Type 2 diabetes mellitus (T2DM) is a disease that is associated with insulin resistance and pancreatic β-cell dysfunction. According to current knowledge on the pathophysiology of this disease, multiple antidiabetic therapies have been developed to improve glycemic control and slow disease progression.

Although numerous antidiabetic medications have been developed, the side effects accompanying the medications, including hypoglycemia, gastrointestinal symptoms, heart failure, weight gain, edema, impaired kidney function, pancreatitis, and genital infections, are disadvantageous (Irondi et al., 2015). The incidence rate of diabetes is higher in low- and middle-income countries, which causes another challenge, as modern therapies are lacking or unaffordable for the majority of diabetic patients in these countries. In this context, plant extracts and their active constituents are important sources for potential new antidiabetic treatments (Furman et al., 2020; International Diabetes Federation, 2021).

In traditional medicine systems, such as traditional Chinese medicine (TCM), Japanese Kampo, Indian Ayurveda, and African, Native American and European traditional medicine, numerous plants are used to treat diabetes. Support for the efficacy of these medicines is anecdotal, although some scientific evidence is present in the literature for more than 800 plants (Furman et al., 2020). In many cases, data on plant extracts and their metabolites are limited. The effect may be measured only in terms of blood glucose levels, and thus, the mechanism underlying the antidiabetic effect (when found) is unknown, and the active constituents responsible for the effect of the extract are often unknown.

For centuries, humans have utilized plants from the Angelica L. (Apiaceae) genus for culinary, ceremonial, and medicinal reasons. Angelica L. roots are widely used as a traditional and folk medicine worldwide and are mentioned in many pharmacopeias and medicinal systems, such as Traditional Chinese Medicine, Ayurveda, and Kampo (Fig. 1).

Angelica archangelica L. syn. Angelica officinalis Hoffm. (accepted species- https://powo.science.kew.org) is native to North and Eastern Europe and Western Asia and had been used for centuries as a spice and vegetable for culinary purposes in these areas (Kaur and Bhatti, 2021). In Western traditional medicine and the Ayurvedic medicinal system, A. archangelica roots are used as an appetite stimulant, an antispasmodic, a sedative, an anxiolytic, and a medication for gastrointestinal symptoms, such as bloating, poor digestion, eructation, and flatulence. Some recent pharmacological studies revealed also a potential trypanocidal (Krishnan et al., 2023) and antiviral activities (Rajtar et al., 2017), cholinesterases inhibitory activity (Wszelaki et al., 2011), monoaminoxidase (MAO) inhibitory activity (Kaur et al., 2020), and a clinical study a usefulness of ferulic acid and Angelica archangelica extract in mild cognitive impairment (Kudoh et al., 2020). Its main constituents are essential oil (α-pinene, limonene, and α-phellandrene) and simple (osthol, osthenol) and furanocoumarins such as imperatorin, bergapten, oxypeucedanin, isopimpinellin, byakangelicin-2′-O-isovalerate, phellopterin, archangelicin (Kaur and Bati, 2021; Wszelaki et al., 2011). At present, it is recognized by the United States and European Pharmacopeias as well as the National Formulary of India (Kaur and Bhatti, 2021). A. archangelica has been naturalized in Eastern North America even though Angelica atropurpurea L, another representative of the Angelica genus with similar properties, naturally present in these regions. Like A. archangelica, A. atropurpurea has been used as a vegetable and spice. Among the Native Cultures of North America, such as the Muscogee, Cherokee, Lenape, and Menominee, the plant was used for ceremonial, nutritional, and medicinal purposes to treat anxiety, back pain, and gastrointestinal disorders (Lewis and Jordan, 2002). Ceremonial and therapeutic uses of Angelica dawsonii S.Watson by the Blackfoot, Angelica breweri A.Gray by the Miwok, Paiute, Shoshoni, and Washo, Angelica genuflexa Nutt. by the Nuxalk and Gitxan, Angelica lineariloba A.Gray by the Paiute, Angelica lucida L. by the Aleut and Inuit, Angelica pinnata S.Watson by the Goshute, Angelica tomentosa S.Watson by the Pomo and Yana and Angelica venenosa (Greenway) Fernald by the Iroquois were also noted (Dexter et al., 2014; Moerman, 1998).

In parts of Europe, North America, and South Asia, Angelica sylvestris L. roots were used as an ethnomedicine. Among the Mi’kmaq of Eastern Canada, the roots were used to treat coughs, colds and sore throats (Moerman, 1998). In Estonia, it was used in folk medicine to treat cancer (Raal et al., 2022), while in Pakistan, it was used to treat rheumatism and muscle pain (Malik et al., 2018). In the Pakistani and Indian Himalayan regions, another angelica root were used, i.e., that of Angelica glauca Edgew. Its roots are commonly used to treat gynecological disorders, such as dysmenorrhea, metrorrhagia, amenorrhea, polycystic ovary syndrome, and gastrointestinal disorders (Ikram et al., 2015; Kumar et al., 2022).

Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav. (accepted species- https://powo.science.kew.org) is widely distributed in Korea, Northeast China, Japan, Mongolia, and Siberia. Its root contains essential oil rich in α-pinene, simple and furanocoumarins (scopoletin, isoimperatorin, imperatorin, oxypeucedanin, bergapten, byakangelicin, phellopterin, byakangelicol, isopimpinellin, xanthotoxol, xanthotoxin, pimpinellin, cnidilin), which are probably responsible for its anti-inflammatory, analgesic, and antioxidative properties. It has been used in TCM, Kampo, and traditional Korean medicine to treat the common cold, rhinitis, headache, toothache, and some skin diseases (Zhao et al., 2022). The Korean Pharmacopeia also mentions the root of Angelica gigas Nakai, which exhibits similar properties and is used to treat the common cold, headaches, neuralgia, arthralgia, and gynecological disorders (Jeong et al., 2015).

In China, the most known Angelica product is perhaps the root of Angelica sinensis (Oliv.) Diels (accepted species- https://powo.science.kew.org), which is also traditionally used to treat gynecological disorders, such as amenorrhea and irregular periods. Its active constituents are phthalides (ligustulide, butylidenephthalide, butylphthalide, senkyunolide A-I, senkyunolide P, senkyunolide K, levistolide A, riligustilide, tokinolide B, neocnidilide), organic acids (mainly ferulic acid 0.02–0.17 %), and polysaccharides included fucose, galactose, glucose, arabinose, rhamnose, and xylose in molar ratio: 1.0:13.6:15.0:8.7:21.3:3. (Wei et al., 2016). A. sinensis was also used in Indonesian and Arabian traditional medicine, and the plant was probably transported to those countries via trade (Alqethami et al., 2020; Kusuma et al., 2022). Angelica acutiloba (Siebold & Zucc.) Kitag. roots are sometimes used in TCM as a substitute for A. sinensis and in Kampo to treat menstrual disorders, amenorrhea, and premenstrual syndrome (Jeong et al., 2015). Chinese Pharmacopeia also lists Angelica anomala Avé-Lall. as a treatment for gynecological disorders (He et al., 2012).

Apart from A. dahurica and A. sinensis roots, the Chinese Pharmacopeia also lists Angelica biserrata (R.H.Shan & Yuan) C.Q.Yuan & R.H.Shan (accepted species- https://powo.science.kew.org), (syn. Angelica pubescens Maxim. f. biserrata R.H.Shan et C.Q.Yuan) roots, which are used in TCM to alleviate pain, fever, and rheumatism. Coumarins such as osthenol, bergapten, xanthotoxin, columbianedin, columbianetin acetate, osthol umbelliferone, columbianetin, angelol-A, angenol-B, angelol-D are their primary constituents and are probably responsible for their biological effects. The plant is widespread in Japan and present in mainland China and Taiwan at significantly lower levels but is not mentioned in the Japanese Pharmacopeia (Ma et al., 2019; Wang et al., 2023). The common Latin name of the pharmacopeial plant material Angelicae pubescentis radix may be misleading, as it applies to the roots of A. biserrata, which is sometimes considered an A. pubescens subspecies. Angelica polymorpha Maxim. is mentioned in the Chinese Pharmacopeia as a substitute for A. pubescentis radix.

Other species used in traditional oriental medicine include Angelica decursiva Franch. & Sav. (syn. Peucedanum decursivum Maxim.), which is also mentioned in the Japanese Pharmacopeia for its anti-inflammatory effects (Zhao et al., 2012), and Angelica tenuissima Nakai, which is used to treat dental pain in Korean folk medicine (Kim and Song, 2011).

Angelica roots are sometimes used to treat T2DM. These include Angelica furcijuga Kitag., Angelica shikokiana Makino ex Y.Yabe, Angelica keiskei Koidz. and Angelica japonica var. hirsutiflora (Liu, Chao & Chuang) T.Yamaz. (Aulifa et al., 2022; Leu et al., 2009; Mira et al., 2013; Yoshikawa et al., 2006). In traditional medicines (Chinese or European) diabetes was described by the symptoms, which also depend on the stage of the disease, such as excessive thirst, hunger and urination. However, in the prediabetic state we also observed a chronic fatigue and weakness, a decrease in concentration ability, and an impairment in wound healing. In TCM the prediabetic stage is described as accompanied with nervousness, distention, and fullness in the chest and rib-side, while the middle stage principal symptoms are abdominal fullness and distention (Guo et al., 2014). Angelica species use in TCM, has been mentioned in treating some symptoms of diabetes: to promote blood circulation, in anti-diabetic prescriptions (Angelica sinensis), diabetes-induced skin ulcer (Angelica dauhurica) (Li et al., 2004; Zhao et al., 2022). Interestingly, the European A. archangelica has pleiotropic actions and is used as a general tonic and stimulant, in various gastrointestinal and biliary disorders (dyspepsia, flatulence, fullness) (Kaur and Bhatti, 2021), however never described as strictly connected with diabetes symptoms.

Moreover, some Angelica L. root extracts were found to possess insulin secretagogue activity (Leu, Y. L. et al., 2009). Osthole isolated from Angelica pubescens alleviated hyperglycemia in a mice model (Liang et al., 2009). In another study, Kim et al. discovered that Korean Angelica reflexa B.Y.Lee and some of its metabolites potentiate glucose-induced insulin secretion (Kim et al., 2023). Lastly, Park et al. screened over 1500 plant extracts for G protein-coupled receptor (GPR) 119 agonistic actions, and A. dahurica root extract was the most active, and its effect on the modulation of insulin secretion was also established. The authors argued that coumarins may be responsible for this activity (Park et al., 2016).

There have been numerous attempts at assessing coumarins' antidiabetic potential, although the researchers mostly target α-glucosidase (Channa Basappa et al., 2020; Hu et al., 2019; Sepehri et al., 2020). Single studies were conducted in vivo and on β-cell models to evaluate the protective and insulin secretion-modulating effects of coumarins. Umbelliferone (7-hydroxycoumarin) β-D-galactopyranoside was found to increase insulin levels in streptozotocin (STZ)-induced diabetic rats at doses ranging from 10 mg/kg to 40 mg/kg (Kumar et al., 2013). In another study, its aglycone (umbelliferone) induced a similar effect in alloxan-induced diabetic rats at 100 mg/kg (Ramu et al., 2016). Daphnetin (7,8-dihydroxycoumarin) was found to protect INS-1 cells from STZ-induced β-cell death and dysfunction (Vinayagam and Xu, 2017). Ahmed et al. studied 13 coumarin sulfur analogs isolated from Clutia lanceolata Forssk on murine pancreatic islets and found that 7 increased glucose-induced insulin secretion, although the concentration used in this study was relatively high (200 μmol/L) (Ahmed et al., 2020). Another coumarin, scopoletin (7-hydroxy-6-methoxycoumarin), increased glucose-induced insulin secretion through ATP-sensitive potassium channel (KATP) and voltage-gated calcium channels (VGCC) dependent pathways in rat insulinoma (INS-1) cells at concentrations below 20 μmol/L (Park et al., 2022). Imperatorin was found to increase plasma GLP-1 levels and increase insulin secretion in STZ-induced diabetic rats at 3–10 mg/kg and to modulate glucose-induced insulin secretion in INS-1 cells at 0.1 mg/mL (370 μmol/L) (Adebajo et al., 2009; Wang et al., 2017). Unfortunately, data on the effect of coumarins on β-cells are scarce and mostly limited to high doses beyond bioavailability.

Pancreatic β-cells play a central role in glucose homeostasis by secreting insulin, a hormone that maintains glycemia within the physiological range (mainly by promoting glucose uptake and utilization by peripheral tissues). Moreover, the progressive decline in β-cell capacity to secrete insulin in response to glucose is a cardinal feature of the pathogenesis and evolution of type 2 diabetes (Rorsman and Ashcroft, 2018). Therefore, considering that some angelica representatives are used to manage diabetes and that medicinal plants may exhibit unknown pharmacological activities, which may pose a risk of undesirable effects, this study aimed to evaluate the effect of the angelica roots monographed in the European Pharmacopeia 11th edition on insulin secretion by pancreatic β-cells and to isolate compounds responsible for this activity. Four plant materials derived from angelica species (Angelicae archangelicae radix, Angelicae dahuricae radix, Angelicae sinensis radix and Angelicae biserratae radix) that are monographed in the European Pharmacopeia (Ph. Eur. 11th) and may be sold in Europe, were phytochemically profiled and evaluated for insulin secretion in the INS-1 β-cell line. Moreover, several coumarins were isolated from those plants materials and their effect on INS-1 β-cells, depending of their structure, was also investigated.