Loren Cordain, Ph.D.Department of Health &

Exercise ScienceColorado State University

Fort Collins, Co USA

An Evolutionary Analysis ofthe Etiology and Pathogenesis

of Juvenile Onset Myopia

Failure to match focal length of eye’s opticswith axial length produces myopia

1. Wallman J . Int Ciba Found Symp 1990;155:1-42. Mutti DO et al. Invest Ophthalmol Vis Sci 1999;40:1577-84

Myopia: An Evolutionary Perspective

Emmetropia

Myopia

Virtually all mammalian & bird eyes are usually slightly hyperopic at birth and move towards emmetropization during growth & development1

Except for recent evidence with domestic dogs2, myopia is unique to humans

Myopia: An Evolutionary PerspectiveIn all free living vertebrates myopia represents a severe developmental defectThat in most cases would result in an early death

Except in certain species of non-visually dependent vertebrates,Clear distance vision is a necessity for survival:Environmental dangers or benefits:Escape from PredatorsFood locationMate locationEtc.

Blind Cave Fish

Gene or gene’s elicitingmyopia would be fatal

Cordain L. et al. Acta Ophthalmol Scand2002;80:12-35

Myopia: An Evolutionary PerspectiveDespite the enormous selective pressures that would tend to eliminate myopic genes in all pre-agricultural and pre-technological human societiesMyopia is extremely prevalent in western societies, afflicting:

25-35 % of European descent populations1

50 % or more of Asian descent populations2

1. Angle J et al . Am J Epidemiol 1980;111:220-282. Au Eong KG et al. Singapore Med J 1993;34:29-32

1. Post RH. Eugen Quart 1962;9:189-212.

Myopia: An Evolutionary PerspectiveIt has been suggested that1:As non-westernized populations acculturate: A relaxation of the evolutionary selective pressure that would normally eliminate the gene or genes that evoke myopia Was responsible for myopia’s increased incidence in westernized societiesMoreover, these selective pressures would have been completely eliminated with the wide scale availability of spectacle lenses in the past 200 yrs.A number of lines of evidence suggest otherwise:

Hunter-Gatherer

Early Farmer

Myopia Incidence in Hunter GatherersUsing a retinoscope and cycloplegia, Holm (1937) refracted 2,364 members (age 20-65 yrs) of several hunter gatherer tribes in GabonOf the 3,624 eyes examined:1. 9 eyes were myopic (-0.50 to -1.00 D)2. 4 eyes were myopic (-3.00 to -9.00 D) Yielding a total population myopia incidence rate of 0.4 %

Holm S. The ocular refractive state of the Palae-Negroids in Gabon, French Equatorial Africa. Acta Ophthalmol Suppl 1937;13:1-299.

Gabon

Skeller E. Anthropological and ophthalmological studies on the Angmagssalik Eskimos. Medr Gronland 1954;107:167-211.

Angmagssalik,Greenland

Myopia Incidence in Hunter GatherersUsing a retinoscope and cycloplegia, Skeller (1954) refracted 775 Angmagssalik Eskimos (age 2-69 yrs)Of the 1,123 eyes examined:1. 9 eyes were myopic (-1.00 D)2. 4 eyes were myopic (-1.25 D) Yielding a total population myopia incidence rate of 1.2%

Young et al. Am J Optom Arch Am Acad Optom 1969;46:676-85

Barrow,Alaska

Myopia Incidence in Hunter GatherersUsing a cycloplegic, Young et al. (1969) refracted 508 recently acculturated Eskimos in Barrow, Alaska1. The right eyes of 131 subjects over 41 yrs of age yielded only two myopic (-0.25 D) eyes (1.5 % of the population)These subjects were born between (1880 and 1927) and most grew up in isolated communities along the coast of Alaska living in traditional ways, without formal schooling.2. The right eyes of 284 subjects between (11 and 40 yrs) of age showed that 51 % had myopia of >0.25 DThese subjects were born between (1928 and 1957) and most had attended the BIA school established at Barrow in 1932

Hence, within ~ a single generation (30 yrs), the incidence

of myopia Increased 34 fold

Morgan et al. (1973)1 reported a similar age related decline in myopia incidence in Indians and Eskimos living in the Yukon and Northwest TerritoriesPossible interpretations:1. Birth Cohort Effect2. Actual changes in refractive error with ageCross sectional studies like these cannot distinguish these effectsProspective Data (The Beaver Dam Study)2 indicate:1. Strong birth cohort effect2. Lesser change in actual refraction:

a. (43-59 yr subjects), the 10 yr change was +0.53 D

b. (>70 yr subjects), the 10 yr change was -0.41

0102030405060

2.5 10 20 30 40 50 60

Eskimo n=2,833Indian n=844

Age (years)

% m

yopi

a ( -1

.00

to -5

.00

D)

1. Morgan RW et al. Refractive problemsIn northern natives. Can J Ophthalmol1973;8:226-2282. Lee KE et al. Invest Opthalmol Vis Sci2002;43:2566-2571.

Myopia Incidence in Hunter Gatherers

Distant Early Warning (DEW Line) Air Defense Warning System:58 sites constructed between 1955-57

Clues to the Myopia Birth Cohort Effect in Canadian Indians & Inuit

Schaefer O. When the Eskimo comes to town. Nutr Today 1971;6:8-16

Myopia Incidence in Amazon Indians

1 1 3 4

15

75

86

42

17

7 52 21 1 2 2

10 9

82

92

32

6 41 2 1

0

25

50

75

100

-5.8 -3.3 -1.8 -0.8 0.2 1.2 2.2 3.2 4.2

OD OS

Num

ber o

f Sub

ject

s

Spherical Equivalent Refractive Error (Diopters)

Thorn F et al. Optom Vis Sci 2005;82:267-72

Only 2.7% of 259 Amazon Indians showed Myopia of -1.00 D or More

Yanomamo Indians

Conclusions: Visual Acuity in Humanity’s Native Hunter-Gatherer Environment:

Myopia occurs in (0-3 %) of the populationWith most refractive errors < -1.00 DModerate to high myopia (-3.00 D to -9.00 D) occurs in ~ (1 person per 1,000)Emmetropia or slight hypermetropia represent the normal refractive state under which the current human genome was selectedWhen novel environmental conditions associated with modern civilization are introduced into the hunter gatherer lifestyle:Within a single generation, myopia incidence rates equal or exceed those in western populationsCordain L. et al. Acta Ophthalmol

Scand 2002;80:12-35

Both Genetics & Environment Influence the Development of Myopia

Within the visual sciences community there is an emerging consensus that myopia develops from:Genetic Factors (currently unknown)1. Twin studies twins1

Environmental Factors (almost exclusively – excessive near work)1. Epidemiological studies of education levels2

2. Animal studies2

3. Prospective studies of microscopists2

1. Dirani M et al. Heritability of refractive error and ocular biometrics: The genes in myopia (GEM) twin study. Invest Opthalmol Vis Sci 2006;47:4756-612. Cordain L. et al. Acta Ophthalmol Scand 2002; 80: 12-35

Vs.

Both Genetics & Environment Influence the Development of Myopia

The exact manner genetic factors interact with environmentalfactors to elicit myopia is unclearModern civilization brings not only literacy, reading and increased near workBut other environmental factors that may disrupt the emmetropization process during growth & development

Cordain L. et al. Acta Ophthalmol Scand 2002; 80: 12-35

Garner et al. (1999) measured visual acuity in 2 groups of genetically similar children but with varying degrees of western acculturation555 children in the urban environ of Kathmandu had a 21.7 %prevalence of myopia270 children living in the rural and village of Khumjung had a 2.9 %rate of myopiaBoth groups had compulsory schoolingKhumjung is an isolated village without electricity, supermarkets, and few western processed foodsGarner LF et al. Prevalence of

myopia in Sherpa and Tibetan children in Nepal. Optom Vis Sci 1999;76:282-85

Kathmandu

Khumjung

Nepal

Refractive Status in Partially Westernized Populations

Garner LF et al. Prevalence of myopia in school children in Vanuatu. Acta Ophthalmol 1985;63:323-36

Vanuatu

Fiji

Refractive Status in Partially Westernized Populations

Garner et al. (1985) measured visual acuity in 977 school children (6-17 yrs) on S. Pacific island of VanuatuOnly 1.3 % of subjects had myopia of > -0.25 DDespite engaging in 8 hrs of schooling per day

Lewallen et al. (1995) examined 352 students attending a teachers college in MalawiStudents came from rural areas where they had complete primary school and 2 yrs of secondary school

Blantyre Teacher’s Training College, Malawi, Africa

Blantyre,Malawi

Refractive Status in Partially Westernized Populations

All engaged in regular readingOnly 4.1 % had a refractive error of more negative or equal to (>) -0.50 D

Lewallen S et al. Ophthalmic Epidemiol 1995:2: 145-149

In rural areas with little exposure to westernized lifestyles, the near work of readingDoes not elicit myopia incidence rates much beyond rates (~ 1- 4 %) than in hunter-gatherersIt could be that the quantity and intensity of rural schooling is lessthan urban schooling It could also be argued that additional environmental factors in urban areas,Which are not present in rural areas influence myopia rates

Conclusions: Refractive Status in Partially Westernized Populations

Cordain L. et al. Acta Ophthalmol Scand 2002; 80: 12-35

Additional urban environmental factors:Electricity, running water, television, radio, automobiles, etc.High availability of western processed foods

Kathmandu, Nepal: Urban Market Center(Myopia Incidence: 21.7 %)

Conclusions: Refractive Status in Partially Westernized Populations

Village of Khumjung, Nepal(Myopia Incidence: 2.9%)

Myopia and IlliteracyIlliterate hunter gatherers and literate rural villagers have similar low myopia rates (~1-4 %)Literate urban dwellers have high myopia rates (20-50 % or >)Illiterate urban dwellers:1. Cairo, Egypt : 1173 subjects (11-39 % of sample had myopia)1

2. 152 Hong Kong fisherman who had never attended school (18. 4 % myopia rate)2

Taken together, the data suggest that environmental factors present in urban environments but not in rural areasIn addition to the near work of reading, may elicit myopia

1. Post RH. Eugen Quart 1962;9:189-212.2. Wong L et al. J Epidemiol Community Health 1993;47:50-53

Myopia and IlliteracyIt is possible that illiterate urban workers engage in other near work besides reading which evokes myopiaAnthropological studies of non-westernized Eskimos1

indicate they may engage in long hours of near work (sewing, tool making etc.) in dimly lit snow housesBut do not develop myopia2-4

1. Stefansson V. My Life with the Eskimo. MacMIllan Co, NY, 1919, 1-528.2. Skeller E. Medr Gronland 1954;107:167-211.3. Young et al. Am J Optom Arch Am Acad Optom 1969;46:676-854. Morgan RW et al. Can J Ophthalmol1973;8:226-228

Inuit women sewing seal skins

Myopia and Illiteracy (cont.)

3 unique qualities of the printed page are potent inducers of form deprivation and hence myopia1:1. Narrow range of luminance2. Achromaticity of text3. High spatial frequency of text reduces activity of non-foveal retinal neuronsTaken Together: These data suggest that environmental factors other than near work in urban illiterates may underlie the development of myopia

1. Chew SJ et al. Singapore Med J 1992;33:489-92

Vs.

Minimally Processed, Wild Plants

Highly Processed, Refined Foods

What Qualities May Adversely Influence Emmetropization?

Minimally Processed, Wild Animals

When Non-Westernized Societies Acculturate, They Not Only Become Literate,

But they Change Their Diets

Urban vs. Rural Environmental Factors Potentially Influencing Myopia:

Sugar Availability

High sucrose diets produce refractive changes in a myopic direction in both rats1 and rabbits2

that did not occur on sucrose free dietsMyopes have more dental carries than non-myopes3,4

Degree of myopia is related to caries incidence4

Progressive myopes have more caries than stable myopes5

1. Gardiner PA et al. Clin Sci 1957;16:433-422. Bardiger M et al. Proc Nutr Soc 1972;31:4A-5A.3. Goldstein JH et al JAMA 1971;218:1572-734. Hirsch MJ et al. Arch Am Acad Optom 1973;50:484-4885. Edwards MH et al. Optom Vis Sci 1995;72: 573-76

Diet, Hyperinsulinemiaand Myopia

Although the excessive near work of reading is almost universally recognized as the sole environmental factor underlying myopiaDiet, particularly the glycemic index, is a well recognized agent underlying chronic hyperinsulinemiaA condition which may play a key role in the pathogenesis of myopia by disrupting hormonally mediated regulation of vitreal chamber growth

??

Cordain L. et al. Acta Ophthalmol Scand 2002; 80: 12-35

15 30 45 60 75 90 120 Minutes

Blo

od S

ugar

Lev

el

Lentils

30 %

15 30 45 60 75 90 120 Minutes

Blo

od S

ugar

Lev

el

Glucose (Reference Food)

100 %

What are High Glycemic Foods:The Glycemic Index (GI)

1. Subject eats an amount of food containing 50 or 25 g CHO2. Over 2 hr period blood glucose is measured at 0,15,30,45,60

90, 120 min & plotted on graph & area under curve calculated3. Response of test food is compared to reference value (usually

glucose with a glycemic index (GI) of 100

Glycemic Indices of FoodWestern Refined Foods Unrefined Traditional Foods

Food Glycemic Food GlycemicIndex Index

Instant rice 91 Baked Potato 85Rice krispie cereal 88 Millet 71Cornflake cereal 84 Maize meal porridge 71Instant potatoes 83 Whole wheat bread 69Tapioca 81 Chapatti bread 57Jellybeans candy 80 Pita bread 57Vanilla wafer cookies 77 Brown rice 55Doughnut 76 Sweet corn 55Waffles 76 Sweet potato 54Cheerio cereal 74 Yam 51Soda crackers 74 Bulgur bread 52Corn chips 73 Barley chapatti bread 42White bread 70 Hominy corn 40Mashed potatoes 70 Tortilla 38Mars bar 68 Lima beans 36Soft drink 68 Lentils 29Green pea soup 66 Fresh peach 28Ice cream 61 Kidney beans 27Pizza 60 Peas 22_________________________________________________________________________

High Glycemic FoodsALMOST ALL REFINED GRAINS HAVE HIGH GLYCEMIC INDICESRice Chex Cereal 89Corn flakes 84Pretzels 83Rice Krispie Cereal 82Rice Cakes 82Rye bread 76Waffles 76Total Cereal 76Graham crackers 74Cheerios 74Bagels 72Short grain white rice 72Corn chips 72White bread 70Whole Wheat bread 69

HIGH G.I. FOODS > 70MEDIUM G.I. FOODS 55-70LOW G.I. FOODS < 55

Foster-Powell K et al. Am J Clin Nutr 2002;76:5-56

Fruits & Vegetables: Low Glycemic Load Carbohydrates

ALMOST ALL FRUITS & VEGGIES HAVE LOW GLYCEMIC LOADS(Glycemic index x CHO content 100 g portion)Parsnips 19.5Sweet Potato 13.1Banana 12.1Yam 11.5Pineapple 8.2Grapes 7.7Carrots 7.5Kiwi fruit 7.4Beets 6.3Apple 6.0Pear 5.4Watermelon 5.2Orange 5.1

Foster-Powell K et al. Am J Clin Nutr 2002;76:5-56

Legumes & Nuts: Low Glycemic Load Carbohydrates

ALMOST ALL Nuts & LEGUMES HAVE LOW GLYCEMIC LOADS(Glycemic index x CHO content 100 g portion)Broad beans 15.5Baked beans 10.4Navy beans 10.0Garbanzo beans 9.0Black eyed peas 8.5Lima beans 7.6Black beans 7.1Peas 6.8Cashews 6.3Kidney beans 6.2Lentils 5.8Peanuts 2.6

Foster-Powell K et al. Am J Clin Nutr 2002;76:5-56

Glycemic & Insulin Response to Animal Foods (Meat, Fish, Eggs)

Animal foods usually contain no carbohydrateHowever, they do elicit both glucose and insulin responsesThe insulin response is caused by a direct stimulatory effect of increased circulating levels of dietary amino acids on the pancreas and by:The secretion of two insulinotropic gut hormones in response to the meal: (1) Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) However, the glucose and insulin response are minimal relative to high GI carbohydrates

Glucose InsulinWhite Bread 100 100Eggs 42 31Beef 21 51Fish 28 59

Holt SHA et al. Am J Clin Nutr 1997;66:1264-76

(Dairy):Glycemic Index/Insulin Metabolism

MILK, SKIM MILK, FERMENTED MILK AND YOGURTS HAVE LOW GLYCEMIC INDICESSkim Milk 32Whole Milk 27Reduced Fat Yogurt 27Non Fat Yogurt 24Fermented Milk (3% fat) 11BUT PARADOXICALLY HAVE INSULIN INDICES SIMILAR TO:White Bread 100Yogurt 115Fermented Milk 98Whole Milk 90Skim Milk 90

Foster-Powell K et al. Am J Clin Nutr 2002;76:5-56Ostman EM et al. Am J Clin Nutr 2001;74:96-100 Hoyt G, Hickey MS, Cordain L. Brit J Nutr

2005;93;175-77.

HIGH G.I. FOODS > 70MEDIUM G.I. FOODS 55-70LOW G.I. FOODS < 55

Nilsson M et al. Am J Clin Nutr 2004;80:1246-53

High Fructose Corn SyrupAlthough pure (100 %) fructose has a low GI (23)It is highly insulinotropic when blood glucose is even moderately elevatedBecause the most common forms of fructose (HFCS 42, 55) are mixtures of high GI glucose & fructoseThe most common manufactured forms of HFCS elicit both high glycemic & insulinotropic responses

(Fructose + Glucose) – 3 versions:1. HFCS 42: 42% fructose (GI = 23) +

53 % glucose (GI = 100)2. HFCS 55: (55% fructose + 42 %

glucose) – soft drinks3. HFCS 90: (90% fructose + 8%

glucose) – “low cal” foods

High Fructose Corn Syrup isA mixture of:

Dunnigan MG et al. Metab 1975;40:629-35; Reiser et al. Am J Clin Nutr 1987;45:580-87

Per Capita Percentages of Highly Glycemic and Highly Insulinemic Foods in the U.S. Diet (1990-99)

18.6

20.3

2.56.3

52.3

Refined Sugars

Refined Grains

Potatoes

Dairy (exceptcheese)Other Foods

47.7 % of the energy in the typical U.S. diet comesfrom foods capable of promoting insulin resistance

Insulin Resistance: What is it?When skeletal muscle resists insulin mediated uptake of glucose:“Clinically defined insulin resistance occurs”Skeletal muscle is principal site of insulin resistance, other tissues develop insulin resistance:1. Adipose tissue2. Liver3. Endothelial cells4. Other peripheral tissues

Insulin

Glucose

Glucose

Insulin Resistance: Compensatory Hyperinsulinemia

When insulin resistance occurs:Long term glucose levels do not necessarily riseBecause the pancreas secretes more insulinThe maintenance of normal glucose via increased insulin secretion is referred to as: COMPENSATORY HYPERINSULINEMIA:The fundamental metabolic disturbance underlying the Metabolic Syndrome

Insulin

Glucose

Glucose

InsulinInsu

lin

Pancreas

Insulin Resistance: Impairment of Signaling Pathway

GLUT4 is the major insulin stimulated glucose transporter &Is the rate controlling stepin insulin mediated glucose uptake in muscleMuscle cell surface GLUT4content is severely reduced in Type 2 DiabeticsThe precise metabolic step or steps impairing GLUT4 expression are still unclearGLUT4

InsulinReceptor

Insulin

TyrosineKinase

Enzyme Phosphorylation Cascades

Glucose

Vesicle

GlucoseTransport

GLUT4

Muscle Cell

Insulin Resistance: Proximate Causes

GLUT4

InsulinReceptor

Insulin

TyrosineKinase

Enzyme Phosphorylation Cascades

Glucose

Vesicle

GlucoseTransport

GLUT4

Muscle

Chronically elevated glucose

Chronically elevated insulin

Chronically elevated non-esterified free fatty acids

Chronically elevated VLDLin the Post-prandial and fasting states

Rosetti et al. Diabetes Care 1990;13:610-30McClain J Diabetes Complications 2002;16:72-80

Del Prato S. et al. Diabetologia 1994;37:1025-35.Thomson, M.J. et al. J. Biol. Chem 1997;272:7759-64

Boden, G. Eur J. Clin. Invest 2002; 32: 14-23

Zammit, V.A. et al. J. Nutr. 2001;131:2074-77.

High Glycemic Foods May Promote the 4 Proximate Causes of Insulin Resistance

Chronically elevated glucose

Chronically elevated insulin

Chronically elevated non-esterified free fatty acids

Chronically elevated VLDLin the Post-prandial and fasting states

Rosetti et al. Diabetes Care 1990;13:610-30McClain, P.A. J. diabetes Complications 2002;16:72-80

Del Prato S. et al. Diabetologia 1994;37:1025-35.Thomson, M.J. et al. J. Biol. Chem 1997;272:7759-64

Boden, G et al. Eur J. Clin. Invest. 32 (suppl 3): 14-23.

InsulinResistance

Zammit, V.A. et al. J. Nutr. 2001;131:2074-77.

High GlycemicFoods

Ludwig D. JAMA 2002;287:2414-23

How May High Glycemic Load Foods

Induce Peripheral Insulin Resistance

High glycemic load carbohydrates elevate VLDL synthesisIncreased triglyceride (TAG) concentration in muscle cells inhibits entry of glucose (insulin resistance) which:Causes increased pancreatic secretion of insulin (hyperinsulinemia)Glucose enters adipocytes, along with VLDL-TAG causing adipose tissue hypertrophy & insulin resistance which,Increases adipocyte lypolysis which elevates NEFA which contributes to muscle insulin resistance Zammit et al. J Nutr 2001;131:2074-77.

GI Affects Day-long Concentrations of Insulin7 healthy male subjects after 3 days of feeding

Kiens and Richter Am J Clin Nutr 1996;63:47

0

50

100

150

200

250

300

7:00 9:00 11:00 13:00 15:00 17:00 19:00

Time of day (h)

Insulin(pmol/L) High GI

Low GI

Meal Meal Snack

P < 0.05

Glycemic Index & Insulin Resistance

Insulin response in 30 patients following Oral Glucose Tolerance Test (OGTT) after 4 weeks on high or low GI diets

Are

a un

der c

urve

Insu

lin(n

mol

/L/m

in)

0102030405060708090

High GI Low GI

Frost et al. Metabolism 1996;45:669-72

*

Relationship of Circulating Insulin Levels to IGF-1 and IGFBP-1 Levels

Free IGF-1 is a potent mitogen (growth stimulator) for all cells in the bodyMost of IGF-1 is not free and is bound to at least 6 IGF Binding ProteinsHence, the presence or lack of IGFBPs determines the concentration of freeIGF-1 in plasma

Pancreas Secretes:1. Insulin

Liver Secretes:1. Insulin like Growth

Factor-1 (IGF-1)2. IGF-1 Binding Protein

(IGFBP-1)

Relationship of Circulating Insulin Concentrations to IGF-1 and IGFBP-1

Concentrations

Blood concentrations of insulin and IGFBP-1 vary inversely throughout the dayThe suppression of IGFBP-1 by insulin elevatescirculating concentrations of free IGF-1

Insulin levels go up

AND:1. IGF-1 Binding Protein

(IGFBP-1) goes downCAUSING:

2. IGF-1 to go up

Brismar K et al. J Clin Endocrinol Metab 1994;79:872-78

Relationship of Circulating Insulin Concentrations to IGF-1 and IGFBP-1

ConcentrationsRecent experiments show that compensatory hyperinsulinemia that characterize adolescent obesity:1. Suppress IGFBP-12. Increase IGF-13. Increase pubertal

development4. Increase Height

Wong et al. J Pediatr 1999;135:296-300

IGF-1 Acts Systemically to Increase Stature & Reduce Pubertal Age:

Low concentrations of IGF-1 are associated with short stature & high levels are associated with increased stature in humansHuman recombinant IGF-1 therapy improves linear growthHyperinsulinemic adolescents with elevated IGF-1 are more sexually mature than subjects with superior insulin sensitivityRecombinant IGF-1 therapy in primates increases tempo of puberty

Ituri Pygmies maintainLow IGF-1 Cordain et al. Acta Ophthal Scand 2002;80:125-135

Relationship of Circulating Insulin Concentrationsto IGFBP-3 and the RXRα Nuclear Receptor

IGFBP-3 inhibits growth and promotes apoptosis (programmed cell death) in many but not all cell lines1

IGFBP-3 is reduced by insulin indirectly via negative feedback upon growth hormone2

IGFBP-3 is a ligand for the RXRα nuclear receptor & interferes with formation of the RXR:RAR heterodimer1

The ligand for the RARα is all trans retinoic acid (ATRA) In sclera, ATRA inhibits glycosaminglycan synthesis, thereby thinning the sclera and promoting axial elongation3

Hence, low concentrations of IGFBP-3 may augment axial elongation by further inhibiting glycosaminglycan synthesis4

Insulin concentrationsgo up

AND:1. IGF-1 goes up

and2. IGFBP-3 goes down

1. Schedlich LJ et al. Arch Biochem Biophys 2007;465:359-692. Brismar K et al. J Clin Endocrinol Metab 1994;79:872-783. Troilo D et al. Invest Ophthalmol Vies Sci 2006;47:1768-774. Fowlkes JL, Serra DM. J Biol Chem. 1996 Jun 21;271(25):14676-9.

High Glycemic Diet

Insulin Resistance

Hyperinsulinemia

Decrease in Hepatic IGFBP-1 synthesis

Increase in Free IGF-1

Enhanced Tissue Growth Unregulated Tissue Growth

Increased Stature, Early Menarche/PubertyMyopia, Acne, Epithelial Cell Cancer Promotion,Skin Tags, Polycystic Ovary Syndrome, Acanthosis Nigricans

Decrease in GH

Decrease in Circulating IGFBP-3

Alteration in Retinoid Receptor Activity

and/or

Increased Androgens, DecreasedSex Hormone Binding Globulin

Male Vertex Balding

Cordain L et al. Comp BiochemPhysiol A Mol Integr Physiol2003; 136:95-112

Insulin Resistance & MyopiaWith myopia the eyeball has grown too long for the refractive power of the lens and corneaThis elongation is chiefly caused by excessive near work resulting in a blurred image in the non-foveal retinaThe blurred retinal image induces axial elongation by increasing the all trans retinoic acid (ATRA) synthesis from the retina/choroid to the scleral chondrodytes1

ATRA inhibits glycosaminglycan synthesis, thereby thinning the sclera and promoting axial elongation1

Diet induced hyperinsulinemia lowers IGFBP-32

Hence, low concentrations of IGFBP-3 may augment axial elongation by further inhibiting glycosaminglycan synthesis3

Normal Eye

Myopic Eye

Focal pointon retina

Focal point in front of retina1. Troilo D et al. Invest Ophthalmol Vies Sci 2006;47:1768-77

2. Brand-Miller JC, Liu V, Petocz P, Baxter RC.Am J Clin Nutr.2005 Aug;82(2):350-4.

3. Fowlkes JL, Serra DM. J Biol Chem. 1996 Jun 21;271(25):14676-9

Insulin Resistance & Myopia:Corroborative Date

Most, but not all studies show myopes to be tallerthan non myopes1,2

Perhaps a diet induced IGF-1 effect2

105115125135145155165

4 8.5 12.5 15.5

Myopes (> -3.0D at 14 yrs)Myopes (< -3.0D at 14 yrs)Controls

Age (years)

Hei

ght (

cm)

1. Gardiner PA. The relation of myopiato growth. Lancet 1954;1:476-792. Cordain L. et al. Acta Opthalmol Scand2002;80:125-135

A FamousMyope

Myopic children have greater body mass indices (Wt/Ht2) than non-myopes1

Perhaps because of insulin resistance & accelerated growth2

15

16

17

18

19

20

21

4 8.5 12.5 15.5

Myopes Controls

Age (years)

BM

I (W

t/Ht2 )

1. Gardiner PA. The relation of myopiato growth. Lancet 1954;1:476-792. Cordain L. et al. Acta Opthalmol Scand2002;80:125-135

Insulin Resistance & Myopia:Corroborative Date

A FamousMyope

Hyperinsulinemia & Insulin resistance occur more frequently in women with early menarche compared to normal menarche 1,2

Cross sectional3,4 andProspective studies5,6

Show an earlier age of menarche in female myopesWho were also taller

1. Loffer FD. Am J Obstet Gynecol 1975;123:180-1842. Ibanez L et al. Diabetologia 1998;41:1057-63.3. Nirmalan PK et al. Opthalmo Vis Sci 2004;45:4273-764. Scholz D. Offentl Gesundheitswes 1970;32:530-35.5. Douglas JWB et al. J Royal Stat Soc Series A (General) 1967;130:479-504

Insulin Resistance & Myopia:Corroborative Date

Observations from a number of Scandinavian studies demonstrate an increasedincidence of myopia in Type 2 diabetics1,2

1. Fledelius HC et al. Acta Ophthalmol 1990;68:275-802. Jacobsen N et al. Acta Ophthalmol 2007; Dec 12; [Epub ahead of print] 1-5.

Insulin Resistance & Myopia:Corroborative Date

A FamousMyope

A FamousMyope

Apolipoprotein A-I (ApoA-I) is the major protein component of high density lipoprotein (HDL) in plasmaA recent molecular proteomics study demonstrated that apoA-1 serves as a cellular “STOP” signal for scleral growth in myopia1

Lowered HDL is a ubiquitous symptom of insulin resistance and the metabolic syndrome2

High glycemic load carbohydrates lower HDLThese data suggest that insulin resistance may enhance vitreal chamber growth by reducing the ApoA-1 STOP signal for scleral tissue

1. Bertrand E et al. Mol Cell Proteomics. 2006 Nov;5(11):2158-66.2. Reaven GM.Physiol Rev. 1995 Jul;75(3):473-86.3. Siri PW, Krauss RM. Curr Atheroscler Rep. 2005 Nov;7(6):455-9.

Insulin Resistance & Myopia:Corroborative Date

Emmetropia

Myopia

Thank You!

2002 2005