Roles of Alkaloids from Medicinal Plants in the Management of Diabetes Mellitus

Medicinal plants play a fundamental part in health sectors via the management of different infectious diseases because of their wide plenitude wellspring of bioactive phytochemicals. Research activities on them have got attention throughout the world in the present days in search of low-cost and safe compounds for the management of diabetes. )is is the literature-based analysis of alkaloids from medicinal plants in preventive or treatment approaches to diabetes. )e most abundant and diversified group of secondary metabolites, i.e., alkaloids, show antidiabetic activity through the inhibition of enzymes (α-amylase, α-glucosidase, aldose reductase, dipeptidyl peptidase-IV, and protein tyrosine phosphatase-1B); inhibition of advanced glycation end products; increment of insulin secretion and its sensitivity; enhancement of glucose uptake; and their antioxidant ability. )e study is useful for the examination of dynamic alkaloids for the advancement of a new medication for mankind.


Introduction
Diabetes mellitus (DM) is an endocrine disorder characterized by hyperglycemia characterized with fasting blood glucose level ≥7.0 mM (126 mg/dL) [1][2][3] caused mainly due to insulin deficiency or insensitivity or inefficiency of disturbing the metabolism of ingested foods, i.e., carbohydrates, fats, and proteins. It is a major public health concern among people, and its prevalence rate is anticipated to be 4.4% in 2030 [4]. Blood glucose level is increased by the action of digestive enzymes on ingested food [5]. If hyperglycemia is not treated, it leads to major complications such as cardiovascular diseases, nerve damage, retinopathy, and nephropathy [6]. According to the ninth edition of the International Diabetes Federation (IDF) report, 463 million adults (20-79 years) of the world lived with diabetes in 2019 and this frequency is estimated to reach 578 million by 2023 and 700 million by 2045 [7].
Among the several types of DM, type 2 accounts for the majority (about 90%) of diabetes cases. Type 2 DM is characterized by impaired insulin secretion and insulin resistance [8] due to impaired function of β-cells of the islet of Langerhans involving the loss of pulsatility, biphasic nature of insulin secretion, decrease in sensitivity to glucose, and decrease in cell masses. In 2017, 657.2 thousand adults were with diabetes and 11,693 died with diabetes-related complications in Nepal [9] which reached 696.9 thousand with a national prevalence of 4% in 2019 [7]. IDF showed about 12% of global health expenditure was spent on diabetes management, which is a huge loss on the economy [10], and the burden is expected to skyrocket in near future.
Various strategies such as diets, medications, and exercises have been carried out to control blood glucose levels and minimize the life-threatening complications of diabetes [11] depending on numerous factors such as the rate of nutrient uptake, action of digestive enzymes on nutrients food items, activity of insulin, and responses of tissues to insulin [12]. α-Glucosidase inhibitors (acarbose, miglitol, and voglibose), biguanides (metformin), insulin secretagogue sulfonylureas (gliclazide, glimepiride, and glyburide), insulin secretagogue nonsulfonylureas (repaglinide and nateglinide), dipeptidyl peptidase-IV (DPP-IV) inhibitor (sitagliptin and saxagliptin) insulin sensitizers or thiazolidinediones (rosiglitazone and pioglitazone), and intestinal lipase inhibitor (orlistat) have been used as orally administered antihyperglycemic agents ( Figure 1) for the treatment of DM [13,14].
Commercial α-glucosidase inhibitors were reported to have several problems such as abdominal distention, meteorism, bloating, and diarrhea [13]. In addition to these, sulfonylureas: hypoglycemia, mild headaches, increased food intake, weight gain, and increased risk of cardiovascular diseases [12]; biguanides: gastrointestinal issues, metallic taste, impairment of vitamin B12 and B9 absorption, lactic acidosis, and hypoglycemia in combination therapy [15][16][17]; thiazolidinediones: anemia, insomnia, headache, dizziness, weight gain, visual disturbances, impotence, fatigue, hepatotoxicity, weight gain, fluid retention, congestive heart failure, and bone fractures [15,18]; incretin mimetics: nausea, vomiting, and diarrhea; incretin-enhancing DPP-IV inhibitors: increased risk of infection and headache; and sodium-glucose cotransporter protein (SGLT-2) inhibitors: increased risk of urinary tract infections and ketoacidosis have the side effects [15]. DM can be managed by different mechanisms of actions such as stimulating β-cells to release insulin, increasing the appetency and sensitivity of insulin receptor site, resisting the digestive enzymes involved in the digestion of carbohydrates, enhancing the glucose uptake in the tissues and organs, clearing away free radicals, resisting lipid peroxidation, and limiting the metabolic disorder of lipids and proteins [19]. About four billion people from the world depend on herbal products directly and indirectly [20] for healthcare with a 15% annual increase [21] in the global economy. A possible synergistic work of different phytochemicals present in plant extract attracts public interest in herbal medicines [20]. More than 1200 plant species are reported as antidiabetic potent [15] and are the promising reservoirs of structurally diverse bioactive compounds. Here, medicinal plant-based alkaloids with potential antidiabetic activities were discussed.

Alkaloids with Antidiabetic Activities along with the Mechanism of Action
Alkaloids are nitrogen (in the form of a primary, a secondary, or a tertiary amine)-containing, low-molecularweight, diverse, basic chemical compounds found in bacteria, fungi, plants, and animals; however, their conveyance inside each kingdom is very restricted [22]. Alkaloids can occur as monomers, dimers, trimers, or tetramers which may be either homo-oligomers or hetero-oligomers. ey are classified based on the chemical structure (heterocyclic/ nonheterocyclic) and biological or natural origin (specific sources). Roughly 20% of plant species [23] are the source of these secondary metabolites with significant bioactivities that fill in as a rich supply for drug disclosure. Around 12,000 alkaloids have been assessed from plants with various pharmaceutical importance [23]. Figure 2 shows the overall mechanism of the antidiabetic activity of alkaloids from medicinal plants.

Inhibition of Aldose Reductase and Protein Tyrosine
Phosphatase-1B. Aldose reductase (AR), a key enzyme in the polyol pathway, catalyzes glucose reduction to sorbitol, leading to the overproduction of reactive oxygen species (ROS) [36]. AR transforms cytosolic glucose into sorbitol, a molecule that poorly penetrates cell membranes and is sometimes slowly metabolized. Hyperglycemia can cause intracellular accumulation of sorbitol and its metabolite, fructose, which can create osmotic swelling and cell dysfunction [37]. Under the normal glycemic condition, it plays a role in detoxifying harmful aldehyde in extrahepatic tissue, production of fructose for sperm, osmoregulatory balance in the kidney, and reduction of steroids and catecholamines [38]. In hyperglycemic conditions, various complications appear because of excessive polyol metabolism, which leads to elevating the sorbitol level and osmotic stress prominent to cataractogenesis [39][40][41]. Additionally, it causes glycative stress, and binding with the receptors increases ROS [4,5]. Prevention or delay of such complications has been suggested using AR inhibitors [42]. In recent years, compounds with both antioxidant and AR inhibitory activities in diabetes have drawn the attention of scientific communities in managing diabetes [43]. Epiberberine, coptisine, and groenlandicine ( Figure 4) isolated from the rhizome of Coptis chinensis Franch showed the antidiabetic activity with the IC 50 of 100.07 ± 0.63, 118.36 ± 0.78, and 140.13 ± 6.50 µM for rat lens AR and 168.10 ± 05.51, 187.27 ± 10.03, and 154.19 ± 07.17 µM for human recombinant AR [44]. e dioxymethylene group and its oxidized form in the D and A ring of protoberberinetype alkaloids are responsible for the AR inhibitory activities [44].
Nonetheless, Coptis japonica root-derived alkaloids, i.e., berberine chloride, berberine sulfate, berberine iodide, palmatine sulfate, and palmatine iodide, showed an inhibitory activity towards AR with an IC 50 of 13.98, 13.45, 32.84, 51.78, and 51.78 nM, respectively [45]. Jatrorrhizine, palmatine, and magnoflorine ( Figure 4) are isoquinoline alkaloids from Tinospora cordifolia stem which inhibited the male Wistar rats lens AR with an IC 50 of 3.23, 3.45, and 1.25 µg/mL, respectively [46]. e protein tyrosine phosphatase-1B (PTP-1B) is involved in multiple signal transduction pathways as it is present in multiple tissues including the skeletal muscle, liver, adipose tissue, and brain [47]. It acts as a negative regulator of insulin as well as leptin signaling, and hence, inhibition of its activity helps in the treatment of diabetes and related complications. Inhibition of PTP-1B results in the enhancement of insulin receptor and insulin receptor substrates 1 and 2 phosphorylation which causes an increase in glucose uptake [15].

Increasement of Insulin Secretion.
e α-cells and β-cells of pancreatic islets of Langerhans secrete glucagon and insulin, respectively, that exert antagonistic effects on peripheral organs to control blood glucose levels. Insulin lowers the glucose levels by stimulating glucose uptake in skeletal muscle via inhibiting hepatic glucose production and by dulling lipolysis. In contrast, glucagon increases blood glucose levels by increasing gluconeogenesis and lipolysis [51]. e two incretin hormones, namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin tropic polypeptide (GIP), stimulate insulin release in healthy individuals in response to ingested meals [52]. GLP-1 produced by the proglucagon gene in L-cells of the small intestine stimulates insulin biosynthesis and secretion reduces glucagon levels reduces appetite, decreases glucagon release, decelerates gastric emptying, and regeneration and differentiation of the pancreatic islet β-cells in response to meals [53,54]. e GIP secreted from K cells (gip gene) of the upper small intestine is broadly engaged with glucose digestion by enhancing the insulin discharge [52,55]. Additionally, it is involved in the metabolism of fats in adipocytes, stimulates lipoprotein lipase activity, controls fatty acid synthesis, and promotes β-cell proliferation and cell survival [56,57]. Due to the action of DPP-IV, GLP-1 and GIP have extremely short half-lives, i.e., 1-2 min for GLP-1 and 4 min for GIP. Inhibiting DPP-IV improves glucose homeostasis due to delays in the activity of GLP-1 and GIP [54]. Various investigations have uncovered that DPP-IV inhibition helps in the increment of β-cell capacity, physiology, and mass through incretin release which influences a constant arrival of insulin after ingestion of food to bring down glucose levels [56,58].
Lupanine, 13-hydoxy-lupanine, and 17-oxo-lupanine (Figure 4) are the quinolizidine alkaloids from Lupinus species that are capable of animating insulin secretion in a glucose-dependent manner [59]. rough the inhibition of ATP-sensitive potassium channel current and enhancement of the expression of insulin-secreting genes, lupanine improves insulin secretion [59,60]. Trigonelline from Trigonella foenum graecum and Mirabilis jalapa L. exhibits antidiabetic activity via incensement of insulin sensitivity [61,62]. Additionally, palmatine and berberine (Figure 4) showed the antidiabetic activity with the inhibition of DPP-IV with an IC 50

Antioxidant Activity.
Hyperglycemia results in oxidative stress and, hence, causes micro-and macrovascular complications [71]. Antioxidant therapy in diabetes helps to lower the complications of diabetes [71,72]. Antioxidants respond to reactive radicals by accepting or donating electron(s) or by declining the formation of free radicals through the hindrance of activities or expressions of free radical-generating enzymes or by upgrading the activities and expressions of enzymes responsible for the production of antioxidants [73].
3.6. Enhancement of Glucose Uptake. Excessive exercise helps in the management of diabetes by translocation of glucose transporter 4 (GLUT-4) [74]. Different alkaloids from medicinal plants are reported with the ability to increase glucose uptake. Vindolicine III (Figure 4) from Catharanthus roseus (L.) G. Don was reported to be involved in glucose uptake in β-TC6 and C2C12 cells as well by the antioxidant activity compared to vindoline I, vindolidine II, and vindolinine IV ( Figure 4) proving to be useful in the management of hyperglycemia [75]. Similarly, vindogentianine from the same plant induces the significant glucose uptake in β-TC6 pancreatic and C2C12 muscle cells [32].

Conclusions
Nowadays, plant-based natural products are broadly utilized in the management of different infections for the improvement of the life span. Natural products contain different metabolites, especially alkaloids that act differently against infectious diseases and accomplished the medical services decreasing the side effects. Although numerous in vitro and in vivo assays have shown alkaloids are good candidates, very few or none of the bioactive compounds have reached the clinical trials. e bioactivity of pure compounds alone and in combination resulting in synergistic effects needs to be properly evaluated. Alkaloids with diverse roles in the management of diabetes need to be further assayed to develop them as ultimate drug candidates or food supplements.
Data Availability e data are available upon request.

Conflicts of Interest
e author declares no potential conflicts of interest.

Authors' Contributions
B.A designed the concept, performed the literature surveys, prepared the draft, and revised the manuscript.