The Beneficial Effects of Geniposide on Glucose and Lipid Metabolism: A Review

Introduction

Glucose and lipid metabolism imbalance is a high-risk etiology leading to various complications, including obesity, diabetes, hyperlipemia, non-alcohol fatty liver disease (NAFLD), and cardiovascular diseases.¹ We are currently in the midst of a global metabolic disease epidemic, with its prevalence increasing with age.^2,3 There has been an increasing interest in investigating effective strategies to control and treat comorbidities associated with glucose and lipid metabolism disorders.⁴ A variety of plants and natural active ingredients derived from plants have been used to combat diseases associated with glycolipid metabolism disorders.⁵ Geniposide is one such naturally active ingredient derived from the fruits of Gardenia Jasminoides Ellis (GJE, popularly called Zhizi in China) and has traditionally been commonly used for hundreds of years in traditional Chinese medicine.⁶

There is an increasing number of pharmacological evidence proving that geniposide exerts various biological activities, including neuroprotective, antidiabetic, hepatoprotective, anti-inflammatory, analgesic, antidepressant-like, cardioprotective, antioxidant, immune-regulatory, antithrombotic, and anti-tumoral effects.^7–11 The anti-inflammatory, hepatoprotective, antidiabetic, and antioxidant properties of geniposide were reviewed before.^9,10,12–15 The most recognized pharmacological effects of geniposide are anti-inflammatory and antioxidant effects;^9,13 however, in recent years, a growing number of studies explored the role of geniposide in regulating glucolipid metabolism. How geniposide regulates the glucolipid metabolism, the specific mechanism, the disadvantages and future research directions have not been elucidated. There are few reviews on the improvement of glucolipid metabolism disorders and metabolic diseases using geniposide. As a consequence, a comprehensive review focusing on geniposide-regulated glucolipid metabolism is necessary to advance the knowledge on geniposide. This review will serve as a reference for researchers to further understand the pharmacological effects of geniposide and develop more valuable applications in the future.

Geniposide at a Glance

Structure and Physicochemical Properties

Geniposide (methyl (1S,4aS,7aS)-1-(β-D-glucopyranosyloxy)-7-(hydroxylmethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate; C17H24O10) is regarded as an iridoid glycoside, namely genipin 1-O-β-D-glucopyranoside (Figure 1).¹⁰ From another perspective, geniposide is also regarded as a C11 methyl ester of geniposidic acid. Its molecular weight is 388,366. Because of its chemical structure, it is also considered a glycoside containing one molecule of genipin and glucose. Geniposide is a white or pale yellow powder with a density of 1.49 g/cm³ and a melting point of 161.53°C.⁷ It is easily dissolved in water, soluble in ethanol, and undissolved in petroleum ether.⁶

Figure 1 Chemical structure of geniposide.

Sources

Geniposide is mainly sourced from GJE, but it is also detected in other commonly used Chinese herbal medicines, such as Eucommia Ulmoides Oliv (EUO), Rehmannia Officinalis (RO), and Radix Scrophulariae (RS) (Figure 2).¹⁶ Among these, GJE contains about 3.3–8.56% geniposide, while RO only contains 0.205–0.4381%, EUO contains 0.0173–0.5811%, and RS contains 0.0699–0.1135% of geniposide. Therefore, GJE is the main geniposide source.¹⁷ The 2015 edition of the Chinese Pharmacopoeia stipulates that geniposide abundance in GJE is no less than 1.8%. Geniposide content in GJE on the market reaches 6%.¹⁸

Figure 2 Main sources of geniposide. (A). Gardenia Jasminoides Ellis (B). Eucommia Ulmoides Oliv (EUO) (C). Rehmannia Officinalis (RO) (D). Radix Scrophulariae (RS).

Pharmacokinetics

We investigated that the concentration of geniposide reached a peak in the liver and spleen 30 min after oral administration, and was detected in the kidney and brain 2 h later.¹⁹ The absolute bioavailability of geniposide was 9.67% after it was metabolized within 12 h. The bioavailability of geniposide is strongly linked to different administration methods. In addition, geniposide can be converted to genipin by an intestinal microbiota enzyme (β-glucosidase) (Figure 3). Geniposide metabolism involves methylation, glucosylation, decarboxylation, taurine conjugation, hydrolysis, demethylation, hydrogenation, hydroxylation, cysteine S-conjugation through dehydration, sulfate conjugation, and other related complex reactions.^20,21 Geniposide is mainly excreted in its original form through the kidneys. The excretion level accounts for a proportion of over 90% of the initial dosage after 10 h.²²

Figure 3 Schematic diagram of the metabolic effect of geniposide by β-glucosidase and esterase.

Main Pharmacological Functions of Geniposide

Geniposide exerts abundant and complicated pharmacological effects, such as anti-inflammatory, antioxidant, hepatoprotective, neuroprotective, analgesic, antidiabetic, antidepressant-like, immune-regulatory, cardioprotective, antithrombotic, and antitumoral effects.⁸ These pharmacological effects have laid a foundation for its application in the improvement of a variety of diseases, such as cardiovascular diseases, diabetes and diabetic complications, hepatic diseases, Parkinson’s disease, Alzheimer’s disease, and ischemia and reperfusion injury. Some of the potential benefits include the influence on the normal and healthy operation of the nervous, endocrine, circulatory, digestive, urinary, muscle, and other different bodily systems.

In particular, the anti-inflammatory and antioxidant effects of geniposide have been widely studied. Geniposide not only fights inflammation-related diseases like swelling, pain, liver disease, Alzheimer’s disease, and others but also inhibits classic inflammatory-related pathways such as NF-κB, MAPK, and TLR4 signaling pathways.¹⁰ Geniposide could delay cell injury via upregulating endogenous antioxidative enzymes. Geniposide can also increase the activity of some important antioxidant enzymes and pathways including hepatic lipid peroxidation (LPO), glutathione-S-transferase (GST), glutathione (GSH), glutathione peroxidase (GPx), and copper- and zinc-containing superoxide dismutase (CuZn-SOD), and protects against oxidative stress injury.^23–25

Pharmacological Effects of Geniposide in Glucose and Lipid Metabolism

Effects on Glucose Metabolism

It is well-known that an imbalanced glucose metabolism triggers many metabolic diseases. An adequate blood glucose level must be maintained at all time. Sources of blood glucose are intestinal absorption, liver glycogenolysis, and gluconeogenesis.²⁶ Glucose-consuming pathways include glucose uptake by various tissues and organs for oxidation, glycogen synthesis, and conversion into other sugars, fats, or amino acids. The balance of blood glucose is mainly regulated by hormones, including insulin, glucagon, adrenaline, and glucocorticoid.²⁷ The interaction between major glucose metabolic pathways, such as glycolysis, gluconeogenesis, glycogenesis, and glycogenolysis, maintains the homeostasis of hepatic glucose metabolism.²⁸ Figure 4 summarizes the pharmacological effects of geniposide on glucose metabolism and the details are exhibited in Table 1.

Table 1 In vivo/In vitro Studies of Geniposide in Glucose Metabolism

Figure 4 Pharmacological effects of geniposide on Glucose Metabolism.

Increasing Glucose Utilization

Skeletal muscle, which is the main organ participating in the uptake and metabolism of glucose, contains slow-twitch and fast-twitch muscle fibers. Fast-twitch fibers generate adenosine triphosphate (ATP) primarily through glycolysis, whereas slow-twitch myofibers rich in mitochondria have high oxidative capacity.²⁹ Geniposide improves glucose homeostasis by promoting a slow-to-fast myofiber switch and glucose utilization. Further studies exposed that geniposide exerts the above effects by regulating forkhead box O1 (FoxO1)/ pyruvate dehydrogenase kinase 4 (PDK4), which controls respiratory substrate selection through pyruvate dehydrogenase.³⁰ From another point of view, in a 2022 study, it was revealed that geniposide regulates respiratory substrate selection, promotes glucose uptake in skeletal muscles, and suppresses glycogen storage by disturbing the synthesis, secretion, and homeostasis of retinol-binding protein 4 (RBP4).³¹

Increasing Insulin Production

Glucose-stimulated insulin secretion (GSIS) is essential to the maintenance of a stable level of blood glucose.³² Guo et al³³ first reported that geniposide could increase GSIS, and the results indicated that glucagon-like peptide 1 receptors (GLP-1R) plays an important role in the geniposide-regulated GSIS. Geniposide regulates GSIS possibly via pyruvate carboxylase-mediated glucose metabolism in pancreatic β cells.³⁴ Exploration from another point of view revealed that GSIS is phosphatidylinositol 3 kinase- dependent and geniposide increases the expression of glucose transporter 2 (GLUT2) in total cell lysates under normal glucose conditions.³⁵ An in-depth study focusing on GLUT2, indicated that it may be related to the regulation of glucosaminyl (N-acetyl) transferase family member 7 (GNT-IVa)-mediated glycosylation of GLUT2 and the residence of glycosylated GLUT2 on the pancreatic β cell membrane.³⁶ A 2021 study found that 5’AMP-activated protein kinase (AMPK) activation also plays an essential role in geniposide-regulated GSIS in pancreatic β cells.³⁷

Protecting Pancreatic Islet β Cells

Diabetes is characterized by pancreatic islet β cell dysfunction or loss. One therapeutic strategy for improving blood glucose homeostasis is to prevent pancreatic islet β cells from failure and promote new pancreatic islet β cell formation.²⁷

Geniposide is a promising pancreatic islet β cell protector, which prevents pancreatic islet β cells from exhaustion and injury resulting from excessive insulin secretion under high glucose conditions. Geniposide administration is a possible way of balancing the oxidative stress of pancreatic β cells by regulating the expression of protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin 1 (ERO1).³⁸ Extensive islet amyloid polypeptide (IAPP) deposits are thought to contribute to pancreatic β cell dysfunction, either by direct cytotoxicity or by reducing the pancreatic islet β cell mass, resulting in impaired insulin secretion. Geniposide prevents human IAPP-induced cytotoxicity in INS-1E cells through the upregulation of (insulin degrading enzyme) IDE.³⁹ Liu et al⁴⁰ suggested that AMPK plays a crucial role in how geniposide antagonizes high glucose-induced pancreatic β cell injury.

Elevated thioredoxin-interacting protein (Txnip) levels induce β cell apoptosis and dysfunction.⁴¹ Geniposide improves GSIS by accelerating Txnip degradation. A further study proved that geniposide-related Txnip degradation attenuates the early-stage apoptosis of pancreatic β cells. Geniposide regulates Txnip degradation and GSIS through endoplasmic reticulum (ER) stress by accelerating the phosphorylation of Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and Inositol-requiring enzyme-1α (IRE1α).⁴²

The main roles of GLP-1R are stimulation of GSIS, induction of pancreatic β-cell proliferation, inhibition of postprandial glucagon release, and delay in gastric emptying.⁴³ Geniposide inhibits the early stage of lipotoxicity-induced β-cell apoptosis, and GLP-1R plays a critical role by counteracting lipotoxicity in INS-1 pancreatic islet β cells.⁴⁴ Cui et al⁴⁵ analyzed the microarray data of INS-1 cells treated with geniposide and identified key lncRNAs and mRNAs in a 2021 study. They found that the lncRNA NONRATT027738 interacts with all three hub mRNAs (Pomc, Htr2a, and Agtr1a). There is also other research focusing on the role of GLP-1R in the beneficial effects of geniposide-medicated pancreatic islet β cell protection. Geniposide potentiates insulin secretion via activating GLP-1R and adenylyl cyclase/cAMP signaling pathways. Researchers also observed Ca⁺² channel activation by geniposide.³⁹

Apart from inhibiting the damage and apoptosis of pancreatic islet β cells, another therapeutic strategy for the protection of pancreatic β cells is to promote their regeneration. Geniposide promotes pancreatic islet β cell regeneration in vivo to balance blood glucose levels and the mechanism includes triggering duct cell differentiation by enhancing TCF7L2 expression and activating the Janus-activated kinase 2 (JAK2) / signal transducer and activator of transcription 3 (STAT3) pathway.⁴⁶

Improving Insulin Resistance (IR)

IR is an important factor, which can lead to the onset of type 2 diabetes. IR occurs when cells in muscles, fat, and liver stop responding to insulin. Geniposide alleviates abnormal glucose tolerance and hyperinsulinemia, indicating that it has an IR-alleviating effect.⁴⁷ Geniposide promotes autophagy in HepG2 cells and significantly improves IR, which may be associated with the dynamic regulation of the P62/NF-κB/GLUT-4 pathway.⁴⁸ Zhao et al⁴⁹ pointed out that geniposide improves insulin signaling deficiency possibly through AMPK-mediated Txnip degradation in 3T3-L1 adipocytes. A regulatory mechanism study considered that geniposide could improve systemic insulin sensitivity by regulating circulating RBP4 levels.³¹

Inhibiting Hepatic Glucose Production

The liver plays a crucial role in maintaining blood glucose homeostasis by coordinating glucose storage, utilization, and production. The ability of the liver to store glycogen is typically diminished in diabetic subjects. Thus, promoting hepatic glycogen synthesis and suppression of hepatic glucose production could be more effective in the improvement of overall glycemic control. Geniposide significantly inhibits hepatic glucose production in a dose-dependent manner and the inhibitory effect is partly through AMPK activation.⁵⁰ Geniposide simultaneously stimulates glycogen synthesis in mice induced by a high-fat diet and streptozotocin injection and HepG2 cells.

Suppressing Gluconeogenesis

Hepatic gluconeogenesis is an important factor in regulating plasma glucose levels. It may be the major source of fasting blood glucose and it has been regarded as one of the main contributors to hyperglycemia in diabetes mellitus. Phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) are the key regulatory enzymes of gluconeogenesis.⁵⁰ Geniposide significantly decreases the expression of glycogen phosphorylase and G6Pase at mRNA and protein levels, as well as their activity, in a dose-dependent manner.⁵¹ The activities of PEPCK and G6Pase were significantly suppressed by geniposide. Geniposide may reduce blood glucose levels and suppress hepatic gluconeogenesis by regulating the AKT serine/threonine kinase (AKT)-FOXO1 pathway.⁵²

Effects on Lipid Metabolism

Lipid metabolism disorder is one of the main risk factors of metabolic diseases, which is characterized by abnormal content or type of triglycerides, fatty acids, or cholesterol in the serum or surrounding tissues.⁵³ Lipid metabolism includes three main aspects as follows: Lipolysis, lipogenesis, and lipid transportation. Regulating lipid metabolism and restoring lipid homeostasis is one of the methods for the prevention and treatment of dyslipidemia and related metabolic diseases.⁵⁴ Figure 5 summarizes the pharmacological effects of geniposide on lipid metabolism and the details are exhibited in Table 2.

Table 2 In vivo/In vitro Studies of Geniposide in Lipid Metabolism

Figure 5 Pharmacological effects of geniposide on Lipid Metabolism.

Promoting Lipolysis

Fat is mostly stored in adipose and other tissues or other non-adipose tissues. Excessive accumulation of triacylglycerols (TAGs) and cholesterol esters (CEs) leads to abnormal lipid metabolism. The lipid droplets (LDs) in the cytoplasm are mainly rich in TAGs and CEs, which are considered dynamic TAG storage pools and take part in several aspects of lipid metabolism.⁵⁵

The primary oxidative pathway for energy production in the liver is β-oxidation which takes place in the mitochondria, the predominant regulators of which are the transcription factors peroxisome proliferators-activated receptors α (PPARα) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc1α).⁵⁶ Geniposide exerts suppressive effects on hepatic lipid accumulation in rats fed with a high-fat diet and the underlying mechanism may be related to the regulation of adipocytokine release and PPARα expression.⁵⁷ Geniposide improves the expression of NF-E2-related factor 2 (Nrf2), PPARγ, PPARα, and heme oxygenase 1 (HO-1) and regulates the AMPK/mTORC signaling pathway in mice. Genipin, the aglycone of geniposide, inhibits intracellular lipid accumulation and significantly increases PPARα mRNA expression.⁴⁷ In the mitochondrion, FAs are oxidatively decomposed by carnitine palmitoyltransferase 1 (CPT1) to provide energy for other physiological processes. Sirtuin 1 (SIRT1), FoxO1, and PGC1α also control the activity of the related enzymes. Geniposide treatment alters the expression of FoxO1, PDK4, p-PDH and PDH at mRNA/protein level in the gastrocnemius of HFD-fed mice.³¹ In agreement with this finding, the inhibitory effects of geniposide on the FoxO1/PDK4/PDH signaling pathway have also been reported.³⁰

Lipophagy (lysosome-mediated autophagy) and cytoplasmic lipolysis are two pathways to decompose TAGs and CEs in LDs. Geniposide increases the levels of autophagy in plaque macrophages via inhibiting the triggering receptors expressed on myeloid cells 2 (TREM2)/mechanistic target of rapamycin kinase (mTOR) axis.⁵⁸ It may block the development of atherosclerosis through this mechanism. The more widely studied effect of geniposide on inflammation and oxidative stress through enhancing autophagy has been extensively studied recently, although further research is warranted.^59–63

Activation of thermogenic adipocytes has great significance in the treatment of lipid metabolism disorders and is related to plenty of metabolic diseases. There is a new study published in 2021 different from the previous studies on the effect of geniposide on lipid metabolism. Thermogenic adipocyte is acknowledged to be a major regulator of energy homeostasis by affecting energy expenditure and glucolipid metabolism. Li et al⁶⁴ suggested that geniposide is an inhibitor of fat thermogenesis in adipocytes through regulating the PKA signaling pathway, indicating that adipocyte thermogenic capacity may be inessential for geniposide to exert its effects in obesity, and the metabolic advantage of geniposide exerted on other organs, except for adipose tissues, can indemnify for the effect of geniposide-induced thermogenic activity of adipocytes. Further research on how geniposide regulates lipolysis through influencing thermogenesis in adipocytes is warranted.

Inhibiting Lipogenesis

Excessive lipid synthesis is a major cause of lipid metabolism disorders. The de novo lipogenesis, FAs obtained from acetyl-CoA to fatty acyl-CoA transformation, is principally regulated by acetyl-CoA carboxylase (ACaCa) and fatty acid synthase (FASN). The central enzymatic node of saturated fatty acids (SFAs) transformed into monounsaturated fatty acids (MUFAs) is stearoyl-CoA desaturase 1 (SCD1), which is regulated by sterol regulatory element-binding transcription factor 1 (SREBP-1c), carbohydrate-responsive element-binding protein (chREBP), and LXR. Transcriptional regulation of Acc and FASN happens mainly via SREBP-1c and chREBP. Geniposide is highly effective in inhibiting lipogenesis and free fatty acid (FFA) levels in hepatic tissues were decreased significantly after geniposide treatment, whereas TG, FASN, ACaCa, and malonyl-CoA levels were significantly reduced in the geniposide group.⁶⁵ Geniposide could significantly suppress hepatic total triglyceride (TG), total cholesterol (TC), and FFA in NAFLD rodents.⁶⁶ Geniposide also decreases the expression of SREBP-1c.⁶⁷

Cholesterol plays a central role in lipid metabolism. TC and/or low-density lipoprotein cholesterol (LDL-c) levels ultimately depend on cholesterol hypersecretion. Significantly, geniposide inhibited TC and LDL production in different animal models. High mobility group box 1 (HMGCR), squalene monooxygenase, and SREBP are all crucial players in cholesterol synthesis (the first two are rate-limiting enzymes in the biosynthetic pathway, and the latter is a master transcriptional regulator of cholesterol synthesis). Geniposide inhibited TC, TG, LDL, and very-low-density lipoprotein (VLDL) production, SREBP1-c expression, and HMGCR expression at the mRNA/protein level in vivo.^67,68 Zheng Y et al published a study focusing on cholesterol metabolism in osteoporosis in 2021, they found that geniposide can effectively ameliorate dexamethasone-induced cholesterol accumulation via activating the GLP-1R/ABCA1 axis in MC3T3-E1 cells.⁶⁹ Geniposide has significant beneficial effects on cholesterol metabolism and lipid accumulation in HepG2 cells. After HepG2 cells were treated with geniposide, the expression of ABCA1 and AMPK mRNA significantly increased, while that of Cytochrome P450 Family 7 Subfamily A Member 1 (CYP7A1) and Liver X receptor alpha (LXRA) mRNA was significantly reduced.⁶⁸ Geniposide and chlorogenic acid combination can significantly reduce hepatic TG, TC, and FFA via SCD-1 suppression in the liver.⁶⁶

Regulating Lipid Transport

Lipid transportation in the blood depends on plasma lipoproteins. High-density lipoproteins (HDL) snatch the cholesterol from other lipoproteins or the peripheral tissues and bring it back to the liver, which is called reverse cholesterol transport (RCT). In the circulation, VLDL, produced in the liver, release TGs and FFA.⁷¹ Hepatic lipase removes TGs from intermediate-density lipoprotein, forming LDL. LDL has a high cholesterol content and it can be removed from circulation through binding to LDL receptors in extrahepatic tissues and the liver.⁷²

Geniposide attenuates the development of atherosclerosis and reduces serum TC, TG, and LDL levels in ApoE-/- mice.⁷⁰ In vitro and in vivo experiments have revealed that geniposide can modify the efflux-related proteins and lipoproteins to regulate cholesterol uptake, thus balancing the lipid transport levels and eventually inhibiting the formation of foam cells. These advantages seem to be mediated by the downregulation of P-p38 mitogen-activated protein kinase (MAPK) and P-AKT.

There are two main methods of assuaging hypercholesterolemia. The first is to increase the transformation of cholesterol into bile acids in the liver and the other is enhanced RCT, through which cholesterol in the plasma can be returned to the liver for catabolism. On the one hand, geniposide improves the hepatic synthesis of bile acids via passivating the negative feedback regulation of bile acids regulated by Farnesoid X receptor (FXR).⁷³ On the other hand, geniposide facilitates the RCT, more cholesterol is directed from the circulation back to the liver, exerting the hypolipidemic effect of geniposide indirectly.⁷³ Hwa-Young Lee⁷⁴ displayed an unusual yet very clear design solution, their study was conducted using the Eucommia ulmoides Oliver extract, and its active constituents, aucubin and geniposide. They found that geniposide reduces hepatic lipid accumulation and secretion of apolipoprotein B, and they believe the mechanism may be linked to ER stress and hepatic dyslipidemia.

Discussion

Glucolipid metabolism is complex and variable, often involving multiple pathological reactions. Over the past few decades, a growing number of animal and cell model studies have revealed the potential of geniposide to ameliorate glucolipid metabolism disorders. We summarized basic information about various in vitro and in vivo studies on the pharmacological effects of geniposide on glucolipid metabolism in this review.

In terms of glucose metabolism, geniposide can increase glucose utilization and insulin production, protect pancreatic islet β-cells, inhibit IR and hepatic glucose production, and suppress gluconeogenesis. In the aspect of lipid metabolism, geniposide can promote lipid decomposition, inhibit lipogenesis, and regulate lipid transport. Geniposide regulates a wide range of factors related to glucose and lipid metabolism, including metabolic regulators AMPK, Glut2\Glut4\GLP-1R, which are indispensable in glucose metabolism, and PPARα/SREBP1c/ LXR/FXR, which regulate lipid metabolism. Such multi-pathway regulation improves the entire glycolipid metabolism network in a three-dimensional manner. However, there are still some challenges that need to be addressed.

First of all, the current research on geniposide is restricted to whole animal and cell experiments and has not included any clinical trials. Therefore, further clinical studies are essential to determine the role of geniposide in clinical therapy.

Secondly, thorough studies and precise targets are required. Studies on the effect of geniposide on glucolipid metabolism are sometimes unconvincing and have not been verified via rigorous experiments using knockout mice or cell lines. There is insufficient evidence supporting the results and conclusions of these studies. At present, research focusing on the pathological mechanisms of geniposide has not included a specific target, and future studies should be more accurate.

Furthermore, the efficacy and toxicity of geniposide need to be confirmed. We investigated several studies on geniposide toxicity that were published in 2021, and found that chronic oral toxicity in rats resulted in an impact on serum biochemical, urinary, and hematological parameters, and affected related organ weights. However, studies which reported that geniposide improves glucose and lipid metabolism have not investigated the potential toxicity of geniposide. Further studies are warranted to verify the feasibility of geniposide as a drug and develop a safe procedure for its administration. Its efficacy should also be compared with that of the current major drugs for metabolic diseases.

Conclusion

Geniposide ameliorates lipid and glucose metabolic disorders, improving the entire glycolipid metabolism network in a three-dimensional manner at the level of molecular mechanism (Figure 6). Accumulating studies, related to the effect of geniposide on glucose and lipid metabolism, have been performed. While full-scale progress has been made, the underlying mechanism of glucolipid metabolism has not yet been utterly elucidated. Future research is warranted to explain both long- and short-term effects of geniposide on glucose and lipid metabolism. Our review affords the first systematic summary of research examining the effect of geniposide on glucolipid metabolism, which will be beneficial in the development of metabolic diseases therapy in the future and in obtaining more reproducible and reliable data.

Figure 6 Molecular mechanisms involved in the regulation of glucolipid metabolism by geniposide.