Introduction

The sorbitol or polyol pathway is a two-step metabolic pathway that converts glucose into fructose. This pathway is thought to play a prominent role in explaining the pathogenesis of complications in patients with end-stage diabetes. In light of this, this activity presents the biochemistry behind this pathway, summarizes the individual reactions and their importance, reviews the prevailing hypothesis explaining why this pathway plays a role in end-stage diabetes, and explores the clinical significance of the polyol pathway with the potential for treatment in diabetic patients.[1]

Fundamentals

Normally, glucose is processed by the glycolysis pathway and is utilized for ATP production and energy. When glucose levels become exorbitantly elevated, other pathways are upregulated to handle the glucose effectively. These pathways include the glycation pathway, the hexosamine pathway, the protein kinase C pathway, the alpha-ketoaldehyde pathway, and the sorbitol pathway.[2][3][4][5][6] Research has indicated that all these pathways share a common characteristic of producing reactive oxygen species.[7] The first step in the sorbitol pathway is the conversion of glucose to sorbitol via the enzyme aldolase reductase. This step utilizes a hydrogen group donated by NADPH. This is also the rate-limiting reaction of this entire pathway. The second step in this pathway is the conversion of sorbitol into fructose via the enzyme sorbitol dehydrogenase.  This step donates a hydrogen group to NAD+, creating a byproduct of NADH.[8] This step is reversible. The sorbitol pathway plays a role in metabolizing glucose and maintains the redox balance by utilizing substrates such as NADPH and NAD+ to drive the reactions.

Issues of Concern

A concern regarding the sorbitol pathway is that not all tissues have the enzyme sorbitol dehydrogenase, including the retina, kidneys, and Schwann cells. As a result, in diabetic patients or those with extremely high glucose levels, sorbitol accumulates to toxic levels and leads to complications within these organs. This pathway provides some explanations of the formation of complications in diabetic patients. Without early intervention and adequate glycemic control, the complications formed from the polyol pathway can become permanent and significantly decrease quality of life.

Cellular Level

Tissues with sorbitol dehydrogenase include the ovaries, seminal vesicles, liver, and lens, albeit at a low level of activity. Tissues without sorbitol dehydrogenase include kidneys, the retina, and Schwann cells. Complications can arise due to the deficient enzyme in these tissues.

Molecular Level

Aldolase reductase is an enzyme part of the alpha-keto reductase superfamily that uses NADPH to drive the forward reaction.[9] Aldolase reductase can reduce a wide variety of aldehydes due to its broad specificity, as first studied by H.G. Hers in 1960.[10] Aldolase reductase is an enzyme with a relatively low affinity for glucose (high Km). This means that under normal glucose levels, the low affinity of aldolase reductase to glucose reduces the activity of the enzyme and the pathway overall. On the other hand, Sorbitol dehydrogenase is a member of the medium-chain dehydrogenase superfamily.[11] NAD+, which drives this reaction forward, oxidizes the carbon in the sorbitol's second position.[12] As the polyol pathway continues metabolizing glucose, an overproduction of fructose in the body occurs. This has several metabolic consequences. The surplus of fructose is metabolized by fructokinase, which requires ATP. This results in acetyl-CoA overproduction and depletion of ATP.[13][14] Overproduction of acetyl-CoA can impair protein function by causing protein acetylation.[15] The surplus in acetyl-CoA has the potential to cause non-alcoholic fatty liver disease since acetyl-CoA is a precursor molecule to fatty acids.[16] Fructose also can chemically glycate proteins via fructose metabolism byproducts fructose-3-phosphate and 3-deoxyglucose, impairing protein function.[17][13] The glucose transporter, GLUT5, is responsible for the transport of free fructose and is found on spermatocytes, small intestinal enterocytes, and kidneys for further metabolism. Overproduction of fructose and subsequent transport through the GLUT5 into these organs can cause further damage.

Function

The function of the polyol pathway is clear - to provide an alternate route of glucose metabolism when the high glucose levels overwhelm the primary glycolytic pathway. However, the polyol pathway also plays a prominent role in disrupting the redox balance of NADP+ and NADPH.[18] As mentioned, aldolase reductase utilizes an NADPH to drive the first step. This eventually results in a significant depletion of NADPH levels in the body. Research has shown a decrease of NADPH in the pancreas and lungs of a diabetic patient and a 15% decrease in the lens of a diabetic patient.[19][20] This decrease impairs several biochemical reactions. Glutathione reductase utilizes NADPH to alleviate the oxidative stress caused by free radicals in the human body. Research has shown that in diabetic patients, the polyol pathway decreases glutathione and NADPH levels due to the low activity of glutathione reductase.[21] This also leads to a subsequent impairment in glucose metabolism. The second step in this pathway, converting sorbitol to fructose, requires NAD+ to drive the reaction forward, inherently producing an NADH molecule. This process has a multitude of deleterious effects. Sirtuins are histone deacetylases that are dependent on NAD+ for their function. The depletion of NAD+ impairs the sirtuin pathway, which is responsible for the deacetylation of proteins in the human body.[22] The surplus of NADH inhibits other glucose metabolic pathways such as the Krebs, glycolytic, and pyruvate dehydrogenase complex.[23] This drives glucose down the polyol pathway for further metabolism. The polyol pathway has also been credited as an explanation of complications in diabetic patients, specifically in the kidney, retina, and nerves.

Mechanism

Two prevailing hypotheses explain the mechanisms for complication formation in diabetic patients: the osmotic hypothesis and the metabolic flux hypothesis. Research has shown that both hypotheses play a role in diabetic complications and often occur simultaneously. The osmotic hypothesis emphasizes the effects of the accumulation of intermediates in the polyol pathway, specifically sorbitol. Sorbitol and fructose are both practically membrane impermeable. In tissues without sorbitol dehydrogenase, such as the retina, kidneys, and Schwann cells, sorbitol intracellularly accumulates fluid into the tissues, leading to elevated osmotic stress.[24] This hypothesis is the prevailing explanation for cataract formation in the lens, which has a low sorbitol dehydrogenase activity. In mice that overexpress aldolase reductase combined with having a sorbitol dehydrogenase deficiency phenotype, elevated glucose levels resulted in a quicker rate of lens sorbitol accumulation and subsequent cataract formation. Additionally, sorbitol accumulation can impair kidney function due to the lack of sorbitol dehydrogenase. Studies have shown that sorbitol accumulation intracellularly leads to enzymuria and proximal tubular cell dysfunction.[25] 

Sorbitol accumulation also impairs Schwann cell function. Schwann cells are responsible for the myelination of peripheral nerves. Sorbitol accumulation results in Schwann cell de-differentiation to immature cells and a decreased expression of IGF-1 in the cells.[26] Metabolic flux is the rate of turnover of metabolites through a pathway. Nuclear magnetic resonance was utilized to examine diabetic cataractogenesis and found that in diabetic patients, there was a 3000% per hour turnover of NADPH. Furthermore, there was a competition for NADPH between glutathione reductase and aldolase reductase.[27] The depletion of NADPH and the surplus of NADH impaired several biochemical reactions, such as lipid metabolism, growth factor formation, and protein kinase C activity.[28] These biochemical disturbances have been credited to being caused by hyperglysolia, a term used to describe elevated cytosolic glucose or rates of glucose metabolism.[29] Research has shown that metabolic flux through the polyol pathway plays a larger role in peripheral neuropathy than sorbitol accumulation. Other hypotheses have clinical and pathological significance, such as protein kinase C overactivation or increased glycolytic flux.[28][30] However, the osmotic and metabolic flux hypotheses have the most dedicated research.

Clinical Significance

The clinical significance of the polyol pathway is tied to diabetes in terms of complications and specific treatment modalities. The complications in a diabetic patient that can arise from the polyol pathway include lens swelling, osmotic imbalance, and peripheral neuropathy.[24]  Research has also shown that the polyol flux is a key component in developing cataracts, especially in diabetic patients.[31] The mechanism is likely due to the overproduction of free radicals and decreased ability to handle those radicals due to the suppressed glutathione reductase activity and the likely accumulation of sugar within the aqueous humor. The polyol pathway also sheds light on potential treatment options for diabetic patients. Aldolase reductase inhibitors have been extensively researched to examine whether they can be effective treatments. The mechanism behind this treatment is that the accumulation of sorbitol is limited by inhibiting the first enzyme of the polyol pathway, aldolase reductase. Aldolase reductase inhibitors include flavonoids, spirohydantoins, and carboxylic acid derivatives.[32] Adverse effects of these drugs include hypersensitivity reactions. Studies have shown that aldolase reductase inhibitors have been effective in the early stages of diabetic complications.[33] Aldolase reductase inhibitors have shown significant results in delaying cataract formation in animals, but minimal research has occurred testing this on humans. Another study has concluded that aldolase reductase inhibitors may provide significant relief to diabetic patients with certain complications.[34] Due to the redox imbalance caused by the polyol pathway, GLP-1 agonists and SGLT-2 inhibitors are efficacious in reducing renal oxidative stress and their effects on glycemic control.[35] The lack of consensus warrants further research into the indications and effectiveness of aldolase reductase inhibitors as a potential breakthrough in diabetic treatment.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Yapar G, Esra Duran H, Lolak N, Akocak S, Türkeş C, Durgun M, Işık M, Beydemir Ş. Biological effects of bis-hydrazone compounds bearing isovanillin moiety on the aldose reductase. Bioorg Chem. 2021 Dec;117:105473. [PubMed: 34768205]

2.

Dunlop M. Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int Suppl. 2000 Sep;77:S3-12. [PubMed: 10997684]

3.

Lyons TJ, Jenkins AJ. Glycation, oxidation, and lipoxidation in the development of the complications of diabetes: a carbonyl stress hypothesis. Diabetes Rev (Alex). 1997;5(4):365-391. [PMC free article: PMC4567260] [PubMed: 26366051]

4.

Feng B, Ruiz MA, Chakrabarti S. Oxidative-stress-induced epigenetic changes in chronic diabetic complications. Can J Physiol Pharmacol. 2013 Mar;91(3):213-20. [PubMed: 23537434]

5.

Schleicher ED, Weigert C. Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int Suppl. 2000 Sep;77:S13-8. [PubMed: 10997685]

6.

Wolff SP, Dean RT. Glucose autoxidation and protein modification. The potential role of 'autoxidative glycosylation' in diabetes. Biochem J. 1987 Jul 01;245(1):243-50. [PMC free article: PMC1148106] [PubMed: 3117042]

7.

Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem. 2004 Oct 08;279(41):42351-4. [PubMed: 15258147]

8.

Kawanami D, Matoba K, Utsunomiya K. Signaling pathways in diabetic nephropathy. Histol Histopathol. 2016 Oct;31(10):1059-67. [PubMed: 27094540]

9.

Penning TM, Jez JM. Enzyme redesign. Chem Rev. 2001 Oct;101(10):3027-46. [PubMed: 11710061]

10.

HERS HG. [Aldose reductase]. Biochim Biophys Acta. 1960 Jan 01;37:120-6. [PubMed: 14401390]

11.

Oates PJ. Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol. 2002;50:325-92. [PubMed: 12198816]

12.

Jedziniak JA, Chylack LT, Cheng HM, Gillis MK, Kalustian AA, Tung WH. The sorbitol pathway in the human lens: aldose reductase and polyol dehydrogenase. Invest Ophthalmol Vis Sci. 1981 Mar;20(3):314-26. [PubMed: 6782033]

13.

Diggle CP, Shires M, Leitch D, Brooke D, Carr IM, Markham AF, Hayward BE, Asipu A, Bonthron DT. Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J Histochem Cytochem. 2009 Aug;57(8):763-74. [PMC free article: PMC2713076] [PubMed: 19365088]

14.

Johnson RJ, Rodriguez-Iturbe B, Roncal-Jimenez C, Lanaspa MA, Ishimoto T, Nakagawa T, Correa-Rotter R, Wesseling C, Bankir L, Sanchez-Lozada LG. Hyperosmolarity drives hypertension and CKD--water and salt revisited. Nat Rev Nephrol. 2014 Jul;10(7):415-20. [PubMed: 24802066]

15.

Baeza J, Smallegan MJ, Denu JM. Site-specific reactivity of nonenzymatic lysine acetylation. ACS Chem Biol. 2015 Jan 16;10(1):122-8. [PMC free article: PMC4301072] [PubMed: 25555129]

16.

Lanaspa MA, Ishimoto T, Li N, Cicerchi C, Orlicky DJ, Ruzycki P, Rivard C, Inaba S, Roncal-Jimenez CA, Bales ES, Diggle CP, Asipu A, Petrash JM, Kosugi T, Maruyama S, Sanchez-Lozada LG, McManaman JL, Bonthron DT, Sautin YY, Johnson RJ. Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun. 2013;4:2434. [PMC free article: PMC3833672] [PubMed: 24022321]

17.

Gugliucci A. Formation of Fructose-Mediated Advanced Glycation End Products and Their Roles in Metabolic and Inflammatory Diseases. Adv Nutr. 2017 Jan;8(1):54-62. [PMC free article: PMC5227984] [PubMed: 28096127]

18.

Yan LJ. Redox imbalance stress in diabetes mellitus: Role of the polyol pathway. Animal Model Exp Med. 2018 Mar;1(1):7-13. [PMC free article: PMC5975374] [PubMed: 29863179]

19.

Wu J, Jin Z, Yan LJ. Redox imbalance and mitochondrial abnormalities in the diabetic lung. Redox Biol. 2017 Apr;11:51-59. [PMC free article: PMC5124358] [PubMed: 27888691]

20.

Kador PF, Kinoshita JH. Role of aldose reductase in the development of diabetes-associated complications. Am J Med. 1985 Nov 15;79(5A):8-12. [PubMed: 3934965]

21.

Bravi MC, Pietrangeli P, Laurenti O, Basili S, Cassone-Faldetta M, Ferri C, De Mattia G. Polyol pathway activation and glutathione redox status in non-insulin-dependent diabetic patients. Metabolism. 1997 Oct;46(10):1194-8. [PubMed: 9322806]

22.

Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013 Mar;56:133-71. [PubMed: 23104101]

23.

Hwang YC, Bakr S, Ellery CA, Oates PJ, Ramasamy R. Sorbitol dehydrogenase: a novel target for adjunctive protection of ischemic myocardium. FASEB J. 2003 Dec;17(15):2331-3. [PubMed: 14525943]

24.

Spector A. Some aspects of Dr Kinoshita's contributions to lens protein chemistry. Exp Eye Res. 1990 Jun;50(6):689-94. [PubMed: 2197109]

25.

Ishii N, Ikenaga H, Ogawa Z, Aoki Y, Saruta T, Suga T. Effects of renal sorbitol accumulation on urinary excretion of enzymes in hyperglycaemic rats. Ann Clin Biochem. 2001 Jul;38(Pt 4):391-8. [PubMed: 11471882]

26.

Hao W, Tashiro S, Hasegawa T, Sato Y, Kobayashi T, Tando T, Katsuyama E, Fujie A, Watanabe R, Morita M, Miyamoto K, Morioka H, Nakamura M, Matsumoto M, Amizuka N, Toyama Y, Miyamoto T. Hyperglycemia Promotes Schwann Cell De-differentiation and De-myelination via Sorbitol Accumulation and Igf1 Protein Down-regulation. J Biol Chem. 2015 Jul 10;290(28):17106-15. [PMC free article: PMC4498049] [PubMed: 25998127]

27.

Cheng HM, González RG. The effect of high glucose and oxidative stress on lens metabolism, aldose reductase, and senile cataractogenesis. Metabolism. 1986 Apr;35(4 Suppl 1):10-4. [PubMed: 3083198]

28.

Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000 Apr 13;404(6779):787-90. [PubMed: 10783895]

29.

Oates PJ, Mylari BL. Aldose reductase inhibitors: therapeutic implications for diabetic complications. Expert Opin Investig Drugs. 1999 Dec;8(12):2095-2119. [PubMed: 11139842]

30.

Yagihashi S. Glucotoxic Mechanisms and Related Therapeutic Approaches. Int Rev Neurobiol. 2016;127:121-49. [PubMed: 27133148]

31.

Chitra PS, Chaki D, Boiroju NK, Mokalla TR, Gadde AK, Agraharam SG, Reddy GB. Status of oxidative stress markers, advanced glycation index, and polyol pathway in age-related cataract subjects with and without diabetes. Exp Eye Res. 2020 Nov;200:108230. [PubMed: 32931824]

32.

Zenon GJ, Abobo CV, Carter BL, Ball DW. Potential use of aldose reductase inhibitors to prevent diabetic complications. Clin Pharm. 1990 Jun;9(6):446-57. [PubMed: 2114249]

33.

Narayanan S. Aldose reductase and its inhibition in the control of diabetic complications. Ann Clin Lab Sci. 1993 Mar-Apr;23(2):148-58. [PubMed: 8457142]

34.

Kirchain WR, Rendell MS. Aldose reductase inhibitors. Pharmacotherapy. 1990;10(5):326-36. [PubMed: 2122421]

35.

Matoba K, Takeda Y, Nagai Y, Yokota T, Utsunomiya K, Nishimura R. Targeting Redox Imbalance as an Approach for Diabetic Kidney Disease. Biomedicines. 2020 Feb 22;8(2) [PMC free article: PMC7167917] [PubMed: 32098346]

Disclosure: Kishan Srikanth declares no relevant financial relationships with ineligible companies.

Disclosure: Josephine Orrick declares no relevant financial relationships with ineligible companies.