|Year : 2021 | Volume
| Issue : 2 | Page : 194-199
Dietary aldose reductase inhibitors and prevention of diabetic complications
Ameena Anjum1, Janamolla Sreeja1, Yarlagadda Swapna1, Rajesh Bolleddu2, Sama Venkatesh1
1 Department of Pharmacognosy, G. Pulla Reddy College of Pharmacy, Hyderabad, Telangana, India
2 Department of Pharmacognosy, Central Ayurveda Research Institute for Drug Development, CCRAS, Ministry of AYUSH, Kolkata, West Bengal, India
|Date of Submission||25-May-2019|
|Date of Acceptance||06-Oct-2020|
|Date of Web Publication||31-May-2021|
Dr. Sama Venkatesh
G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad - 500 028, Telangana
Source of Support: None, Conflict of Interest: None
Prolonged exposure to hyperglycemia can lead to the development of complications such as cataracts, retinopathy, neuropathy, and nephropathy. Several mechanisms are supposed to be involved in this process such as increased aldose reductase (AR)-related polyol pathway, increased formation of advanced glycation end products, and excessive oxidation stress in the body. AR is the principal enzyme of the polyol pathway in the development of secondary complications of diabetes, and its inhibition provides a significant strategy to prevent these complications. Synthetic aldose reductase inhibitors (ARIs) have been developed, but they suffer drawbacks and safety issues demanding research on natural sources for potential ARIs. Many dietary substances and phytochemicals were reported as being good source of ARIs including Spinacia oleracea, Ocimum sanctum, Foeniculum vulgare, Momordica charantia, Cinamomum zeylencium, and Cuminum cyminum. This review was undertaken to provide an insight into the use of dietary ARIs for prevention, delay, or management of the secondary complications and to serve as a guide for further research for their optimum and effective use and also to create awareness among the diabetics.
Keywords: Aldose reductase inhibitors, diabetes, diabetic complications, phytochemicals
|How to cite this article:|
Anjum A, Sreeja J, Swapna Y, Bolleddu R, Venkatesh S. Dietary aldose reductase inhibitors and prevention of diabetic complications. Indian J Health Sci Biomed Res 2021;14:194-9
|How to cite this URL:|
Anjum A, Sreeja J, Swapna Y, Bolleddu R, Venkatesh S. Dietary aldose reductase inhibitors and prevention of diabetic complications. Indian J Health Sci Biomed Res [serial online] 2021 [cited 2021 Jun 17];14:194-9. Available from: https://www.ijournalhs.org/text.asp?2021/14/2/194/317393
| Introduction|| |
Diabetes is a chronic metabolic disorder characterized by chronic hyperglycemia with disturbances of carbohydrate, fat, and protein metabolism. It, in turn, produces damaging effects on the body systems, particularly blood vessels and nerves. The main purpose in providing therapy to the patients is to restore metabolism to normal, to avoid symptoms due to hyperglycemia and glucosuria, and to prevent short-term complication and long-term consequences.
However, failure to control blood glucose within normal range for prolonged period in diabetics can result in the development of various complications such as cataracts, retinopathy, neuropathy, and nephropathy. As per the report of the US National Health and Nutrition Examination Survey (1999–2004), nearly 60% of patients with diabetes suffer from more than one complication caused by chronic diabetes. Diabetic complications are said to be the leading cause of morbidity and death in diabetic patients.,
Researchers are showing great interest to search for drugs that can help diabetics by alleviating the various symptoms of diabetic complications. Studies suggest that chronic hyperglycemia may play a vital role in the pathogenesis of the complications through a variety of mechanisms such as increased aldose reductase (AR)-related polyol pathway, increased formation of advanced glycation end products, and excessive oxidation stress. Among these increased AR-related polyol pathway flux is an important one; it can be a significant strategy or an approach to prevent or delay some of the secondary complications of diabetes.
This review is an effort to describe briefly the role of AR in polyol pathway and create awareness about some magical aldose reductase inhibitors (ARIs) from natural sources which can be of significance in the prevention or delay of diabetes complications.
| Aldose Reductase|| |
AR is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of aldehydes and carbonyls, including monosaccharide, primarily the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism. It is found in nonuniform levels in most mammals with high levels in eye (cornea, retina, and lens), kidney, and the myelin sheath – tissues that are often involved in diabetic complications.
Mechanism of development of diabetic complications
In normoglycemic condition, only a small portion of glucose (about 3%) is metabolized via polyol pathway because the primary pathway for glucose metabolism is glycolysis where it is phosphorylated by the enzyme hexokinase to fructose-6-phosphate. However, chronic hyperglycemia in diabetics significantly increases the glucose metabolism through polyol pathway [Figure 1] as high as 33% in some tissues which are not sensitive to insulin such as lens of the eye, peripheral nerves, and kidney glomerulus. The sorbitol produced gets accumulated in the tissue because of low permeability, leading to increased osmotic pressure and damage the tissue by causing it to swell., Increased flux through polyol pathway leads to more consumption of NADPH and NADP+ (nicotinamide adenine dinucleotide phosphate) which are cofactors for AR, and sorbitol dehydrogenase enzymes are not available for their utilization in other metabolic processes, leading to the development of oxidative stress. The osmotic stress as a result of sorbitol accumulation and oxidative stress produced due to changes in the ratio of NADPH/NADP+ and their reduced forms (NADH/NAD+) are the major causes for complications. It can be inferred that inhibition of the AR enzyme can be a strategic approach against diabetic complications.,
| Aldose Reductase Inhibitors|| |
Some of the synthetic ARIs developed are alrestatin, tolrestatin, epalrestat (noncompetitive and reversible ARI used for the treatment of diabetic neuropathy), and salfredin B11, and ranirestat, ponalrestat, rinalrestat, risarestat, sorbinil, and berberine are currently in clinical trials., Because of the drawbacks faced with synthetic drugs such as low efficacy, poor permeation property, and safety issues, finding new effective and safe ARIs from natural source is gaining interest. Investigations on natural sources reported various potential candidates. Some of them are Indian gooseberry, spinach, cumin seeds, fennel seeds, basil leaves, lemon, black pepper, orange, curry leaves, cannabis, cinnamon, and lichen. Some common edible and dietary substances that showed aldose reductase inhibition are listed as follows.
Aldose reductase inhibitors from diet
Flavonoids are a class of phytoconstituents commonly ingested from fruits and vegetables in the diet, known for their antioxidant properties. Thus, food rich in antioxidants and flavonoids should be a part of diet of diabetics as oxidative stress is also a mechanism for the development of complications. Flavonoids such as quercetin, rutin, quercitrin, myrcitrin, morin, hesperetin, 2-carbethoxyoxy-5, 7-dihydroxy-40-methoxyisoflavone, and robinin were determined in vitro for inhibitory action on rat lens AR. Among the tested compounds, quercetin, quercitrin, and myrcitrin were found as potent inhibitors than the previously known ARIs- [1, 2-dioxo-1H-benz-(de) isoquinoline-2 (3H) acetic acid] or tetramethyleneglutaric acid. Quercitrin also inhibits sorbitol accumulation upon incubation of rat lens in high sugar medium., This indicates that flavonoids are potent inhibitors of the AR enzyme in addition with antioxidant properties, thus providing double defense mechanism against the complications. Use of fruits and vegetables rich in flavonoids (onion, apple, grapes, broccoli, citrus fruits, green tea, coffee, red wine, and buck wheat) can be fruitful for uncontrolled diabetics in preventing complications.
Camellia sinensis (green tea)
Green tea possesses various health benefits. One among them is the antioxidative potential which is its major action. These properties of green tea lead the researchers to assess its possible potential in inhibiting AR. Various phytoconstituents present in it are catechin, epicatechin, gallocatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate. Epicatechin gallate inhibited AR potently with IC50 = 38 mmol/L followed by epicatechin (IC50 = 79 mmol/L), and gallocatechin showed very weak inhibition whereas epigallocatechin (IC50 = 620 mmol/L) showed lack of activity. The results suggested that catechol-type catechins inhibited the enzyme more strongly than pyrogallocatechins and those epi-type catechins with a galloyl group were strong inhibitors than those without. Unlike the inhibitory actions of flavones and flavonols, the inhibitory activity of each catechin appears to be irreversible, because the inhibition was partially restored by adding the enzyme.
Manilkara indica (Sapota, chiku)
The fruit of Manilkara indica upon bioassay-guided fractionation leads to the isolation of isoaffinetin (5, 7, 3', 4', 5'-pentahydroxyflavone-6-C-glucoside), which exhibited specific inhibition against the AR enzymes in rat lens, porcine lens, and recombinant human forms, but no action against aldehyde reductase and NADH oxidase. It can be inferred that substances rich in isoaffinetin should be part of diabetic diet as the specificity of the compound provided added advantage of selective action against the primary enzyme of polyol pathway.
Zingiber officinalis (ginger)
The hot water extract of the ginger rhizome was investigated by Kato et al. Among the 16 phenolic compounds isolated, five compounds showed good inhibition on Human Recombinant Aldose Reducatse (HRAR). 2-(4-hydroxy-3-methoxyphenyl) ethanol (IC50 = 19.2 ± 1.9 μM) and 2-(4-hydroxy-3-methoxyphenyl) ethanoic acid (IC50 = 18.5 ± 1.1 μM) possessed good inhibition. Further investigation revealed suppression of accumulation of sorbitol in human red blood cells (RBCs) and lens galactitol in galactose-fed cataract rat models. It can be suggested that ginger constituents are effective not only in preventing the onset of complications but also in preventing the worsening of condition, thus eliminating any uncertainty about its activity.
Health benefits of pigmented rice owing to the antioxidant potential of the phenolic compounds intrigued Yawadio et al. to investigate the secondary metabolites present in black and brown varieties. Two anthocyanins isolated from black rice were identified as cyanidin-3-O-b-glucoside and peonidin-3-O-b-glucoside, while the major component of brown rice was identified as ferulic acid. These isolated compounds showed inhibitory activity on HRAR, with peonidin-3-O-b-glucoside (IC50 = 8.7 mg/mL) showing the highest activity compared to that of quercetin (IC50 = 11.4 mg/mL). The presence of such magical phenolic compounds in pigmented rice is of significant importance, exhibiting marked activity in preventing diabetic complications and should be a in the diet plan of diabetics.
Eleusine coracana (finger millet/ragi)
It is a good source of polyphenols among cereals. Phenolic constituents such as gallic acid, protocatechuic acid, p-hydroxy benzoic acid, p-coumaric acid, vanillic acid, syringic acid, ferulic acid, transcinnamic acid, and quercetin are present, which inhibited cataract effectively by reversible noncompetitive inhibition of enzyme. Apart from ARI, it is a good source of dietary fibers. Consumption of finger millet might not only prevent the onset of complications but also reduce postprandial hyperglycemia.
Origanum vulgare (oregano)
Origanum vulgare is a traditional herb in Morocco used for the control and treatment of diabetes.
To assess its role in diabetes, an in vitro study was conducted for inhibition against rat lens AR. The polar extracts of the herb yielded three phenolic acids: caffeic acid, rosmarinic acid, and lithospermic acid B. Lithospermic acid B was found to be most active, showing 96% inhibition at a dose of 100 μM, but these acids were less potent in vivo. The study revealed the potential of oregano in preventing the complications.
Standardized extract of Ocimum gratissimum (wild basil or African basil) and its major constituent such as ursolic acid were tested for AR inhibitory activities in rat lens AR, rat kidney AR, and HRAR enzymes. Both the extract and purified ursolic acid showed a significant inhibition of the enzyme. Further investigation on ursolic acid in vivo showed potent inhibition of galactitol accumulation in lens than three plants used in the study. The study suggests the presence of compounds other than ursolic acid in the extract, which possess AR inhibition capacity. Utilization of this herb may produce additive effect against AR and inhibition of polyol accumulation.
Syzygium cumini (Java plum, jamun)
Syzygium cumini (Java plum, jamun) belongs to the family Myrtaceae. A study conducted on standardized extract and its major constituent such as ellagic acid showed that both of them possess significant AR inhibition. Ellagic acid was also found to suppress galactitol accumulation in galactose-fed rats in in vivo experiments, but less than ursolic acid of Ocimum.
Emblica officinalis (amla)
In a study conducted by Suryanarayana et al., Emblica officinalis extract inhibited rat lens aldose reductase (RLAR) and HRAR, showing an IC50 value 0.72 and 0.88 mg/ml, respectively. The major constituent, ascorbic acid, showed a lack of activity against AR. Further investigation on hydrolysable tannoids of the fruit revealed them to be the responsible agents in inhibiting AR as they showed remarkable activity against both RLAR and HRAR with an appreciative IC50 value of 6 and 10 μg/ml, respectively. It was concluded that this inhibition by E. officinalis tannoids was 100 times higher compared to aqueous extract and was comparable or better than quercetin (standard). It also prevented sugar-induced osmotic changes. As it possesses better inhibition than standard quercetin, its use should be encouraged among diabetic population for significant outcome. Preparations of tannoid principles of amla should be introduced in the market and assessed for effect on long-term usage by patients.
Curcuma longa (turmeric)
It contains some essential oils (0.4%), pigmented compounds curcuminoids and zingiberaceous starch grains. It is known to possess various activities such as antioxidant, antibacterial, galactogogue, and anti-HIV. A study carried out at NIN (National Institute of Nutrition), Hyderabad, on curcumin revealed that in addition to antioxidant property, it lowered the activity of AR. Curcumin-fed diabetic rat lens exhibited decreased enzyme activity when compared to untreated group, thus indicating the possibility of AR inhibition by curcumin. It was concluded that curcumin can effectively delay cataractogenesis in streptozotocin-induced diabetic rat. In 2006, curcumin, demethoxycurcumin, and bisdemethoxycurcumin from Curcuma longa also showed remarkable inhibition on bovine lens aldose reductase, with curcumin showing high activity (IC50 value of 6.8 mM). Later, Muthenna et al. provided an insight on the mechanism of AR inhibition, specificity, and physiological significance of curcumin. The results of that study suggested the selective and noncompetitive inhibition of AR. Physiological significance of curcumin was determined by measuring ability to block AR in fresh human RBCs. Upon incubation of RBCs under high glucose concentration and in the presence of curcumin, there was a reduction in intracellular accumulation of sorbitol in a dose-dependent manner, showing inhibition at 100 μM curcumin [Figure 2]. Curcumin not only inhibit AR but is also significant physiologically as it prevents the accumulation of sorbitol in RBCs.
|Figure 2: Effect of curcumin on sorbitol accumulation in RBC sorbitol level in red blood cells normal glucose concentration, 5.5 mM (bar 1); under high glucose concentration, 55 mM in absence of curcumin (bar 2); and presence of 25 μM, 50 μM, and 100 μM curcumin (bars 3–5, respectively)|
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Phenolic compounds from kernels of purple corn (Zea mays) inhibited RLAR and also found to significantly suppress galactitol accumulation in rat lens and RBCs. One of the isolated compounds, hirsutrin, showed potent competitive inhibition against RLAR (IC50 4.78 μM) and also inhibited formation of galactitol in rat lens and RBC samples incubated with high galactose concentration. Thus, hirsutrin may be potential in dealing with complications of diabetes.
Psidium guajava (guava)
An in vitro study on effect of different extracts of plant of Psidium guajava on glucose uptake at cellular level and inhibitory action against AR revealed methanol extract exhibiting an enhancement in glucose uptake and protein expression of IRß, IRS-1, PI3K, and GLUT4 proteins along with significant inhibition of AR at a dose of 500 μg/ml concentration. The study also suggested enhancement of glucose uptake by cells to be the antidiabetic mechanism. It can be inferred that the plant can be ideal in diabetic population, as it possesses antidiabetic potential along with AR inhibition. In-depth research on the methanolic extract can provide a potential agent to be used as a combined therapy in achieving hypoglycemia and preventing onset of complications.
Carica papaya (Papaya)
In 2017, methanol extract of the leaves of Carica papaya was assessed for its inhibitory action against AR. The extract was proven effective against both aldehyde reductase (ALR1) and aldose reductase (ALR2) with IC50 values 1.22 ± 0.63 μg/mL and 1.22 ± 0.06 μg/mL, respectively, better than their standards: valproic acid (57.4 ± 10 μg/mL) and sorbinil (3.10 ± 0.20 μg/mL).
Litchi chinensis (Litchi)
Methanolic extract and ethyl acetate fractions of litchi fruits were reported to exhibit potent inhibition with IC50 value 3.6 and 0.3 μg/mL, respectively. Ethyl acetate fraction on chromatography leads to isolation of four compounds, of which delphinidin 3-O-bgalactopyranoside-30-O-b-glucopyranoside was the most potent (IC50 = 0.23 μg/mL).
Dried M. oleifera leaves' hydroalcoholic extract inhibited the recombinant human aldose reductase (rhAR) activity with an IC50 value of 3.55 μg/mL.
Ethyl acetate fraction of hydroalcoholic extract of propolis inhibited human AR by IC50 value of 1.12 mg/mL.
P. fulgens root phenolic/terpenoid fraction inhibited human AR with IC50 value of 0.152 mg/ml.
Ingredients used in Indian culinary
The Department of Biochemistry Division, NIN, India, in collaboration with the Department of Ophthalmology and Visual Sciences, Washington University, USA, performed a study on various common plants and natural products which are regularly used in Indian culinary to evaluate their potential for inhibiting AR. About 22 plant materials were evaluated for their activity against RLAR and HRAR. A summary of their work is given in [Table 1].
|Table 1: Inhibition of rat lens and human recombinant aldose reductase by aqueous extracts of dietary agents along with half-maximal inhibitory concentration values|
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According to the study, most of the culinary ingredients used in India possess AR inhibition property. As the study suggests, Spinach is the most potent agent effective in both RLAR2 and hRALR2. Other potential agents include cumin, fennel, fenugreek, black pepper, basil leaves, fruits of orange, lemon and bitter gourd, curry leaves, and cinnamon. Few others substances showed activity in RLAR2, but were inactive in hRALR2. The activity of these dietary substances can be attributed to certain constituent's presence such as flavonoids, polyphenols, phenolic acids, and others. Although guava plant extract showed antidiabetic and inhibitory activities, guava fruit was inactive when tested on hRALR2, which might be due to lack of certain constituents.
| Conclusion|| |
AR is the key enzyme of polyol pathway represents AR inhibition as a significant strategy. ARIs from natural sources including dietary agents are seeking attention of the people, as their utilization is convenient and easy to follow. Most of the ingredients used in Indian food have shown promising effect against the enzyme. Consumption of the above-mentioned substances as a diet routine can help the diabetics in preventing or delaying diabetes complications. Most of the mentioned sources contain flavonoids and various phenolic compounds which suggest the possibility of this specific class of phytoconstituents to be responsible for AR inhibitory activity. Dietary intake of these flavonoids and phenols provides an added benefit by inhibiting oxidative stress and in some cases osmotic stress. Suggested best inhibitors include quercetin present in fruits and green leafy vegetables, catechins from green tea, phenols from ginger, phenolics and other constituents of wild basil, phenolics present in pigmented rice, hydrolysable tannins of amla, and turmeric curcuminoids. These dietary sources of the ARI and food rich in antioxidants can be a 'Naturopathic' step in managing diabetes-related problems. This information will be very useful to create awareness and educate diabetics regarding the use of these common materials to prevent and delay the complications or to prevent their progress.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]