INTRODUCTION:

Diabetes mellitus is a chronic condition that describes a person's body's reaction to blood sugar. It may result from either insufficient insulin production or ineffective insulin processing. As a result, rather than being delivered to the many cells that require energy, sugar builds up in their blood. Their organs, nerves, and blood vessels may suffer harm if their blood sugar levels stay high for an extended period of time¹. Recognize their condition early on and treat them to prevent such issues.²

Diabetes is broadly classified into type 1 diabetes, type 2 diabetes, gestational diabetes, and secondary diabetes.

· Type 1 Diabetes Mellitus:

Type 1 diabetes is an autoimmune condition where the body's immune system targets and harms the pancreatic cells that produce insulin³. As a result, the body is unable to produce insulin. It is impossible for glucose to enter the muscles and fat cells when the body does not have enough insulin. causes the liver to break down fat, which raises blood glucose levels and produces ketones. Diabetic ketoacidosis is the term for this illness.⁴

· Type 2 Diabetes Mellitus:

The metabolic disease known as type 2 diabetes is characterized by the body's inability to use insulin efficiently and the progressive loss of insulin-producing cells.⁵ In an effort to catch up, the body first overproduces insulin, but the tissues are unable to utilize it effectively. The pancreatic cells that make insulin deteriorate with time and are unable to produce enough of the hormone. This results in elevated blood sugar, increased hepatic synthesis of sugar, and improper tissue absorption of sugar.⁶

Diabetic neuropathy:

Long-term high blood sugar levels can lead to diabetic neuropathy, a chronic microvascular condition. It is a significant issue that impacts people with diabetes.⁷ The body's nerve tissues, particularly those in patients' feet and legs, are most affected. It results in issues like weakness, tingling, numbness, and pain.⁸ Diabetes mellitus causes oxidative stress, inflammation, and reduced blood supply to the nerves, among other metabolic and vascular processes that contribute to neuron degeneration. In order to stop diabetic neuropathy from getting worse, early diagnosis and blood glucose management are crucial. Diabetic neuropathy has a variety of implications on a patient's quality of life and requires comprehensive therapy strategies that address both the cause and the symptom; otherwise, potentially fatal complications may arise.⁹

Diabetic neuropathy is classified into several types based on the affected nerve and clinical presentation. The main types include

a) Peripheral Neuropathy: The common form mainly affects the hands and feet, as well as the distal portions of the limbs, especially the legs and feet. Burning pain, numbness, tingling, loss of vibration, pain perception, and weakness are some of its symptoms.¹⁰

b) Autonomic Neuropathy: involves autonomic nerve system injury (cardiovascular—orthostatic hypotension, GI—gastroparesis and diarrhea), which impacts bodily processes like blood pressure, heart rate, digestion, and bladder control.¹¹

c) Proximal Neuropathy (Diabetic Amyotrophy): involves autonomic nerve system injury (cardiovascular—orthostatic hypotension, GI—gastroparesis and diarrhea), which impacts bodily processes like blood pressure, heart rate, digestion, and bladder control.¹²

d) Focal Neuropathy: Abrupt weakening or discomfort (peripheral or cranial) in a particular nerve or group of nerves, as those governing the face, body, or eyes. ¹³

Introduction on Herbal Plants Used in Diabetes and Diabetic Neuropathy:

Because they offer safe, natural substitutes for pharmaceutical treatments, medicinal herbs have been used for many years to manage diabetes. Actually, many plants contain active phytochemicals such flavonoids, alkaloids, terpenoids, saponins, and tannins that have strong antioxidant or antihyperglycemic effects.¹⁴ Medicinal herbs have a long history of being used to treat diabetes because they offer safe, natural substitutes for modern treatments and can take their place. Flavonoids, alkaloids, terpenoids, saponins, and tannins are examples of active phytochemicals found in many plants that have strong antioxidant or antihyperglycemic effects.¹⁵ Because a single herb contains several phytoconstituents, it can treat a variety of illnesses, including diabetes, through various ways. For example, certain herbs can help lower blood glucose levels and manage diabetes by activating the pancreatic β-cell to secrete insulin. Additionally, this specific herb can increase glucose entry by making muscle and adipose tissues more responsive to insulin. Additionally, this herbal remedy can inhibit the action of enzymes like α-amylase and α-glucosidase, which delays the breakdown of carbohydrates.¹⁶ Strong antioxidant and anti-inflammatory qualities found in anti-diabetic herbs save β cells from oxidative damage and postpone their demise. Some of these plants help prevent diabetic problems such diabetic neuropathy, foot ulcers, and fever by reducing gluconeogenesis in the liver, while others can repair injured nerve, kidney, or retinal cells. This plant's multifaceted action makes it possible to manage diabetes and its complications holistically.¹⁷

The etiology of diabetes mellitus:

It is a complex disorder in respect to metabolism, specifically insulin production and function. In Type 1 diabetes, it is due to autoimmune damage to pancreatic beta-cells, resulting in near-total insulin deficiency.¹⁸Insulin deficiency causes an inability to take up glucose from muscle and fat cells, resulting in extremely high blood sugar levels in Type 1 diabetes, while in Type 2, it is due to a combination of peripheral resistance to insulin and a relative deficiency of insulin from beta-cell dysfunction¹⁹. The compensation for the overproduction of insulin is achieved by the body, but eventually, β-cells are no longer able to secrete adequate insulin. Consequently, this leads to chronic hyperglycemia because of reduced glucose uptake.²⁰

These metabolic imbalances result in a long-standing increase in blood glucose level, contributing to complications such as diabetic neuropathy.²¹The pathophysiology of diabetic neuropathy involves metabolic and vascular factors, including oxidative stress, inflammation, and impaired blood flow to nerves leading to degeneration and dysfunction of nerve fibers.²²

The etiology of diabetic neuropathy:

It is a very complex process involving alterations in metabolism and blood flow, caused mainly by chronic episodes of hyperglycemia in diabetes mellitus. Chronic elevations in blood glucose concentrations initiate a series of pathophysiological alterations like oxidative stress, inflammation, and decreased blood flow to nerves. These contribute to the deterioration and dysfunction of nerves. In particular, elevated glucose in diabetes leads to alterations in metabolism, such as accumulation of advanced glycosylation end-products, activation of the polyol pathway, and mitochondrial dysfunction, which act cumulatively to cause damage to nerves.²³ Moreover, decreased blood flow to nerves leads to a loss of nutritional and oxygen supply to peripheral nerves, causing further damage to nerves in diabetes-induced neuropathy.²⁴

RESULT AND DISSCUSSION:

Major receptors in diabetes and mode of action:

a) Insulin receptor

b) GLP-1, GIP receptors

c) Glucagon receptor

d) PPAR-γ

e) KATP channels

f) SGLT2/SGLT1

g) Leptin, Adiponectin receptors

h) TLR4, TNF-α receptors

a) Insulin Receptor:

These phytochemicals have strong antidiabetic properties, mainly through the interaction of the insulin receptor (IR) and their intracellular pathways. The active principles of these plants include berberine, quercetin, kaempferol, mangiferin, curcumin, EGCG, chlorogenic acid, diosgenin, and ginsenosides.²⁵ These improve the sensitivity of the body to insulin by increasing the level of the functional insulin receptor in skeletal muscles, fat, and liver cells.²⁶

A major part of their action involves the surface expression of insulin receptors in increased abundance either due to the stimulation of IR gene expression, as well as the inhibition of receptor internalization and degradation, and this ensures receptor persistence. These compounds include curcumin and berberine, which are known to facilitate the autophosphorylation of the β-subunit of the insulin receptor; this receptor activation is essential for the activation of the tyrosine kinase activity of the receptor.²⁷

On activation of the receptor, these phytochemicals enhance downstream signaling by increasing the phosphorylation of insulin receptor substrate-1 (IRS-1) and the binding of the IRS-1/PI3K complex, which is the gateway to the insulin signaling cascade. The activated PI3-kinase triggers the activation of protein kinase B, an amplification step that leads to the enhanced production and translocation of glucose transporter type 4 to the cell membrane, thereby bringing about a significant decrease in blood glucose levels.²⁸

Furthermore, polyphenolic antioxidants like quercetin, kaempferol, EGCG, and resveratrol reduce oxidative and inflammatory stress through suppression of the mediators of TNF-α and IL-6, which impede insulin receptor phosphorylation. The suppression of these pro-inflammatory pathways by phytoconstituents thus restores sensitivity of insulin receptors or inhibits serine phosphorylation of IRS-1 (the principal mechanism in insulin resistance).²⁹

In addition, mangiferin, ginsenosides, and other phytochemicals activate AMPK, thereby augmenting insulin action by facilitating glucose uptake independently of insulin action³⁰. Collectively, these phytochemicals augment insulin binding, increase responsiveness to the insulin receptor, activate downstream receptors, and augment the IR → IRS-1 → PI3K → AKT → GLUT-4 cascade, hence making significant contributions to glucose regulation in type-2 diabetes mellitus.³¹

b) GLP-1 Receptor (GLP-1R):

The phytoconstituents from these plants act on the GLP-1 receptor agonistically, promoting the secretion of insulin by activating the GLP-1 receptor in pancreatic cells.³² They increase the secretion of insulin in a glucose-dependent manner, reduce the secretion of glucagon, slow gastric emptying, and improve the survival of beta cells in the pancreatic islets.³³

Phytoconstituents Acting on GLP-1R:³⁴

· Berberine – enhances endogenous GLP-1 secretion

· Resveratrol – increases GLP-1 receptor sensitivity

· Mangiferin – stimulates GLP-1 release

· Catechins (EGCG) – potentiates incretin effect

· Curcumin – improves GLP-1 signaling

· Chlorogenic acid – increases GLP-1 hormone levels

· Ginsenosides (Rg1, Rb1) – activate GLP-1 receptor pathways

c) GIP Receptor (GIPR):

These phytochemicals stimulate glucose-mediated insulin secretion by activating the GIP receptors present on pancreatic β-cells.³⁵GIPRActivation of GIPR increases the intracellular concentration of cyclic AMP, insulin secretory granule exocytosis, β-cell growth, as well as glucose handling postprandially stimulation increases intracellular cAMP levels, promotes insulin granule exocytosis, supports β-cell growth, and improves postprandial glucose handling.³⁶

Phytoconstituents Acting on GIPR:³⁷

· Quercetin – increases GIP secretion and receptor responsiveness

· Kaempferol – enhances GIP-mediated insulin release

· Resveratrol – improves GIP signaling through cAMP activation

· Berberine – modulates GIP receptor activity indirectly via gut hormones

· Chlorogenic acid – boosts GIP incretin effect

· Anthocyanins – stimulate GIP secretion after meals

d) Glucagon Receptor (GCGR):

The glucagon receptor is a G-protein-coupled receptor predominantly located on liver cells. It plays a crucial role in the regulation of hepatic glucose production by stimulating glycogenolysis and gluconeogenesis³⁸ Phytoconstituents that work through glucagon receptors decrease the activation of receptors in general or inhibit glucagon release. They suppress excessive hepatic glucose production through inhibition of GCGR signalling. This results in reduced cAMP generation, downregulated PKA activity, and low levels of the enzymes responsible for gluconeogenesis and glycogenolysis, which also finally contribute to an improvement of blood glucose in diabetes.³⁹

The phytochemicals include berberine, quercetin, resveratrol, curcumin, EGCG, mangiferin, chlorogenic

e) PPAR-γ (Peroxisome Proliferator–Activated Receptor Gamma):

PPAR-γ is a nuclear hormone receptor, predominantly expressed in adipose tissue, as well as in the liver, skeletal muscle, and macrophages. It plays a key role in glucose metabolism, lipid metabolism, adipogenesis, and insulin sensitivity.⁴⁰

Phytochemicals: Curcumin, resveratrol, quercetin, kaempferol, mangiferin, berberine, chlorogenic acid, omega-3 fatty acids.

f) KATP Channels (ATP-Sensitive Potassium Channels):

KATP channels are ion channels mainly found in pancreatic β-cells, cardiac muscle, skeletal muscle, and neurons. In diabetes, the β-cell KATP channels play a significant role because they regulate insulin secretion.⁴¹ Generally, phytoconstituents acting on KATP channels inhibit [close] the channels in pancreatic β-cells. Closure of the KATP channel depolarizes the membrane, opening voltage-gated calcium channels, increasing intracellular Ca²⁺, and triggering insulin release, thus lowering blood glucose and improving pancreatic function. Some phytochemicals may also open KATP channels in the cardiac tissue to exert cardioprotective effects.⁴²

Phytochemicals:

Quercetin, kaempferol, berberine, curcumin, resveratrol, EGCG, ginsenosides, genistein, diosgenin, naringenin

DPN Receptors and Mode of Action:

a) TRPV1 Inhibitors (reduce burning pain & hyperalgesia):

This receptor is a heat and pain-sensitive ion channel that is present in sensory nerve cells. In diabetic neuropathy, there is a marked overactivation of this receptor by both oxidative stress and inflammation, giving rise to burning pain and thermal hyperalgesia.⁴³

Table 1: TRPV1 inhibitor with MOA⁴⁴

Plant/Phytoconstituent	MOA on TRPV1
Curcumin (Curcuma longa)	Direct TRPV1 desensitization →
Capsazepine	Competitive TRPV1 antagonist →
Resveratrol (Grapes)	TRPV1 overexpression was reduced
Quercetin (Onion, Asplenium nidus)	Suppresses TRPV1 activation by reducing ROS.

b) RPA1 Inhibitors (reduce mechanical/cold allodynia)

TRPA1 stands for the cold sensing and mechano-sensitive receptor that responds to potentially painful stimuli within the body. TRPA1 in DPN overreacts to reactive oxygen species to cause allodynia due to cold as well as stabbing pain.⁴⁵

Table 2: TRPA1 Inhibitor with MOA

Phytoconstituent	MOA on TRPA1
Cinnamaldehyde (Cinnamon)	TRPA1 channel desensitizer
Allicin (Garlic)	Reduces ROS/NO →
Epigallocatechin gallate (Green tea)	Antioxidants
Kaempferol (Asplenium nidus)	Reduces oxidative stress →

c) Sodium Channel (Nav1.7 / Nav1.8) Modulators:

These voltage-gated sodium channels are responsible for regulating neuronal excitability and pain transmission. These channels work in excess in cases where there is chronic hyperglycemia, leading to spontaneous pain fiber firing in diabetic neuropathy patients.⁴⁶

Table 3: Sodium channel blocker with MOA⁴⁷

Phytoconstituent	MOA
Lidocaine-like alkaloids (Erythroxylum spp.)	Blocking
Harpagide	Modulates Nav1.7 →
Berberine (Berberis spp.)	It inhibits
Luteolin	Stabilizes neuronal

d) Potassium Channels (KATP / Kv) Activator:

Potassium channels regulate the resting membrane potential and control action potential in nerves. In DPN, dysfunction of potassium channels results in increased neuronal excitability and decreased conduction velocity in nerves.⁴⁸

Table 4: potassium channels activator with MOA

Phytoconstituent	MOA
Resveratrol	Activates KATP → restores membrane potential.
Ginsenosides (Panax ginseng)	Stimulating
Quercetin	Opens K+ channels →
Luteolin	It enhances

e) NMDA Receptor Inhibitors:

These were the NMDA receptors, which are glutamate calcium channels responsible for central pain sensitization, whose overactivation in diabetes excites spinal pain pathways, leading to chronic neuropathic pain.⁴⁹

Table 5: NMDA receptor inhibitor with MOA

Phytoconstituent	MOA
Huperzine	NMDA receptor antagonist →
Curcumin	Downregulates NMDA NR2B subunit.
Resveratrol	Blocks
Baicalein	It reduces

f) GABA-A/GABA-B Enhancers:

GABA receptors are critical for inhibitory neurotransmission within the central nervous system. In diabetes, a reduction in GABAergic tone leads to lesser pain inhibition and increased neuropathic symptoms.⁵⁰

Table 6: GABA-A enhancers with MOA

Phytoconstituent	MOA
Magnolol (Magnolia bark)	Activation of
Valerenic	GABA-A agonist.
Linalool (Lavender)	Positive GABA-A modulator.
Asarone	It enhances

g) Opioid Receptor Agonist Phytochemicals:

Opioid receptors regulate pain perception by inhibiting nociceptive signaling. Their dysfunction or reduced activation intensifies the pain pathways in diabetic neuropathy.⁵¹

Table 7: Opioid receptor agonist with MOA

Phytoconstituent	MOA
Salvinorin	Kappa-opioid receptor agonist.
Mitraphylline	μ-opioid partial agonist
Corydine	Weak opioid receptor activation →

h) NGF/TrkA Enhancers (neurotrophic support):

NGF-TrkA signaling plays a role in neuronal development and survival. In DPN, the relative deficiency in nerve growth factor (NGF) leads to deficiencies in axonal durability and regeneration, causing neuropathy.⁵²

Table 8: NGF enhancer with MOA⁵³

Phytoconstituent	MOA
Curcumin	Increased
Paeoniflorin	Enhances TrkA
Ginsenosides	Promotes
Withanolides	Stimulates

i) PPAR-γ Activators (anti-inflammatory + improves nerve function):

PPAR-γ is a nuclear receptor that modulates inflammation, lipid homeostasis, as well as mitochondrial biology. PPAR-γ activity decreases the effects of DPN, increasing oxidative stress, nerve dysfunction, inflammation.⁵⁴

Table 9: PPAR-γ activator with MOA

Phytoconstituent	MOA
Curcumin	Natural PPAR-γ ligand →
Resveratrol	Activation of
Ginsenosides	Boost PPAR-γ expression.
Kaempferol	Enhances PPAR-γ activity.

List of herbal plants and phytoconstituents used in diabetic and diabetic neuropathy.

Table 10: Herbal plants and their phytoconstituents.

Herb (Part Used)	Family	Common Names	Major Phytoconstituents
Citrullus	Cucurbitaceae	Bitter apple, Colocynth	Cucurbitacins
Crocus sativus (Stigma)	Iridaceae	Saffron, Kesar	Crocin, crocetin,
Curcuma longa (Rhizomes)	Zingiberaceae	Turmeric, Haldi	Curcuminoids, turmerones, zingiberene, sesquiterpenes
Emblica	Phyllanthaceae	Amla, Indian gooseberry	Vitamin C, emblicanin A/B, ellagic acid, gallic acid
Elaeagnus angustifolia (Fruit)	Elaeagnaceae	Russian olive,	Flavonoids, organic acids, tannins, fatty acids
Ferula	Apiaceae	Hing, Asafoetida	Ferulic acid, coumarins, resin acids, volatile oils
Ginkgo biloba (Leaf)	Ginkgoaceae	Ginkgo, Maidenhair tree	Ginkgolides, bilobalide,
Momordica	Cucurbitaceae	Bitter gourd, Karela	Charantin
Mitragyna	Rubiaceae	Kratom	Mitragynine
Nigella sativa (Seeds/Flower)	Ranunculaceae	Black cumin, Kalonji	Thymoquinone.
Ocimum	Lamiaceae	Clove basil	Eugenol, thymol.
Ocimum sanctum (Leaf)	Lamiaceae	Tulsi, Holy basil	Eugenol.
Olea europaea (Fruits)	Oleaceae	Olive	Oleuropein.
Phoenix dactylifera (Fruits)	Arecaceae	Date palm, Dates	Flavonoids, carotenoids, tannins, sugars, sterols
Phyllanthus	Phyllanthaceae	Bhui	Phyllanthin
Pterodon	Fabaceae	Faveira	Vouacapans
Rosmarinus officinalis (Leaf)	Lamiaceae	Rosemary	Carnosic
Gymnema	Apocynaceae	Gurmar	Gymnemic
Trigonella	Fabaceae	Fenugreek	Diosgenin, galactomannan, trigonelline, flavonoids
Allium sativum (Bulb)	Amaryllidaceae	Garlic	Allicin, ajoene,
Cinnamomum verum (Bark)	Lauraceae	Cinnamon	Cinnamaldehyde, eugenol, polyphenols
Panax ginseng (Root)	Araliaceae	Asian ginseng	Ginsenosides (Rb1, Rg1), polysaccharides
Zingiber officinale (Rhizome)	Zingiberaceae	Ginger	Gingerols, shogaols
Syzygium	Myrtaceae	Jamun, Java plum	Jamboline
Azadirachta	Meliaceae	Neem	Nimbin
Moringa oleifera (Leaf)	Moringaceae	Drumstick tree, Moringa	Quercetin, chlorogenic acid
Pterocarpus marsupium (Heartwood)	Fabaceae	Vijaysar	Pterostilbene, epicatechin, tannins
Capsicum annuum (Fruit)	Solanaceae	Red pepper, Mirchi	Capsaicinoids
Silybum marianum (Seeds)	Asteraceae	Milk thistle	Silymarin, silybin, flavonolignans
Withania	Solanaceae	Ashwagandha	Withanolides
Bacopa	Plantaginaceae	Brahmi	Bacosides, saponins, flavonoids
Vitis vinifera (Seed/Skin)	Vitaceae	Grape, Grape seed	Proanthocyanidins, resveratrol
Terminalia	Combretaceae	Haritaki	Chebulinic
Coccinia	Cucurbitaceae	Ivy gourd	Cucurbitane
Commiphora	Burseraceae	Guggul	Guggulsterones
Rubia cordifolia (Root, Leaf, Stem, Fruit)	Rubiaceae	Manjistha	Anthraquinones (alizarin), purpurin,
Berberis aristata (Root/Bark)	Berberidaceae	Indian barberry,	Berberine,
Ficus racemosa (Bark/Fruit)	Moraceae	Cluster fig, Gular	Lupeol, β-sitosterol, flavonoids
Aloe vera (Leaf gel)	Asphodelaceae	Aloe,	Aloin,
Vaccinium myrtillus (Berry)	Ericaceae	Bilberry	Anthocyanins,
Ocimum	Lamiaceae	Sweet basil	Linalool, eugenol,
Cuscuta	Convolvulaceae	Amarbel	Cuscutin
Aegle	Rutaceae	Bael	Marmelosin
Eriobotrya japonica (Leaf)	Rosaceae	Loquat	Triterpenes,
Punica granatum (Fruit peel)	Lythraceae	Pomegranate	Punicalagins, ellagic acid, anthocyanins
Coriandrum sativum (Seeds/Leaves)	Apiaceae	Coriander, Dhania	Linalool, quercetin, coumarins
Camellia sinensis (Leaf)	Theaceae	Green tea	Catechins (EGCG), theanine, flavonoids
Tamarindus indica (Seed)	Fabaceae	Tamarind	Proanthocyanidins, tartaric acid, flavonoids
Piper nigrum (Fruit)	Piperaceae	Black pepper	Piperine, essential oils, flavonoids
Piper longum (Fruit/Root)	Piperaceae	Long pepper,	Piperlongumine
Anacardium occidentale (Leaf/Bark)	Anacardiaceae	Cashew	Anacardic
Mentha piperita (Leaf)	Lamiaceae	Peppermint	Menthol, menthone,
Hordeum vulgare (Seed)	Poaceae	Barley	Beta-glucans, phenolics, lignans
Foeniculum vulgare (Seeds)	Apiaceae	Fennel	Anethole, fenchone, flavonoids
Lavandula angustifolia (Flower/Leaf)	Lamiaceae	Lavender	Linalool, linalyl acetate, coumarins
Artocarpus heterophyllus (Leaves)	Moraceae	Jackfruit leaves	Artocarpin

Phytoconstituents Mostly act on DPN and Diabetics:

1. Flavonoids:

Flavonoids are the most studied phytochemicals for neuropathy because they can repair nerve damage and reduce oxidative stress.

a) Quercetin:

Quercetin is useful for diabetic peripheral neuropathy because of its multi-target protective action, which counteracts the predominant mechanisms of nerve damage that accompany diabetes. It decreases oxidative stress due to hyperglycemia by eliminating free radicals, increasing glutathione, and acting through the Nrf2 antioxidative pathway. It also decreases inflammation by inhibiting NF-κB signaling, thereby decreasing the expression of pro-inflammatory cytokines like TNF-α and IL-6, which are mediators of nerve damage. Moreover, it inhibits aldose reductase, thereby decreasing sorbitol accumulation, which is responsible for osmatic stress in schwann cells.⁵⁵ It also decreases the accumulation of advanced glycosylation end-products and improves microcirculatory blood flow, thereby increasing the supply of nutrients to peripheral nerves. It also helps with the regeneration of nerves by increasing the levels of neurotrophic factors like NGF and BDNF, mitochondrial integrity, and pain circuit modulation, thereby decreasing neuropathic pain and increasing nerve functio.⁵⁶

Quercetin is a naturally occurring flavonoid compound with properties of a supportive drug for managing diabetic peripheral neuropathy based on its multi-target approach for the treatment of nerve injuries.⁵⁷The main issues caused due to the chronic condition of hyperglycemia in diabetes include oxidative stress, inflammation, sorbitol accumulation, and microvascular damage, all of which lead to the degeneration of nerves. The compound works as a counter-agent for the different issues as it reduces the oxidative stress effects caused due to ROP, activating Nrf2 pathways for the activation of the internal antioxidant enzyme system, as well as inhibiting the NF-kB-induced expression of inflammation-generating cytokines.⁵⁸ It also inhibits the polyol pathway by preventing aldose reduce transferase activity, decreases the accumulation of advanced glycation end-products, and enhances the blood supply to the nerves, resulting in better axonal protection and decreased neuropathic pain. However, due to the poor absorption of natural quercetin, several novel commercial forms have been developed to improve the efficacy of this compound in the context of DPN. The Phytosome brand of supplements, such as Quercefit (by Indena) and Thorne Quercetin Phytosome, enhances the cell-surface binding of quercetin with phospholipids.⁵⁹ The bioavailable compounds, for example, EMIQ (by Natural Factors), promote the rapid absorption of the compound with higher plasma concentration. The regular form of the supplement, namely NOW Foods and HealthVit, promotes the general antioxidant properties of the compound, while the combination of the supplement with vitamin C, rutin, and bromelain as in the Solgar Quercetin Complex and Source Naturals Activated Quercetin, respectively, exerts increased vascular and anti-inflammatory properties.⁶⁰ The highly concentrated forms, namely the NatureBell Quercetin (Found at the webpage of the Product www.naturebell.com) (1000mg) and Vaastavik Quercetin (500mg), provides increased dosing opportunities with increased oxidative properties⁶¹. These novel forms of the supplement promote improved blood delivery of the compound, ensuring diffuse neuroprotection for the prevention of diabetic peripheral neuropathy.⁶²

b) Alkaloids:

Alkaloids are an diverse class of nature-derived biologically important nitrogen compounds that demonstrate marked clinical potential in treating diabetic peripheral neuropathy (DPN. This is attributed to the potential of alkaloids to modulate various biochemical hurdles that cause nerve injury.⁶³ Hyperglycemia triggers oxidative stress, inflammation, mitochondrial dysfunction, and neuronal trophic factor deprivation in diabetes. Altogether, it contributes to the degeneration of peripheral nerves. Various plant-derived alkaloids counteract diabetes-associated neuropathic injuries through actions such as correcting the redox disturbance and modulating neurotransmitter release.⁶⁴ Alkaloids like berberine, indole morphine-like compounds, vincristine derivatives, and ajmaline compounds show robust antioxidant and anti-inflammatory properties and can modulate cytokines responsible for neuropathic pain. ⁶⁴Alkaloids can reduce sorbitol buildup in Schwann cells through the inhibition of aldose reductase and can modulate and restore nerve growth factor (NGF). The action of certain other compounds can modulate ion channels involved in the perception of neuropathic pain. It can therefore be an important therapeutic modality that reduces the associated neuropathic pains associated with diabetic neuropathy. Even though clinical-grade compounds are not well-formulated and well-advertised in the treatment of diabetic neuropathies, there are formulations that can effectively modulate berberine and quinoline compounds that can demonstrate potential therapeutic activitiesTheir ability to modulate several targets such as oxidative stress, neuroinflammation, and neuronal repair makes alkaloids an important source in managing DPN induced by diabetes mellitus type II⁶⁵

c) Terpenoids and triterpenoids:

Terpenoids and triterpenoids are huge classes of phytochemicals that are largely identified in plants that are known to counter metabolism and neurological disorders.⁶⁶ It has been observed that in the case of Diabetic Peripheral Neuropathy (DPN), terpenoids and related compounds demonstrate great potential and can be effectively used as an adjunct treatment for their ability to protect and preserve neurons. This is because the key pathophysiologies in the case of DPN include oxidative stress and impairment of nerve conduction.⁶⁷

From the array of plant terpenoids, trigonelline (from fenugreek) and curcumin (from turmeric) have received much attention as drugs. Both are already marketed as various preparations to optimize their bioavailability and patient compliance.⁶⁸

CONCLUSION:

Diabetic Peripheral Neuropathy (DPN) refers to a hard-to-manage, debilitating complication of diabetes mellitus where the available conventional treatment provides only symptomatic relief to the patient. Based on the results of the current review, it could be said that the use of medicinal plants and their bioactive compounds offers a potentially broad approach to managing the metabolic and neuropathic changes of Diabetic Peripheral Neuropathy. Bioactive compounds such as flavonoids, terpenoids, alkaloids, saponins, and polyphenolic compounds in the plant extracts interact to improve the sensitivity of receptors to insulin, improve the overall regulation of important receptors of diabetes and neuropathic disorders, reduce the neural toxicity induced by oxidative stress and inflammation, improve the overall microvascular integrity, and promote and aid the repair and regeneration of the neurons in the nervous pathways. Compounds such as Quercetin, Berberine, Curcumin, Ginsenosides, and Mangiferin have consistently proved to have the property to modulate the insulin and glucagon-like insulin pathways and to regulate the Aldose Reductase Activity along with the property to modulate the Neuroinflammatory mediators such as Toll Like Receptor 4 and TNF Alpha to promote the Neuroregulatory support. The fact that more than 45 plants have been documented for their medicinal properties, along with the isolation of their active chemical compounds, forms a strong basis for the rational development of medicines for diabetic peripheral neuropathy. Finally, in the context of this paper, it is concluded that the pharmacologically active compounds found among plants constitute a useful resource for effective medicines for diabetic peripheral neuropathy. However, apart from the current prospects among these pharmacologically active compounds, significant studies are required for the validation of their efficacy, potency, and applicability for the prevention and management of DPN.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 16.01.2026 Revised on 27.02.2026

Accepted on 30.03.2026 Published on 04.07.2026

Available online from July 18, 2026

Asian J. Pharm. Tech. 2026; 16(3):322-330.

DOI: 10.52711/2231-5713.2026.00045

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