The Synergistic Effects of Polyol Pathway-Induced Oxidative and Osmotic Stress in the Aetiology of Diabetic Cataracts

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a great paper and i have found no issues worth mentioning. 

 

Congratulations!

Author Response

Reviewer 1

This is a great paper and i have found no issues worth mentioning. 

Congratulations!

We would like to thank this reviewer for your positive comments.

Reviewer 2 Report

Comments and Suggestions for Authors

In this manuscript it s not clear wether the main cause of diabetic cataract is the osmotic effect related to the higher levels of sorbitol , or the fructose metabolites that contributes to oxidant stress. I think that must be  deeply discussed in the conclusions section.

Author Response

Reviewer 2

In this manuscript it is not clear whether the main cause of diabetic cataract is the osmotic effect related to the higher levels of sorbitol , or the fructose metabolites that contributes to oxidant stress. I think that must be  deeply discussed in the conclusions section.

Thank you for raising this point.  We have amended parts of the manuscript in  order to  more clearly  emphasise the combined contribution of the roles of both osmotic and oxidative stress in diabetic cataract. Please note the following changes, highlighted in the re-submitted manuscript:

Abstract-see highlighted sentence (lines 12-15)

In rat models of diabetic cataract, this damage has been shown to result from osmotic stress and oxidative stress due to accumulation of intracellular sorbitol, the depletion of NADPH which is used to regenerate glutathione and the generation of fructose metabolites via the polyol pathway.

Conclusion-see highlighted sentences (Lines 708-733)

Hyperglycemia results in the upregulation of the polyol pathway and the generation of sorbitol, fructose and fructose derived metabolites, contributing to lenticular oxidative stress and the modification of proteins, including proteins linked to maintaining redox balance and regulating cell volume. The control of water content and movement at both the cellular and organ level is fundamental to the function and transparency of the human lens. For this reason, the lens possesses regulatory mechanisms that respond quickly to osmotic stress to maintain steady state fiber cell and whole lens volume. However, over time, hyperglycemia induced oxidative stress and irreversible protein modifications impair the volume regulation machinery of the lens, resulting in the osmotic cell swelling characteristic of diabetic cortical cataract.

It is now more widely recognised that it is the synergistic effects of both osmotic stress, oxidative stress and irreversible AGE formation that results in the gradual loss of the homeostatic responses that normally regulate cell volume and redox balance, coinciding with the chronic onset of diabetic cataracts several years after diagnosis of diabetes. The increased flux of glucose through the polyol pathway results in amplification loops which exacerbate ROS production, increase oxidative stress, increase the formation of AGEs, and ultimately lead to protein damage. However, there are still significant gaps in our knowledge, particularly related to fructose metabolism in the lens and its exact contribution to oxidative stress and osmotic stress. These physiological aspects must be better understood to successfully target therapies for the prevention of diabetic cataract in humans, but given that species differences exist in the uptake and metabolism of glucose in the lens, careful consideration is required around the selection of an appropriate animal model. With this in mind, the targeting of a specific glucose and/or fructose metabolic pathway that alleviates oxidative stress and protects the cell volume machinery of the lens may delay the onset of cataract and avoid the looming cataract epidemic caused by our increasing diabetic population.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors of the manuscript ijms-3125686 entitled The synergistic effects of polyol pathway induced oxidative and osmotic stress in the aetiology of diabetic cataracts, have prepared an interesting  manuscript. However, it requires a modification.
The authors cite many studies, but there is no information on the key. Which publications were included and which were excluded. No research methodology. The review manuscript should be prepared according to PRISMA principles. Furthermore, it is difficult to find clinical aspects in the manuscript. There are no studies per se in the case of diabetic cataract. The literature is largely review and very old. For example,
95. KINOSHITA JH. Carbohydrate metabolism of Lens. AMA Archives of Ophthalmology. 1955;54(3):360-8
83. Davies PD, Duncan G, Pynsent PB, Arber DL, Lucas VA. Aqueous humour glucose concentration in cataract patients and its effect on the lens. Experimental Eye Research. 1984;39(5):605-9
85. Kuck JF, Jr. CARBOHYDRATES OF THE LENS IN NORMAL AND PRECATARACTOUS STATES. Invest Ophthalmol. 1965;4:638-42.
92. Merriman-Smith BR, Donaldson PJ, Kistler J. Differential expression of facilitative glucose transporters GLUT1 and GLUT3 the lens. Investigative Ophthalmology and Visual Science. 1999;40(13):3224-30. 912
93. Merriman-Smith BR, Krushinsky A, Kistler J, Donaldson PJ. Expression patterns for glucose transporters GLUT1 and GLUT3 in the normal rat lens and in models of diabetic cataract. Invest Ophthalmol Vis Sci. 2003;44(8):3458-6
It is advisable for authors to demonstrate the limitations of the topic being researched.

Author Response

Reviewer 3

The authors of the manuscript ijms-3125686 entitled The synergistic effects of polyol pathway induced oxidative and osmotic stress in the aetiology of diabetic cataracts, have prepared an interesting  manuscript. However, it requires a modification.
The authors cite many studies, but there is no information on the key. Which publications were included and which were excluded. No research methodology. The review manuscript should be prepared according to PRISMA principles. Furthermore, it is difficult to find clinical aspects in the manuscript. There are no studies per se in the case of diabetic cataract. The literature is largely review and very old. For example,
95. KINOSHITA JH. Carbohydrate metabolism of Lens. AMA Archives of Ophthalmology. 1955;54(3):360-8
83. Davies PD, Duncan G, Pynsent PB, Arber DL, Lucas VA. Aqueous humour glucose concentration in cataract patients and its effect on the lens. Experimental Eye Research. 1984;39(5):605-9
85. Kuck JF, Jr. CARBOHYDRATES OF THE LENS IN NORMAL AND PRECATARACTOUS STATES. Invest Ophthalmol. 1965;4:638-42.
92. Merriman-Smith BR, Donaldson PJ, Kistler J. Differential expression of facilitative glucose transporters GLUT1 and GLUT3 the lens. Investigative Ophthalmology and Visual Science. 1999;40(13):3224-30. 912
93. Merriman-Smith BR, Krushinsky A, Kistler J, Donaldson PJ. Expression patterns for glucose transporters GLUT1 and GLUT3 in the normal rat lens and in models of diabetic cataract. Invest Ophthalmol Vis Sci. 2003;44(8):3458-6
It is advisable for authors to demonstrate the limitations of the topic being researched.

Thank you for highlighting this point. We should emphasis that this is not a systematic review, but rather a review of the literature that has led to out current view of the role of osmotic and oxidative stress contribution of the pathogenesis of diabetic cataracts. The  papers cited are “old” but are the original papers that have laid the foundation for our view on the molecular mechanism that contribute to diabetic cataracts. However, we have taken the reviewers comment on board and have commented on the type of review this is (making it clear it is not a systematic review)  and perhaps in turn why  certain “historic” papers were selected as part of this review. Please refer to lines 91-104:

 

This is not a systematic review proper, but instead a review in which we have focused on identifying pathways, old and new, that contribute to cataract formation and examining how they differ between animal and human lenses to provide a greater understanding of the pathobiology of diabetic cataracts. This has led to identifying gaps in our knowledge and hence areas of future research which may promote further research on the topic and assist the goal of developing improved therapies to prevent the looming diabetic cataract epidemic. To provide a context for this current review, we first describe the diabetic cataract damage phenotype before providing an overview of how the structure and function of the lens results in variations to the uptake and metabolism of glucose in the morphologically distinct regions of the lens. We provide an overview of the physiological adaptations that maintain lens transparency that are vulnerable to damage during hyperglycaemia, before discussing how the biochemical changes arising from altered glucose metabolism in hyperglycaemia may impact these adaptations, eventually manifesting as the distinctive cortical cataract phenotype observed in human diabetic patients.

Reviewer 4 Report

Comments and Suggestions for Authors

The review article with the title “The synergistic effects of polyol pathway induced oxidative and osmotic stress in the aetiology of diabetic cataracts” was submitted to MDPI International Journal of Molecular Sciences.

The article nicely summarises the current evidence on cataract formation based on biochemical and metabolic pathways. The article is therefore relevant and generates hypothesis and research questions which may promote further research on the topic.

Please respond to the following comments and questions and address them in the manuscript:

L31-32: “In contrast, type 2 diabetes increases proportionally with increasing body mass index [2], and is associated with insulin resistance and a lack of appropriate compensation by β cells leading to insulin deficiency [1].”
A) Whether the risk increases proportionally or exponentially is subject to discussion. It may be better not to go into detail or provide a clear reference.
B) Diabetes mellitus type 2 has a strong genetic background. Please put this into relevant context in the review article and support it with adequate references.

L53-54: “For these reasons, cataract surgery for diabetic patients is not recommended until vision deteriorates to 20/100 to 20/200 [17]. This leads to greater delays to receiving surgery, further diminishing the quality of life for diabetic patients.”
A) If surgeons wait longer to operate on a patient, I would assume that this would reduce delays in receiving surgery because some patients may die or there may be more flexibility in planning.
B) The guidelines are different on when to operate a diabetic cataract. I am not sure how important the guidelines are in this context. Therefore it may be better to avoid the discussion due to the biochemical focus of the publication.
C) In general: It is recommended to differentiate further what a diabetic patient is. Diabetic patients can or cannot have ocular manifestations or complications of the disease. Among the patients who have, there are important differences in severity (which are described with clinical classifications). A diabetic patient who does not have any ocular manifestation may thus have an almost normal risk for cataract surgical complications whereas a patient with advanced diabetic eye disease may have a very important increase in risks for complication.
D) It may be sensible to clarify in the review that despite an increased risk profile in diabetic patients, cataract surgery is still a very effective treatment for this patient cohort.

L71: “light scattering observed in the cortex.”
The eye can conceptually be divided into an optical and neurosensory part, the latter beginning with the retina. A light scatter can therefore not be” observed” in the cortex. The light scatters in the optical part which then leads to a neuro-sensory processing in the brain. The process should be describes logically using an appropriate reference.

L108-109: “Detailed morphological examination of human diabetic cataractous lenses is lacking since cataract surgery typically involves emulsification of the lens.”

The intended meaning of this sentence is unclear. The lens can be examined with the slitlamp, imaging (OCT, ultrasound) or histologically.

 

Is there any literature on other types of Diabetes mellitus (for instance MODY types). Is it possible to comment on cataract formation? Are there any differences between the different Diabetes types? Are genetic diabetes types (for instance MODY) explored for their relevance in studying the cataract formation process in diabetics?

Author Response

Reviewer 4

The article nicely summarises the current evidence on cataract formation based on biochemical and metabolic pathways. The article is therefore relevant and generates hypothesis and research questions which may promote further research on the topic.

 

We appreciate the reviewer’s positive comments

Please respond to the following comments and questions and address them in the manuscript:

L31-32: “In contrast, type 2 diabetes increases proportionally with increasing body mass index [2], and is associated with insulin resistance and a lack of appropriate compensation by β cells leading to insulin deficiency [1].”
A) Whether the risk increases proportionally or exponentially is subject to discussion. It may be better not to go into detail or provide a clear reference.

1. B) Diabetes mellitus type 2 has a strong genetic background. Please put this into relevant context in the review article and support it with adequate references.

 

Thank you for this comments. We have amended our sentence, and added appropriate reference. Please refer to lines 32-35

Type 2 diabetes also has a strong genetic predisposition [2, 3], but is associated with increasing body mass index [2] and insulin resistance, with a lack of appropriate compensation by β cells leading to insulin deficiency [1].

L53-54: “For these reasons, cataract surgery for diabetic patients is not recommended until vision deteriorates to 20/100 to 20/200 [17]. This leads to greater delays to receiving surgery, further diminishing the quality of life for diabetic patients.”
A) If surgeons wait longer to operate on a patient, I would assume that this would reduce delays in receiving surgery because some patients may die or there may be more flexibility in planning.
B) The guidelines are different on when to operate a diabetic cataract. I am not sure how important the guidelines are in this context. Therefore it may be better to avoid the discussion due to the biochemical focus of the publication.

Thank you for these comments. We agree that that its better to avoid this discussion, so we have removed this sentence all together.

1. 
   C) In general: It is recommended to differentiate further what a diabetic patient is. Diabetic patients can or cannot have ocular manifestations or complications of the disease. Among the patients who have, there are important differences in severity (which are described with clinical classifications). A diabetic patient who does not have any ocular manifestation may thus have an almost normal risk for cataract surgical complications whereas a patient with advanced diabetic eye disease may have a very important increase in risks for complication.
   D) It may be sensible to clarify in the review that despite an increased risk profile in diabetic patients, cataract surgery is still a very effective treatment for this patient cohort.

This is an excellent point. We have amended out text  as we were referring to diabetic patients with cataracts as opposed to diabetic patients. Please refer to lines 55-63

For diabetic patients with cataracts, the risk of complications associated with cataract surgery are higher than the general population. These risks include enhanced progression of diabetic retinopathy [17], the development of photic retinopathy [18], and macular oedema [19]. More complex surgical procedures are also required to manage the additional risks for diabetic patients with cataracts [20] and post-surgical healing is reported to be slower in these patients [21, 22]. Diabetic patients with cataracts also experience more issues with replacement lenses, and the options are more limited due to possible contraindications with the materials that some intraocular implants are made from [23-26].

 L71: “light scattering observed in the cortex.”
The eye can conceptually be divided into an optical and neurosensory part, the latter beginning with the retina. A light scatter can therefore not be” observed” in the cortex. The light scatters in the optical part which then leads to a neuro-sensory processing in the brain. The process should be describes logically using an appropriate reference.

We agree that the term ‘observed’ may be misleading in this context, and so have made an amendment to the text. Please refer to line 72-74

Questions remain on how the elevated glucose levels associated with diabetes evoke these localised changes in lens fiber cell volume that manifests as cell swelling and opacification in the cortex.

L108-109: “Detailed morphological examination of human diabetic cataractous lenses is lacking since cataract surgery typically involves emulsification of the lens.”

The intended meaning of this sentence is unclear. The lens can be examined with the slitlamp, imaging (OCT, ultrasound) or histologically.

Thank you for pointing this out. We were referring to  morphological changes at  a cellular level which require sectioning of an intact (not fragmented) human diabetic cataractous lens.  We have amended the text to make this clearer to readers. Please refer to lines 112-115

Due to the phacoemulsification technique used in cataract surgery where the lens is fragmented, very few studies have been able to examine at the cellular-level localised morphological changes occurring in intact human diabetic cataractous lenses.  

 

Is there any literature on other types of Diabetes mellitus (for instance MODY types). Is it possible to comment on cataract formation? Are there any differences between the different Diabetes types? Are genetic diabetes types (for instance MODY) explored for their relevance in studying the cataract formation process in diabetics?

Thank you for raising this. While the most commonly recognized forms of diabetes mellitus include type 1 and type 2 diabetes, the reviewer is correct is that other forms of diabetes exist including  Maturity-onset diabetes of the young (MODY). However, cataracts to not appear to be a classic feature and so the overall prevalence of cataract formation MODY has not been previously reported. There is one case of bilateral cataracts reported in an adolescent female with an HNF1B (MODY5) mutation, but there is no further description about this cataract.

We have made mention of this type of diabetes and cataract formation, but because so little is known about the cataract mechanisms involved, we haven’t speculated around the relevance in studying cataract formation with  this type of diabetes.  Please refer to lines 35-39

While the most commonly recognized forms of diabetes include type 1 and type 2 diabetes, other forms of diabetes exist including Maturity-onset diabetes of the young (MODY). However, cataracts do not appear to be a classic feature and so the overall prevalence of cataract formation in MODY is unknown [4]. On the other hand, a frequent complication of both type 1 and type 2 diabetes is cataract.

Reviewer 5 Report

Comments and Suggestions for Authors

Polyol pathway coupled with oxidative and osmotic stress has long been identified as the main contributing factor for the development of age-related and diabetic cataract. A huge body of knowledge exist in this specific area that seem partly explaining the origin of diabetic cataract (Assocuated with both the Type 1 and Type 2 diabetes mellitus). Because of larger variation in the species-specific genetic makeup of the ocular lens and the associated metabolic diversity no single explanation has been proven to be uniformly explaining the origin and sequence of events that lead to diabetic cataract development and that seems to be a big hurdle in devising a management plan for diabetic cataract in human.

The current manuscript is a review article and has been mentioning the word ‘examine’ in the abstract section (Page 1, line 17) is giving a false impression of a research paper. This issue needs to be clearly resolved. Considering existence of large number of review articles systematically summarizing the issue of redox imbalance, osmotic stress and diabetic cataract the advanced knowledge gain in the concerned subject area is incremental.

Author Response

Reviewer 5

The current manuscript is a review article and has been mentioning the word ‘examine’ in the abstract section (Page 1, line 17) is giving a false impression of a research paper. This issue needs to be clearly resolved. Considering existence of large number of review articles systematically summarizing the issue of redox imbalance, osmotic stress and diabetic cataract the advanced knowledge gain in the concerned subject area is incremental.

Thank you for your comments.  Having considered your comments together with comments from other reviewers, we have amended the abstract of this manuscript to more accurately define the purpose and scope of this review article. While we agree that the published literature around hyperglycaemic polyol metabolism and redox imbalance in diabetic cataract has been well reviewed by others, we wish to emphasize that this is the first instance in which these concepts have been reviewed together with the relevant aspects of lens physiology and, specifically, fiber cell volume control, in order to understand how these tissue stresses may actually be resulting in a localised  phenotype observed in cortical cataract. We have amended our abstract to better reflect this.

Abstract: Cataract is the world’s leading cause of blindness, and diabetes is the second leading risk factor for cataracts after old age. Despite this, no preventative treatment exists for cataract. Altered metabolism of excess glucose during hyperglycaemia is known to be the underlying cause of diabetic cataractogenesis, resulting in localised disruptions to fiber cell morphology and cell swelling in the outer cortex of the lens. In rat models of diabetic cataract, this damage has been shown to result from osmotic stress and oxidative stress due to accumulation of intracellular sorbitol, the depletion of NADPH which is used to regenerate glutathione and the generation of fructose metabolites via the polyol pathway. However, differences in lens physiology and the metabolism of glucose in the lenses of different species has prevented the translation of successful treatments in animal models into effective treatments in humans. Here, we review the stresses that arise from hyperglycaemic glucose metabolism, and link this to the regionally distinct metabolic and physiological adaptations in the lens that are vulnerable to these stressors, highlighting the evidence that chronic oxidative stress together with osmotic stress underlies the aetiology of human diabetic cortical cataracts. With this information, we also highlight fundamental gaps in knowledge that could help to inform new avenues of research if effective anti-diabetic cataract therapies are to be developed in the future.

Round 2

Reviewer 5 Report

Comments and Suggestions for Authors

The authors have taken great care in addressing my comments and concerns. The responses provided by the authors addressing my concerns are satisfactory and they have made necessary edits/changes in the manuscript. The revised version of the manuscript appears much improved.