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.

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}

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.

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

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 (Ca ²⁺) 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}

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}