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Biochemistry, Polyol Or Sorbitol Pathways
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
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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.
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