|
 
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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 5
| Issue : 4 | Page : 380-388 |
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Diabetic microvascular complications and proposed interventions and approaches of management for patient care
Anmar Al-Taie1, Assem Sabbah Elseidy2, Arueyingho Oritsetimeyin Victoria3, Abdul Hafeez4, Shmmon Ahmad4
1 Department of Clinical Pharmacy, Faculty of Pharmacy, Istinye University, Istanbul, Turkey
2 Department of Pharmacy, Faculty of Pharmacy, Girne American University, Mersin, Turkey
3 EPSRC Centre for Doctoral Training in Digital Health and Care, University of Bristol, Bristol, United Kingdom
4 Department of Pharmaceutics, Glocal School of Pharmacy, Glocal University, Saharanpur, Uttar Pradesh, India
| Date of Submission | 22-Jul-2021 |
| Date of Acceptance | 13-Sep-2021 |
| Date of Web Publication | 14-Dec-2021 |
Correspondence Address:
Anmar Al-Taie
Department of Clinical Pharmacy, Faculty of Pharmacy, Istinye University, Istanbul
Turkey
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/bbrj.bbrj_153_21
Patients with diabetes mellitus are more likely to suffer microvascular complications, such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy, which, if undiagnosed or untreated, may have a debilitating effect on patients' quality of life and pose a substantial financial strain on health-care providers. Glycemic regulation and diabetes length are the most powerful risk factors; nevertheless, other modifiable risk factors including hypertension, hyperlipidemia, and smoking, as well as unmodifiable risk factors, including age at onset of diabetes and genetic factors can all play a role. In addition to the involvement of potential risk factors, several links have been discovered between diabetic microvascular complications and one another, which seems to be significant associations for the development of these different microvascular complications. However, in order to help mitigate morbidity and mortality, considering the initiation and progression of all three complications as interconnected must be identified and managed at an early stage. Therefore, a variety of approaches to developing therapies to mitigate the negative effects of these complications are currently being studied in clinical trials which may contribute to potential long-term benefits in the management of different diabetic microvascular complications. This literature review summarizes the cellular and molecular pathways that lead to diabetic microvascular pathologies with emphasis on the clinical benefits of a variety of therapeutic approaches and insights into simple, comprehensive therapeutic interventions for clinical practice which could be optimal to reduce the risk and severity of different diabetic microvascular complications.
Keywords: Diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, microvascular complications, supplements
How to cite this article:
Al-Taie A, Elseidy AS, Victoria AO, Hafeez A, Ahmad S. Diabetic microvascular complications and proposed interventions and approaches of management for patient care. Biomed Biotechnol Res J 2021;5:380-8 |
How to cite this URL:
Al-Taie A, Elseidy AS, Victoria AO, Hafeez A, Ahmad S. Diabetic microvascular complications and proposed interventions and approaches of management for patient care. Biomed Biotechnol Res J [serial online] 2021 [cited 2023 Mar 23];5:380-8. Available from: https://www.bmbtrj.org/text.asp?2021/5/4/380/332450 |
| Introduction | |  |
Diabetes mellitus (DM) is a category of metabolic disorders marked by hyperglycemia caused by insulin resistance, insufficient insulin secretion, or excessive glucagon secretion. In 2017, the American Diabetes Association noted that diabetes is a dynamic, chronic disease that necessitates ongoing medical treatment and multifactor risk reduction measures beyond glycemic regulation, including continuous patient self-management education and assistance as crucial issues for preventing acute complications and lowering the risk of long-term complications.[1] There are two types of diabetes: Type 1 and Type 2. Type 1 DM is an autoimmune illness in which the beta-cells of the pancreas are damaged. Type 2 DM is a condition in which glucose tolerance is progressively harmed due to a combination of faulty pancreatic beta-cells and insulin resistance.[2]
In diabetic patients, vascular disorders are the leading cause of morbidity and mortality. These are the results of associations between structural metabolic disorders including hyperglycemia and dyslipidemia, as well as genetic and epigenetic modulators and local tissue responses to toxic metabolites. Atherosclerotic/thrombotic obstructions, such as those seen in coronary, spinal, and peripheral artery disorders, are examples of macrovascular complications. Retinopathy, nephropathy, and neuropathy are common microvascular pathologies, although the liver, myocardium, skin, and other tissues may also be affected.[3] Since these tissues are subjected to glucose levels that directly correspond with blood glucose levels, microvascular disease is most common in tissues where glucose absorption is independent of insulin production (e.g. kidney, retina, and vascular endothelium). These metabolic injuries result in improvements in blood supply, endothelial permeability, extravascular protein accumulation, and coagulation, leading to organ dysfunction and microvascular complications.[4] Furthermore, there is a strong link between DM and periodontal disease.[5]
| Diabetic Nephropathy | | |
Diabetic nephropathy (DN), also known as diabetic kidney disease, is a condition caused by abnormally high levels of albumin excretion in the urine, diabetic glomerular lesions, and a decrease in the glomerular filtration rate (GFR) in diabetics.[6] DN is characterized as persistent severely elevated albuminuria of more than 300 mg/24 h (or >200 pg/min) or an albumin–creatinine ratio of more than 300 mg/g creatinine, reported in at least two out of three samples, with diabetic retinopathy (DR) and absence of signs of other types of renal disease in both Type I and Type 2 diabetes.[7] Diabetic kidney failure is a leading cause of death and morbidity in people with diabetes. Indeed, diabetes-related excess mortality occurs mostly in proteinuric diabetic patients and is caused by both end-stage renal disease and cardiovascular disease, the latter of which is especially prevalent in Type 2 diabetic patients.[8]
The pathogenesis of DN is unknown. Renal cell hypertrophy, extracellular matrix (ECM) proliferation, and increased levels of profibrotic growth factor and transforming growth factor all stem from elevated extracellular glucose level.[9] The major histological observations in DN are thickening of the glomerular basement membrane, accompanied by diffuse or nodular deposition of increasing quantities of ECM in the mesangial regions. Another form of DN characteristic lesion is hyaline content aggregation as a result of plasma protein exudation. Arteriolar hyalinosis, which affects both the afferent and efferent arterioles, is one of them. Hyaline deposits may also form on the inner side of Bowman's capsule, known as the capsular drops.[10] It was discovered that a higher serum uric acid level (420 mol/L for men and 360 mol/L for women) is independently associated with diabetes nephropathy, as well as a more severe proteinuria and worse estimated GFR.[11]
| Management of Diabetic Nephropathy | | |
Nonpharmacological approaches
Glycemic control
In those with proven DN, excellent glycemic regulation will avoid the initiation of microalbuminuria, reverse glomerular hypertrophy and hyperfiltration, and stabilize or reduce proteinuria. Except in those with history of impaired glycemic regulation, intensive therapy to near-normal glycemia may delay the onset or progression of DN. Insulin doses may be measured using glucose counting principles to help patients achieve better diabetes management. Carbohydrate counting is a way of measuring the amount of carbohydrates eaten in a meal in grams or servings. Fifteen grams of starch equals one carbohydrate serving. The insulin-to-carbohydrate ratios should be used to change the insulin dosage at mealtime. Patients at risk of hypoglycemia benefit from this treatment because proper insulin dosing based on the patient's metabolic needs and food consumption tends to reduce hypoglycemia.[12]
Physical activity
Exercise is a scheduled, organized, and routine physical activity conducted with the goal of improving energy consumption above the average. Physical exercise increases insulin sensitivity, body weight, cardiovascular risk factors, physical health, lipid levels, blood pressure, and general well-being, while further lowering the risk of cardiovascular morbidity and mortality.[13] As muscle glycogen supplies are exhausted from sustained exercise, free fatty acids obtained from the breakdown of triglycerides are used as a source of energy for muscle function. Increased translocation and expression of glucose transporter 4 (GLUT4, an isoform of glucose transporter) from intracellular storage depots to plasma membrane, as well as increased insulin sensitivity, improve glucose absorption and use of skeletal muscles.[14]
Pharmacological approaches
Novel agents such as sodium-dependent glucose cotransporter (SGLT-2) inhibitors, aldose reductase inhibitors, dipeptidyl peptidase-IV inhibitors have been tested for the treatment of diabetes-related vascular disorders, such as DN.[15] In addition, a combination of metformin and/or sitagliptin attenuates T2DM-induced oxidative stress (OS) and such a combination is recommended to reduce glucolipotoxicity and related OS injury.[16]
Angiotensin receptor blockers
Since hyperglycemia causes renal vasodilation and an increase in GFR, intraglomerular hypertension and glomerular hypertrophy play important roles in the initiation of DN. The compensatory reaction of remaining nephrons accelerates the rise in intraglomerular pressure after subsequent nephron failure. The renin–angiotensin–aldosterone system antagonists, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (angiotensin receptor blockers [ARBs]), are often used in diabetic patients to regulate blood pressure. Because of their ability to relieve both intraglomerular pressure and proteinuria by preferentially dilating the efferent arteriole, these medications are considered superior to other antihypertensive medication types in the treatment of DN. Proteinuria in glomerular disease has a causal relationship with intraglomerular pressure; hence, a treatment-induced decrease in protein excretion results in a desirable reduction in intraglomerular pressure, which increases renal outcome.[17]
Aldosterone antagonists
The final portion of the RAS cascade is aldosterone. Fibrosis, inflammation, and the development of reactive oxygen species (ROS) are all promoted by aldosterone, as are endothelial dysfunction, cell formation, and proliferation.[18] Spironolactone tends to suppress proteinuria in both Type 1 and Type 2 diabetics whether used alone or in conjunction with an ACE inhibitor or an ARB.[19] The use of aldosterone antagonists in conjunction with other RAS inhibitors raises the risk of hyperkalemia, and there is no long-term evidence on renal function loss with combination blockade.
Calcium channel blocker
A nondihydropyridine calcium channel blocker can be helpful. In Type 2 diabetics, both verapamil and diltiazem have been shown to reduce proteinuria. Verapamil was found to be additive to lisinopril or trandolapril therapy in lowering albuminuria and GFR decrease.[20]
Anti-lipid agents
Apolipoprotein B and high-density lipoprotein cholesterol levels were separate risk factors for progression to overt nephropathy in Type 2 diabetics. Triglycerides and high-density lipoprotein cholesterol were linked to a higher risk of DN. Elevated cholesterol levels (>220 mg/dL) were also linked to the development of DN.[21] Lipid-lowering medications have been linked to a decrease in proteinuria in patients with DN, but not to a significant increase in kidney outcome, according to clinical trials.[22]
Allopurinol
Lowering uric acid with allopurinol can reduce the severity of proteinuria and possibly delay the progression of renal failure. The mechanism of a xanthine oxidase inhibitor's beneficial effect may be linked to avoiding uric acid-induced renal inflammation.[23]
Vitamin D
Vitamin D has been linked to a variety of biological functions, with the ability for Vitamin D to protect DN receiving particular interest. Supplementation with Vitamin D or its active derivatives has been shown to enhance endothelial cell damage, reduce proteinuria, reduce renal fibrosis, and thereby slow DN progression.[24]
| Diabetic Retinopathy | | |
DR is a vision-related disorder of diabetes and is a common cause of vision loss and blindness in diabetics. DR is a condition in which the retinal vasculature becomes progressively dysfunctional as a result of persistent hyperglycemia, causing structural damage to the neuronal retina. Diabetes impairs insulin synthesis and sensitivity, and hence glucose absorption, resulting in elevated blood sugar levels. In DR, macular edema is the most common cause of visual loss. Macular ischemia, retinal and vitreous hemorrhages, and tractional retinal detachment are some of the other reasons of visual loss in DR.[25]
Harm to the blood vessels of the light-sensitive retina, which allows for vision, can occur when blood sugar levels are elevated. High blood sugar levels will widen or block the retinal arteries, resulting in decreased or no blood flow to the retina. As a result, endogenous pathways cause angiogenesis, which allows for the formation of new blood vessels, but these result in further complications. These retinal modifications impair vision which can lead to blindness in diabetics.[26]
Inflammation and retinal neurodegeneration, in addition to microvascular changes, can lead to diabetic retinal damage in the early stages of DR. DR develops from minor nonproliferative defects, which are marked by increased vascular permeability, to moderate to extreme nonproliferative DR (PDR), which is characterized by vascular closure, to PDR, which is characterized by the formation of new blood vessels on the retina and the posterior surface of the vitreous. Macular edema, which is described as retinal thickening caused by leaky blood vessels, may occur at any level of retinopathy.[27]
| Management of Diabetic Retinopathy | | |
Nonpharmacological approaches
Laser photocoagulation
For the prevention of DR, laser photocoagulation may be seen in two cases. By forming a modified grid at the posterior pole, it can be used to treat macular edema.[28] It may also be used to monitor neovascularization by performing panretinal coagulation. It is commonly used to treat proliferative retinopathy in its early stages.[29] Efforts are currently being made to create new laser techniques that can reduce side effects. Pattern scanning laser is a modern laser technique to prevent laser-induced retinal damage by allowing for more accurate laser monitoring and shorter treatment times. The use of a navigated laser device (NAVILAS) has recently improved the accuracy of laser spots added to the retina, resulting in better visual outcomes. Laser technology advancements in future can improve the safety and efficacy of laser photocoagulation in the treatment of DR.[30]
Pharmacological approaches
Anti-angiogenic therapy
The introduction of anti-vascular endothelial growth factor (VEGF) therapy has changed the way DR is handled. Anti-VEGF medications currently in clinical trials for DR therapy include the Food and Drug Administration-approved pegaptanib, ranibizumab, aflibercept, and the off-label intravitreal bevacizumab. Ranibizumab has been the most thoroughly studied of these drugs in clinical trials.[31] Aside from anti-VEGF inhibitors, other anti-angiogenic compounds are currently being studied in clinical trials. Squalamine inhibited various angiogenic causes, resulting in greater vision healing in patients with macular edema than control groups (VEGF, PDGF, and b-FGF).[32]
Anti-inflammatory therapy-intravitreal steroids
Intravitreal corticosteroids have become increasingly effective, especially in cases where anti-VEGF therapy has failed. Multiple cytokines are thought to be involved in refractory cases. Corticosteroids target a wide range of mediators involved in the pathogenesis of DR, including VEGF, tumor necrosis factor (TNF)-α, chemokines, leukostasis, and phosphorylation of tight junction proteins, as potent anti-inflammatory agents.[33]
Alpha-lipoic acid
Alpha-lipoic acid (ALA) is a mitochondria-specific antioxidant enhancing the effects of such endogenous antioxidants as glutathione (GSH), Vitamin C, and E by recycling. Lipoic acid supplementation increases available GSH.[34] Supplementation with ALA has been linked to a reduction in hyperglycemia and hyperglycemic vascular endothelial dysfunction,[35] protection of the retina, particularly the ganglion and pigment epithelial cells from ischemia and apoptosis,[36] and increased vision contrast and acuity in patients with diabetes.[37]
Darapladib
The lipoprotein-associated phospholipase A2 (Lp-PLA2) enzyme has been linked to damage during DR. Lp-PLA2 could be used as a therapeutic target to prevent retinal vasopermeability during diabetes related to changes in macular edema.[38]
Vitamins
Increased OS and inflammatory mediators have been linked to the development of DR, and antioxidants have been shown to avoid it. DR is prevented by nutritional supplementation, which also preserves proper retinal activity, mitochondrial homeostasis, and inflammatory mediators. As a result, this supplementation may be a feasible and affordable adjunct therapy for preventing retinopathy, a slow-progressing disorder that diabetic patients dread the most.[39]
Vitamin A is a group of fat-soluble retinoids extracted from animals that are needed for cell development, differentiation, immunity, and vision. Vitamin A is a part of rhodopsin, the light-sensitive pigment in the retina. It is also required for the maintenance of healthy corneal and conjunctival membranes. Where there is widespread malnutrition, deficiency is normal, and it is linked to night blindness, conjunctival xerosis, and corneal ulceration.[40]
B vitamins are a category of water-soluble cofactors that help control important metabolic processes in the body. Vitamin B1 (thiamin) is a potent free radical scavenger that controls intracellular glucose and inhibits the activation of the polyol pathway, which is triggered by high intracellular glucose.[41] Hyperglycemia-induced polyol pathway dysfunction is believed to cause DR. Furthermore, thiamin protects the vascular endothelium from advanced glycation end product (AGE) injury.[42] Vitamin B2 (riboflavin) is a flavonoid vitamin that plays a role in intermediate metabolism, energy synthesis, and mitochondrial function. Riboflavin, in the form of flavin adenine dinucleotide, is needed for the production of L-methylfolate, the methyl source for methylcobalamin, which reduces serum homocysteine (Hcy).[43] The supplementation of riboflavin increases glucose uptake and appears to protect the retina from OS, hyperglycemia, and Hcy-induced injury.[44]
Vitamin B12, cobalamin, is a complex water-soluble cofactor that has essential functions which impact vision and DR. These include cell synthesis, DNA regulation, Hcy metabolism, myelin synthesis, nerve growth, and neuron maintenance.[45] DM causes retinal small vessel damage, structural loss of capillary endothelium with ischemia, initial mitochondrial dysfunction and Müller cell impairment followed by neurons, and photoreceptors contributing to the pathogenesis of DR. All these lead to retinal microaneurysms, exudates, cotton wool spots, capillary dropout, retinal edema, and retinal atrophy.[46],[47]
Vitamin D is essential for stimulating pancreatic beta insulin secretion and sensitivity, reduction of inflammation, arterial stiffness, Type 2 DM, and risk and severity of DR.[48],[49] Lower Vitamin D is associated with retinal microvascular damage and a higher risk and severity of DR in patients with DM.[50] Therefore, this suggests that Vitamin D supplementation is highly important to reduce the risk and severity of DR.
Lutein and zeaxanthin are water-soluble carotenoids derived from plants that quickly pass through the blood–brain and blood–retina barriers. They are needed for vision but cannot be produced by the human body. DM lowers lutein and zeaxanthin levels in the serum and retina, making carotenoids some of the most effective antioxidants. They serve as strong antioxidants in the macula lutea, stabilizing cell membranes and guarding against OS. They are thought to guard against age-related macular degeneration and DR.[51]
| Diabetic Neuropathy | | |
Diabetic neuropathy (DN) is a common condition characterized as signs and symptoms of peripheral nerve dysfunction in a patient with DM who has ruled out all possible causes of peripheral nerve dysfunction. Motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; and autonomic changes such as urinary symptoms are also possible symptoms depending on the location of nerve injury.
DN may affect sensory neurons, motor neurons, and the autonomic nervous system among other peripheral nerves. As a result, DN can affect almost any organ system and cause a wide variety of symptoms. Depending on which organ systems are involved, there are many different syndromes.[52] The most prevalent kind of DN is distal symmetrical neuropathy, which accounts for 75% of all cases. Asymmetrical neuropathies can affect cranial nerves, thoracic nerves, or limb nerves, and they usually develop quickly after a vasa nervosa ischemic infarction. Diabetic amyotrophy is thought to be caused by immunological alterations. Types of DN include peripheral neuropathy, focal neuropathies, proximal neuropathy, sensorimotor polyneuropathy, and autonomic neuropathy.[53],[54]
DN's pathological process cannot be described by a particular source, and many explanations have been suggested. A key factor in the pathogenesis of DN has been identified as altered peripheral nerve polyol metabolism. Aldose reductase uses nicotinamide adenine dinucleotide phosphate (NADPH) as a coenzyme to convert glucose to sorbitol (polyol). The bypass polyol pathway of glucose metabolism is formed when sorbitol is transformed to fructose by sorbitol dehydrogenase, which uses nicotinamide adenine dinucleotide (+) as a coenzyme. During diabetes-related hyperglycemia, cellular glucose levels rise independently of insulin, resulting in increased aldose reductase activity, which raises intracellular sorbitol levels and, as a result, intracellular osmotic pressure. Tissue and cells suffer from functional and structural defects as a result of this disorder.[55] Sorbitol accumulation lowers intracellular myoinositol content, inhibiting phosphoinositide metabolism and lowering protein kinase C and Na+/K+/ATPase activities in peripheral nerves, in addition to raising osmotic pressure.[56]
Hyperglycemia also stimulates the development of diacylglycerol, an endogenous protein kinase C activator. Permeability, contractile force, and cell differentiation and proliferation are all affected by increased vascular protein kinase C. Increased vascular permeability and thickening of the basement membrane caused by excessive protein kinase C activity cause ischemia of peripheral nerves, resulting in neuropathy.[57]
In addition, hyperglycemia increases the expression of NADPH oxidase and the uncoupling reaction of endothelial nitric oxide (NO) synthase in vascular endothelial cells, resulting in excessive superoxide output. Endothelial cells need NO to work properly. By binding to NO, excess superoxide reduces NO, promoting the secondary synthesis of ROS, such as peroxynitrite and hydroxyl radicals.[58] The cytotoxicity of ROS is high, and an increase in ROS causes neurosis. Finally, in a diabetic condition, bone marrow-derived proinsulin and TNF-producing cells emerge. Both cells cause cell fusion in the dorsal root ganglions and peripheral nerves (axon and Schwann cells). Ca2+ homeostasis is disrupted and apoptosis is induced in fused cells. Insulin treatment eliminates the appearance of these abnormal cells.[4],[59]
| Management of Diabetic Neuropathy | | |
Nonpharmacological approaches
The type of treatment for peripheral neuropathy is determined by the cause. Lifestyle changes, such as diet and physical exercise are effective therapies that could delay the progression of neuropathy by encouraging small nerve fiber regeneration.[12] Smoking has a negative impact on blood supply. Less oxygenated blood can pass into the narrowed blood vessels. Peripheral neuropathy may cause increased numbness and pain if blood supply is poor. Smoking cessation can help to alleviate symptoms.[60] Exercise will help manage discomfort and improve physical health. Being physically active can help to lower blood sugar levels, and it can help to prevent or delay nerve injury. Exercise also improves blood supply to the arms and legs, thus lowering tension levels. Both of these causes contribute to the reduction of irritation and injury.[14] Taking a warm bath can be relaxing and can also help with neuropathy pain symptoms. Warm water improves blood pressure in the body, reducing numbness-related pain effects.[61] Acupuncture stimulates the body's pain points, promoting natural healing. This method causes the nervous system to release chemicals that alter pain perception and threshold. Acupuncture aids in the body's energy balance, which can impair mental well-being.[62]
Pharmacological approaches
Antidepressants
Duloxetine is a selective norepinephrine and serotonin reuptake inhibitor appears to improve the quality of life of patients with DN. Tricyclic antidepressants may be used as well, especially amitriptyline.[63]
Anticonvulsants
Pregabalin, a calcium channel subunit α2-δ binder approved for painful DN, whereas gabapentin could be used as a second-line therapy after pregabalin to manage this complication.[62]
Opioids
Tapentadol in a prolonged-release formulation is approved for painful DN as a centrally acting opioid analgesic that exerts its analgesic effects by inhibiting the μ-opioid receptor and noradrenaline uptake.[64]
B vitamins
B vitamins represent a group of chemically heterogeneous essential substances ,including B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B7 (biotin), B9 (folate), and B12 (cobalamin). B vitamin deficiencies are linked to certain forms of peripheral neuropathy and severe nerve damage. Nerve well-being necessitates the use of B vitamins to improve neuropathy, motor control, nociceptive, and neuropathic pain. Although B vitamins may be obtained from food, it is advisable to take a supplement.[65]
Vitamin D
Earlier literature reported that serum Vitamin D is lowered in patients with DN and its deficiency could promote the development of this diabetic complication and more balance disturbance by triggering hyperglycemia and inflammation with increased pain sensitization.[66],[67],[68] In addition, DN is associated with decreased neuronal nerve growth factor (NGF) expression. This lowered level can be corrected by Vitamin D intake as it increases neuronal NGF synthesis.[69],[70] Vitamin D has been described as a neurotrophic hormone and has a neuroprotective effect through upregulation of Vitamin D receptor expression and downregulation of L-type calcium channel expression.[71],[72] Furthermore, Vitamin D improves both axonogenesis and sensory neural response in peripheral nerve and electrophysiological recovery.[73] Based on all these findings, Vitamin D supplementation has beneficial effects on neuropathic pain, prevents neuronal degeneration, and may improve balance.[74]
Cayenne pepper
Cayenne pepper contains capsaicin, a spicy compound used in chili peppers. For its pain-relieving qualities, capsaicin has been used in topical creams. It reduces the amount of pain signals transmitted to the brain. Cayenne pepper in the diet or a capsaicin supplement may help to alleviate neuropathy pain. While it may burn at first, repeated use may help to alleviate neuropathy symptoms.[75]
Essential oils
Some essential oils, such as chamomile and Roman lavender, have the ability to support the body's circulation. They may have anti-inflammatory and pain-relieving effects, which can help with healing. Basic oils should be diluted (a few drops) in 1 ounce of a carrier oil like olive oil. The stinging and tingling pains associated with peripheral neuropathy can be alleviated by applying these diluted oils to the affected region.[76]
Supplementary medicines used as additional approaches in the management of diabetic microvascular complications
Ginkgo biloba
Ginkgo biloba has a variety of properties, including the ability to scavenge ROS. By lowering OS, G. biloba extract may inhibit AGE formation and downregulate receptors for RAGE expressions, as well as boost the renal tissue structure and function of DN rats. Furthermore, G. biloba extract protects mesangial cells from glomerulosclerosis in diabetic patients and improves albuminuria and kidney function during the early stage (characterized by microalbuminuria) of DN. G. biloba reduced blood glucose level, serum creatinine, blood urea nitrogen, urinary protein, and the severity of the OS in DN rats, according to the findings. AGE, collagen IV, laminin, TGF-1 mRNA, mesangium hyperplasia, and glomerular basement membrane thickness were all decreased.[77],[78]
Turmeric
It's a polyphenol (diferuloylmethane), and it is the most active ingredient in turmeric, which comes from the Curcuma longa L. plant. Curcumin has a number of antidiabetic properties, which are thought to be due to its antioxidant properties. Curcumin, at a dosage of 500 mg/day, was observed to significantly decrease urinary microalbumin excretion, lower plasma MDA levels, and increase the Nrf2 system-specific regulated protein, as well as other anti-oxidative enzymes in diabetic patients' blood lymphocytes. There was an improvement in IB, an inhibitory protein, after curcumin administration.[79],[80]
Green tea
Green tea (Camellia sinensis L.) has anti-inflammatory and antioxidant properties. It contains antioxidative flavonoids in high concentrations. Green tea polyphenols have been shown to be useful in the treatment of inflammatory conditions associated with OS in renal tissues and shown to decrease albuminuria in diabetic patients.[81]
Ginger
Ginger has antioxidant properties, and more than 50 antioxidants have been extracted from ginger rhizomes. Antioxidants, anti-inflammatory, anticancer, anticlotting, antihyperglycemic, diuretic, and analgesic properties were also found in ginger. It lowers blood glucose levels. In diabetic rats, a mixture of honey and ginger potentiate superoxide dismutase (SOD) and catalase (CAT) enzymes. This could lower malondialdehyde (MDA) levels, and restore GSH and the GSH/GSSG ratio to normal levels. Ginger works by interacting with the 5-HT3 receptor to improve insulin release and sensitivity.[82],[83]
Coenzyme Q10
Coenzyme Q10 (ubiquinone) is an endogenous vitamin that functions as a natural antioxidant and free radical scavenger and a part of the electron transport chain. It is present in the membranes of many organelles and is used as an electron carrier in aerobic cellular respiration to generate energy. Intake of Coenzyme highly improves endothelial function, thereby reducing diabetic microvacular complications, including vasculopathy, nephropathy, retinopathy and neuropathy.[84]
Guava
Guava (Psidium guajava), a common tropical fruit high in Vitamin C, carbohydrate, and phenolic compounds, is one of the most popular fruits. Psidium cattleianum Sabine (Myrtaceae) is high in Vitamin C and phenolic compounds, the main components of which are epicatechin and gallic acid. It was thought to be an excellent source of natural antioxidants. In diabetic mice, the flavonoid fraction of guava leaf extract inhibits NO and PGE2 formation, as well as TNF, interleukin (IL)-1, IL-10, iNOS, COX-2, and LPS-induced NFB transcriptional activity.[85]
Vitamins C and E
Vitamin C is important for the antioxidant protection mechanism as well as apoptosis. Vitamin C levels were shown to be lower in DN patients. Vitamin C exclusion from tubular epithelial cells in diabetes has been shown to deprive the cells of antioxidant capacity and could contribute to ROS accumulation due to rivalry between glucose and dehydroascorbate for a popular transport mechanism.[86] Vitamin C has reduced lipid peroxidation and increased the activities of antioxidant enzymes such as SOD, CAT, and GSH peroxidase (GPx), as well as reversing the effects of aging. In diabetic rats' kidneys, Vitamin C lowered lipid peroxidation and increased the activities of antioxidant enzymes SOD, CAT, and GPx, as well as lowering albuminuria and GBM thickness. In DN rats, Vitamin C reduced blood urea nitrogen, serum creatinine, and urinary albumin excretion while increasing creatinine clearance. Vitamin C was discovered to shield renal lesions in DN by inhibiting Type IV collagen expression. Enhances HO-1 protein expression in a concentration-and time-dependent manner.[87]
Vitamin E has been shown to elevate baseline creatinine clearance in Type 1 diabetic patients and helped lower their HbA1C levels. The combination of vitamin E and C in type 2 DM improves kidney function and reduces the incidence of albuminuria.[87]
In addition, OS, which is elevated in DR, is decreased after treatment with Vitamin E.[88]
Zinc
Zinc is a trace metal with significant biochemical roles and functions as a cofactor for a variety of enzymes. It is required for cell division, DNA synthesis, immune function, as well as the metabolism of carbohydrates and proteins. Furthermore, it is a necessary part of a number of proteins involved in the OS protection mechanism in part due to zinc protection against lipid peroxidation and pericyte protection. Because of elevated urinary excretion and reduced food consumption, patients with DM are likely to suffer from zinc deficiency.[89],[90],[91] Serum zinc levels fall progressively with increased duration of DM and correlated with the duration of DM, elevated HbA1c, and severity of diabetic microvascular complications. Therefore, zinc supplementation could improve glucose intolerance and insulin resistance.[90],[92]
| Conclusion | | |
This review provides an insight into the physiological mechanisms of diabetic microvascular complications which in the majority are overlap and that the treatments are similar. This review also provides focus on the current speculations on the effectiveness of a variety of approaches including supplements and antioxidants in the treatment of these diabetes complications. These would help to reduce the risk and severity along with mitigating the negative effects of these complications and contribute to potential long-term benefits in their management with positive health, social, and economic impact.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | American Diabetes Association. Standards of Medical Care in Diabetes-2017 abridged for primary care providers. Clin Diabetes 2017;35:5-26.  |
| 2. | Blair M. Diabetes mellitus review. Urol Nurs 2016;36:27-36. |
| 3. | Barrett EJ, Liu Z, Khamaisi M, King GL, Klein R, Klein BE, et al. Diabetic microvascular disease: An endocrine society scientific statement. J Clin Endocrinol Metab 2017;102:4343-410. |
| 4. | Li TC, Kardia SL, Li CI, Chen CC, Liu CS, Yang SY, et al. Glycemic control paradox: Poor glycemic control associated with higher one-year and eight-year risks of all-cause hospitalization but lower one-year risk of hypoglycemia in patients with type 2 diabetes. Metabolism 2015;64:1013-21. |
| 5. | Franco R, Basili M, Miranda M, Basilicata M, Bollero P. The effects of topical application of melatonin on periodontal Disease in diabetic patients. BBRJ 2021;5:129-33. |
| 6. | Lim AK. Diabetic nephropathy – Complications and treatment. Int J Nephrol Renovasc Dis 2014;7:361-81. |
| 7. | Cao Z, Cooper ME. Pathogenesis of diabetic nephropathy. J Diabetes Investig 2011;2:243-7. |
| 8. | Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA 2016;316:602-10. |
| 9. | Shields J, Maxwell AP. Managing diabetic nephropathy. Clin Med (Lond) 2010;10:500-4. |
| 10. | Roelofs JJ, Vogt L. Diabetic Nephropathy. Cham, Switzerland: Springer; 2019. p. 270-91. |
| 11. | Wen-Linga L, Peng-Huib W. Uric acid in diabetic nephropathy. J Chin Med Assoc 2020;83:794. |
| 12. | Fu S, Li L, Deng S, Zan L, Liu Z. Effectiveness of advanced carbohydrate counting in Type 1 diabetes mellitus: A systematic review and meta-analysis. Sci Rep 2016;6:37067. |
| 13. | Wadén J, Tikkanen HK, Forsblom C, Harjutsalo V, Thorn LM, Saraheimo M, et al. Leisure-time physical activity and development and progression of diabetic nephropathy in Type 1 diabetes: The FinnDiane Study. Diabetologia 2015;58:929-36. |
| 14. | Gonzalez JT, Fuchs CJ, Betts JA, van Loon LJ. Liver glycogen metabolism during and after prolonged endurance-type exercise. Am J Physiol Endocrinol Metab 2016;311:E543-53. |
| 15. | Tripathi YB, Yadav D. Diabetic nephropathy: causes and managements. Recent Pat Endocr Metab Immune Drug Discov 2013;7:57-64. |
| 16. | Abdul-Hadi MH, Naji MT, Shams HA, Sami OM, Al-Harchan NA, Al-Kuraishy HM, et al. Oxidative stress injury and glucolipotoxicity in Type 2 diabetes mellitus: The potential role of metformin and sitagliptin. BBRJ 2020;4:166-72 |
| 17. | Fried LF, Lewis J. Rebuttal of the pro view: Albuminuria is an appropriate therapeutic target in patients with CKD. Clin J Am Soc Nephrol 2015;10:1095-8. |
| 18. | Tang SC, Chan GC, Lai KN. Recent advances in managing and understanding diabetic nephropathy. F1000Res 2016;5:v1000-44. |
| 19. | Mulder S, Perco P, Oxlund C, Mehdi UF, Hankemeier T, Jacobsen IA, et al. Baseline urinary metabolites predict albuminuria response to spironolactone in Type 2 diabetes. Transl Res 2020;222:17-27. |
| 20. | Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996;50:1641-50. |
| 21. | Chen HY, Pan HC, Chen YC, Chen YC, Lin YH, Yang SH, et al. Traditional Chinese medicine use is associated with lower end-stage renal disease and mortality rates among patients with diabetic nephropathy: A population-based cohort study. BMC Complement Altern Med 2019;19:81. |
| 22. | Srivastava SP, Shi S, Koya D, Kanasaki K. Lipid mediators in diabetic nephropathy. Fibrogenesis Tissue Repair 2014;7:12. |
| 23. | Momeni A. Serum uric acid and diabetic nephropathy. J Renal Inj Prev 2012;1:37-8. |
| 24. | Hu X, Liu W, Yan Y, Liu H, Huang Q, Xiao Y, et al. Vitamin D protects against diabetic nephropathy: Evidence-based effectiveness and mechanism. Eur J Pharmacol 2019;845:91-8. |
| 25. | Rübsam A, Parikh S, Fort PE. Role of inflammation in diabetic retinopathy. Int J Mol Sci 2018;19:E942. |
| 26. | Schorr SG, Hammes HP, Müller UA, Abholz HH, Landgraf R, Bertram B. The prevention and treatment of retinal complications in diabetes. Dtsch Arztebl Int 2016;113:816-23. |
| 27. | Nentwich MM, Ulbig MW. Diabetic retinopathy – Ocular complications of diabetes mellitus. World J Diabetes 2015;6:489-99. |
| 28. | Lattanzio R, Cicinelli MV, Bandello F. Intravitreal steroids in diabetic macular edema. Dev Ophthalmol 2017;60:78-90. |
| 29. | Jorge EC, Jorge EN, Botelho M, Farat JG, Virgili G, El Dib R. Monotherapy laser photocoagulation for diabetic macular oedema. Cochrane Database Syst Rev 2018;10:CD010859. |
| 30. | Moutray T, Evans JR, Lois N, Armstrong DJ, Peto T, Azuara-Blanco A. Different lasers and techniques for proliferative diabetic retinopathy. Cochrane Database Syst Rev 2018;3:CD012314. |
| 31. | Frank RN. Diabetic retinopathy and systemic factors. Middle East Afr J Ophthalmol 2015;22:151-6. [ PUBMED] [Full text] |
| 32. | Ellis D, Burgess PI, Kayange P. Management of diabetic retinopathy. Malawi Med J 2013;25:116-20. |
| 33. | Wroblewski JJ, Hu AY. Topical squalamine 0.2% and intravitreal ranibizumab 0.5 mg as combination therapy for macular edema due to branch and central retinal vein Occlusion: An open-label, randomized study. Ophthalmic Surg Lasers Imaging Retina 2016;47:914-23. |
| 34. | Park S, Karunakaran U, Jeoung NH, Jeon JH, Lee IK. Physiological effect and therapeutic application of alpha lipoic acid. Curr Med Chem 2014;21:3636-45. |
| 35. | Xiang GD, Sun HL, Zhao LS, Hou J, Yue L, Xu L. The antioxidant alpha-lipoic acid improves endothelial dysfunction induced by acute hyperglycaemia during OGTT in impaired glucose tolerance. Clin Endocrinol (Oxf) 2008;68:716-23. |
| 36. | Voloboueva LA, Liu J, Suh JH, Ames BN, Miller SS. (R)-alpha-lipoic acid protects retinal pigment epithelial cells from oxidative damage. Invest Ophthalmol Vis Sci 2005;46:4302-10. |
| 37. | Gębka A, Serkies-Minuth E, Raczyńska D. Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with Type 1 and Type 2 diabetes. Mediators Inflamm 2014;2014:131538. |
| 38. | Wang W, Lo AC. Diabetic retinopathy: Pathophysiology and treatments. Int J Mol Sci 2018;19:E1816. |
| 39. | Shi C, Wang P, Airen S, Brown C, Liu Z, Townsend JH, et al. Nutritional and medical food therapies for diabetic retinopathy. Eye Vis (Lond) 2020;7:33. |
| 40. | Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: Systematic review and meta-analysis. BMJ 2011;343:d5094. |
| 41. | Luong KV, Nguyen LT. The impact of thiamine treatment in the diabetes mellitus. J Clin Med Res 2012;4:153-60. |
| 42. | Pácal L, Kuricová K, Kaňková K. Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco and lipotoxicity by rational supplementation? World J Diabetes 2014;5:288-95. |
| 43. | McNulty H, Strain JJ, Hughes CF, Ward M. Riboflavin, MTHFR genotype and blood pressure: A personalized approach to prevention and treatment of hypertension. Mol Aspects Med 2017;53:2-9. |
| 44. | Alam MM, Iqbal S, Naseem I. Ameliorative effect of riboflavin on hyperglycemia, oxidative stress and DNA damage in type-2 diabetic mice: Mechanistic and therapeutic strategies. Arch Biochem Biophys 2015;584:10-9. |
| 45. | Satyanarayana A, Balakrishna N, Pitla S, Reddy PY, Mudili S, Lopamudra P, et al. Status of B-vitamins and homocysteine in diabetic retinopathy: Association with vitamin-B12 deficiency and hyperhomocysteinemia. PLoS One 2011;6:e26747. |
| 46. | Wu MY, Yiang GT, Lai TT, Li CJ. The oxidative stress and mitochondrial dysfunction during the pathogenesis of diabetic retinopathy. Oxid Med Cell Longev 2018;2018:3420187. |
| 47. | Nghiem AZ, Nderitu P, Lukic M, Khatun M, Largan R, Kortuem K, et al. Comparing diabetic retinopathy lesions in scanning laser ophthalmoscopy and colour fundus photography. Acta Ophthalmol 2019;97:e1035-40. |
| 48. | Kramer CK, Swaminathan B, Hanley AJ, Connelly PW, Sermer M, Zinman B, et al. Prospective associations of Vitamin D status with β-cell function, insulin sensitivity, and glycemia: The impact of parathyroid hormone status. Diabetes 2014;63:3868-79. |
| 49. | Long M, Wang C, Liu D. Glycated hemoglobin A1C and Vitamin D and their association with diabetic retinopathy severity. Nutr Diabetes 2017;7:e281. |
| 50. | Mutlu U, Ikram MA, Hofman A, de Jong PT, Uitterlinden AG, Klaver CC, et al. Vitamin D and retinal microvascular damage: The Rotterdam study. Medicine (Baltimore) 2016;95:e5477. |
| 51. | Neelam K, Goenadi CJ, Lun K, Yip CC, Au Eong KG. Putative protective role of lutein and zeaxanthin in diabetic retinopathy. Br J Ophthalmol 2017;101:551-8. |
| 52. | Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgrad Med J 2006;82:95-100. |
| 53. | Kobayashi M, Zochodne DW. Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications. J Diabetes Investig 2018;9:1239-54. |
| 54. | Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care 2017;40:136-54. |
| 55. | Flyvbjerg A. The role of the complement system in diabetic nephropathy. Nat Rev Nephrol 2017;13:311-8. |
| 56. | Keating ST, van Diepen JA, Riksen NP, El-Osta A. Epigenetics in diabetic nephropathy, immunity and metabolism. Diabetologia 2018;61:6-20. |
| 57. | Kumar P, Raman T, Swain MM, Mishra R, Pal A. Hyperglycemia-induced oxidative-nitrosative stress induces inflammation and neurodegeneration via augmented Tuberous Sclerosis Complex-2 (TSC-2) activation in neuronal cells. Mol Neurobiol 2017;54:238-54. |
| 58. | Al-Taie A, Sancar M, Izzettin FV. Cancer: Oxidative Stress and Dietary Antioxidants. 2nd ed. Academic Press-Elseiver, London, UK. 2021 . |
| 59. | Goel K, Rajput R, Kharb S. Association of Vitamin D levels with blood pressure changes and mean arterial pressure in prediabetics. BBRJ 2019;3:253-7. |
| 60. | Clair C, Cohen MJ, Eichler F, Selby KJ, Rigotti NA. The effect of cigarette smoking on diabetic peripheral neuropathy: A systematic review and meta-analysis. J Gen Intern Med 2015;30:1193-203. |
| 61. | Mooventhan A, Nivethitha L. Scientific evidence-based effects of hydrotherapy on various systems of the body. N Am J Med Sci 2014;6:199-209. |
| 62. | Theysohn N, Choi KE, Gizewski ER, Wen M, Rampp T, Gasser T, et al. Acupuncture-related modulation of pain-associated brain networks during electrical pain stimulation: A functional magnetic resonance imaging study. J Altern Complement Med 2014;20:893-900. |
| 63. | Ardeleanu V, Toma A, Pafili K, Papanas N, Motofei I, Diaconu CC, et al. Current pharmacological treatment of painful diabetic neuropathy: A narrative review. Medicina (Kaunas) 2020;56:E25. |
| 64. | Vadivelu N, Huang Y, Mirante B, Jacoby M, Braveman FR, Hines RL, et al. Patient considerations in the use of tapentadol for moderate to severe pain. Drug Healthc Patient Saf 2013;5:151-9. |
| 65. | Calderón-Ospina CA, Nava-Mesa MO. B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. CNS Neurosci Ther 2020;26:5-13. |
| 66. | Pinelli NR, Jaber LA, Brown MB, Herman WH. Serum 25-hydroxy vitamin d and insulin resistance, metabolic syndrome, and glucose intolerance among Arab Americans. Diabetes Care 2010;33:1373-5. |
| 67. | Alam U, Nelson AJ, Cuthbertson DJ, Malik RA. An update on Vitamin D and B deficiency in the pathogenesis and treatment of diabetic neuropathy: A narrative review. Future Neurol 2018;13:135-42. |
| 68. | Timar B, Timar R, Gaiţă L, Oancea C, Levai C, Lungeanu D. The impact of diabetic neuropathy on balance and on the risk of falls in patients with Type 2 diabetes mellitus: A cross-sectional study. PLoS One 2016;11:e0154654. |
| 69. | Anand P, Terenghi G, Warner G, Kopelman P, Williams-Chestnut RE, Sinicropi DV. The role of endogenous nerve growth factor in human diabetic neuropathy. Nat Med 1996;2:703-7. |
| 70. | Fukuoka M, Sakurai K, Ohta T, Kiyoki M, Katayama I. Tacalcitol, an active Vitamin D3, induces nerve growth factor production in human epidermal keratinocytes. Skin Pharmacol Appl Skin Physiol 2001;14:226-33. |
| 71. | Taniura H, Ito M, Sanada N, Kuramoto N, Ohno Y, Nakamichi N, et al. Chronic Vitamin D3 treatment protects against neurotoxicity by glutamate in association with upregulation of Vitamin D receptor mRNA expression in cultured rat cortical neurons. J Neurosci Res 2006;83:1179-89. |
| 72. | Chabas JF, Stephan D, Marqueste T, Garcia S, Lavaut MN, Nguyen C, et al. Cholecalciferol (Vitamin D3) improves myelination and recovery after nerve injury. PLoS One 2013;8:e65034. |
| 73. | Chabas JF, Alluin O, Rao G, Garcia S, Lavaut MN, Risso JJ, et al. Vitamin D2 potentiates axon regeneration. J Neurotrauma 2008;25:1247-56. |
| 74. | Putz Z, Martos T, Németh N, Körei AE, Vági OE, Kempler MS, et al. Is there an association between diabetic neuropathy and low Vitamin D levels? Curr Diab Rep 2014;14:537. |
| 75. | Derry S, Rice AS, Cole P, Tan T, Moore RA. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017;1:CD007393. |
| 76. | Gok Metin Z, Arikan Donmez A, Izgu N, Ozdemir L, Arslan IE. Aromatherapy massage for neuropathic pain and quality of life in diabetic patients. J Nurs Scholarsh 2017;49:379-88. |
| 77. | Zhang L, Mao W, Guo X, Wu Y, Li C, Lu Z, et al. Ginkgo biloba extract for patients with early diabetic nephropathy: A systematic review. Evid Based Complement Alternat Med 2013;2013:689142. |
| 78. | Zhang MH, Feng L, Zhu MM, Gu JF, Jiang J, Cheng XD, et al. The anti-inflammation effect of moutan cortex on advanced glycation end products-induced rat mesangial cells dysfunction and High-glucose-fat diet and streptozotocin-induced diabetic nephropathy rats. J Ethnopharmacol 2014;151:591-600. |
| 79. | Lu M, Yin N, Liu W, Cui X, Chen S, Wang E. Curcumin ameliorates diabetic nephropathy by suppressing NLRP3 inflammasome signaling. Biomed Res Int 2017;2017:1516985. |
| 80. | Kim BH, Lee ES, Choi R, Nawaboot J, Lee MY, Lee EY, et al. Protective effects of curcumin on renal oxidative stress and lipid metabolism in a rat model of Type 2 Diabetic nephropathy. Yonsei Med J 2016;57:664-73. |
| 81. | Borges CM, Papadimitriou A, Duarte DA, Lopes de Faria JM, Lopes de Faria JB. The use of green tea polyphenols for treating residual albuminuria in diabetic nephropathy: A double-blind randomised clinical trial. Sci Rep 2016;6:28282. |
| 82. | Afshari AT, Shirpoor A, Farshid A, Saadatian R, Rasmi Y, Saboory E, et al. The effect of ginger on diabetic nephropathy, plasma antioxidant capacity and lipid peroxidation in rats. Food Chem 2007;101:148-53. |
| 83. | Al Hroob AM, Abukhalil MH, Alghonmeen RD, Mahmoud AM. Ginger alleviates hyperglycemia-induced oxidative stress, inflammation and apoptosis and protects rats against diabetic nephropathy. Biomed Pharmacother 2018;106:381-9. |
| 84. | Al-Taie A, Victoria AO, Hafeez A. Potential therapeutic use of coenzyme Q10 in diabetes mellitus and its complications: An algorithm of scoping clinical review. SN Compr Clin Med 2021;3:989-1001. |
| 85. | Sen SS, Sukumaran V, Giri SS, Park SC. Flavonoid fraction of guava leaf extract attenuates lipopolysaccharide-induced inflammatory response via blocking of NF-κB signalling pathway in Labeo rohita macrophages. Fish Shellfish Immunol 2015;47:85-92. |
| 86. | Chen L, Jia RH, Qiu CJ, Ding G. Hyperglycemia inhibits the uptake of dehydroascorbate in tubular epithelial cell. Am J Nephrol 2005;25:459-65. |
| 87. | Kedziora-Kornatowska K, Szram S, Kornatowski T, Szadujkis-Szadurski L, Kedziora J, Bartosz G. Effect of Vitamin E and Vitamin C supplementation on antioxidative state and renal glomerular basement membrane thickness in diabetic kidney. Nephron Exp Nephrol 2003;95:e134-43. |
| 88. | Chatziralli IP, Theodossiadis G, Dimitriadis P, Charalambidis M, Agorastos A, Migkos Z, et al. the effect of Vitamin E on oxidative stress indicated by serum malondialdehyde in Insulin-dependent Type 2 diabetes mellitus patients with retinopathy. Open Ophthalmol J 2017;11:51-8. |
| 89. | Prasad AS. Discovery of human zinc deficiency: Its impact on human health and disease. Adv Nutr 2013;4:176-90. |
| 90. | Miao X, Sun W, Miao L, Fu Y, Wang Y, Su G, et al. Zinc and diabetic retinopathy. J Diabetes Res 2013;2013:425854. |
| 91. | Luo YY, Zhao J, Han XY, Zhou XH, Wu J, Ji LN. Relationship between serum zinc level and microvascular complications in patients with Type 2 diabetes. Chin Med J (Engl) 2015;128:3276-82. |
| 92. | Adachi Y, Yoshida J, Kodera Y, Kiss T, Jakusch T, Enyedy EA, et al. Oral administration of a zinc complex improves type 2 diabetes and metabolic syndromes. Biochem Biophys Res Commun 2006;351:165-70. |
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