Molecules Isolated from Mexican Hypoglycemic Plants: A Review

Like in many developing countries, in Mexico, the use of medicinal plants is a common practice. Based on our own field experience, there are at least 800 plants used for treating diabetes nowadays. Thus, their investigation is essential. In this context, this work aims to provide a comprehensive and critical review of the molecules isolated from Mexican hypoglycemic plants, including their source and target tested. In the last few years, some researchers have focused on the study of Mexican hypoglycemic plants. Most works describe the hypoglycemic effect or the mechanism of action of the whole extract, as well as the phytochemical profile of the tested extract. Herein, we analyzed 85 studies encompassing 40 hypoglycemic plants and 86 active compounds belonging to different classes of natural products: 28 flavonoids, 25 aromatic compounds, other than flavonoids, four steroids, 23 terpenoids, 4 oligosaccharides, and 1 polyalcohol. These compounds have shown to inhibit α-glucosidases, increase insulin secretion levels, increase insulin sensitivity, and block hepatic glucose output. Almost half of these molecules are not common metabolites, with a narrow taxonomic distribution, which makes them more interesting as lead molecules. Altogether, this analysis provides a necessary inventory useful for future testing of these active molecules against different hypoglycemic targets, to get a better insight into the already described mechanisms, and overall, to contribute to the knowledge of Mexican medicinal plants.


Introduction
Diabetes mellitus is a long-term condition that occurs when there are high glucose levels in a person's blood because their body cannot produce any or enough insulin or cannot effectively use the insulin it produces. Type 2 diabetes (T2D), due to a progressive loss of adequate β-cell insulin secretion frequently on the background of insulin resistance [1], accounts for nearly 90% of cases. The International Diabetes Federation estimated 463.0 million people living with T2D worldwide, Mexico ranks in sixth place, with 12.8 million diabetics [2]. Due to the idiosyncrasy of the Mexican population, normally, type 2 diabetic patients mainly in the rural areas of the country use a combination of medicinal plants and prescribed medicines [3]. In Mexico, at least 300 plants have been reported as hypoglycemics [4] but based on our own field experience [5,6], we estimate that at least 800 plants are used nowadays for treating diabetes.
Medicinal plants have been a resource for healing in local communities around the world. Still, 85% of the world's population depends on plants for primary healthcare [7]. In addition, they are an important resource for drug discovery, with 80% of all synthetic drugs deriving from them [8]. It is important to remark that medicinal plants can lead us to the discovery of new molecules useful for the development of new drugs for treating T2D and its complications.
Diverse strategies are utilized for control T2D; first, a combination of diet and exercise is in order; then, patients are prescribed oral hypoglycemic agents, initially a single drug, and later, a combination of two or more drugs. Patients can remain with exercise, diet, and oral hypoglycemic agents for a long time, providing they follow a healthy lifestyle. When this does not happen, they receive an oral hypoglycemic, first as monotherapy and then as a combination; if this does not control the blood glucose levels then external insulin is prescribed. The starting point for living well with diabetes is an early diagnosis, the longer a person lives with undiagnosed and untreated diabetes, the worse their health outcomes are likely to be. The World Health Organization (WHO) recommends a series of cost-effective interventions to improve patient outcomes. These interventions include blood glucose control through diet, physical activity, and, if necessary, medication [9]. While the American Diabetes Association (ADA) remarks that lifestyle changes such as dietary modification and increased physical activity can be very effective in improving glycemic control, over the long-term, most individuals with T2D will require medications to achieve glycemic control [10].
Until the beginning of the 1990s, sulfonylureas and metformin were the essential oral hypoglycemic agents available. Since then, new therapeutic agents have appeared in the pharmaceutical market. For example, acarbose, an alfa glucosidase inhibitor (AGI), was launched in Germany in 1990; the thiazolidinediones (TZD) insulin sensitizers, in 1996; exenatide, a glucagon-like peptide 1 (GLP1) receptor agonist, in 2005; sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in 2006; and canagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, in 2013 [11]. All these compounds have targets never described before. Acarbose and exenatide are natural products; other AGIs derive from natural products while metformin and canagliflozin are inspired by natural products. New targets to control hyperglycemia continuously appear, as we understand better the pathophysiology of T2D.
The research of traditional medicine can lead us to the discovery of new hypoglycemic compounds, associated with the traditional use of the plant. From an ethnopharmacological perspective, it is a start line to prove molecules isolated from plants traditionally used to treat T2D, although it is an intrinsically complex task demanding a highly sophisticated multidisciplinary approach.
In the last few years, some researchers have focused on the study of Mexican hypoglycemic plants. Most works describe the hypoglycemic effect or the mechanism of action of the whole extract, as well as the phytochemical profile of the tested extract. In the best of the cases, molecules are isolated from organic extracts but not tested against specific targets.
This work aims to provide a comprehensive and critical review of the molecules isolated from Mexican hypoglycemic plants. The studies analyzed included those reporting the hypoglycemic effect (i.e., any effect useful for potentially treating diabetes, in vivo or in vitro) of Mexican medicinal plants, and which possess at least one compound related to this activity. This review will be useful to construct a database useful for future testing of these molecules against different hypoglycemic targets.
In vivo: WE: AHT, OGTT, and OSTT in healthy and STZ-treated mice using half-log interval doses (31.6, 100, and 316.2 mg/kg of bw of the extract and 3.2, 10, and 31.6 mg/kg of bw of compounds for all experiments) [13].

55
Could prevent functional changes in vascular reactivity in diabetic rats through nitric oxide-and no prostaglandin-dependent pathways [110].
In vivo: WE tested in OSTT (100, 300, and 500 mg/kg of bw) in healthy rats. The dose of 20 for OSTT was 50 mg/kg of bw).
20 ( In vivo: WE and BE assayed in AHT (7 and 13, 8 and 16 mg/kg of bw for WE and BE, respectively) in STZ-treated rats. WE tested in AHT (330 mg/kg of bw) in type 2 diabetic patients. BP: Glucose, TG, cholesterol, and glycated hemoglobin. OMTT (96 mg/kg of bw) and PTT (330 mg/kg of bw) in STZ-treated rats. Dose not reported for 62 in AHT.
70 Acts as hypoglycemic and anti-obesity agent mainly through reducing the absorption of glucose, decreasing endogenous glucose production, increasing insulin sensitivity, improving lipid homeostasis, and weight regulation [111].
In vivo: EWE and WE tested in AHT (30 and 300 mg/kg of bw, and 60 and 600 mg/kg of bw for EWE and WE, respectively) in STZ-NA-treated rats. ME assayed in CHT (35, 75 and 150 mg/kg of bw) in healthy and STZ-treated rats [53,54]. In vitro: Y-AG for ME (IC 50 = 78.3 µg/mL). 112 Exhibits significant potential as an antidiabetic agent by suppressing the progression of type 2 diabetic states that is suggested by attenuation of hepatic glucose output and enhancement of adipocyte glucose uptake, insulin secretion, and antioxidant capacity [112]. 113 improves insulin sensitivity in high fat diet-fed mice and inhibits AG [113,114]. In vivo: extracts tested in AHT in healthy and alloxan-treated mice (ip administration; the doses of WE were 150, 300, 600, and 850mg/kg of bw; dose for J, DE, and ME: 300 and was 600 mg/kg of bw). WE: Tested in a murine model of obesity and hyperglycemia, induced by a high-calorie diet; the relationship of these effects with hepatic oxidation were observed. In vitro: WE was assayed for glucose uptake in insulinsensitive, and insulin-resistant murine and human cultured adipocytes; both in the absence or the presence of insulin signaling pathway inhibitors, and on murine and human adipogenesis [60][61][62][63][64].
In vivo: EE tested in OSTT (100 mg/kg of bw) in healthy and STZ-NA-treated rats. Effect on the glucose uptake in insulin-sensitive and insulin-resistant murine 3T3-F442A and human subcutaneous adipocytes [66].

169
169 Induces hypoglycemic effect in normal and in alloxan-induced diabetic rats; inhibits GLUT4 mediated glucose uptake in differentiated 3T3-L1 cells by interfering with the insulin signaling pathway, and by directly interacting with membrane GLUT4 [116,117].
In vivo: WE tested in AHT (50, 100, 200, or 400 mg/kg of bw) in healthy and alloxan mice; in OGTT (dose not specified) in healthy rabbits; CHT (150 mg/kg of bw) in rats with 12 weeks fructose feeding. ME and HE tested in AHT (50,100,200, or 400 mg/kg of bw for both extracts) in healthy mice. The doses of 180-183 for AHT were 50 and 100 mg/kg of bw [74][75][76][77]. In vitro: Compounds tested in diazoxide-induced relaxation of male rat aortic rings precontracted with phenylephrine.
In vivo: WE tested in CHT and OGTT in mice with 12 weeks fructose feedings [78]. --
In vivo: WE tested in AHT, OGTT, and OSTT in healthy and STZ-NA-treated mice. Doses of 31.6, 100 and 316 mg/kg of bw for all experiments. The doses for 213 and 214 for OSTT were 3.1, 10, and 31.6 mg/kg of bw, and 1, 3.1, and 10 mg/kg of bw, respectively.

(63 µg/mL) 219
219 Induces effects that might contribute to the protection of β cells in diabetes; it reduces insulin secretion in animals with hyperinsulinemia [120,121].
In vivo: ME assayed in AHT in normoglycemic and alloxan-treated mice. The doses of 234 for AHT were 1 and 5 mg/kg of bw. In vitro: Y-AG [95].
It is important to mention that most compounds listed in Table 1; Table 2 were isolated from organic extracts, and in a few cases from the traditionally aqueous preparation. Only in one case, the active principle of a hypoglycemic essential oil was established [28,29].
From the nine types of pharmacological agents currently used to treat T2D (sulfonylureas, meglitinides, biguanides, thiazolidinediones, alpha glucosidase inhibitors, DPP-4 inhibitors, bile acid sequestrants, dopamine agonists, and sodium-glucose transport protein 2 inhibitors), the compounds obtained from Mexican hypoglycemic plants share one or more of their mechanisms of action. The mechanisms most frequently found were α-glucosidase inhibition, insulin secretion or sensitization, and/or inhibition of hepatic glucose output (HGO). The α-glucosidase inhibitory effect is clear from the assays; the hypoglycemic effect is only throughout the inhibition of the enzyme. In addition, the assays required to demonstrate the activity in vivo or in vitro are easier to perform. When the compounds increase insulin plasmatic levels, the mechanism action, however, is not straightforward because they can target the pancreatic β-cells, increase GLP1 production in the gut, inhibit DPP4, or even act through unknown mechanisms. Those behaving as insulin sensitizers might be affecting different pathways.

Glucosidases Inhibitors
α-Glucosidase is the key enzyme involved in the digestion of carbohydrates; inhibitors of this enzyme can slow down the liberation of absorbable monosaccharides from dietary complex carbohydrates. The action mechanism of AGIs causes a decrease in glucose levels as well as osmotic effects. The disaccharides which are not digested will endure in the intestinal lumen and may lead to side effects such as diarrhea, flatulence, and abdominal pain [122]. AGIs block the enzymatic reaction particularly because of their nitrogen component. Thus, they must be present at the site of enzymatic action at the same time as the carbohydrates. Three AGIs are now in therapeutic use worldwide; acarbose isolated from culture filtrates of Actinoplanes, was first described by Schmidt in 1977 and introduced onto the market in 1990; miglitol, a semisynthetic derivative of 1-deoxynojirimycin, from Bacillus and Streptomyces spp; and voglibose, which is prepared from validamycin A, a product of Streptomyces hygroscopicus [84]. In Mexico, only acarbose is available.

Effect over Insulin Secretion
Different types of compounds increase insulin secretion. The first group described were the sulphonylureas, SUs, which stimulate the β-cells of the pancreas to release insulin. SUs binds to the SU receptor (SUR), a subunit of the potassium ATP-dependent (KATP) channels in the β-cell membrane, which eventually blocks the potassium channels and facilitates the influx of Ca 2+ into the cell, leading to membrane depolarization and subsequently insulin exocytosis. The main side effect is hypoglycemia; in Mexico, the most used SU is glibenclamide [123].
The glinides include drugs such as repaglinide (the only one available in Mexico), which belong to the group of nonsulfonylurea insulin secretagogues, with a rapid onset and reduced interval of action. They act by binding to the SUR1 receptor of the pancreatic β-cells (in a different site than SUs), they have less affinity for the receptor in comparison to SUs. Unfortunately, the glinides produce many adverse effects such as nausea, vomiting, diarrhea, constipation, gastrointestinal upsets, and abdominal pain. Due to their short duration of action, the associated hypoglycemia is much less recurrent than SUs [124].
Incretin-based medicines; after the intake of oral glucose, a phenomenon called incretin effect occurs, which increases insulin secretion up to 50-70%. The incretin hormones, Glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP) are intestinal peptides released after ingestion of food; they augment the pancreatic islet function by increasing insulin release and suppressing the synthesis of glucagon. The incretin-based medications include two classes of drugs, dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists. Both medications diminished the glycemic abnormalities. The incretin hormones GLP-1 and GIP inhibited gastric emptying, decreased appetite and food intake, and reduced glucagon's secretion. The life span of GLP-1 is very short, as DPP-4 converts GLP-1 into an inactive form. While DPP-4 inhibitors increase the life span of the incretin hormones, the GLP1 agonists imitate the glucoregulatory actions of GLP-1 and diminish the release of glucagon, thus improving the glucose-dependent secretion of insulin. At the same time, common symptoms associated with the use of GLP-1 receptor agonists include gastrointestinal symptoms, mainly nausea and vomiting, headaches, reactions at the site of injection, and nasopharyngitis [125,126]. In Mexico, exenatide (a GLP1 agonist) is available as well as the DPP-4 inhibitor (sitagliptin).
Based on the reported experiments, a few molecules isolated from Mexican plants can increase insulin levels; the most common were again phenylpropanoids and flavonoids. The first group includes the phenylpropanoids ρ-coumaric acid (3) and caffeic acid (112). The relevant flavonoids were eupatilin (23) and jaceosidin (24) which increased insulin secretion with no specific mechanism; but with the involvement of K + -ATP sensitive and Ca 2+ -voltage-dependent channels, which play an important role in insulin secretion [21,22]. The flavonol kaempferol (46) (116) and other 4-phenylcoumarins, which increase insulin secretion in rats [55]. Compounds 109 and 116 stimulated AMPK phosphorylation in vitro in C2C12 myoblast cells. Thus, these compounds activate the AMPK pathway, which, in turn, could stimulate insulin secretion [127]. Based on these structures, Wang and collaborators in 2017 [128] synthesized a few substituted 4-phenylcoumarins derivatives analogs of compound 109; their pharmacological investigation showed that those 4-phenylcoumarins possessing adjacent 7,8-dihydroxy groups were equipotent to the standard drug glibenclamide as hypoglycemic agents in vivo. In addition, these compounds inhibited aldose reductase and advanced glycation end-product formation. Altogether, this shows the potential of 4-phenylcoumarins for the development of therapeutic agents for treating diabetes, and how products discovered during the investigation of Mexican hypoglycemic plants are useful as templates for the development of more active compounds [128]. The sesquiterpene lactone arglanin (25) was investigated as a hypoglycemic agent in Mexico for the first time. Its nonspecific mechanisms also involved K + -ATP sensitive and Ca 2+ -voltage-dependent channels [22]. Finally, the cyclitol l-chiro-inositol (14), is also a well-known hypoglycemic agent.
Inositol derivatives (among them compound 14), have been reported to help the action of insulin stimulating glucose uptake in skeletal muscle cells, so they also work as insulin sensitizers [18,129].

Insulin Sensitizers
As mentioned above, T2D has two main components, insulin resistance and a progressive failure in insulin secretion. Insulin Resistance (IR) leads to a loss of response from the peripheral insulin target tissues (mainly the liver, adipose, and muscle tissues) to insulin. IR impairs the ability of the pancreatic cells to synthesize and secrete enough insulin to address the metabolic needs of the body. Insulin sensitizers help target cells in liver, skeletal muscle, and adipose tissue to respond properly to insulin, resulting in their ability to efficiently uptake and metabolize glucose [130].
Glitazones (TZDs) are insulin sensitizers used for treating T2D. TZDs are selective agonists of PPARγ, a transcription factor involved in the regulation of the expression of specific genes present in fat cells and other tissues. TZDs primarily act in adipose tissue where expression of PPARγ predominates. They interfere with the expression and release of mediators of IR (e.g., free fatty acids, adipocytokines, resistin, adiponectin) that originate in adipose tissue, thus resulting in improvement of insulin sensitivity in muscle and liver [131]. Treatment with TZDs might produce adverse hepatic, cardiovascular, osteological, and carcinogenic events [132]; therefore, TZDs were withdrawn for the market in several European countries; in Mexico, rosiglitazone is still available. Because of the importance of insulin sensitizers in the treatment of T2D, new-generation insulin sensitizers classified as direct PPARγ agonists, selective PPARγ modulators, and PPARγ-sparing compounds are in development [130].

Inhibitors of Hepatic Glucose Output (HGO)
One important action of insulin is the signaling over the liver when there is not enough insulin or there is some degree of insulin resistance in the hepatic cell, the result is an augmentation of glucose output. The liver plays a crucial role in maintaining blood glucose levels during fasting by converting its stored glycogen to glucose (glycogenolysis) and by synthesizing glucose, mainly from pyruvate and amino acids (gluconeogenesis) [133].
In T2D subjects with mild to moderate fasting hyperglycemia (140-200 mg/dL), basal hepatic glucose production increases by~0.5 mg/kg min. Consequently, during the overnight sleeping hours (22.00 to 8.00 h), the liver of an 80 kg diabetic individual with modest fasting hyperglycemia adds 35 g of glucose to the systemic circulation. In T2D, insulin resistance in the liver reflects hyperinsulinemia's failure to suppress gluconeogenesis, resulting in fasting hyperglycemia and decreased liver glycogen storage in the postprandial state. Increased hepatic glucose production occurs early during diabetes, although the increase is more obvious after the onset of insulin secretory abnormalities and insulin resistance in skeletal muscle. T2D is characterized by impaired glucose homeostasis partly due to abnormally elevated HGO [134].
Metformin, the main insulin sensitizer in use worldwide, acts by different mechanisms, diminishing the intestinal glucose absorption, increasing peripheral uptake and use of glucose, and lowering the hepatic synthesis of glucose [122]. Although metformin is an insulin sensitizer, its action over the HGO is also significant; metformin induces mild energy stress in the liver, leading to an increase in AMP concentration that allosterically inhibits the enzyme fructose-1,6-bisphosphatase-(FBP1) to lower HGO. This is a very important mechanism, as the subsequent increase in F-1,6-P2, will activate PK and increase glycolytic flux. Because AMP-inhibited FBP1, a rate-controlling enzyme in gluconeogenesis, it functions as a major contributor to the therapeutic action of metformin [135].
Although in the international literature, polyphenols like kaempferol or caffeic acid have been related to the blockage of the enzyme G6Pase, from Mexican plants, chlorogenic acid a well-characterized inhibitor of the G6Pase T1 translocase system [19]; thus, it can block HGO, has been reported. ρ-Coumaric acid (3) inhibits fructose-1,6-bisphosphatase, which also leads to the block of HGO; however, this mechanism has not been explored in molecules isolated from Mexican plants.

Discussion
T2D is an important health problem in many countries; Mexico is not an exception. Like in many developing countries, in Mexico the use of medicinal plants is a common practice, for these two main reasons, plants play an essential role in how the Mexican population treats T2D, this situation is beside the institutional medical attention. It is important to understand how these plants produce a hypoglycemic effect for future isolation of promissory molecules for the development of new hypoglycemic agents.
In the present manuscript, we document 86 molecules isolated from Mexican plants, intending to provide a necessary inventory for further studies. Almost half of these molecules are not common metabolites, with a narrow taxonomic distribution, which makes them more interesting as lead molecules. Some of the most complex molecules (i.e., the limonoids, cucurbitans, or the oligosaccharides) are good candidates for fragment-based drug discovery. The studies summarized in Tables 1 and 2 along with chemical informatics methods and network pharmacology provides useful information for the development of new phytopharmaceutical preparations. In addition, because some of these molecules are present in plants worldwide, Table 2 will be a useful reference for promoting the testing of these compounds in other targets, known or news, and a better insight into the already described mechanisms.
When hypoglycemic plants are studied it is imperative to set the goal of the study; one point is to prove if the plant has a hypoglycemic effect, which can explain the traditional use but another point is to escalate the study to produce a phytomedicine or a single isolated compound, like metformin. The fact that a plant possesses a hypoglycemic effect does not necessarily mean that it will be of clinical use; for this reason, it is essential to study single molecules in known and new pharmacological targets, aiming to have novel hypoglycemic agents of clinical relevance.
In recent years, the investigation of medicinal plants used to treat diabetes in Mexico has improved. However, we still need to achieve the final goal, contributing with a hypoglycemic agent or phytomedicines of significant clinical efficacy; we are just in the initial steps documenting hypoglycemic plants, and progressing in preclinical testing. The works have been narrowed in scope, both from the pharmacological and chemical point of view. The number and diversity of small molecules to address all the different binding sites in the complex biology of diabetes are still awaiting to be isolated from the plants in Table 1, and other plants yet to be discovered. The essential oils of these plants, plenty of small molecules suitable for the development of hypoglycemic agents remain unexplored. The constituents of the essential oils offer good prospects for drug discovery. These constituents meet most conditions required for good drug candidates and offer attractive opportunities for lead optimization or even fragment-based drug discovery. New technologies such as metabolomics can accelerate dereplication and identification of compounds with novel skeletons; routine incorporation of protein-metabolite interaction and cell-based assays, which require small amounts of samples are essential.
Most compounds in Table 1 require testing as glucose reabsorption inhibitors, incretin analogs, DDP4 blockers, bile acid sequestrants, or dopamine agonists. The effect of these molecules over gut microbiota also needs attention since these bacteria play an important role in the control of T2D. We consider essential to test these molecules as glucose reabsorption inhibitors in the kidney because many plants traditionally used for treating T2D are also employed to treat "Mal de Orin", an entity that people detect when you have urination problems; this type of plants augment the urine flux. The inhibition of hepatic glucose output is also an important target to assess. From there compounds with similar actions like metformin could upsurge.
A single molecule can have more than one mechanism of action. This might be targeting different proteins within the same (network pharmacology) or different (polypharmacology) signaling pathways In the context, of a botanical mixture, a pool of molecules, perhaps in low concentrations, acting by biochemical synergism can lead to the desired effect, hypoglycemic action, without the presence of a major highly bioactive compound. This has been the classic paradigm of phytotherapy. The advantages of dealing with polyvalent drugs are a decrease of drug-drug interactions, less cost for the patient to bear, increased adherence due to lower side effects, the possibility of treating concomitant diseases, just to mention a few. In this review, we found some examples of compounds possessing more than one mechanism. Thus, protocatechuic acid (1) is an insulin sensitizer and secretagogue. Quercetin (47) is an insulin sensitizer and secretagogue, as well as the inhibitor of α-glucosidases. Epicatechin (113) inhibits α-glucosidase and behaves as an insulin sensitizer. Kaempferol (46) inhibits hepatic gluconeogenesis, is an insulin sensitizer and inhibits α-glucosidases. Caffeic acid (112) induces insulin secretion, decreases hepatic glucose output, inhibits alpha glucosidases, and is an insulin sensitizer. Furthermore, 2-Hydroxy-destigloyl-6-deoxyswietenine acetate (221) stimulates insulin secretion due to a partial blockade of K + -ATP channels, and a serotonergic modulation on 5-HT2 receptors inhibited hepatic glucose-6-phosphatase, and stimulated muscle glucose uptake and basal oxygen consumption in muscle cells [91]. The 4-phenylcoumaris affects glucose absorption, insulin secretion, and glucose utilization. With these examples, we want to remark the importance of testing 86 described compounds over different action mechanisms.

Materials and Methods
This study was performed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) [136]. To obtain pertinent literature, without author bias, peer-reviewed research articles were obtained from the following databases: PubMed, MEDLINE, EMBASE, SCOPUS, SciFinder, and Clarivate Analytics. Inclusion criteria were studies reporting the hypoglycemic effect of Mexican medicinal plants, and at least one pure compound was isolated and selected.

Conclusions
The use of medicinal plants to manage diabetes is an overwhelming reality that requires being set into the correct health care perspective. Indeed, these plants will keep providing promissory agents for the development of new antidiabetic drugs or phytotherapeutic products. In this review, we summarize new and known hypoglycemic agents from the reported Mexican hypoglycemic plants. These compounds represent only a small fraction of the chemical space of Mexican Medicinal plants. Some of the compounds' scaffolds are common, in particular those of the phenylpropanoids and flavonoids. Among the terpenoids and steroids, the ursanes and stigmastanes are widespread in nature, while the remaining terpenoids are less common and restricted to some genus of some family plants. Finally, the other aromatic compounds and the resin glycosides are also limited to a few vegetal species. Except for the flavonoids and phenylpropanoids, the hypoglycemic properties and/or the chemical structures of most compounds were discovered in Mexico, following an ethnopharmacological hypothesis. Their mechanisms of actions involved inhibition of α-glucosidase, insulin secretion or sensitization, and/or inhibition of hepatic glucose output. Some of the less common compounds are multitarget which makes them attractive for drug development.