A review on diabetes mellitus: complications, synthetic anti-diabetic agents and herbal treatment

Toluwani Tella; Carolina Pohl; Kovalchuk Igor

doi:10.12688/f1000research.141015.1

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Review

A review on diabetes mellitus: complications, synthetic anti-diabetic agents and herbal treatment

[version 1; peer review: 1 approved with reservations]

Toluwani Tella¹, Carolina Pohl², Kovalchuk Igor¹

PUBLISHED 19 Feb 2024

Author details Author details

¹ Department of Biological Sciences, Faculty of Arts and Science, University of Lethbridge, Lethbridge, Alberta, Canada
² Department of Microbiology and Biochemistry, Faculty of Natural and Agricultural Sciences, University of the Free State, Bloemfontein, Free State, South Africa

Toluwani Tella
Roles: Conceptualization, Data Curation, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing

Carolina Pohl
Roles: Project Administration, Resources, Writing – Review & Editing

Kovalchuk Igor
Roles: Data Curation, Investigation, Project Administration, Resources, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Global Public Health gateway.

Abstract

Background

Diabetes mellitus is a metabolic disorder with multiple symptoms and complications. The management of these conditions involve the use of synthetic anti-diabetic agents, natural products and medicinal plants. Synthetic anti-diabetic agents are associated with side effects whereas medicinal plants have minimal side effects and are less expensive. The aim of this work is to highlight various (i) complications associated with diabetes (ii) synthetic anti-diabetic agents used for treatment (iii) medicinal plants as anti-diabetic agents.

Methods

Electronic databases such as Web of Science, Google Scholar, Science Direct, Springer, Pub Med, Medline and Scopus were searched to identify complications linked with diabetes, synthetic anti-diabetic agents, and herbs used in the management of diabetes mellitus.

Results

The present article is an updated review of the published literature on types of diabetes and their complications, synthetic anti-diabetic drugs and medicinal herbs used for management of diabetes.

Conclusions

Given the complications associated with diabetes mellitus, a search for medicinal herbs with anti-diabetic properties will be useful in the management of this disease.

Keywords

Diabetes, medicinal plants, synthetic antidiabetic agents, toxicology

Corresponding author: Kovalchuk Igor

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2024 Tella T et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Tella T, Pohl C and Igor K. A review on diabetes mellitus: complications, synthetic anti-diabetic agents and herbal treatment [version 1; peer review: 1 approved with reservations]. F1000Research 2024, 13:124 (https://doi.org/10.12688/f1000research.141015.1) First published: 19 Feb 2024, 13:124 (https://doi.org/10.12688/f1000research.141015.1) Latest published: 19 Feb 2024, 13:124 (https://doi.org/10.12688/f1000research.141015.1)

Introduction

It is estimated that 70-80% of people worldwide depend on herbal medicine to meet their health care needs.¹ Globally, millions of people depend on medicinal plants for income generation.² Sales of herbal-based medicines range between 7.5-108 billion US$ worldwide annually, the latter number representing sales of processed medicines.³ Studies revealed that in Canada, annual market sales of medicinal plants reached USD 400 million in 2001⁴ and are growing at a pace of 15% annually.⁵ Diabetes mellitus (DM) and the complications associated with it constitute a major public health challenge, rates of these complications can decline with improvements in the management of this disease with synthetic anti-diabetic agents and medicinal herbs. Here, we cover various types of diabetes and their complications, synthetic drugs used for treatment of these conditions, and medicinal herbs used for treatment of diabetes.

Methods

The present review is a comprehensive report on DM, incorporating the literature published before 2023. All the current information on DM, complications associated with it, synthetic anti-diabetic agents and medicinal herbs used in the management of the disease was collected via an electronic search using PubMed (RRID:SCR 004846), Science Direct, Springer, Web of Science (RRID:SCR 022706), MEDLINE (RRID:SCR 002185), Google Scholar (RRID:SCR 008878), and Scopus (RRID:SCR 022559) databases. Various articles about DM have been selected from peer-reviewed journals.

Types of diabetes mellitus

Diabetes is a disorder characterized by increased blood glucose levels. The most common classifications include Type I and Type II DM, gestational diabetes mellitus (GDM), maturity onset diabetes of young (MODY), neonatal diabetes mellitus (NDM), Type 3c diabetes (also known as pancreatogenic DM), latent autoimmune diabetes in adults (LADA) and Brittle diabetes (also called labile diabetes). The different types of diabetes, clinical features and mutations associated with diabetes are presented in Table 1.

Table 1. Types of diabetes mellitus and their clinical features.

Type of diabetes	Clinical features and associated mutations	References
Type I diabetes	Leads to absolute insulin deficiency leaving the patient relying on exogenous insulin, there are two types: Immune mediated and Idiopathic.	⁶
Type II diabetes	Relative insulin deficiency and/or insulin resistance.	⁶
Maturity onset diabetes of the young (MODY)	MODY is characterized by impaired insulin secretion. Associated mutations include: • Chromosome 2q, neurogenic differentiation1 • Chromosome 9, carboxyl ester lipase • Chromosome 7p, glucokinacse • Chromosome 12q, HNF-1 alpha • Chromosome 20q, HNF-4 alpha • Chromosome 17q, HNF-1 beta • Chromosome 13q, insulin promoter factor-1	⁶
Gestational diabetes	A glucose tolerance disorder that occurs during pregnancy and it is linked with several complications for the baby in utero. Hyperinsulinemia is observed in the fetus of women suffering from gestational diabetes, which promotes growth and subsequent macrosomia.	⁷
Neonatal diabetes	Abnormal development of pancreas or islets. Transient neonatal diabetes is associated with mutation in ZAC encoding zinc finger protein, chromosome 6p22 or 6p24. Permanent neonatal diabetes is associated with mutation in chromosome 11p15.	⁸
Type 3c diabetes	It is characterized by abdominal pain, steatorrhea, glucose intolerance, loss of islets cells, decreased glucagon secretion.	⁹^,¹⁰
Latent autoimmune diabetes in adults	Clinical features are similar to both Type I and Type II diabetes	¹¹
Brittle diabetes	Characterized by sudden and extreme fluctuation in blood sugar levels from very low (hypoglycemic) to very high (hyperglycemic) or vice-versa.	¹²

Complications associated with diabetes mellitus

People with diabetes suffer from several complications that develop rapidly or overtime affecting many organs/system. These complications are discussed below.

Diabetic nephropathy

Diabetes causes damage to kidneys making it difficult to remove waste or extra fluid from the body. Diabetic nephropathy (DNep) is characterized by loss of glomerular filtration rate (GFR), presence of pathological quantities of urine albumin excretion, diabetic glomerular lesions in individuals with diabetes. Some factors that contribute to the development of DNep are hyperglycemia, high blood pressure and dyslipidemia.¹³

Diabetic neuropathy

High blood sugar levels in people with diabetes can cause nerve damage, making it difficult for nerves to carry information or messages between the brain and every part of our body. Hyperglycemia contributes to diabetic neuropathy (Dneu) by producing advanced glycation end products (AGEs).¹⁴^,¹⁵ Various forms of DNeu include mononeuropathy, radiculopathy, autonomic neuropathy, cranial neuropathy, symmetric polyneuropathy.

Diabetic cardiomyopathy

Diabetic cardiomyopathy (DC) affects the myocardium in patients with diabetes, some structural disorders caused by DC include microvascular disease, hypertension, epicardial atherosclerosis, obesity, endothelial and autonomic dysfunction and left ventricular hypertrophy. Impairment in left ventricular systolic and diastolic function can cause heart failure in individuals with diabetes.¹⁶

Diabetic retinopathy

High blood sugar level damages the blood vessels in the retina. This disease is called diabetic retinopathy (DR), symptoms include blurriness, floaters, macular oedema, microaneurysms, cotton wool spots, hemorrhages, dark areas of vision and difficulty perceiving colors.¹⁷

Diabetic encephalopathy

Impairment/damage to neurochemical and structural changes leads to cognitive dysfunction causing a disorder called diabetic encephalopathy (DE) in people suffering from diabetes. There is increased risk of dementia observed in individuals with diabetes.¹⁸

Periodontal disease

Periodontitis is common among people suffering from diabetes. Clinical features of advanced periodontitis include gingival bleeding, recession, erythema and oedema. Individuals with Type II diabetes who have undergone periodontal treatment have improved blood sugar levels.¹⁹

Cellulitis

People suffering from diabetes are prone to develop diabetic foot ulcerations, which can progress into infections due to neuropathy, motor, and/or autonomic disturbances.²⁰

Musculoskeletal disorders

A variety of musculoskeletal conditions are prevalent among people with diabetes such as adhesive capsulitis, Dupuytren’s contracture, carpal tunnel syndrome, muscle infarction, and sclerodactyly.²¹

Infections

People with diabetes are susceptible to mucocutaneous fungal infections (e.g., oral and vaginal candidiasis), genitourinary infections, bacterial foot infections, gastrointestinal, respiratory infections, skin and soft tissue infections.²²

Non-alcoholic fatty liver disease

Individuals with type II diabetes are susceptible to non-alcoholic fatty liver disease. It can also occur in people with dyslipidemia, obesity, metabolic syndrome in the absence of DM.²³

Macrovascular disease

Studies have shown that macrovascular complications are associated with Type II diabetes. Symptoms are peripheral arterial disease, transient ischemic attacks and strokes, angina pectoris and myocardial infarction, cardiomyopathy, arrhythmias.²⁴

Erectile dysfunction

Erectile dysfunction (ED) is a sexual dysfunction in both men and women and is one of the long term complications of DM.²⁵

Gastroparesis

High blood glucose causes nerve damage in the body, one of the nerves that is damaged is the vagus nerve, it causes the muscles in the digestive tract and stomach not to function properly, as a result, it slows down the movement of food through the digestive system.²⁶

Alzheimer’s disease

Diabetes increases the risk of developing Alzheimer’s disease. In vitro and animal studies revealed that insulin resistance can lead to the pathogenesis of Alzheimer’s disease.²⁷

Depression and anxiety

Depression occurs more in individuals with diabetes, a number of risk factors have been identified as relevant for the occurrence of depression and diabetes such as lifestyle, low birth weight, obesity and adverse events in childhood.²⁸ Studies also revealed that people with DM had an increased risk of anxiety and eating disorders.²⁹^–³¹

Sarcoidosis

Sarcoidosis is an inflammatory granulomatosis that has the ability to affect any organ, most often the lungs in the human body. Studies revealed that diabetes is more prevalent in patients with sarcoidosis.³²

Cancer

Diabetes has been linked to various types of cancer including bladder cancer, liver cancer, gastrointestinal cancer, kidney cancer, pancreatic cancer, colorectal cancer, endometrial cancer, breast cancer and ovarian cancer.³³^–³⁶ Hyperglycemia increases the production of reactive oxygen species and downregulate antioxidant activity. Markers of inflammation, including secreted cytokines play a vital role in the link between cancer and diabetes. Hyperglycemia also contributes to systemic inflammation.³⁷^,³⁸

Sleep disturbance

Obstructive sleep apnea (OSA) occurs frequently in patients with diabetes. Findings revealed a link between OSA and Type II diabetes, where dysregulation of the autonomic nervous system leads to abnormal breathing pattern in patients with diabetes.³⁹^–⁴¹

Loss of workplace productivity

DM is reported to impact on productivity outcomes, studies revealed that DM is linked with, increased time off work, decreased productivity while at work and early dropout from the work force.⁴²^,⁴³

Management of diabetes

There are several strategies involved in the management of DM. Below are the modern approaches for diabetes management.

Lifestyle modification

Lifestyle modification plays an important role in diabetes management. Healthy diets (such as vegetables, whole grains, fruits, lean meats, non-fat dairy), exercises, increased physical activities, reduced sedentary lifestyle, total abstinence from alcohol, cigarettes, avoid or limit foods that are high in fat/sugar are some of the recommended lifestyle modifications that will help patients with diabetes.⁴⁴

Medical nutrition therapy (MNT)

MNT is an evidence-based nutrition therapy provided by a qualified dietician and can either be prescribed in a hospital or outpatient setting and involves a comprehensive assessment, nutritional diagnosis and treatment plan. MNT has been employed for the treatment of GDM.⁴⁵

Gene therapy

Gene therapy modifies human cells to treat a particular disease. It reconstructs or repair defective or damaged genetic material in the body. Gene therapy is a promising technique in the treatment of DM, gene therapy for DM focuses on Type I diabetes mellitus (TIDM). In TIDM, the absence of islets leads to insulin deficiency, which results in hyperglycemia, gene therapy employs viral and non-viral methods in the treatment of TIDM.⁴⁶

Gene editing

Gene editing is slightly different from gene therapy, it reprograms the body’s DNA or cut out the bad parts of the DNA. The focus of gene editing is to create islet cells, encapsulate them and implant them into the body. Encapsulated cells are safe from an immune response (beta cell attack) that people with TIDM experience. In a study, induced pluripotent stem cells produced from the skin of a patient with Wolfram syndrome were transformed into insulin producing cells, CRISPR-Cas9 (a gene-editing tool) was used to correct the genetic defect that caused the syndrome. The insulin producing cells were implanted into lab mice and cured diabetes in those mice.⁴⁷

Nanotechnology

Nanoparticles (<100 nm) are manufactured through the manipulation of individual atoms or molecules in a substance. Current issues for nanomedicine involve toxicity and environmental impact of nanoscale materials. The benefit of nanotechnology in diabetes includes non-invasive insulin delivery, beta cell mass, detection of immune cell activity, inventive diabetes diagnosis, and monitoring of glucose level.⁴⁸

Synthetic anti-diabetic agents

Management of DM involves the use of insulin and synthetic anti-diabetic agents such as biguanides and sulfonylureas. The functions of synthetic anti-diabetic agents used in the management of DM are shown in Table 2.

Table 2. Synthetic anti-diabetic agents used in the management of diabetes mellitus.

Drugs	Functions	References
Insulin	The beta cells of the pancreas are responsible for the production of insulin, which inhibits the production of glucose by the liver. Several insulin analogues are available e.g., aspart, lyspro, detemir and glargine.	⁴⁹^,⁵⁰
Sulfonylureas	It triggers the pancreas to produce and release more insulin, thereby reducing blood glucose levels. Examples include glimepiride, glipizide, glibenclamide, gliclazide, glyburide and chlorpropamide.	⁵¹
Biguanides	It reduces the production and release of glucose by the liver. There is also improvement in the activity of insulin in the body e.g., metformin.	⁵²
Thiazolidinediones	Enhances the activity of insulin in the body by increasing glucose uptake into liver, muscles and fat e.g., including pioglitazone, rosiglitazone, troglitazone and lobeglitazone.	⁵³
Alpha glucosidase inhibitors	It slows down the breakdown of carbohydrates and reduces the absorption of glucose from the gut, which in turn reduces blood glucose. Examples include acarbose, voglibose and miglitol.	⁵⁴
Dipeptidyl peptidase 4 (DPP-4) inhibitors	Stimulates the pancreas to produce insulin after meals. They also reduce the quantity of glucose released by the liver e.g., gemigliptin, alogliptin, saxagliptin, linagliptin and sitagliptin.	⁵⁵
SGLT2 inhibitors (also called sodium-glucose cotransporter 2 inhibitors)	Triggers the kidneys to clear blood glucose e.g., empagliflozin, canagliflozin and dapagliflozin.	⁵⁶
Bile acid sequestrants	Reduces the quantity of blood sugar and cholesterol level in the body e.g., colesevelam, colestipol, and cholestyramine.	⁵⁷
Dopamine agonist	Used in the treatment of Type II diabetes. An example is bromocriptine.	⁵⁸
Glinides (also called meglitinides)	Stimulates the pancreas to release insulin, which in turn reduces blood glucose e.g., nateglinide and repaglinide.	⁵⁹
GLP-1 analogues (also called incretin mimetics or glucagon-like peptide-1 receptor agonists)	Reduces the production of glucose by the liver, it also increases the release of insulin e.g., dulaglutide, exenatide, albiglutide, semaglutide and liraglutide.	⁶⁰
Tirzepatide	Used for the treatment of Type II diabetes. It targets the receptors of hormones such as GLP-1 (Glucagon-like peptide-1 receptor) and GIP (Glucose-dependent insulinotropic polypeptide). GLP-1 acts by stimulating insulin secretion and suppressing glucagon release during hyperglycemia, while GIP triggers glucagon release during hypoglycemia.	⁶¹

Medicinal plants with anti-diabetic properties

Several studies reported various side effects associated with the use of synthetic anti-diabetic drugs such as hypoglycemia, weight gain, vomiting, diarrhea, nausea, headache. Medicinal plants with anti-diabetic properties will be beneficial in the management of diabetes. The medicinal plants below have been reported to improve insulin sensitivity and act through various metabolic and cellular targets. Some active compounds present in the medicinal plants include: thyrotundin, tagitinin A, luteolin, multiflorine, sparteine, specioside, lapachol, verminoside, naringenin, monoterpene, sobrerol, nimbidiol, erythribyssin N, lophenol, cycloartanol, annonacin, reticuline, aculeatin borapetoside, quercetin, quercetin 3-O glycoside, methylswertianin, bellidifolin, aloin, aloe-emodin, amorfrutins, 5-bromo-8-(5-nitrosalicylideneamino) quinoline hydrochloride, protocatechuic acid, guavanoic acid, mangiferin, decursin, oleanolic acid, 2α-Hydroxyursolic acid, chlorogenic acid, procyanidin oligomers and ratanhiaphenol.⁶²^–⁶⁴ Table 3 shows the list of medicinal plants with reported anti-diabetic properties. Some work has already been performed on a limited number of these plants and it has been found that Abelmoschus moschatus improves insulin signaling transductions by modification of Serine/Threonine phosphorylation.⁶⁵ Insulin signaling is also improved by Artemisia herba-alba, which reduces insulin resistance, and by Astragalus membranaceus, which reduces the activity and expression of protein tyrosine phosphatase 1B (which dephosphorylates insulin receptor signaling proteins) in skeletal muscles.⁶⁶^,⁶⁷ Erythrina abyssinica has also been reported to inhibit PTP1B activity.⁶⁸ Cornus kousa also stimulates insulin signaling and glucose uptake through peroxisome proliferator-activated receptor gamma (PPAR $γ)$ activation as well as 5’ adenosine monophosphate-activated protein kinase (AMPK) activities.⁶⁹ Another plant that promotes glucose transport is Justicia adhatoda, which activates glucose transporter type 4 (GLUT-4) transporter and increases phosphatidylinositol 3-kinase (PI3-K) and Insulin receptor substrate 1 (IRS-1) levels.⁷⁰ Rehmannia glutinosa enhances the gene expression of resistin and also improves glucose consumption.⁷¹ Vigna unguiculata promoted Akt phosphorylation in rat skeletal muscles.⁷² In addition, Psidium guajava decreased the activity of hormone sensitive lipase (HSL) in adipose tissue and liver of diabetic rats.⁷³

Table 3. List of medicinal plants with anti-diabetic properties.⁷⁸^–⁹¹

No	Scientific names	Part of plant with anti-diabetic effect	Preparation
A.	Abelmoschus moschatus Abutilon indicum Abies balsamea Achyranthes aspera Achillea millefolium Aconitum napellus Ageratum conyzoides Ajuga decumbens Ajuga dictyocarpa Ajuga iva Ajuga nipponensis Ajuga pygmaea Ajuga taiwanensis Albuca setosa Allium sativum Amelanchier alnifolia Alnus incana Aloe vera Alpinia pricei Alyssum desertorum Amaranthus hybridus Amorpha fruticosa Anabasis articulata Anacyclus pyrethrum Ananas comosus Anemarrhena asphodeloides Angelica gigas Anvillea radiata Arctium lappa Artemisia afra Artemisia herba-alba Artemisia sphaerocephala Artocarpus heterophyllus Astragalus membranaceus Atractylis japonica Atriplex halimus Aucklandia lappa Avena sativa Averrhoa bilimbi Azadirachta indica	Inflorescence, leaves, seed, shoot, root, glumelle, fruit, bark	Acetone, butanol, ethanol, ethyl acetate extracts, boiled and steamed
B.	Belamcanda chinensis Berberis integerima Bidens pilosa Bombax ceiba Brachylaena discolour Brassica juncea Brassica oleracea Bumelia sartorum	Fruit, leaves, skin, whole plant and roots	Boiled and steamed
C.	Caesalpinia bonducella Cajanus cajan Calotropis gigantean Cannabis sativa Canna indica Capsicum annuum Caralluma tuberculata Carpobrotus edulis Carica papaya Catha edulis Catharanthus roseus Cayratia trifolia Cecropia obtusifolia Cerasus microcarpa Centaurium erythraea Centella asiatica Chrysanthemum fuscatum Cinnamomum cassia Cinnamomum verum Cistus salviifolius Citrus junos Citrus limon Citrus sinensis Citrullus colocynthis Cladonia rangiferina Cleome droserifolia Conyza scabrida Coriandrum sativum Coronilla varia Cornus kousa Cornus officinalis Crataegus aronia Crataegus oxycantha Crocus sativus Cryptolepis sanguinolenta Cucurbita maxima Curcuma comosa Cyclea peltata Cymbopogon citrates	Fruit, seed, skin, roots, leaves	Boiled and raw
D.	Dianthus thunbergii Dryopteris fragrans	Leaves, whole plant	Boiled and lyophilized
E.	Echinacea purpurea Elaeis guineensis Empetrum nigrum Enicostemma littorale Equisetum arvense Erythrina abyssinica Euclea natalensis Euclea undulata Euryale ferox	Leaves, roots, stem bark, vegetative and reproductive parts	Boiled
F.	Ferula assa-foetida Ficus carica Ficus deltoidea	Leaves	Boiled, lyophilized, ethanol or methanol extracts
G.	Ganoderma lucidum Garcinia buchananii Gastrodia elata Gaultheria hispidula Gleditsia sinensis Glycyrrhiza foetida Gongronema latifolium Grewia flavescens Guazuma ulmifolia Gynandropsis gynandra	Leaves, roots, stem bark	Soaked in water and lyophilized
H.	Hedysarum polybotrys Helichrysum odoratissimum Helichrysum nudifolium Helichrysum petiolare Helianthus tuberosus Hypericum attenuatum Hypoxis colchicifolia Hypoxis hemerocallidea Hyoscyamus albus Helicteres isora	Leaves	Boiled and lyophilized
I.	Ilex hunanensis Indigofera arrecta	Leaves	Boiled in water, ethanol extract
J.	Juglans regia Juniperus communis Justicia adhatoda Justicia spicigera	Fruit, leaves and skin	Boiled in water
K.	Kalmia angustifolia Kigelia africana Kigelia pinnata Krameria lappacea	Leaves	Water, methanol or petroleum ether extracts
L.	Lagerstroemia speciosa Lamium album Larix laricina Leonotis leonorus Leonotis ocymifolia Lessertia microphylla Leymus mollis Lindera aggregata Litsea coreana Lycium barbarum Lycopodium clavatum Lyophyllum decastes.	Leaves, roots	Boiled and lyophilized
M.	Malva parviflora Mangifera indica Magnolia dealbata Marantodes pumilum Marrubium vulgare Momordica charantia Momordica foetida Moringa oleifera	Leaves, seeds	Boiled, ethanol extract
N.	Nasturtium officinalis Nepeta bracteate Nepeta meyeri Nigella sativa Nyctanthes arbortristis	Leaves, root	Boiled and steamed
O.	Olea europaea Ophiopogon japonicas Opuntia dillenii Oxalis corniculata	Leaves	Boiled in water
P.	Panax ginseng Papaver rhoeas Passiflora nitida Persea americana Phellodendri cortex Picea glauca Picea mariana Pinus banksiana Pistacia lentiscus Polygonum aviculare Pongamia pinnata Populus balsamifera Prosopis glandulosa Prunus mume Prunus persica Psacalium peltatum Psidium guajava Pterocarpus marsupium Pueraria thomsonii Punica granatum	Leaves, seed, roots	Boiled in water
R.	Rehmannia glutinosa Rhodiola crenulate Rhododendron groenlandicum Rhododendron tomentosum Rhus coriaria Rosa foetida Rosa hybrid Rumex sculantus	Fruit, leaves	Boiled or raw
S.	Salix planifolia Salvia nemorosa Sambucus nigra Sanguisorba minor Saponaria officinalis Sarracenia purpurea Scoparia dulcis Schkuhria pinnata Schisandra chinensis Senna italica Sesbania sesban Smallanthus sonchifolius Solanum aculeastrum Solanum aethiopicum Solanum indicum Solanum melongena Solenostemma argel Sophora alopecuroides Sorbus decora Spergularia purpurea Sphagnum fuscum Steganotaenia araliacea Stevia rebaudiana Suaeda fruticose Sutherlandia frutescens Swertia punicea Symplocos cochinchinensis Syzygium cumini Syzygium jambo Syzygium mundagam Syzygium samarangense	Fruit, leaves, whole plant, roots, flowering offshoot, seeds	Boiled, chloroform, ethanol, methanol, hexane, petroleum ether extracts.
T.	Tarchonanthus camphoratus Tecoma stans Terminalia arjuna Tetrastigma obtectum Teucrium cubense Teucrium orientale Teucrium polium Tinospora cordifolia Tinospora crispa Tinospora fragosa Tithonia diversifolia Toddalia asiatica Trifolium pratense Trifolium purpureum Trigonella foenum-graecum	Leaves, bark, roots, stem	Boiled, ethyl acetate, methanol and petroleum ether extracts
U.	Urtica dioica	Seed	Boiled
V.	Vaccinium myrtillus Vaccinium vitis-idaea Vaccinium angustifolium Vaccinium macrocarpon Vaccinium uliginosum Vatairea macrocarpa Vernonia colorata Vernonia amygdalina Vernonia oligocephala Vigna unguiculata	Leaves, seed	Boiled in water, methanol or ethanol extracts.
X.	Xanthium strumarium	Leaves	Water, ethanol extract
Z.	Zanthoxylum armatum Ziziphus mucronata Zingiber officinale Ziziphus spina-christi	Bark, fruit, leaves, roots	Water, methanol or ethyl acetate extracts

Several plants influence glucose production in the liver, including Artemisia sphaerocephala, which increases liver glycogen and glucokinase and reduces accumulation of fat in the liver; Malva parviflora, which restores glucose-6-phosphatase, glucokinase and hexokinase activities in liver. Bumelia sartorum inhibits glycogenolysis in the liver and increases glucose uptake in skeletal muscle, while Nigella sativa reduces the activities of enzymes involved in the neoglucogenesis pathway in the liver and Stevia rebaudiana reduces the expression of phosphoenolpyruvate kinase enzyme thereby inhibiting the production of glucose by the liver.⁷⁴

Selected tyrosine sites on receptor substrates are phosphorylated, thereby activating pathways leading to increased protein synthesis, glycogen synthesis, glucose uptake and lipogenesis. Phellodendri cortex reduces tyrosine dephosphorylation and enhances tyrosine phosphorylation, which will aid in the management of diabetes. Intracellular calcium (Ca²⁺) is the primary signal that stimulates insulin exocytosis by glucose, other cell signals activated by glucose that are involved in this process, are cyclic adenosine monophosphate (cAMP) and inositol 1,4,5-trisphosphate (IP3), cAMP may be the most important one for increasing insulin secretion. Studies revealed that Ziziphus spina-christi increases serum pyruvate level and pancreatic c-AMP levels while Vaccinium angustifolium reduces the plasma concentrations of C-reactive protein, interleukin-6 and tumor necrosis factor-α.⁷⁵^–⁷⁷

Toxicity

The degree of medicinal plant toxicity depends on several factors such as method of extraction, species, dosage, route of administration and victim susceptibility. Human organs and systems are affected by some toxic compounds from plants. The toxicity properties of plants in this review have been reported. Findings revealed that the seed of Erythrina abyssinica are traditionally known to be poisonous, at high doses, it may cause paralysis, anesthesia and even death by respiratory failure.⁹² The fruit and leaf extracts of Annona muricata (106 mg/kg body weight) given to rats intravenously for 28 days showed acute neurotoxicity in rats.⁹³ Phytochemicals such as annonacin and anthraquinones in Annona muricata and Aloe vera, respectively, have also been reported for their toxicity.⁹⁴^,⁹⁵

Conclusions

As presented in this review, a search for medicinal plants and natural products with anti-diabetic properties will be useful in the management of this disease. Given the complications associated with DM, steps must be taken to increase the awareness of emerging complications, synthetic anti-diabetic agents and medicinal plants used in the management of this disease. Further studies are required to determine the mechanism of action, identify and isolate bioactive compounds in some of these medicinal plants. In addition, studies are needed to guarantee the safety/toxicity of the long term consumption of these medicinal plants in people with diabetes.

Data availability

No data are associated with this article.

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¹ Department of Biological Sciences, Faculty of Arts and Science, University of Lethbridge, Lethbridge, Alberta, Canada
² Department of Microbiology and Biochemistry, Faculty of Natural and Agricultural Sciences, University of the Free State, Bloemfontein, Free State, South Africa

Toluwani Tella
Roles: Conceptualization, Data Curation, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing

Carolina Pohl
Roles: Project Administration, Resources, Writing – Review & Editing

Kovalchuk Igor
Roles: Data Curation, Investigation, Project Administration, Resources, Writing – Review & Editing

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No competing interests were disclosed.

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The author(s) declared that no grants were involved in supporting this work.

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Tella T, Pohl C and Igor K. A review on diabetes mellitus: complications, synthetic anti-diabetic agents and herbal treatment [version 1; peer review: 1 approved with reservations]. F1000Research 2024, 13:124 (https://doi.org/10.12688/f1000research.141015.1)

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Reviewer Report 22 Aug 2024

Pranav Kumar Prabhakar, Research and Development Cell, Parul University, Vadodara, Gujarat, India

Approved with Reservations

https://doi.org/10.5256/f1000research.154426.r289684

The title accurately reflects the content of the manuscript. However, consider specifying the scope of the review, such as including "A Comprehensive Review" to emphasize the depth of coverage.
The content specially the management section need to elaborate in ... Continue reading

The title accurately reflects the content of the manuscript. However, consider specifying the scope of the review, such as including "A Comprehensive Review" to emphasize the depth of coverage.
The content specially the management section need to elaborate in detail. The mechanism of action of the plants will increase the strength of the paper. Currently the paper looks like preliminary data. It need to be reworked in detail. The merits and demerits of using herbal druhs, their dosing and toxicity studies need to documented properly.

Is the topic of the review discussed comprehensively in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

References

1. Prabhakar PK, Doble M: A target based therapeutic approach towards diabetes mellitus using medicinal plants.Curr Diabetes Rev. 2008; 4 (4): 291-308 PubMed Abstract | Publisher Full Text
2. Prabhakar PK, Doble M: Mechanism of action of natural products used in the treatment of diabetes mellitus.Chin J Integr Med. 2011; 17 (8): 563-74 PubMed Abstract | Publisher Full Text
3. Grover J, Vats V: Shifting Paradigm: From Conventional to Alternative Medicines — An Introduction on Traditional Indian Medicines. Asia-Pacific Biotech News. 2001; 05 (01): 28-32 Publisher Full Text

Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Pranav Kumar Prabhakar, Parul University, Vadodara, India

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22 Aug 2024 | for Version 1

Pranav Kumar Prabhakar, Research and Development Cell, Parul University, Vadodara, Gujarat, India

5 Views Cite this report Responses(0)

Approved With Reservations

The title accurately reflects the content of the manuscript. However, consider specifying the scope of the review, such as including "A Comprehensive Review" to emphasize the depth of coverage.
The content specially the management section need to elaborate in detail. The mechanism of action of the plants will increase the strength of the paper. Currently the paper looks like preliminary data. It need to be reworked in detail. The merits and demerits of using herbal druhs, their dosing and toxicity studies need to documented properly.

Is the topic of the review discussed comprehensively in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

References

1. Prabhakar PK, Doble M: A target based therapeutic approach towards diabetes mellitus using medicinal plants.Curr Diabetes Rev. 2008; 4 (4): 291-308 PubMed Abstract | Publisher Full Text
2. Prabhakar PK, Doble M: Mechanism of action of natural products used in the treatment of diabetes mellitus.Chin J Integr Med. 2011; 17 (8): 563-74 PubMed Abstract | Publisher Full Text
3. Grover J, Vats V: Shifting Paradigm: From Conventional to Alternative Medicines — An Introduction on Traditional Indian Medicines. Asia-Pacific Biotech News. 2001; 05 (01): 28-32 Publisher Full Text

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Respond to this report

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[16] 16. Paolillo S, Marsico F, Prastaro M, et al.: Diabetic Cardiomyopathy: Definition, Diagnosis, and Therapeutic Implications. Heart Fail. Clin. 2019; 15: 341–347. Publisher Full Text

[17] 17. Xu H, Curtis T, Stitt A: Pathophysiology and Pathogenesis of Diabetic Retinopathy. Diapedia. 2014; 7104343513(14). Publisher Full Text

[18] 18. Chun W, Juan L, Shidi Z, et al.: Diabetic encephalopathy causes the imbalance of neural activities between hippocampal glutamatergic neurons and GABAergic neurons in mice. Brain Res. 2020; 1742: 146863. Publisher Full Text

[19] 19. Preshaw PM, Alba AL, Herrera D, et al.: Periodontitis and diabetes: a two-way relationship. Diabetologia. 2012; 55: 21–31. PubMed Abstract | Publisher Full Text | Free Full Text

[20] 20. Khan MJ: Complications of Cellulitis in Diabetic Foot Infections. US Pharmacist. 2011; 36: 63–66.

[21] 21. Sözen T, Başaran NÇ, Tınazlı M, et al.: Musculoskeletal problems in diabetes mellitus. Eur. J. Rheumatol. 2018; 5: 258–265. PubMed Abstract | Publisher Full Text | Free Full Text

[22] 22. Zhou K, Lansang MC: Diabetes Mellitus and Infections.Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc; 2021. Reference Source

[23] 23. Hazlehurst JM, Woods C, Marjot T, et al.: Non-alcoholic fatty liver disease and diabetes. Metab. 2016; 65: 1096–1108.

[24] 24. Viigimaa M, Sachinidis A, Toumpourleka M, et al.: Macrovascular Complications of Type 2 Diabetes Mellitus. Curr. Vasc. Pharmacol. 2020; 18: 110–116. Publisher Full Text

[25] 25. Defeudis G, Mazzilli R, Tenuta M, et al.: Erectile dysfunction and diabetes: A melting pot of circumstances and treatments. Diabetes Metab. Res. Rev. 2022; 38: e3494. Publisher Full Text

[26] 26. Owyang C: Phenotypic Switching in Diabetic Gastroparesis: Mechanism Directs Therapy. Gastroenterology. 2011; 141: 1134–1137. Publisher Full Text

[27] 27. Nguyen TT, Ta QTH, Nguyen TKO, et al.: Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. Int. J. Mol. Sci. 2020; 21(9): 3165. PubMed Abstract | Publisher Full Text | Free Full Text

[28] 28. Sartorius N: Depression and diabetes, Dialogues. Clin. Neurosci. 2018; 20: 47–52.

[29] 29. Grigsby AB, Anderson RJ, Freedland KE, et al.: Prevalence of anxiety in adults with diabetes a systematic review. J. Psychosom. Res. 2022; 53: 1053–1060.

[30] 30. Smith KJ, et al.: Association of diabetes with anxiety: a systematic review and meta-analysis. J. Psychosom. Res. 2013; 74: 89–99. PubMed Abstract | Publisher Full Text

[31] 31. Young V, et al.: Eating problems in adolescents with type1 diabetes: a systematic review with meta-analysis. Diabet. Med. 2013; 30: 189–198. PubMed Abstract | Publisher Full Text

[32] 32. Benmelouka AY, Abdelaziz A, Ahmed SEM, et al.: Association between sarcoidosis and diabetes mellitus: a systematic review and meta-analysis. Expert Rev. Respir. Med. 2021; 15: 1589–1595. PubMed Abstract | Publisher Full Text

[33] 33. Anothaisintawee T, et al.: Risk factors of breast cancer: a systematic review and meta-analysis. Asia-Pac. J. Public Health. 2013; 25: 368–387. Publisher Full Text

[34] 34. Jiang Y, et al.: Diabetes mellitus and incidence and mortality of colorectal cancer: a systematic review and meta-analysis of cohort studies. Eur. J. Epidemiol. 2011; 26: 863–876. PubMed Abstract | Publisher Full Text

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A review on diabetes mellitus: complications, synthetic anti-diabetic agents and herbal treatment

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Types of diabetes mellitus

Table 1. Types of diabetes mellitus and their clinical features.

Complications associated with diabetes mellitus

Management of diabetes

Table 2. Synthetic anti-diabetic agents used in the management of diabetes mellitus.

Table 3. List of medicinal plants with anti-diabetic properties.78–91

Toxicity

Conclusions

Data availability

References

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Table 3. List of medicinal plants with anti-diabetic properties.⁷⁸^–⁹¹