Description

Background

Diabetes mellitus (DM) is a common clinical disease, frequently-occurring, has gradually become one of the most major chronic non-communicable diseases in the world, the incidence is increasing year by year. Diabetes is a serious long-term disease that has a significant impact on the lives and well-being of individuals, families and societies around the world. It is one of the top 10 causes of death in adults, with an estimated 4 million deaths worldwide in 2017. In 2017, global health spending on diabetes was estimated at $727 billion ^[1].

The three main types of diabetes are Type 1 diabetes (T1D), Type 2 diabetes (T2D), and gestational diabetes (GDM). Since 2000, the International Diabetes Federation (IDF) has reported on the prevalence of diabetes at national, regional and global levels. In 2009, an estimated 285 million people had diabetes (T1D and T2D combined) ^[2], increasing to 366 million in 2011 ^[3], 382 million in 2013 ^[4], 415 million in 2015 ^[5], and 425 million in 2017 ^[1]. The global prevalence of diabetes among people aged 20-79 years is estimated at 10.5% (536.6 million people) in 2021 and will rise to 12.2% (783.2 million people) by 2045 ^[6].

Current status of diabetes treatment

Diabetes diagnosis and treatment is not only time-consuming and laborious, but also costly. Worldwide diabetes-related health spending has been rising since 2006, and by 2021 it will have almost quadrupled from 15 years earlier, at an estimated cost of $996 billion. This may seem like a lot of money, but the amount spent per person with diabetes is very large. In high-income countries, total health expenditures related to diabetes can reach more than $600 billion, and the average health expenditure per person with diabetes is still more than $6,000.

At present, there is no effective drug or means to cure diabetes, which can only control blood sugar to reach a certain range to reduce and delay the occurrence of complications. Diabetes drugs are mainly divided into oral drugs and injectable drugs. Among them, the oral drugs include: metformin, α glucosidase inhibitors, insulin secretagogues (sulfonylureas and glenides), thiazolidinedione (TZD), DPP4 inhibitors, SGLT2 inhibitors 6 varieties. Injectable drugs include: GLP1 receptor agonists and insulin. However, these drugs have the problems of high production cost, high price and easy to produce drug interaction and adverse reactions. Therefore, there is an urgent need to find new low-cost diabetes treatment drugs with few side effects, and natural ingredients in some plants are gradually getting attention.

Isoorientin

Isoorientin is a bioactive compound extracted from amaranth family. It has hypoglycemic, antibacterial, anti-inflammatory and antitumor effects. Among them, its hypoglycemic effect is one of the most important. Isoorientin modulated glucose metabolism and decreased blood glucose level in many ways, which had therapeutic effect on diabetes mellitus.

Insulin is a key hormone regulating blood sugar, isoorientin can promote the secretion of insulin, so as to reduce blood sugar level. Isoorientin improved diabetes by regulating insulin signaling pathway. The sensitivity of tissues and organs of diabetic patients to insulin decreased, and isoorientin could increase the sensitivity of tissues and organs to insulin, thus promoting the normal operation of insulin signaling pathway and reducing the level of blood sugar ^[8]. Glycogen is stored in the liver and muscles and is important for maintaining blood sugar balance. Isoorientin can inhibit the activity of liver glycogenase, thereby reducing the breakdown of glycogen, promoting the storage of glycogen, and regulating the level of blood sugar ^[9]. Meanwhile, studies have shown that isoorientin can inhibit the activity of α-glucase, thus slowing down the decomposition of postmeal carbohydrate and regulating postmeal blood glucose ^[10,11].

Isoorientin is widely distributed in a variety of plants, such as orientin, hawthorn, buckwheat, passion flower, bitter herb, kudzu root, corn beard, bamboo leaves, thousands of grass, iris, duck plantgrass, herryweed, ruo leaves and many other plant medicinal or edible parts. Polygonum polygonum Polygonum Polygonum is a dried whole grass of polygonum polygonum family. Although some isoorientin was extracted from bamboo leaves and Baizhu, it is difficult to prepare them because of their low concentration and complex composition. Therefore, large-scale, low-cost production has become very important.

C-glycosyltransferase

C-glycosyltransferases (CGTs) bind receptor molecules, 2-hydroxyflavanones or favanones such as luteolin and apigenin, to activated sugar molecules such as UDp-sugars, Various C-glycosylation natural products are generated.

There are two types of C-glucosyltransferase, the first type cannot directly produce C-glycosylflavonoid in Escherichia coli, and the second type of C-glucosyltransferase directly C-glucosylates the C-6 position of flavonoids ^[12].. Currently, only one type II C-glucosyltransferase (Gt6CGT) has been found in Gentian Triflorum.

C-glycosyltransferase (Gt6CGT) directly glycosylated the C-6 position of lutein and other flavonoids to produce C-glycosylflavonoid, isoorientin.

Our goal

Based on the above research background, it is hoped that by constructing Gt6CGT recombinant Escherichia coli strain and using luteolin as substrate, isoorientin was biosynthesized to provide a certain reference for the industrial production of isoorientin, thus laying a foundation for the large-scale application of isoorientin in the treatment of diabetes.

Reference

[1] International Diabetes Federation. IDF Diabetes Atlas, 8th ed. Brussels, Belgium: International Diabetes Federation; 2017.

[2] International Diabetes Federation. IDF Diabetes Atlas, 4th ed. Brussels, Belgium: International Diabetes Federation; 2009.

[3] International Diabetes Federation. IDF Diabetes Atlas, 5th ed. Brussels, Belgium: International Diabetes Federation; 2011.

[4] International Diabetes Federation. IDF Diabetes Atlas, 6th ed. Brussels, Belgium: International Diabetes Federation; 2013.

[5] International Diabetes Federation. IDF Diabetes Atlas, 7th ed. Brussels, Belgium: International Diabetes Federation; 2015.

[6] Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022 Jan;183:109119.

[7] Magliano DJ, Boyko EJ; IDF Diabetes Atlas 10th edition scientific committee. IDF DIABETES ATLAS [Internet]. 10th ed. Brussels: International Diabetes Federation; 2021.

[8] Alonso-Castro AJ, Zapata-Bustos R, Gómez-Espinoza G, Salazar-Olivo LA. Isoorientin reverts TNF-α-induced insulin resistance in adipocytes activating the insulin signaling pathway. Endocrinology. 2012 Nov;153(11):5222-30.

[9] Kasangana PB, Eid HM, Nachar A, Stevanovic T, Haddad PS. Further isolation and identification of anti-diabetic principles from root bark of Myrianthus arboreus P. Beauv.: The ethyl acetate fraction contains bioactive phenolic compounds that improve liver cell glucose homeostasis. J Ethnopharmacol. 2019 Dec 5;245:112167.

[10] Dao TB, Nguyen TM, Nguyen VQ, Tran TM, Tran NM, Nguyen CH, Nguyen TH, Nguyen HH, Sichaem J, Tran CL, Duong TH. Flavones from Combretum quadrangulare Growing in Vietnam and Their Alpha-Glucosidase Inhibitory Activity. Molecules. 2021 Apr 26;26(9):2531.

[11] Borges PHO, Pedreiro S, Baptista SJ, Geraldes CFGC, Batista MT, Silva MMC, Figueirinha A. Inhibition of α-glucosidase by flavonoids of Cymbopogon citratus (DC) Stapf. J Ethnopharmacol. 2021 Nov 15;280:114470.

[12] Chong Y, Lee SW, Ahn JH. Phenolic C-glycoside synthesis using microbial systems. Curr Opin Biotechnol. 2022 Dec;78:102827.