On Myopia

Discussion in 'Blood Sugar' started by Travis, Nov 22, 2017.

  1. Travis

    Travis Member

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    The cause of myopia is not difficult to understand. There are tons of data sitting right before our eyes that can elucidate the basic mechanism of these vision changes. By reading published clinical case reports, biological optics, enzyme kinetics, and analytical chemistry articles, the answer plainly reveals itself:

    "Before accepting a theory it is necessary not only to prove its own merit but also to explain why other theories are either wrong or not applicable." ―Paul Riordan Eva

    I. Paul Riordan Eva


    Much insight can be gained through the observations of Paul Riordan Eva, who critically examined the data regarding myopia. He had published an excellent review article in 1982, shown below:

    Eva, Paul Riordan. "Refractive change in hyperglycaemia: hyperopia, not myopia." British Journal of Ophthalmology (1982)​

    In which he makes sense of the long‐noted observations of hyperglycemia on refractive changes—the propensity of the lens to bend light, and only real way to explain myopia. Trying to explain myopia through any other way leads to a contradiction: When imagining myopia to simply have as its cause the inability to focus, or a problem in controlling the iris, leads nowhere fast. That idea immediately falls apart when it's realized that anyone with nearsightedness can focus just fine, with glasses, and can easily bring objects far away into focus. The great majority of myopic changes are not a problem with the iris or any other muscle.

    So a change in the refractive index has always been the primary focus among scientists, since there's no other logical way to explain it. The lens refractive index can actually change very quickly with raised blood glucose levels: Here are some quotes from Paul Riordan Eva to give you an idea of just how quick and drastic these changes can occur:

    II. Case Reports—Excerpts

    "Until that time she had had no visual symptoms since the onset of her diabetes in 1967, but within 3 hours of the first injection of 10 units of regular insulin she noticed blurring of vision in both eyes. She could not see with her glasses (OD −3·25), but she could see near without them. [...] An increase in the dosage of insulin led to gradual lowering of the blood sugar, followed later by a reversal of the refractive change. In January 1973 the refractive errors had returned to −3·25 in the right eye and −3·50 in the left with the same astigmatic corrections." ―Paul Riordan Eva

    "In December 1980 he suddenly developed severe polydipsia and polyuria. On 15 December investigation by his internist showed a full blood sugar value of 350 mg/dl (19 mmol/l). Chlorpropamide, one tablet per day, was started. Although the patient discontinued this treatment within a few days because of side effects, frequent blood sugar estimations continued to show improvement. About 2 weeks after initiation of treatment the patient noticed a sudden change in his vision in that he could no longer see street signs while driving unless he took his glasses off. Examination by an optometrist on 8 January 1981 showed best visual acuity of 20/25 with corrections of −1·75 in each eye. Referral back to an ophthalmologist was advised. The patient's prediabetic refractive error was found to have returned on 27 February 1981. One other patient (patient 8) gave a similar history of suddenly being able to see in the distance without glasses, despite previously being myopic, about 2 weeks after starting oral medication for newly diagnosed diabetes." ―Paul Riordan Eva

    III. History of the Observation

    "The occurrence of transitory refractive changes in diabetic patients has been recognised since 1873." ―Paul Riordan Eva

    These observations are in fact common, and have been noted for over a century. The diabetic cataract is certainly a well‐recognized pathology, and the diabetic refractive changes are recognized as well. Paul Riordan Eva documents observations along these lines dating back over a century:

    "Duke-Elder in 1925 concluded that hyperopia is less common than myopia and that 'the refractive power of the eye tends to vary directly as the sugar content of the blood; that is, there is a tendency to hypermetropia with decreased sugar, with increased sugar to myopia." ―Paul Riordan Eva

    The premise of Paul Riordan Eva's article appears to be a reminder to opthalmologists that hyperglycemia actually produces hyperopia, not myopia as sometimes thought. This is an important point to make note of, since this fact will be needed both to explain myopia itself and to suggest ways to improve it.

    "More recently Duke Elder's rule has been refuted by Planten's study of 23 patients of whom only 2 became myopic with hyperglycaemia, the remainder all showing transient hyperopia." ―Paul Riordan Eva

    "Every case showed transient hyperopia developing prior to the diagnosis of diabetes or soon after treatment was started," ―Paul Riordan Eva

    The prevalence of myopic changes in hyperglycemia is fairly common, much more common than in non‐diabetic people. I think you'd be forced to agree that glucose plays a fundamental role in the refractive changes of the lens.

    "Granstrom reported refractive change occurring as an initial symptom in 34% of diabetics and as an asymptomatic change in another 47%." ―Paul Riordan Eva

    IV. The 'Explanation'

    "Myopia with hyperglycaemia was then explained as being due to osmotic hydration of the lens due to salt retention." ―Paul Riordan Eva

    Glucose became so well‐known to cause refractive changes off the lens that theoreticians felt obliged to explain it. Back then, in the early twentieth century, osmotic forces seemed the only logical way for doing so.

    "Most authors accept Duke Elder's theory that refractive changes in diabetes are due to alterations in the power of the lens because of osmotic interactions between the lens and aqueous." ―Paul Riordan Eva

    "...and provided an elaborate exposition of the possible role of osmotic forces, which established the concept without truly explaining the mechanism." ―Paul Riordan Eva

    But there are flaws with such a theory. An influx of water caused by the hygroscopic forces of glucose would be expected to increase refraction, but the opposite is seen. What followed was a period of Rube Goldberg‐like ad hoc explanations of considerable magnitude.

    "The resultant influx of water has been used to explain either a myopic or a hyperopic change, according to whether shape or refractive index is considered more important in determining overall refractive power." ―Paul Riordan Eva

    And in fact, aldose reductase inhibitors have been shown in many studies to prevent these refractive changes in rabbits. It can no longer be argued that osmotic forces play a role in determining the width, shape, or refractive index of the lens itself. What is necessary to explain the effect of glucose on the lens necessarily lies downstream of aldose reductase, and none of those products are any more hygroscopic than glucose itself.

    "Hyperglycæmia-induced refractive changes have been prevented in rabbits by aldose reductase inhibitors, although similar work in human subjects has yet to be published." ―Paul Riordan Eva

    V. Aldose Reductase

    This enzyme is an offshoot off normal glucose metabolism, and is only really active with the overflow of glucose seen in hyperglycemia. Under this enzyme, glucose is reduced to sorbitol. While not a dangerous molecule in itself, it doesn't have the protective phosphate group as it should. Too much glucose in the extracellular fluid—largely under the action of aldose reductase—leads to high amounts of trioses, acetol, and methylglyoxal: a common finding in diabetic blood.

    "Methylglyoxal is also produced nonenzymatically during glucose metabolism." ―David L. Vander Jagt

    What is unique about methylglyoxal, among all things, is its ability to form a covalent adduct with arginine. This forms a cyclic imidazalone ring, which is fluorescent. This species is often referred to as 'MG‐H,' with subscipts denoting subtle variations. Although sometimes called an 'adduct,' this is misleading as it implies simple addition—not the transformation which actually occurs. The end result is actually an imidazalone, a fluorescent ring.

    myopia10.png reaction process depicted; click to embiggen

    (This ring is also sometimes called hydroimidazolone, but this isn't a very good name. The name that would make IUPAC the most happy would be Nᵟ‐(5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl)‐L‐ornithine. For short: it's better to accentuate the methyl group than the hydro and call it ornithyl‐methylimidazalone, or simply methylimidazalone. This name is used in publications found in the Journal of the American Chemical Society, so other people agree. The hydro is less conspicuous, and hence less deserving to be named. But of course, anyone can choose to name it after the much smaller hydrogen if they'd like. The point is: If anyone should decide to research this molecule, keep in mind that it goes by many names. It is even sometimes simply called an MG–arginine adduct. There's over six different names commonly used to describe this.)

    Diabetic blood proteins are more fluorescent than normal people's for this reason, and taking L-arginine as a supplement has actually been used to counteract this. Such modifications are very well‐known among diabetes researchers.

    "The glycation theory presents a quite different view of diabetic complications. In this theory, nonenzymatic modification of proteins by glucose, especially modification of longlived proteins such as lens crystalline or matrix proteins, is considered the critical event in the development of complications." David L. Vander Jagt

    The lens is about 90% protein, and roughly 10% carbohydrate. The primary protein of the lens is called crystallin, for obvious reasons. This protein can certainly be covalently modified by methylglyoxal, and acetol to a lesser—but still significant—extent. David Vander Jagt had shown this in 1992.

    myopia9.png γ-crystallin from uniprot.org (click to embiggen)

    The protein crystallin has many arginine residues, and thus would be expected to be covalently modified by methylglyoxal and acetol—products of the aldose reductase pathway.

    "There are 10 to 20 arginine residues in the human crystallin isoforms. There is therefore an expectation that 10% to 20% of crystallin molecules have a MG-H modification." ―Naila Ahmed

    VI. Proof of Imidazalone in the Lens

    "Recently, we have found similar high concentrations of MG-H₁ in protein extracts of human blood cells and tissues of laboratory rats." ―Naila Ahmed

    Though it may be fun to theorize about—analyze kinetic rates and blood glucose concentrations in attempt to estimate—we don't even have to. These covalent methylglyoxal and acetol adducts have been determined in the human lens in both hypoglycemic and euglycemic individuals.

    Ahmed, Naila. "Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins." Investigative ophthalmology & visual science (2003)​

    It was found, predictably, that the diabetics had more methylimidazalone rings on the crystallin proteins—which constitute around 90% of the lens.

    "We conclude that MG-H is a major AGE in human lens proteins quantitatively. The modification of lens crystallins by methylglyoxal led to a decrease in arginine residues and loss of positive charge." ―Naila Ahmed

    "The formation of argpyrimidine is favored by high concentrations of methylglyoxal and oxidative processes." ―Naila Ahmed

    At this point, things are becoming clear. The high glucose predictably leads to higher methylglyoxal and acetol concentrations, turning the arginine side‐chains of crystallin into fluorescent methylimidazalone side‐chains. Could this be expected to change the refractive index? I think so, and Naila Ahmed implies such a thing—giving us permission for thinking so (although we really don't need her permission).

    "The increased glycation of proteins in cataractous lenses—particularly the higher extent of glycation by MG-H—may induce protein conformational changes that stimulate further glycation and oxidation and trigger protein aggregation leading to cataract." ―Naila Ahmed
    myopia 1.png myopia2.png click to embiggen

    VII. The Molecular Refractive Index

    "Furthermore, knowing the molecular refractive index contribution of macromolecular components is crucial for understanding the optical properties, structure, and function of different tissues in the eye." ―Huaying Zhao

    Proteins have a refractive index, usually given as the 'increment.' This increment is a ratio of the refractive index over the concentration, given as dn/dc. The 'n' denotes the Snell refractive index, and the 'c' indicates concentration (why it has units of ml/g). The 'd' indicates the derivative, but I'll use the partial differential symbol '∂' to accentuate this. The reason an increment is given, and the reason it's a fraction with unexpected units, is that it depends on the concentration. When an aqueous protein solution is put in a tube with light shining through, the refraction of light depends also on concentration. Luckily however, the graph of refraction over concentration is constant, and what is arrived at is a constant number: the refractive index increment, or ∂n/∂c.

    myopia3.pngmyopia4.pngmyopia5.png click to embiggen

    Different proteins have different refractive index increments, a value determined based only on the amino acids present. Since we're dealing with light, the amino acids tryptophan, tyrosine, and phenylalanine are of obvious significance.

    "Clearly, there are considerable differences in the refractive properties of the amino acids, ranging from dn/ dc of 0.165 ml/g for proline to 0.277 ml/g for tryptophan. Amino acids with high polarizability and refractive index increment are those containing aromatic rings, sulfur, or double-bonds in the R-group, the highest ones being tryptophan, phenylalanine, tyrosine, histidine, cysteine, arginine, and methionine." ―Huaying Zhao

    "We observed that the predicted dn/dc value correlates well with the fraction of residues being Arg, Asp, Cys, His, Met, Phe, Trp, or Tyr, which are those with the highest eight values. This correlation indicates that high dn/dc values are predominantly determined by the presence of these amino acids." ―Huaying Zhao

    Relevant to the topic of myopia: the refractive index increment of crystallin—the protein of the eye—is found to be higher than any other protein. What would you expect? This protein was designed for this of course:

    "Prominent examples of more extreme values include titin, with a predicted dn/dc 0.177 ml/g, and γ-crystallins with values in excess of 0.199 ml/g." ―Huaying Zhao

    The types of amino acids present dictate the refractive index. Protein folding has surprisingly little effect. So powerful is this difference in only the amino acids themselves, they alone can actually reliably predict the refractive index increment of an entire protein.

    "In the 1960s, McMeekin and colleagues determined the refractivities of amino acids, and proposed protein dn/dc values to be estimated from their amino acid composition. This approach compared very well with experimental protein dn/dc data." ―Huaying Zhao

    So the osmolarity of glucose solution isn't the only way to change the refractive index of the lens, even if that explanation could ever be made to make sense. All that needs to be done—based on scientific measurements and described by Huaying Zhao's equations—is to change the relative proportions of the amino acids of the protein, with special emphasis given to the aromatic and fluorescent amino acids. To explain the observations of Paul Riordan Eva—that hypergylcemia is characterized by hyperopia—all one needs to explain is the change in one amino acid, or the transformation of arginine to fluorescent methylimidazalone: A covalent product formed from arginine and either methylglyoxal or acetol. This is the very same thing you'd expect from hyperglycemia—an increase in methylimidazalone—and the very same chemical species found by Naila Ahmed in human diabetic lens protein.

    "In hyperopia, the image focuses behind the retina." ―Optics 101

    An image focusing behind the retina would represent an increase in the refractive index increment (∂n/∂c) or the lens. The ∂n/∂c of tryptophan, tyrosine, phenylanine are the highest among the amino acids with values of 0.277, 0.240, and 0.244·ml/g, respectively (Zhao, Table 1). The ∂n/∂c of arginine is 0.206·ml/g, and is less than the aromatics. Since all aromatics—and histidine too—have a higher refractive index increment than those not cyclic, you'd expect methylimidazalone have a higher refractive index increment than arginine. For this reason, you would expect higher concentrations of methylglyoxal and acetol in the lens to increase the total refractive index and create hyperopia. This confirms all observations and leaves nothing wanting—with no paradox.

    "The development of refractive abnormalities in response to hyperglycaemia is characterised by rapid onset followed by prolonged regression. In all our cases the hyperopic change occurred suddenly, never taking more than a few hours to appear. Return to the previous refractive state often required weeks, depending on how rapidly and reliably the blood glucose level was controlled." ―Paul Riordan Eva

    The osmotic hypothesis cannot explain why hyperopia would form suddenly, and then take weeks to reverse. An osmotic theory would be depending on glucose, in real time, and also be at the whims of sodium concentration—never considered to be a factor in refractive changes. The sudden onset in the above case observed by Paul Eva can be explained by the transformation of arginine into methylimidazalone in the lens protein crystallin, thereby increasing the refractive index of said protein. The gradual recovery can be explained by the relatively‐slow protein turnover rate.

    VIII. Myopia

    "Previous investigators have generally believed refractive changes in diabetes, whether they be myopic or hyperopic, to be completely reversible." ―Paul Riordan Eva

    Looking back on the analytical determinations of Ahmed, you can see that both the normal lens and the cataract lens have methylimidazalone. The diabetic lens has more, but only about twice as much as the controls—victims of 'injury or trauma.' It would then appear that the lens is normally modified by the products of methylglyoxal and acetol as a result of glucose metabolism: The lens naturally has some degree of methylimidazalone in place of arginine. There is no amino acid one‐letter code for this, and you could never see it denoted in the protein sequence anyway because it's a post‐translational modification—you could never really predict which arginine would be modified. Nonetheless, they exist. These fluorescent species with higher ∂n/∂c are found in the normal human lens (Ahmed, Table 1).

    Hypoglycemia would be expected to cause myopia by attenuating the amount of methylimidazalone formed. This would lower refractive index increment back to that of arginine, and lower the global refractive index of the entire lens. This would cause the light to bend less, dropping short of the retina.

    "In myopia, the image focuses before it gets to the retina." ―Optics 101

    You would not expect myopia to form as quickly as hyperopia since the reversion back to arginine requires new protein synthesis, in the relative absence of glucose.

    "There are 10 to 20 arginine residues in the human crystallin isoforms. There is therefore an expectation that 10% to 20% of crystallin molecules have a MG-H modification." ―Naila Ahmed

    IX. Metabolic Considerations


    The sorbitol pathway of the lens has been thoroughly‐studied: Enzyme's have been analyzed; they have been homogenized and centrifuged, then precipitated and further refined through column chromatography. Two glycolytic enzymes found in the lens have been kinetically measured under a variety of substrates. These two enzymes, aldose reductase and polyol dehydrogenase, are dependent on their cofactor NADH. This means that either a paucity of niacin or a change in redox balance could theoretically change methylglyoxal concentrations, and subsequent changes in lens refractive index. Also, if present, glutathione working through glyoxylase I & II would be expected to play a role. Glutathione would be expected to lower methylglyoxal concentrations through the well‐characterized glyoxal cycle (see Thornally).

    "His idea of a decrease in the osmotic pressure of the aqueous in the face of hyperglycaemia, with consequent hydration of the cortical layers of the lens, has been reiterated by other authors. However, recent physiological evidence is to the contrary." ―Paul Riordan Eva
    myopia6.pngmyopia7.pngmyopia8.png click to embiggen

    X. Wikipedia is Wrong

    "Near-sightedness is due to the length of the eyeball being too long, far-sightedness the eyeball too short..." ―Wiki

    Wikipedia is wrong, but that's only because I haven't yet gotten around to making the edit. Besides their wrongness in this particular case, they are also quite wrong about many other things.

    XI. Miscellaneous Quotes

    "Experimental data suggest that glucose diffuses into the lens and permeates the small extracellular space, which accounts for 5-10% of the lens volume," ―Paul Riordan Eva

    "However, if glucose levels in the surrounding medium are increased, lens fibres seem to accumulate glucose [and produce methylglyoxal], and more especially-because of the apparent diversion of this substrate into the sorbitol pathway the metabolites sorbitol and fructose [and methylglyoxal and acetol]." ―Paul Riordan Eva

    "The reason is probably saturation of the enzyme hexokinase, the starting point of the glycolytic and pentose phosphate pathways in combination with the markedly higher Km of aldose reductase, the first enzyme of the sorbitol pathway." ―Paul Riordan Eva

    "The net result is an accumulation of fructose and sorbitol [and methylglyoxal and acetol downstream of that], both of which penetrate lens membranes poorly and are further metabolised to only a limited extent." ―Paul Riordan Eva

    "Experiments with human lenses have shown that lens tissue is capable of forming sufficiently high levels of sorbitol [and methylglyoxal] with 24 hours of continuous hyperglycaemia," ―Paul Riordan Eva

    "It would thus appear that a decrease in the refractive indices within the anterior portions of the lens might produce the hyperopia associated with hyperglycaemia." ―Paul Riordan Eva

    "Recently, we have found similar high concentrations of MG-H₁ in protein extracts of human blood cells and tissues of laboratory rats." ―Naila Ahmed

    "The formation of argpyrimidine is favored by high concentrations of methylglyoxal and oxidative processes." ―Naila Ahmed


    "The activity of glyoxalase I and the concentration of triosephosphates are important variables controlling methylglyoxal concentration and related glycation in cultured rat lens." ―Naila Ahmed

    "In this report, we found that MG-H was indeed the major methylglyoxal-derived AGE and that it was present at high concentration." ―Naila Ahmed

    "The availability of accurate protein refractive indices is also crucial for understanding the biophysics of eyes. For example, dn/dc enters as a key parameter in models for light transmission and scattering in the cornea. Similarly, lens protein concentrations are often estimated from measured lens refractive indices on the basis of assumed crystallin dn/dc values." ―Huaying Zhao

    "In a forthcoming communication, we show by systematic sequence analysis of crystallins of different members of the crystallin family that lens crystallins have indeed specifically evolved toward an elevated refractive index increment." ―Huaying Zhao

    "As a consequence, the protein amino acid composition represents the major determinant for the protein refractive index increment, dn/dc." ―Huaying Zhao

    "Physically, the refractive index of particles in the visible spectrum of light is a result of the local polarizability of the atoms and chemical groups due to deformation of the electron configuration about nuclei, and therefore insensitive to the long-range structure of macromolecules, and long known to be to a good approximation additive toward macromolecular refractivity." ―Huaying Zhao

    "For a spherical lens, in which the refractive index distribution depends only on the distance from the lens centre, equations for the paths of rays through the lens can be derived from a knowledge of the refractive index distribution within the lens (Born and Wolf, 1970)." ―Melanie C.W.Campbell

    XII. References

    Bloemendal, Hans. "Lens protein." Critical Reviews in Biochemistry (1982)
    Zhao, Huaying. "On the distribution of protein refractive index increments." Biophysical journal (2011)
    Campbell, Melanie. "Measurement of refractive index in an intact crystalline lens." Vision Research (1984)
    Eva, Paul Riordan. "Refractive change in hyperglycaemia: hyperopia, not myopia." British Journal of Ophthalmology (1982)
    Jedziniak, Judith A. "The sorbitol pathway in the human lens: aldose reductase and polyol dehydrogenase." Invest Ophthalmol Vis Sci (1981)
    Ahmed, Naila. "Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins." Investigative ophthalmology & visual science (2003)
    Vander Jagt. "Reduction of trioses by NADPH-dependent aldo-keto reductases. Aldose reductase, methylglyoxal, and diabetic complications." Journal of Biological Chemistry (1992)
    Petchey, Michael. "Analysis of carbohydrates in lens, erythrocytes, and plasma by high-performance liquid chromatography of nitrobenzoate derivatives." Journal of Chromatography (1984)


    @noordinary @lisaferraro @meatbag @Amazoniac @Such_Saturation @Koveras @ecstatichamster @haidut
     
  2. Israelibacon

    Israelibacon Member

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    This is absolutely wonderful. Thank you for your hard work.
     
  3. lisaferraro

    lisaferraro Member

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    @Travis OMG...THANK YOU! This has put so many pieces together for me:

    *Myopia occurred when I was around 10yrs. during a time of extreme familial stress (parents filed for divorce a few years later). Stress flooded my system with cortisol, adrenaline, ffa, PUFA (see below, my Mom poured PUFA in my system) downregulated my metabolism and metabolic energy and most likely caused hypoglycemia.

    *I was most likely hypothyroid all my life and immune problems. As a newborn had staff infection from hospital. Had signs of hypothyroidism: knock knees, weight gain, fatigue etc.

    *Cardiovascular disease in my family caused my mother to use “healthy” margarine, veg oils etc etc.

    Circling back around, I can see how PUFA’s contributed to lifelong hypothyroidism most likely being hypoglycemic and not measuring. And seems to confirm Ray’s metabolic explanation.

    I found this interesting. From the Wikipedia link to aromatic - the substituted aromatics. Aspirin appears...

    5C99C8E2-55EC-4A07-8980-8497B5E3A1AB.png
     
  4. Janelle525

    Janelle525 Member

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    So if blood glucose dysregulation is the cause then how come people have reversed it through slowly decreasing lens strength and getting outside to look into the far distance often? I personally went from -4.25 with -1.25 astygmatism to no astyg correction and -3.00 in a couple yrs of working on eye habits. And I have had yrs of good health with no change in eyesight. And relatively bad health with better eyesight with the eye habits. I think maybe the glucose dysregulation is the trigger but putting glasses on (thanks eye Drs!) and changing the focal point is the cause of ever worsening myopia. Either way this research is something to consider.
     
  5. lisaferraro

    lisaferraro Member

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    I stopped wearing my glasses 99% of the time and definitely slowed progression. I have not reversed it.
     
  6. Such_Saturation

    Such_Saturation Member

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    This is interesting. But why do people have myopia at the same glucose levels as normal sighted people?
     
  7. pimpnamedraypeat

    pimpnamedraypeat Member

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    I didn't know astygmatism was curable. Is you vision less blurry? I don't understand how glasses can fix that, I thought the problem was causes by a deformity in your lenses.
     
  8. Janelle525

    Janelle525 Member

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    The deformity doesn't happen at birth though, it usually appears after yrs of looking up close or wearing glasses. I see fine without the correction but I reduced it slowly. Over the course of a yr I got rid of the correction. My left eye is the one that still appears to struggle with it, as it is the weaker eye, but it doesn't effect my vision, and I probably need to actually reduce the strength of the dominant eye to help the weaker one gain some more strength.
     
  9. OP
    Travis

    Travis Member

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    The refractive index of the lens is determined primarily by the refractive index of the lens protein crystallin, which constitutes ~90% of the lens by mass. This, however, says nothing about the retina. The G‐protein‐coupled receptor rhodopsin is what captures the photons, and this needs to be at the focal point for perfect vision. I would expect the precise location of rhodopsin to be slightly variable, and able to compensate for slight changes in refractive index of the lens. The microtubules can grow quickly in vitro, and you'd expect the body to be capable of adapting slightly—changing the location of rhodopsin along the line intersecting the saggital and transverse planes by small spatial translations under the influence of microtubule growth, perhaps with the cis/trans isomerism of retinal playing a leading role by functioning as either a tubulin or rhodopsin polymerization inhibitor. It could perhaps do this—stop the lengthening of retinal cone and rod cells—perhaps through the simply steric hindrance of its cis conformation, or photoactivated state. In this way, or perhaps some other, the body will eventually adapt to position the protein rhodopsin directly at the focal point—within reason. In this way, the retinal protein structure itself can become entrained by the incoming light. So the refractive index of the lens itself is only half the story; the position of rhodopsin in rod and cone cells relative to the focal point of incoming light is what truly dictates the acuity of vision.
     
  10. noordinary

    noordinary Member

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    Are you on the East coast? 4 am PT a bit early for a post lol
    WoW, thank you @Travis rereading for the 5th time.
     
  11. noordinary

    noordinary Member

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    @Travis I'm confused: Paul Riordan Eva in "Refractive change in hyperglycaemia: hyperopia, not myopia" reports various cases including a myopic (patient 8) patient who's eyesight suddenly improved 2 weeks after starting oral medication for his diabetes. Some diabetic patients eyesight returned to where it was before treatment.
    I looked up anecdotal stories from diabetic patients who experienced improved eyesight (some hyperopia some myopia) for 2-3-4 weeks after treatment started (both via insulin or metformin) and later experienced the "rebound" to what they had before treatment and some even report their eyesight getting worse after the "rebound".
    Another thing: hypoglycimia is not plain low blood glucose, it is followed by blood glucose spikes (as in hyperglycemia) after initial stress response.
    I know that from personal experience: my morning blood glucose during my low carb days was about 105 and sometimes about 115 (after my last meal was afternoon previous day and low in carbs).
    @Travis you are definitely onto something! I mean your findings and explanation are amazing!
    I keep thinking about
    So the question is: what did insulin injections or metformin (and other drugs, used to treat diabetes) do to the patients to improve their eyesight temporally?

    Meanwhile:
    "Experimental data suggest that glucose diffuses into the lens and permeates the small extracellular space,which accounts for 5-10% of the lens volume, and that at normal levels of glucose in the blood and aqueous humour the rate of glucose utilisation by the lens fiber cells is equal to its rate of entry, so that the cell are essentially glucose-free. However, if the glucose levels in the surrounding medium are increased, lens fiber seem to accumulate glucose, and more especially - because of the apparent diversion of this substrate into the sorbitol pathway - the metabolites sorbitol and fructose."
    Paul Riordan Eva "Refractive change in hyperglycaemia: hyperopia, not myopia"

    Sugar or honey eyedrops anyone? Can that create "glucose levels in the surrounding medium are increased" situation?
    And if niacin is added to change the redox balance towards NADH? Are eyes sensitive to niacin water solution?
    Do they get absorbed into eyeball and reach the crystal?
     
  12. DrJ

    DrJ Member

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    Wow, fantastic stuff. Thank you!

    It also makes me wonder. In one of Ray's articles (Diabetes, scleroderma, oils and hormones) he comments how among older OB-GYN doctors it was well-known that 'diabetic' mothers (high blood sugar) had intellectually precocious children. Beyond the stereotype, there seems to be a legit correlation between smart people and the need to wear glasses. Not sure if smart folks tend to have more myopia or hyperopia, but I think it's myopia that is more common in general by a good bit. Maybe the mother's blood sugar gets high to support the baby, but baby doesn't take it up so mother's blood sugar is very elevated (but baby has low blood sugar) and baby eventually develops myopia. Or alternatively, mother's blood sugar is high, provides lots of sugar to baby for development (intelligence), but leads the baby to not be able to keep normal blood sugar on it's own after birth, so baby has low blood sugar and eventually develops myopia. Probably crazy talk, but I couldn't help but notice the coincidence.
     
  13. shepherdgirl

    shepherdgirl Member

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    Thank you for this post, @Travis - it is fascinating!
    This bit about elongated eyeballs causing myopia is not only mentioned on Wikipedia but appears in many books i have read. Are you saying that it is false, that eyeball measurements have not borne it out? Wouldn't an elongated eyeball have its focal point in front of the retina? Are there cases of myopia in normal or even shortened eyeballs?
     
  14. Such_Saturation

    Such_Saturation Member

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    But I can't see far away in my normal state :ss
     
  15. Amazoniac

    Amazoniac Member

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    Brilliantine, isolated from Travisord's brain tissue.

    The transparency of life: Cataracts as a model of age-related disease

    Cataracts: water, energy, light, and aging.
     
  16. sladerunner69

    sladerunner69 Member

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    Well then, rigorous and impressive work indeed. Were you paid to form this research or just out of personal interest?
     
  17. Amazoniac

    Amazoniac Member

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  18. Diokine

    Diokine Member

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    Your capacity for detailed analysis is stunning, and your insights into the molecular mechanisms behind the development of myopia were fantastic. I had a few thoughts I wanted to share.

    Glucose in the eye

    You explained beautifully how high glucose in the eye can lead to structural changes in proteins, which will progress to myopia or hyperopia. What causes the high glucose, or is contributing to its effects? A deficiency or loss in solubility of Riboflavin has been shown to contribute to increased NADPH+, potentially increasing activity of aldose reductase and glycation products. Riboflavin deficient lenses in rats with cataracts have also been shown to be deficient in glutathione.

    What about other effects, or thiol groups in alpha-crystallin? The effects of oxidative stress and reductions in glutathione would be something to consider. Methylglyoxal can react with thiol groups directly.

    ____________________________________________________

    Insulin, IGF-1, Growth Hormone, Prolactin

    I think it's hard to get a complete picture of what's happening in a set of myopic eyes without considering the long term adaptations to disregulated glucose metabolism in the eye. I think it's essentially similar to aging and fibrosis processes elsewhere in the body, and requires the action of the long term pleiotropic effects of the pituitary through IGF-1, Growth Hormone, and prolactin. I look at it as essentially "pseudo-acromegaly of the eye."

    Hyperglycemia in the eye leads to hyperinsulinemia, which has been fundamentally implicated in the progression of juvenile onset myopia. This hyperinsulinemia will lead to changes in response to IGF-1 and growth hormone, and these changes are the same kind seen in chronic stress-adapted cells elsewhere in the body.

    Changes in Refraction Caused by Induction of Acute Hyperglycemia in Healthy Volunteers

    Somatostatin works to antagonize the hyperglycemic effects of growth hormone signalling.


    ____________________________________________________


    From this article, incidence of myopia in pseudo-indigenous populations plotted as a function of age. It's clear to see that myopia drastically increases around the time of puberty - precisely when the growth-hormone signalling pathways are becoming active.

    [​IMG]

    ____________________________________________________

    Dopamine

    Proper maintenance of the lens structure is dependent on the retina - the process of accommodation and emmetropization requires the proper perception and feedback of image formation on the retina, through the optic nerve and other nervous structures. Dopamine, in part, works to oppose the action of the pituitary hormones and to act as a "stop" signal in eye growth. Dopaminergic signalling in the eye is enhanced by exposure to light, which partly explains the correlation between time spent outdoors and development of myopia.

    Colchicine causes excessive ocular growth and myopia in chicks

    Colchicine, a powerful inhibitor of microtubule formation, leads to derangement in the shape of the eye. It also destroys retinal ganglion and amacrine cells, which require dopamine for proper signalling.

    ____________________________________________________

    Therapy

    So, is it possible to reverse classical myopia? I wear contact lenses close to -2.5, and I have experienced near perfect vision without lenses under the influence of dopamine agonists and altered states of mind. To me this indicates it is possible to reverse some of the nervous factors involved, but what about structural changes? I was experimenting with a CO2 face mask for some time in an effort to reduce the effects of glycated proteins, though I didn't find much success.


    I think with the understanding of how glucose metabolism is disturbed in the eye, as an adaptation to chronic stress, it becomes much more straightforward to interpret the factors involved.
     
  19. lisaferraro

    lisaferraro Member

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    How I understand it as well. Ray’s metabolic health explanation makes the most sense to me especially as correlated with chronic stress as you highlighted. The high consumption of PUFA’s seems highly causal as well. Travis has broken down the mechanism and pathway to the problem. I am convinced the initial problem lies in overall sustained metabolic stress...
     
  20. OP
    Travis

    Travis Member

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    I'm a midwesterner.
    I would think—based on the tentative model—that less amounts of the more refractive methylimidazalone would be formed on the euglycemic state. This should decrease the refractive index of the lens after a few weeks—or however long it takes to form a new lens. I would also think the velocity of the change would depend on where exactly the rhodopsin is located relative to the focal point, and there being less change in those concomitantly wearing glasses. If the retina remodels faster than the lens, can keep‐up with the varying refractive index, you could perhaps expect less noticeable change.

    Raising methylglyoxal to increase the refractive index might could be a thing to try. The two best ways for doing this, in my opinion, are by using a glyoxylase I inhibitor and/or L-threonine. Paul Thornally has written extensively on the glyoxylase system, and has published an excellent review. It basically consists of two enzymes—glyoxylase I and glyoxylase II—which transform endogenous methylglyoxal into lactate in a step-wise fashion, in series. The first step is methylglyoxal spontaneously associating with the thiol of glutathione: this new complex is the substrate for glyoxlase I, which simply isomerizes this and letting glyoxylase II do the rest—releasing lactate and regenerating glutathione. Inhibiting this enzyme leads to a higher steady‐state methylglyoxal level. The best inhibitors that I've seen were β-lapachone and lapachol, both found in pau d'arco. These molecules have the lowest ki values (~5·μM), and are both small and soluble—making them better options than the others. Curcumin—for instance—inhibits in vitro isolated glyoxylase I to a similar degree, but can barely penetrate the cell; in fact, it's barely absorbed at all. All the pharmacokinetic studies measure essentially zero blood levels after consuming even gram amounts.

    But probably just as good for raising methylglyoxal is L-threonine. This is the only amino acid which becomes methylglyoxal directly in high amounts—a process process even mentioned by Vander Jagt in an article cited above.

    "Methylglyoxal can also be made from aminoacetone during the catabolism of L-threonine (6)." —Vander Jagt

    He cited (6) an article published in 1959, but there are better ones out there. The article he cites isn't experimental proof, but I've read articles that do actually prove this.

    And it's easy to see why this should happen: After decarboxylation, threonine becomes aminoacetone; this is then acted-upon by monoamine oxidase forming methylglyoxal:

    A general scheme in accordance with known facts

    myopia12.png click to embiggen

    The best way (and safest way) for raising methylglyoxal levels, in my opinion, is by consuming pau d'arco tea—in a french press, with coffee—while taking anywhere between 500 – 3,000 milligrams of L-threonine per day. Pau d'arco is actually an inner tree bark, like ceylon cinnamon, and tastes somewhat like cinnamon.

    Thornalley, Paul J. "The glyoxalase system in health and disease." Molecular aspects of medicine (1993)
    Thornalley Paul J. "Inhibitors of glyoxalase I: design, synthesis, inhibitory characteristics and biological evaluation." Biochemical Society transactions (1993)
    Vander Jagt, D. L. "Reduction of trioses by NADPH-dependent aldo-keto reductases. Aldose reductase, methylglyoxal, and diabetic complications." Journal of Biological Chemistry (1992)


    Well, check‐out the prevalence of refractive change in Asia:

    myopia11.png click to embiggen

    I used to think that they wore glasses just to look smart, but.. . . ..but have you seen the List of Chinese inventions on Wikipædia? Not bad, if I may say so myself. The Japanese and Chinese could very well deserve the stereotype.
    I think that it must be false, or misleading, in most cases. Hyperglycemia can cause refractive changes in minutes, and aldose reductase inhibitors prevent this from happening. This proves that glycolytic metabolism downstream of aldose reductase can cause refractive changes, and also deftly refutes the osmotic theories since sorbital or triose don't have any higher osmotic potential than glucose itself—or sodium for that matter. Of course, a change in the eyeballs's shape—or the position of the retina—would very likely produce changes in light perception (unless two parameters change simultaneously, thereby off‐setting eachother), but the associations between blood glucose levels are undeniable. This isn't the only way to produce myopia/hyperopia, but I think that's its the primary factor in the majority of cases. For some reason, this idea isn't popular; this could perhaps be the result of politics, or that most people prefer a simpler explanation—or a mix of the two.
    You will! Hang in there. We need to read more about rhodopsin, microtubules, and cone cells. . . but not to discount the role of the refractive index of the lens itself—changed through a post‐translational modification or the lens protein crystallin, thereby producing an nonconventional amino acid higher refractive index.

    I am willing to bet that we could find scientific articles describing how the morphology and growth rate of retinal cone cells change on exposure to light. These cells need to occupy the space of the focal point of the lens, and play a role in all of this.
    Is this Ray Peat talking about the "glycation" of crystallin? I think this is a misleading term, as its too close to "glycosylation;" this almost implies that glucose itself is adding to the protein. This is not the case. Certain trioses are reacting with arginine side‐chains in a cyclicization reaction, in a manner which can probably be best described as a post‐translational modification. Thrornally has shown just recently that that methylglyoxal can induce or suppress DNA→mRNA transcription in this manner—by modifying a transcription factor in cell's nucleus (mSin3A).

    And 'glycation' is also misleading for the obvious reason that methylglyoxal can be produced from either glycerol of threonine.

    Yao, Dachun. "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry (2007)
    Wang, Tina. "Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones." Journal of the American Chemical Society (2012)


    I had realized a few days ago that I had to look into this, and that glucose must be involved–somehow. When reading about it, it because clear what was going on. This led directly into a more familiar territory form me: the methylglyoxal–arginine adducts, what I find most interesting.
    You'd expect this to occur, but γ-crystallin has only eight cysteines; compare that to the twenty arginines. The methylglyoxal–thiol bond is a bit more labile that the condenstation of methylglyoxal and arginine, which forms a species so resilient that it can be detected in urine. Thiol–acyl bonds, as is acetyl–CoA, are routinely formed and cleaved by low-energy enzymes within the body during (fatty acid metabolism). The carbon–sulfur bond isn't one of the strongest, and I'd assume any methylglyoxal–thiol bonds to be transient (as in the case of methylglyoxal–glutathione); sulfur binds most strongly to mercury.

    Glutathione is needed to turn methylglyoxal into lactic acid, and can perhaps be considered a cofactor. Glutathione is a prerequisite for the methylgyloxal→lactic acid conversion through the glyoxylase system. High methylglyoxal leads to less-active glutathione as it's occupied by such, on the thiol group. This hasn't been overlooked in attempting to explain how methylglyoxal reverses cancer; it has been speculated that this occupation of glutathione is the primary reason. While it's true that gluationine is needed for mitosis, I think a bit differently: I think that methylglyoxal works mostly by adding to a specific arginine side-chain in NADH-dependent glycolytic enzymes, which all have an arginine which bonds the phosphodiester of it's cofactor—NADH. Arginine is always found at this location in such enzymes in a highly‐intuitive interaction: The fully-positive or ∂-positive charges of arginine—found on the γ-nitrogens—interact noncovalently with the negative oxygen atoms of the phosphodiester—like the well-known 'salt bridge' between glutamate and lysine, for instance. These NADH-dependent enzymes simply cannot bind the cofactor without this arginine, and point-mutational analysis fully confirm this. This would explain why glyolytic rates drop quickly with 3‐bromopyruvate or methylglyoxal: They work on glycolytic enzymes directly by abrogating their ability to bind NADH—their cofactor—by permanently‐modifying a key arginine residue while it's being assembled in the ribosome . . . or shortly thereafter.
    That's a very interesting observation, and an interesting graph. Growth hormone does raise insulin, right? leading to lower blood glucose and methylglyoxal—leading then further to a lower percentage of arginine transformed into methylimidazolone resulting in a negative shift of the lens' refractive index.
    This is interesting. I know that glutamate and GTP both powerfully influence the polymerization rates of tubulin in vitro, and had a thought that dopamine was perhaps involved in this. If you look at colchicine, you'll realize it has multiple methoxy groups. You may also realize that over 95% of molecules classified as "microtubule inhibitors" have methoxy groups—you can find dozens of examples of this. Dopamine can be methylated on one of the catechol oxygens, leading to methoxytyramine—or methyldopamine (synonymous). The enzyme catechol‐O‐methyltransferase is responsible for doing this, and the low‐activity methionine‐encoding allele of the gene is often correlated with higher IQ. There are dozens of studies on catechol‐O‐methyltransferase and IQ, and methoxytyramine has been implicated in Parkinson's dyskinesia (caused by ingesting too much L-DOPA.)

    I don't find it hard to believe that the ratio of dopamine to methyldopamine could influence microtubules in vivo, since the methoxy groups seems almost a prerequisite for a powerful microtubule polymerization inhibitor/destabilizer (see colchicine, methoxyestradiol, and many more.)

    Perez, Edith A. "Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance." Molecular cancer therapeutics (2009)
    Bishop, Sonia J. "COMT val¹⁵⁸met genotype affects recruitment of neural mechanisms supporting fluid intelligence." Cerebral Cortex (2008)


    Yeah. You'd think that polyunsaturated fatty acids would activate the Randall Cycle, likely through PPARγ upregulating the fatty acid synthase and the β-oxidation enzymes. Too many fatty acids of the wrong type certainly seem capable of influencing glucose balance. Anything that effects glucose metabolism—or modulates the glyoxylase system—would be expected to modify the refractive index of crystallin. The higher prevalence of myopia among adolescents can perhaps be explained by the action of growth hormone, through raising insulin (Diokene, 2017); and the hyperopia seen in diabetes can certainly by caused by hyperglycemia (Eva, 1982).

    I'm reading about the PPAR receptors (I know that's a redundant acronym, but it reads better) and think they can rightly be considered our "unsaturated fatty acid and eicosanoid receptors"—althought they do also interact with retinoic acid, steroids, and vitamin D. These things seem somewhat nonselective, and can bind many types of cell lipids. I'm under the impression that PPARβ and PPARδ directly antagonize PPARα and PPARγ, and think it's through primarily these interactions that fatty acids and eicosanoids exert their hormonal effects.

    When I first heard about eicasanoids from Ray Peat I thought they were . . . boring. I had bought a book on eicosanoids and never read it; this was about ten years ago. Eicosanoids have funny names, they sound silly, and don't have the allure that steroid hormones do. It's even somewhat difficult, initially, to even believe that these lipids could have hormonal effects.

    But now I think they're interesting, especially after reading about phospholipase A₂ and how plants make similar molecules called defensins: lipids with reactive epixide and peroxide groups ostensibly made to destroy invaders. Prostaglandins were the initial cellular defense mechanism, formed with the lipids of the cell membrane itself (and O₂, or H₂O₂).

    Thomma, Bart P. "Plant defensins." Planta (2002)
     
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