Biomedical and Biotechnology Research Journal (BBRJ)

: 2021  |  Volume : 5  |  Issue : 4  |  Page : 380--388

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

Correspondence Address:
Anmar Al-Taie
Department of Clinical Pharmacy, Faculty of Pharmacy, Istinye University, Istanbul


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.

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;5:380-388

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 2022 Jan 18 ];5:380-388
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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]


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]


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]


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


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]


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]


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]


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 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 (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 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]


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


Conflicts of interest

There are no conflicts of interest.


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