that black American girls were more advanced in their pubertal development and taller than a comparable group of white American girls. Further, circulating levels of IGFBP-1 were lower in the black group than in the white group, while circulating levels of insulin and free IGF-I were higher in the black group than in the white group. This suggests that the metabolic cascade (insulin resistance – hyperinsulinaemia – decrease in hepatic IGFBP-I production – increase in circulating free IGF-I – accelerated growth) may take place. Collectively, this evidence supports the view that increased levels of IGF-1 act systemically to cause increased stature and an earlier onset of puberty.

As consumption of refined carbohydrates has the capacity to acutely and chronically elevate insulin levels, which in turn increase circulating levels of free IGF-1, it might be assumed that epidemiological studies would indicate a relationship between the consumption of high glycaemic foods and increased stature and earlier onset of puberty. Further, it might be expected that myopes would tend to consume foods of a higher glycaemic index, be taller, have an earlier pubertal age and present more frequently with type II diabetes than non-myopes.

Industrialized countries have witnessed a steady and progressive secular increase in stature and reduction in pubertal age over the 200–250 years since the advent of the industrial revolution (Malina 1990). The standard explanation for this trend has been that improvements in nutrition, particularly increases in protein and fat from animal sources, and improvements in hygiene operate to increase stature (Roche 1979). In contrast to this explanation, Ziegler (1967, 1969) has demonstrated that the secular increase in stature correlates highly with sucrose consumption in the UK, Japan, Netherlands, Sweden, Norway, Denmark, the USA and New Zealand. In support of Ziegler's hypothesis, Schaefer's (1970) data on recently acculturated Eskimos shows that during the 30-year period (1938–68) when a several fold increase in the consumption of sucrose and refined carbohydrates occurred, the group's average stature increased (by 4.6 cm in men and 2.9 cm in women), while its average age of onset of puberty (by − 2.0 years). Moreover, animal protein intake during the period declined by 60%. Since then, a study examining the relationship of dietary fibre to the age of menarche in girls from 46 countries has demonstrated a strong positive correlation (r = 0.84) (Hughes & Jones 1985). Because dietary fibre is inversely related to the glycaemic index (Foster-Powell & Brand Miller (1995); Salmeron et al. 1997), this relationship supports the hypothesis that increasing consumption of refined carbohydrates may accelerate pubertal development. Further, multiple studies have demonstrated that hyperinsulinaemia and insulin resistance occurs more often in women with premature menarche than in compared to women with normal menarche (Loffer 1975; Ibanez et al. 1998). Taken together, these studies indicate that intakes of high glycaemic carbohydrates correlate well in time and space with the secular trends for increased stature and decreased pubertal age.

Many surveys of myopes have shown them to be taller than non-myopes (Johansen 1950; Gardiner 1954; Pendse & Bhave 1954; Gardiner 1955; Gardiner 1956a; Benoit 1958; Gardiner 1958; Douglas et al. 1967; Scholz 1970; Johnson et al. 1979; Krause et al. 1982; Teikari 1987; Teasdale & Goldschmidt 1988). However, not all surveys have shown myopes as taller (Young et al. 1954; Sorsby et al. 1961; Gawron 1981; Parssinen et al. 1985; Rosner et al. 1995). In a study examining the refractive errors in an isolated Labrador community of Eskimos, mixed Eskimo-Caucasians, and Caucasians, Johnson et al. (1979) demonstrated that the children of the Eskimos and mixed race population were taller than their parents, had greater axial eyeball lengths, and were more myopic. These researchers showed that the rise in the incidence of myopia, increased axial eyeball length and stature occurred coincidentally with the increasing volume of store foods (mainly in the form of carbohydrates) that had become available in the preceding 30 years. Gardiner (1955, 1956a, 1964) has extensively studied the growth patterns of myopes and has concluded that ‘myopic children grow and mature faster than other children and that the more myopic they are, the more these trends are exhibited’. Figure 3 demonstrates differences in stature among 3–16 year-olds, comparing high and moderate myopes with a control group. Figure 4 shows that the body mass index in myopes is also higher than in non-myopes. Gardiner has not only shown that myopic children are taller than their non-myopic counterparts, but has presented both cross sectional (Gardiner 1954) and prospective (Gardiner 1964) evidence of an earlier age of menarche in female myopes. This evidence has been corroborated by two other large epidemiological studies (Douglas et al. 1967; Scholz 1970) showing that myopes were both taller and had an earlier age of menarche than non-myopes.


Figure 3. Height from ages 3–16 years in myopes (> − 3.0 D at age 14 years; n= 74), myopes (< − 3.0 D at age 14 years; n= 98) and non-myopic controls (n = 277). Adapted from Gardiner (1954).

Download figure to PowerPoint


Figure 4. Body mass index (BMI) from ages 3–16 years in myopes (myopia developed at any age) and non-myopic controls. Adapted from Gardiner (1954).

Download figure to PowerPoint

Gardiner (1964) suggested that accelerated growth patterns in myopes were linked to their refractive errors, and that diet may represent an underlying environmental factor common to both the development of myopia and generalized accelerated growth. In a number of studies, Gardiner (1956a, 1956b) indicated that myopes consumed significantly lower amounts of animal protein than non-myopes. Further, he was able to show that by increasing the level of animal protein in the diets of myopic children, the progression of their myopia slowed when compared to a control group receiving no dietary modification during a year long experiment (Gardiner 1958). Dietary protein generally results in lower rises in both plasma glucose and insulin when compared to carbohydrate (Brand Miller et al. 2000). Hence, it is possible that the increased animal protein levels in Gardiner's 1958 experiment may have attenuated postprandial and chronic insulin levels in his subjects, thereby reducing free IGF-1, elevating IGFBP-3 and enhancing RXR signaling which in turn slowed scleral axial growth and the progression of myopia. The benefits of reduced intake of carbohydrate and increased intake of animal protein on the progression of human myopia have also been reported elsewhere (Walkingshaw 1964).

Observations from Scandinavian studies (Fledelius 1983; Fledelius 1986; Fledelius et al. 1990) demonstrating increased incidence of myopia among type II adult diabetics compared to non-diabetics support the hormonal cascade linking insulin resistance to myopia. In the diabetic group, 37.9% of the subjects were myopic compared to 27.5% in the non-diabetic group (Fledelius 1983).

Although diseases of insulin resistance including type II diabetes have an important environmental aetiological component, they also have a crucial genetic basis (Neel et al. 1998; Barroso et al. 1999). Population studies have demonstrated that people of Asian and Chinese descent tend to be more insulin resistant than people of European descent (Beischer et al. 1991; King & Rewers 1993). The prevalence of myopia is also higher in Asian populations than it is in European populations (AuEong et al. 1993; McCarty et al. 1997); it is possible that the higher rates of myopia in Asian populations may, in part, be due to their increased genetic susceptibility to insulin resistance. Although some population studies have shown Asian groups to be shorter than people of European descent (Duignan et al. 1975; Chin et al. 1997), these data do not necessarily invalidate the presumed relationships between insulin resistance, myopia and height because of other known genetic determinants of adult stature, independent of insulin resistance, which vary between racial groups (Katzmarzyk & Leonard 1998). Hence, the comparison of stature between Asian myopes and non-myopes would represent a more logical and meaningful evaluation of the relationships between insulin resistance, adult stature and the development of myopia.

A number of human studies have shown that myopes have more dental caries than non-myopes (Goldstein et al. 1971; Hirsch & Levin 1973), and that the degree of myopia may be related to the caries incidence (Hirsch & Levin 1973). Recently, it has been shown that progressive myopes have higher amounts of dental caries than stable myopes (Edwards & Chan 1995). The mechanistic nature of this relationship remains obscure. However, as we now know that high glycaemic load carbohydrates, such as sucrose and refined cereal products made with sucrose, may induce hyperinsulinaemia, and that hyperinsulinaemia increases free IGF-1, lowers IGFBP-3 and reduces RXR signaling, we may suppose that the causal mechanism probably involves sucrose's well known cariogenic effect and its hyperinsulinaemic effect.High sucrose, low protein diets in both rabbits (Gardiner & MacDonald 1957) and rats (Bardiger & Stock 1972) have been shown to lower the degree of hypermetropia (i.e. produce refractive changes in a myopic direction); this had not proved possible with a sucrose free diet (Bardiger & Stock 1972). In summary, these studies suggest that high glycaemic load carbohydrate diets may induce permanent changes in the development and progression of refractive errors, particularly during periods of growth.


  1. Top of page
  3. The evolutionary perspective
  4. Dietary induced hyperinsulinaemia and myopia
  5. References
  • Adams DW & McBrien NA (1992): Prevalence of myopia and myopic progression in a population of clinical microscopists. Optom Vis Sci 69: 467473.
  • Angle J & Wissmann DA (1980): The epidemiology of myopia. Am J Epidemiol 111: 220228.
  • Attia N, Tamborlane WV, Heptulla R, Maggs D, Grozman A, Sherwin RS & Caprio S (1998): The metabolic syndrome and insulin-like growth factor I regulation in adolescent obesity. J Clin Endocrinol Metab 83: 14671471.
  • Au Eong KG, Tay TH & Lim MK (1993): Race, culture and myopia in 110 236 young Singaporean males. Singapore Med J 34: 2932.
  • Bardiger M & Stock AL (1972): The effects of sucrose-containing diets low in protein on ocular refraction in the rat. Proc Nutr Soc 31: 4A5A.
  • Barroso I, Gurnell M & Crowley VE et al. (1999): Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402: 880883.
  • Beck-Nielsen H, Pedersen O & Lindskor HO (1980): Impaired cellular binding and insulin sensitivity induced by high-fructose feeding in normal subjects. Am J Clin Nutr 33: 273278.
  • Beck-Nielsen H, Pedersen O & Sorensen NS (1978): Effects of diet on cellular insulin binding and the insulin sensitivity in young healthy subjects. Diabetologia 15: 289296.
  • Beischer NA, Oats JN, Henry OA, Sheedy MT & Walstab JE (1991): Incidence and severity of gestational diabetes mellitus according to country of birth in women living in Australia. Diabetes 40: 3538.
  • Benoit A (1958): Biotypologie de 1'homme myope. Arch Opht (Paris) 18: 734752.
  • Binoux M & Gourmelen M (1987): Statural development parallels IGF I levels in subjects of constitutionally variant stature. Acta Endocrinol 114: 524530.
  • Bitzer M, Feldkaemper M & Schaeffel F (2000): Visually induced changes in components of the retinoic acid system in fundal layers of the chick. Exp Eye Res 70: 97106.
  • Blum WF, Albertsson-Wikland K, Rosberg S & Ranke MB (1993): Serum levels of insulin-like growth factor I (IGF-I) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab 76: 16101616.
  • Brand JC & Colagiuri S (1994): The carnivore connection: dietary carbohydrate in the evolution of NIDDM. Diabetologia 37: 12801286.
  • Brand Miller JC, Colagiuri S & Gan ST (2000): Insulin sensitivity predicts glycaemia after a protein load. Metabolism 49: 15.
  • Brismar K, Fernqvist-Forbes E, Wahren J & Hall K (1994): Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-1 in insulin dependent diabetes. J Clin Endocrinol Metab 79: 872878.
  • Camacho-Hubner C, Woods KA, Miraki-Moud F, Clark A & Savage MO (1999): Effects of recombinant human insulin-like growth factor I (IGF-I) therapy on the growth hormone-IGF system of a patient with a partial IGF-I gene deletion. J Clin Endocrinol Metab 84: 16111616.
  • Cass E (1966): Ocular conditions amongst the Canadian western arctic Eskimo. In: Weigelin, E (ed.). Proceedings of the XX International Congress of Ophthalmology. Excerpta Medica Foundation. New York, USA. 10411053.
  • Cass E (1973): A decade of northern ophthalmology. Can J Ophthalmol 8: 210217.
  • Chew SJ & Balakrishnan V (1992): Myopia produced in young chicks by intermittent minimal form visual deprivation – can spectacles cause myopia. Singapore Med J 33: 489492.
  • Chiba H, Clifford J, Metzger D & Chambon P (1997): Distinct retinoid X receptor-retinoic acid receptor heterodimers are differentially involved in the control of expression of retinoid target genes in F9 embryonal carcinoma cells. Mol Cel Biol 17: 30133020.
  • Chin K, Evans MC, Cornish J, Cundy T & Reid IR (1997): Differences in hip axis and femoral neck length in premenopausal women of Polynesian, Asian and European origin. Osteoporosis Int 7: 344347.
  • Cleave TL (1974): The Saccharine Disease. John Wright & Sons Ltd. Bristol, UK. 627.
  • Cordain L (1999): Cereal grains: humanity's double-edged sword. World Rev Nutr Diet 84: 1973.
  • Cordain L, Brand Miller J, Eaton SB, Mann N, Holt SH & Speth JD (2000): Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets. Am J Clin Nutr 71: 682692.
  • Coulston AM, Liu GC & Reaven GM (1983): Plasma glucose, insulin and lipid responses to high-carbohydrate low-fat diets in normal humans. Metabolism 32: 5256.
  • Daniel M, Rowley KG, McDermott R, Mylvaganam A & O'Dea K (1999): Diabetes incidence in an Australian aboriginal population. An 8-year follow-up study. Diabetes Care 22: 1993–1998.
  • Dirlewanger M, Schneiter P, Jequier E & Tappy L (2000): Effects of fructose on hepatic glucose metabolism in humans. Am J Physiol Endocrinol Metab 279: E907E911.
  • Douglas JWB, Ross JM & Simpson HR (1967): The ability and attainment of short-sighted pupils. J Royal Stat Soc Series A (General) 130: 479504.
  • Duignan NM, Studd JW & Hughes AO (1975): Characteristics of normal labour in different racial groups. Br J Obstet Gynaecol 82: 593601.
  • Eaton SB, Eaton SB III & Konner MJ (1997): Paleolithic nutrition revisited: a 12-year retrospective on its nature and implications. Eur J Clin Nutr 51: 207216.
  • Eaton SB & Konner M (1984): Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med 312: 283289.
  • Ebbesson SO, Schraer CD, Risica PM et al. (1998): Diabetes and impaired glucose tolerance in three Alaskan Eskimo populations. The Alaska-Siberia project. Diabetes Care 21: 563569.
  • Edwards MH & Chan JCY (1995): Is there a difference in dental caries between myopic and non-myopic children. Optom Vis Sci 72: 573576.
  • Evans TRJ & Kaye SB (1999): Retinoids: present role and future potential. Br J Cancer 80: 18.
  • Ferry RJ, Cerri RW & Cohen P (1999): Insulin-like growth factor binding proteins: new proteins, new functions. Horm Res 51: 5367.
  • Fischer AJ, Wallman J, Mertz JR & Stell WK (1999): Localization of retinoid binding proteins, retinoid receptors, and retinaldehyde dehydrogenase in the chick eye. J Neurocytol 28: 597609.
  • Fledelius HC (1983): Is myopia getting more frequent? A cross sectional study of 1416 Danes aged 16 years+. Acta Ophthalmol 61: 545559.
  • Fledelius HC (1986): Myopia and diabetes mellitus with special reference to adult-onset myopia. Acta Ophthalmol 64: 3338.
  • Fledelius HC, Fuchs J & Reck A (1990): Refraction in diabetics during metabolic dysregulation, acute or chronic. With special reference to the diabetic myopia concept. Acta Ophthalmol 68: 275280.
  • Foster-Powell K & Brand Miller J (1995): International tables of glycaemic index. Am J Clin Nutr 62: 871S893S.
  • Frost G, Leeds A, Trew G, Margara R & Dornhorst A (1998): Insulin sensitivity in women at risk of coronary heart disease and the effects of a low glycaemic diet. Metabolism 47: 12451251.
  • Gardiner PA (1954): The relation of myopia to growth. Lancet 1: 476479.
  • Gardiner PA (1955): Physical growth and the progress of myopia. Lancet 2: 952953.
  • Gardiner PA (1956a): Observations on the food habits of myopic children. Br Med J 2: 699700.
  • Gardiner PA (1956b): The diet of growing myopes. Trans Ophthalmol Soc 76: 171180.
  • Gardiner PA (1958): Dietary treatment of myopia in children. Lancet 1: 11521155.
  • Gardiner PA (1964): Factors associated with the development of myopia in the growing child. In: The First International Conference on Myopia. The Professional Press Inc. Chicago, USA. 2932.
  • Gardiner PA & MacDonald I (1957): Relationship between refraction of the eye and nutrition. Clin Sci 16: 435442.
  • Garner LF, Kinnear RF, Klinger JD & McKellar MJ (1985): Prevalence of myopia in school children in Vanuatu. Acta Ophthalmol 63: 323326.
  • Garner LF, Owens H, Kinnear RF & Frith MJ (1999): Prevalence of myopia in Sherpa and Tibetan children in Nepal. Optom Vis Sci 76: 282285.
  • Gawron VJ (1981): Differences among myopes, emmetropes and hyperopes. Am J Optom Physiol Opt 58: 753760.
  • Gentle A & McBrien NA (1999): Modulation of scleral DNA synthesis in development of and recovery from induced axial myopia in the tree shrew. Exp Eye Res 68: 155163.DOI: 10.1006/exer.1998.0587
  • Goldschmidt E (1968): On the aetiology of myopia: an epidemiologic study. Acta Ophthalmol Suppl 98: 1172.
  • Goldstein JH, Vukcevich WM, Kaplan D, Paolino J & Diamond HS (1971): Myopia and dental caries. JAMA 218: 15721573.
  • Gourmelen M, Le Bouc Y, Girard F & Binoux M (1984): Serum levels of insulin-like growth factor (IGF) and IGF binding proteins in constitutionally tall children and adolescents. J Clin Endocrinol Metab 59: 11971203.
  • Grimberg A & Cohen P (2000): Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J Cell Physiol 18: 19.
  • Hirsch MJ & Levin JM (1973): Myopia and dental caries. Am J Optom Arch Am Acad Optom 50: 484488.
  • Holly JMP (1991): The physiological role of IGFBP-1. Acta Endocrinol 124: 5562.
  • Holm S (1937): The ocular refraction state of the Palae-Negroids in Gabon, French Equatorial Africa. Acta Ophthalmol Suppl 13: 1299.
  • Hughes RE & Jones E (1985): Intake of dietary fibre and age of menarche. Ann Hum Biol 12: 325332.
  • Ibanez L, Potau N, Chacon P, Pascual C & Carrascosa A (1998): Hyperinsulinaemia, dyslipaemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia 41: 10571063.
  • Johansen EV (1950): Simple myopia in schoolboys in relation to body height and weight. Acta Ophthalmol 111: 220228.
  • Johnson GJ, Matthews A & Perkins ES (1979): Survey of ophthalmic conditions in a Labrador community. I. Refractive errors. Br J Ophthamol 63: 440448.
  • Juul A, Scheike T, Nielsen CT, Krabbe S, Muller J & Skakkebaek NE (1995): Serum insulin-like growth factor I (IGF-1) and IGF-binding protein 3 levels are increased in central precocious puberty: effects of two different treatment regimens with gonadotropin-relating hormone agonists, without or in combination with an antiandrogen (cyproterone acetate). J Clin Endocrinol Metab 80: 30593067.
  • Katzmarzyk PT & Leonard WR (1998): Climatic influences on human body size and proportions. ecological adaptations and secular trends. Am J Phys Anthropol 106: 483503.DOI: 10.1002/(SICI)1096-8644(199808)106:4<483::AID-AJPA4>3.0.CO;2-K
  • King H & Rewers M (1993): Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. WHO Ad Hoc Diabetes Reporting Group. Diabetes Care 16: 157177.
  • Klein S (2001): Outcome success in obesity. Obes Res 9 (Suppl 5): S354S358.
  • Krause U, Krause K & Rantakallio P (1982): Sex differences in refraction errors up to the age of 15. Acta Ophthalmol 60: 917926.
  • Kusakari T, Sato T & Tokoro T (1997): Regional scleral changes in form-deprivation myopia in chicks. Exp Eye Res 64: 465476.DOI: 10.1006/exer.1996.0242
  • Lam CS, Edwards M, Millodot M & Goh WS (1999): A 2-year longitudinal study of myopia progression and optical component changes among Hong Kong schoolchildren. Optom Vis Sci 76: 370380.
  • Lewallen S, Lowdon R, Courtright P & Mehl GL (1995): A population-based survey of the prevalence of refractive error in Malawi. Ophthalmic Epidemiol 2: 145149.
  • Lin LL, Shih YF, Lee YC, Hung PT & Hou PK (1996): Changes in ocular refraction and its components among medical students—a 5-year longitudinal study. Optom Vis Sci 73: 495498.
  • Lindgren BF, Segovia B, Lassarre C, Binoux M & Gourmelen M (1996): Growth retardation in constitutionally short children is related both to low serum levels of insulin-like growth factor-I and to its reduced bioavailability. Growth Regul 6: 158164.
  • Liu VR (2000): The glycaemic index and the insulin-like growth factor system. Honours Thesis. Human Nutrition Unit, Department of Biochemistry, University of Sydney, Sydney, Australia.
  • Liu B, Lee HY, Weinzimer SA, Powell DR, Clifford JL, Kurie JM & Cohen P (2000): Direct functional interaction between insulin-like growth factor-binding protein-3 and retionoid X receptor-alpha regulate transcriptional signaling and apoptosis. J Biol Chem 275: 3360733613.
  • Loffer FD (1975): Decreased carbohydrate tolerance in pregnant patients with an early menarche. Am J Obstet Gynecol 123: 180184.
  • Malina RM (1990): Research on secular trends in auxology. Anthropol Anz 48: 209227.
  • McBrien NA & Adams DW (1997): A longitudinal investigation of adult-onset and adult-progression of myopia in an occupational group. Refractive and biometric findings. Invest Ophthalmol 38: 321333.
  • McCarty CA, Livingston PM & Taylor HR (1997): Prevalence of myopia in adults: implications for refractive surgeons. J Refract Surg 13: 229234.
  • Merimee TJ, Rimoin DL & Cavalli-Sforza LL (1972): Metabolic studies in the African Pygmy. J Clin Invest 51: 395401.
  • Mertz JR & Wallman J (2000): Choroidal retinoic acid synthesis: a possible mediator between refractive error and compensatory eye growth. Exp Eye Res 70: 519527.DOI: 10.1006/exer.1999.0813
  • Meyer C, Mueller MF, Duncker GI & Meyer HJ (1999): Experimental animal myopia models are applicable to human juvenile-onset myopia. Surv Ophthalmol Suppl 44: 93102.
  • Morgan RW & Munro M (1973): Refractive problems in northern natives. Can J Ophthalmol 8: 226228.
  • Mori M, Ghyselinck NB, Chambon P & Mark M (2001): Systemic immunolocalizaton of retinoid receptors in developing and adult mouse eyes. Invest Ophthalmol Vis Sci 42: 13121318.
  • Mutti DO, Zadnik K & Adams AJ (1996): Myopia. The nature vs. nurture debate goes on. Invest Ophthalmol Vis Sci 37: 952957.
  • Mutti DO, Zadnik K & Murphy CJ (1999): Naturally occurring vitreous chamber-based myopia in the Labrador retriever. Invest Ophthalmol Vis Sci 40: 15771584.
  • Nam SY, Lee EJ, Kim KR, Cha BS, Song YD, Lim SK, Lee HC & Huh KB (1997): Effect of obesity on total and free insulin-like growth factor (IGF) -1, and their relationship to IGF-binding protein (BP) -1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 21: 355359.
  • Neel JV, Weder AB & Julius S (1998): Type I diabetes, essential hypertension, and obesity as ‘syndromes of impaired genetic homeostasis’: the ‘thrifty genotype’ hypothesis enters the 21st century. Perspect Biol Med 42: 4474.
  • Nesse RM & Williams GC (1994): Why We Get Sick. Times Books. New York, USA. 91106.
  • Norton TT & Siegwart JT Jr (1995): Animal models of emmetropization: matching axial length to the focal plane. J Am Optom Assoc 66: 405414.
  • O'Dea K (1984): Marked improvement in carbohydrate and lipid metabolism in diabetic Australian Aborigines after temporary reversion to traditional lifestyle. Diabetes 33: 596603.
  • Parssinen O, Era P & Leskinen AL (1985): Some physiological and psychological characteristics of myopic and non-myopic young men. Acta Ophthalmol Suppl 173: 8587.
  • Pendse GS & Bhave B (1954): Refractive and body growth. Indian Medical Research Memoirs 38. Job Press Ltd. Kapur. India.
  • Post RH (1962): Population differences in vision acuity: a review, with speculative notes on selection relaxation. Eugen Quart 9: 189212.
  • Raviola E & Wiesel TN (1985): (1985): An animal model of myopia. N Engl J Med 312: 16091615.
  • Reaven GM (1994): Insulin resistance, compensatory hyperinsulinaemia, and coronary heart disease. Diabetologia 37: 948952.
  • Reiser S, Bohn E, Hallfrisch J, Michaelis OE IV, Keeney M & Prather ES (1981): Serum insulin and glucose in hyperinsulinaemic subjects fed three different levels of sucrose. Am J Clin Nutr 34: 23482358.
  • Reiser S, Handler HB, Gardner LB, Hallfrisch JG, Michaelis OE IV &Prather ES, 1979): Isocaloric exchange of dietary starch and sucrose in humans. II. Effect on fasting blood insulin, glucose, and glucagon and on insulin and glucose response to a sucrose load. Am J Clin Nutr 32: 22062216.
  • Riccardi G & Rivellese AA (2000): Dietary treatment of the metabolic syndrome - the optimal diet. Br J Nutr 83: S143S148.
  • Roche AF (1979): Secular trends in human growth, maturation, and development. Monogr Soc Res Child Dev 44: 1120.
  • Rosner M, Laor A & Belkin M (1995): Myopia and stature: findings in a population of 106 926 males. Eur J Ophthalmol 5: 16.
  • Salmeron J, Ascherio A, Rimm EB et al. (1997): Dietary fibre, glycaemic load, and risk of NIDDM in men. Diabetes Care 20: 545550.
  • Schaefer O (1969): Carbohydrate metabolism in Eskimos. Arch Environ Health 18: 144147.
  • Schaefer O (1970): Pre- and post-natal growth acceleration and increased sugar consumption in Canadian Eskimos. Can Med Assoc J 103: 10591068.
  • Schaefer O (1971): When the Eskimo comes to town. Nutr Today 6: 816.
  • Schaefer O (1977): Changing dietary patterns in the Canadian North: Health, social and economic consequences. J Can Diet Assoc 38: 1725.
  • Scholz D (1970): Relations between myopia and school achievements, growth and social factors. Offentl Gesundheitswes 32: 530535.
  • Seko Y, Tanaka Y & Tokoro T (1995): Influence of bFGF as a potent growth stimulator and TGF-beta as a growth regulator on scleral chondrocytes and scleral fibroblasts in vitro. Ophthalmic Res 27: 144152.
  • Skeller E (1954): Anthropological and ophthalmological studies on the Angmagssalik Eskimos. Meddr Gronland 107: 167211.
  • Sorsby A, Benjamin B & Sheridan M (1961): Refraction and its components during the growth of the eye from the age of three. Medical Research Council. Special Report Series no. 301. Stationary Office. London, UK. 167.
  • Sperduto RD, Seigel D, Roberts S & Rowland M (1983): Prevalence of myopia in the United States. Arch Ophthalmol 101: 405407.
  • Spielman RS, Fajans SS, Neel JV, Pek S, Floyd JC & Oliver WJ (1982): Glucose tolerance in two unacculturated Indian tribes of Brazil. Diabetologia 23: 9093.
  • Stefansson V (1919): My Life with the Eskimo. MacMillan Company. New York, USA. 1538.
  • Teasdale TW & Goldschmidt E (1988): Myopia and its relationship to education, intelligence and height. Preliminary results from an on-going study of Danish draftees. Acta Ophthalmol Suppl 185: 4143.
  • Teikari JM (1987): Myopia and stature. Acta Ophthalmol 65: 673676.
  • Teuteberg HJ (1986): Periods and turning-points in the history of european diet. a preliminary outline of problems and methods. In: FentonA & KisbanE (eds.). Food in Change. Eating Habits from the Middle Ages to the Present Day. Humanities Press Inc. New Jersey, USA. 1123.
  • Thorburn AW, Brand JC, O'Dea K, Spargo RM & Truswell AS (1987a): Plasma glucose and insulin responses to starchy foods in Australian Aborigines: a population now at high risk of diabetes. Am J Clin Nutr 46: 282285.
  • Thorburn AW, Brand JC & Truswell AS (1987b): Slowly digested and absorbed carbohydrate in traditional bushfoods. a protective factor against diabetes? Am J Clin Nutr 45: 98106.
  • Travers SH, Labarta JI, Gargosky SE, Rosenfeld RG, Jeffers BW & Eckel RH (1998): Insulin-like growth factor binding protein-I levels are strongly associated with insulin sensitivity and obesity in early pubertal children. J Clin Endocrinol Metab 83: 19351939.
  • Troilo D & Wallman J (1991): The regulation of eye growth and refractive state: an experimental study of emmetropization. Vision Res 31: 12371250.
  • Trowell H (1985): Dietary fibre: a paradigm. In: TrowellH, BurkittD, HeatonK & DollR (eds.). Dietary Fibre, Fibre-Depleted Foods and Disease. Academic Press. New York, USA. 120.
  • Valentinis B, Bhala A, DeAngelis T, Baserga R & Cohen P (1995): The human insulin-like growth factor (IGF) binding protein-3 inhibits the growth of fibroblasts with a targeted disruption of the IGF-I receptor gene. Mol Endocrinol 9: 361367.
  • Vessby B (2000): Dietary fat and insulin action in humans. Br J Nutr 83: S91S96.
  • Walkingshaw R (1964): Control of progressive myopia through modification of diet. In: The First International Conference on Myopia. The Professional Press. Chicago, USA. 5574.
  • Wallman J (1990): Myopia and the control of eye growth. Introduction Ciba Found Symp 155: 14.
  • Wallman J (1994): Nature and nurture of myopia. Nature 371: 201202.
  • Wendling O, Chambon P & Mark M (1999): Retinoid X receptors are essential for early mouse development and placentogenesis. Proc Natl Acad Sci U S A 96: 547551.
  • Wilson ME (1998): Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys. J Endocrinol 158: 247257.
  • Wingert TA (1995): Epidemiology of ametropia of US army recruits. Mil Med 160: 8991.
  • Wolever TM, Jenkins DJ, Jenkins AL & Josse RG (1991): The glycaemic index: methodology and clinical implications. Am J Clin Nutr 54: 846854.
  • Wong L, Coggon D, Cruddas M & Hwang CH (1993): Education, reading, and familial tendency as risk factors for myopia in Hong Kong fishermen. J Epidemiol Community Health 47: 5053.
  • Wong WW, Copeland KC, Hergenroeder AC, Hill RB, Stuff JE & Ellis KJ (1999): Serum concentrations of insulin, insulin-like growth factor-I, and insulin-like growth factor binding proteins are different between white and African American girls. J Pediatr 135: 296300.
  • Yang Q, Mori I, Shan L et al. (2001): Biallelic inactivation of retinoic acid receptor B2 gene by epigenetic change in breast cancer. Am J Pathol 158: 299303.
  • Young FA, Beattle R & Newby FJ (1954): The Pullman study: a visual survey of Pullman school children. Am J Opt 31: 111.
  • Young FA, Leary GA, Baldwin WR, West DC, Box RA, Harris E & Johnson C (1969): The transmission of refractive errors within Eskimo families. Am J Optom Arch Am Acad Optom 46: 676685.
  • Zadnik K, Mutti DO, Friedman NE & Adams AJ (1993): Initial cross-sectional results from the Orinda Longitudinal Study of Myopia. Optom Vis Sci 70: 750758.
  • Ziegler E (1967): Secular changes in the stature of adults and the secular trend of modern sugar consumption. Z Kinderheilkd 99: 146166.
  • Ziegler E (1969): Height and weight of British men. Lancet 1: 1318.
  • Zylbermann R, Landau D & Berson D (1993): The influence of study habits on myopia in Jewish teenagers. J Pediatr Ophthalmol Strabismus 30: 319322.