The potential effect of polyphenols in emerging pharmacological liver targets for glucose regulation and insulin resistance: a review

Abstract

In type 2 diabetes mellitus (DM), there is a combination of impaired insulin secretion and resistance in the target tissues. In the case of the liver, these events lead to decreased insulin effectiveness and increased glucagon levels, resulting in an imbalance that promotes excessive hepatic gluconeogenesis and glycogenolysis, contributing to hyperglycemia. Effective management of hyperglycemia and insulin resistance is crucial, underscoring the need for innovative liver-specific interventions. Polyphenols, renowned for their diverse biological activities, have emerged as promising candidates to treat type 2 DM. Based on a literature review spanning the last decade, this comprehensive systematic review thoroughly evaluates the effectiveness of polyphenols in targeting hepatic pathways for managing type 2 DM. The focus will be on assessing how polyphenols affect key targets, including protein tyrosine phosphatase 1B (PTP1B), the glucagon receptor, glucokinase, glycogen phosphorylase, and fructose 1,6-bisphosphatase. While there has been considerable attention on polyphenols as PTP1B inhibitors, studies on their impact on other targets have been comparatively limited. Notably, there is a lack of studies exploring polyphenols as glucagon receptor antagonists. Among polyphenols, flavonoids exhibit significant potential across diverse pathways, with hydroxy groups playing a pivotal role in their biological activities. However, further research, especially in cellular and animal models, is warranted to thoroughly validate their efficacy.

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Sónia Rocha

Sónia Rocha completed her PhD in Pharmaceutical Sciences, specializing in Medicinal and Pharmaceutical Chemistry, at the Faculty of Pharmacy of the University of Porto (FFUP) in 2024. She obtained her Master's degree in Quality Control, also from FFUP, where she graduated in 2018. She earned her Bachelor's degree in Biology from the University of Aveiro in 2016. Her doctoral research focused on the study of novel antidiabetic drugs targeting the liver. Her current research interests include high-throughput screening of compounds for pharmacological activities, diabetes, metabolism, and ciliopathies.

Inês Santos

Inês Santos has a Bachelor's degree in Biochemistry from the Faculty of Sciences (FCUP) and the Institute of Biomedical Sciences Abel Salazar (ICBAS) at the University of Porto, completed in 2023. She is currently a master's student in Quality Control at the FFUP. Her research explores the protective effects of both natural and synthesized compounds, with a particular focus on their antioxidant and anti-inflammatory properties.

M. Luísa Corvo

M. Luísa Corvo is a principal researcher with Habilitation in the Faculdade de Farmácia, Universidade de Lisboa and integrated researcher at iMed.ULisboa (Drug Delivery & Immunoengineering Group – BioNanoScience). Her research focuses on the development of lipidic drug carrier nanosystems for the delivery of anti-inflammatory and anticancer drugs, ranging from small molecules to biopharmaceuticals, including enzymes. Particularly, she has worked on the development and optimization of liposomes for the treatment and/or imaging of inflammatory diseases and cancer.

Eduarda Fernandes

Eduarda Fernandes concluded her PhD in Pharmaceutical Chemistry in 1996, at FFUP. Presently, she is Associate Professor with Habilitation at the Laboratory of Applied Chemistry, Department of Chemical Sciences, FFUP, and a researcher at the LAQV-REQUIMTE. In 2002, she created a research unit (Free Radicals and Antioxidants Unit-FRAU), which she has been coordinating to the present, focused on the development and application of methodologies for the study of antioxidant, anti-inflammatory, antidiabetic, antiobesogenic and anti-cancer properties of natural and synthetic compounds, in non-cellular, cellular and in vivo models.

Marisa Freitas

Marisa Freitas completed her PhD in Pharmaceutical Sciences in 2010 at FFUP. She is currently an Assistant Researcher at LAQV-REQUIMTE, working in the Laboratory of Applied Chemistry at FFUP. Her research focuses on three key areas: (i) investigating the antioxidant, anti-inflammatory, and anti-diabetic effects of natural and synthetic compounds; (ii) studying the harmful inflammatory effects of nanoparticles and exploring agents that can protect against these impacts; (iii) examining the obesogenic and diabetic effects of endocrine disruptors and their implications for metabolic health.

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1. Introduction

The epidemic of diabetes mellitus (DM) and its associated complications presents a major global health challenge. As a complex chronic illness, DM substantially increases the risk of developing microvascular and macrovascular complications. Its rising incidence and prevalence are particularly concerning, highlighting the urgent need for effective prevention and management strategies worldwide.¹

Various pharmacological interventions for DM aim to lower blood glucose levels. However, current therapeutic approaches have inherent limitations and adverse effects, including hypoglycemia, gastrointestinal disturbances, urinary tract infections, weight gain, and cardiovascular risk. These challenges underscore the need for novel treatment strategies to improve DM management.² Given the liver's crucial role in glucose regulation, liver-targeted therapies are essential for glycemic control. However, the limited development of treatments directly addressing hepatic dysfunction reflects a prevailing challenge in current therapeutic strategies.^3,4

A diverse range of bioactive compounds derived from plant-based sources, including vegetables, fruits, and edible leaves, has exhibited promising pharmacological properties, with polyphenols standing out as particularly significant.^5–9 Despite the growing interest in the pharmacological potential of polyphenols, a comprehensive review of their effects on hepatic targets in the context of DM is still lacking. A comprehensive review of the existing literature on polyphenolic structures that have been investigated is crucial for identifying research gaps and potential therapeutic applications. This review aims to bridge this knowledge gap by summarizing current findings on polyphenols and their modulation of liver-related targets involved in glucose homeostasis and insulin resistance. Specifically, it explores polyphenols as inhibitors of protein tyrosine phosphatase 1B (PTP1B), glucagon receptor antagonists, glucokinase (GK) activators, glycogen phosphorylase (GP) inhibitors, and fructose 1,6-bisphosphatase (FBPase) inhibitors.

2. Diabetes mellitus

According to the World Health Organization, noncommunicable diseases (NCDs), including cardiovascular diseases, cancer, DM and chronic respiratory diseases, represent the leading cause of death globally, being responsible for 74% of deaths worldwide.¹⁰ Among the NCDs, DM stands out as a significant global health concern. In 2024 alone, nearly 3.4 million individuals lost their lives due to complications related to DM.¹ Despite being one of the most extensively studied diseases, being first mentioned in ancient Egyptian medical texts,¹¹ DM still demands continuous medical attention.¹² The revolutionary discovery of insulin, 100 years ago, marked the turning point in the lifespan of DM patients from a fatal diagnosis into a medically manageable condition.¹³ Insulin is a 51-residue anabolic protein secreted by pancreatic β cells of the islets of Langerhans, comprising two chains, a 21-residue A chain and a 30-residue B chain, linked by disulfide bonds.¹⁴ Over the past 50 years, major discoveries concerning the mechanisms involved in insulin action and insulin resistance have provided important insights into the pathophysiology and management of DM.¹⁵

DM manifests clinically as hyperglycemia and can be classified, according to the Standards of Medical Care in Diabetes (2022) of the American Diabetes Association, into type 1 DM, type 2 DM, specific types of DM due to other causes, and gestational DM.¹⁶ Among all individuals with DM, 10–15% have type 1 DM,¹⁷ while over 90% have type 2 DM, making it the most prevalent form of the condition.¹²

In type 1 DM, hyperglycemia develops as the consequence of the loss of the pancreatic islet β cells. Two forms of type 1 DM have been described, type 1A (autoimmune) and type 1B (idiopathic) DM. Type 1B is far less common and its pathogenesis remains unclear. Type 1A represents around 70–90% of patients, and displays evidence of an autoimmune response against pancreatic β cells.¹⁷ Despite the exact mechanisms remaining unclear, recent studies indicate that the β cell response is more complex than being just a passive target. The classic view considers that β cell loss is mediated by autoimmune mechanisms, where autoreactive T cells erroneously destroy healthy β cells. However, new insights have been recently proposed, considering β cells as key contributors to the disease. β Cells rapidly respond to glucose variations to maintain normal glucose levels. However, this constant demand for insulin release results in endoplasmic reticulum stress and accumulation of misfolded proteins, creating vulnerability and β cell exposure to the immune system.^18–20 These new insights into β cell vulnerability and type 1 DM aetiology are creating novel opportunities for treatment.¹⁸

Type 2 DM is characterized by the occurrence of insulin resistance in insulin-sensitive tissues and impaired insulin secretion due to progressive dysfunction of β cells.¹² However, the interplay between these two defects remains undefined in terms of primary cause-and-effect. The prevailing paradigm defends the idea that insulin resistance precedes impaired insulin secretion.²¹ In this case, to offset the imbalance due to insulin resistance, β cells increase insulin secretion, leading to hyperinsulinemia. This chronic adaptation of β cells, together with environmental and genetic factors, results in β cell malfunction and a progressive decline of insulin secretion. Subsequently, hyperglycemia and type 2 DM develops when the β cells are incapable of compensating for this imbalance.^12,21 The less cited paradigm proposes an opposing viewpoint, suggesting that the primary defect leading to the development of type 2 DM is insulin hypersecretion, or hyperinsulinemia. This condition ultimately results in insulin resistance and eventual β cell failure. However, it is important to note that these paradigms are not fully understood.^21–23

3. Hepatic glucose homeostasis and diabetes mellitus

Glucose serves as the primary source of energy for most tissues in the human body. Hence, maintaining the balance of glucose throughout the body involves a complex regulatory system.²⁴ Generally, to balance glucose homeostasis, insulin is released after the post-prandial increase in glucose levels, a process known as glucose-stimulated insulin secretion.²⁵ After consuming carbohydrates, there is an immediate increase in circulating glucose resulting from absorption in the intestine, leading to insulin secretion. Glucose homeostasis is mainly regulated by direct effects on skeletal muscle, adipocytes and the liver, with distinct roles in metabolic homeostasis. In skeletal muscle, insulin enhances glucose uptake and glycogen synthesis. Adipose tissues respond to insulin by suppressing lipolysis and increasing glucose uptake, leading to lipid accumulation by lipogenesis. In the liver, insulin activates glycogen synthesis, promotes lipid accumulation via lipogenesis and decreases glucose release (Fig. 1).²⁶ In a fasting state, the pancreatic α cells secrete glucagon, a catabolic hormone that opposes the effects of insulin. Glucagon plays a crucial role in maintaining circulating glucose levels during fasting conditions. In the liver, glucagon stimulates hepatic glucose output by glycogenolysis and gluconeogenesis, while in adipocytes, it enhances lipolysis (Fig. 1).³

Fig. 1 Schematic representation of glucose metabolism during the postprandial and fasting states in skeletal muscle, adipose tissue, and liver.

The liver represents one of the most important organs for glucose metabolism. Hepatocytes express several enzymes with actions depending on glucose concentrations. In the postprandial state, blood glucose enters hepatocytes by the glucose transporter type 2 (GLUT2), an energy-independent membrane-bound transporter (Fig. 2).²⁷ Once inside the hepatocyte, glucose is phosphorylated to glucose 6-phosphate by GK, lowering intracellular glucose concentrations and increasing glucose uptake. Glucose transporters are not able to transport glucose 6-phosphate, so it remains retained inside the hepatocyte. Glucose 6-phosphate may be further metabolized in glycolysis, a critical ten-step process to generate energy. Also, in the postprandial state, glucose 6-phosphate is used to synthesize glycogen by glycogen synthase, the process known as glycogenesis (Fig. 2).²⁸ The accumulation of glycogen, which consists of polymerized glucose, during the postprandial state in the liver, is an essential storage form of glucose, which can be utilized during fasting conditions.²⁹ In the fasting state, hepatic glucose production accounts for nearly 90% of endogenous glucose production,³⁰ providing glucose for other tissues such as the brain and muscle. Initially, hepatic glucose production starts with the release of glucose from stored glycogen, a process known as glycogenolysis (Fig. 2), with GP playing a major role. During prolonged periods of starvation, liver glycogen stores are depleted, and de novo glucose synthesis is initiated through gluconeogenesis. The primary source of new glucose is generated from non-carbohydrate precursors such as lactate, glycerol, and amino acids.²⁹ These two pathways, gluconeogenesis and glycogenolysis, lead to an increase in glucose release into the bloodstream, with a consequent uptake of glucose by the peripheral tissues (Fig. 2).³

Fig. 2 Key pathways of hepatic glucose metabolism highlighted, featuring pivotal enzymes in glucose metabolism, glycogen phosphorylase (GP), fructose 1,6-bisphosphatase (FBPase), and glycogen synthase (GS). GLUT2: glucose transporter 2; TCA: tricarboxylic acid.

Typically, glucose levels within the normal range fall between 70 to 90 mg per dL. Type 2 DM develops when insulin levels are insufficient to counteract insulin resistance.¹² In individuals with type 2 DM, the hepatic glucose production is increased and the suppression of glucose metabolism by insulin is impaired both in the fasted and postprandial states. However, DM is not solely characterized by insulin deficiency. Elevated levels of glucagon are characteristic of type 2 DM patients, leading to increased gluconeogenesis and glycogenolysis, contributing to hyperglycemia.^3,12 Additionally, individuals with insulin resistance often exhibit enhanced de novo lipogenesis, resulting in fat accumulation in the liver and increased secretion of triglycerides, leading to elevated blood lipid levels.³¹ Type 2 DM frequently coexists with non-alcoholic fatty liver disease (NAFLD), now recognized as metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD encompasses steatosis (non-alcoholic fatty liver, NAFL) and non-alcoholic steatohepatitis (NASH), with increasing hepatic fibrosis, which can progress to cirrhosis, liver cancer, end-stage liver disease, and death.^32,33 The global prevalence of MAFLD in patients with type 2 DM is estimated to be around 56%, posing an increased risk of adverse hepatic and extra-hepatic clinical outcomes.³⁴

Prolonged hyperglycemia in DM is associated with micro- and macrovascular complications, such as damage to the kidneys, blood vessels and eyes. Treating hyperglycemia is of utmost importance in type 2 DM patients, with the liver being an important target organ for glucose homeostasis. Therefore, drugs that can target glucose metabolism or glucose uptake in the liver have the potential to improve hyperglycemia.³ The increased hepatic glucose output, a hallmark of liver dysregulation in type 2 DM, is not directly addressed by the currently prescribed antidiabetic medications, except for metformin.³⁵ This biguanide compound derivative, unlike most commercial drugs, is derived from a natural product used in herbal medicine, the plant Galega officinalis, and is the most widely prescribed drug for type 2 DM therapy. Despite being used clinically for 60 years, its exact mechanism of action remains incompletely understood.³⁶ Metformin acts primarily through the improvement of blood glucose levels by suppressing hepatic gluconeogenesis.³⁰ However, despite being the first-line agent for the treatment of type 2 DM, metformin is associated with various side effects, with up to 25% of patients experiencing gastrointestinal symptoms such as abdominal pain, diarrhea, nausea and vomiting, and approximately 5% are unable to tolerate metformin.³⁷ It is essential to find novel targets for decreasing hepatic glucose production or to promote liver glucose storage with minimal side effects. Other liver-targeted agents have been investigated in the clinic for the treatment of type 2 DM, including PTP1B inhibitors, glucagon receptor antagonists, GK activators, GP inhibitors, and FBPase inhibitors.³

3.1 Protein tyrosine phosphatase 1B

Insulin is secreted into the portal vein, exposing the liver to insulin concentrations two- to three-fold higher than those in the general circulatory system. The insulin signaling pathway initiates equally in all cellular types, with the binding of insulin to the insulin receptor (IR) on the cellular membrane and the consequent autophosphorylation of the IR at the tyrosine residues. This receptor comprises two α-chains and two β-chains, where insulin binds to the extracellular α-subunits of the IR (Fig. 3).³⁸ The activation of the IR triggers a downstream metabolic signaling pathway, with the recruitment of diverse substrates. In this way, the activated IR recruits the insulin receptor substrates (IRS), being subsequently phosphorylated at the tyrosine residues. The major IRS isoforms expressed in the hepatocytes are IRS1 and IRS2. The phosphorylated IRS serves as docking for phosphoinositide 3-kinase (PI3K), which phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP₂) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP₃). The activation of PIP₃ allows the recruitment of 3-phosphoinositide-dependent protein kinase-1 (PDK1), which leads to the phosphorylation of protein kinase B (PKB, also known as Akt) at Thr308. In addition, Akt is also activated by phosphorylation by mammalian target of rapamycin (mTORC) 2 at Ser473. Fully activated Akt enables the signal of multiple metabolic processes, including glycogen synthase kinase-3 (GSK3), the transcription factor forkhead box O1 (FOXO1), and multiple regulators of mTORC1 activity.^31,38 As represented in Fig. 3, Akt induces glycogen synthesis through inactivation of GSK3, allowing the activation of glycogen synthase. Also, Akt inhibits gluconeogenesis and induces GK expression by phosphorylating and inhibiting FOXO1. In addition, Akt activates mTORC1, resulting in stimulation of protein synthesis. mTORC1 promotes sterol regulatory element-binding protein 1c (SREBP1c) to increase lipid synthesis. Moreover, the carbohydrate response element binding protein (ChREBP) also activates lipogenesis.^31,39

Fig. 3 Hepatic insulin signaling pathway and the effects of insulin on glucose utilization, as well as the synthesis of glycogen, proteins, and lipids. Representation of the inhibition of the negative regulatory actions of PTP1B. AKT: protein kinase B; ChREBP: carbohydrate response element binding protein; FOXO1: forkhead box O1; GSK3: glycogen synthase kinase-3; IRS: insulin receptor substrate; mTORC: mammalian target of rapamycin; PDK1: 3-phosphoinositide-dependent protein kinase-1; PI3K: phosphoinositide 3-kinase; PIP₂: phosphatidylinositol (4,5)-bisphosphate; PIP₃: phosphatidylinositol (3,4,5)-trisphosphate; PTP1B: protein tyrosine phosphatase 1B; SREBP1c: sterol regulatory element-binding protein 1c.

In the cells, protein phosphorylation occurs mainly on tyrosine (Tyr), serine (Ser) and threonine (Thr) residues, with protein kinases and protein phosphatases being the two super-enzyme families responsible for phosphorylation and dephosphorylation, respectively.⁴⁰ Each step in the insulin signaling pathway involves a reversible enzymatic reaction, where the activated kinases of the pathway can be dephosphorylated by a phosphatase to stop their action. The discovery of the tyrosine kinase activity of the IR and IRS prompted a search for tyrosine phosphatases that could terminate their activation. PTP1B, a member of the protein tyrosine phosphatases super-family, is a negative regulator of the insulin signaling pathway through the dephosphorylation of the tyrosine residues of IR and IRS (Fig. 3).⁴¹ In fact, since PTP1B is a negative regulator of the insulin signaling pathway, increasing evidence demonstrates that inhibitors of this enzyme might increase the levels of phosphorylation of IR and its substrates, improving insulin sensitivity. Therefore, PTP1B is considered a potential target for the management of type 2 DM.⁴² PTP1B is an intracellular PTP comprising 431 amino acids with a molecular size of 50 kDa. It is ubiquitously expressed, being localized at the cytoplasmic face of the endoplasmic reticulum (Fig. 3). The catalytic domain of PTP1B possesses near 40% sequence homology with the other PTPs.⁴³ In addition to insulin signaling, PTP1B also displays actions in the leptin signaling pathway through the dephosphorylation of Janus kinase 2 (JAK2), leading to its deactivation. Therefore, PTP1B inhibition could decrease leptin resistance, being a possible therapeutic strategy for weight loss.^40,44 Obesity is one of the epidemics of the 21^st century and is associated with the development of type 2 DM and MAFLD, among other adverse pathological conditions.⁴⁵ It is considered one of the major risk factors for developing type 2 DM, where around 90% of type 2 DM patients are overweight or obese.^46,47 Indeed, as PTP1B can play several roles in different signaling pathways, increasing attention has been dedicated to this enzyme as an interesting therapeutic target.^40,44

Up to now, only a few PTP1B inhibitors have reached clinical trials, including trodusquemine, ertiprotafib, and JTT-551. However, these inhibitors were discontinued from clinical trials due to reduced efficacy, lack of specificity, and adverse side effects.^40,43 Taking this into account, it is crucial to find novel effective, selective, and safe PTP1B inhibitors.

3.2 Glucagon receptor

Glucagon is a linear peptide hormone composed by 29 amino acids secreted by the pancreatic α cells. As already mentioned, in opposition to insulin, glucagon serves as an antagonist hormone, stimulating hepatic glucose production by glycogenolysis and gluconeogenesis to avert hypoglycemia.⁴⁸ Glucagon is secreted in response to various stimuli, with hypoglycemia, certain amino acids, central nervous system, and the incretin hormone gastric inhibitory polypeptide (also known as glucose-dependent insulinotropic polypeptide; GIP) being among the most notable inducers. In contrast, glucagon secretion is suppressed by high glucose levels, by insulin, amylin, somatostatin, and by another incretin, glucagon-like peptide-1 (GLP-1). In a healthy individual, all the factors are coordinated to regulate glucagon secretion,⁴⁹ where the levels of glucagon in the blood ranges from 6–12 pM (∼20–40 pg mL⁻¹) after an overnight period of fasting, and from 3–5 pM (∼10–17 pg mL⁻¹) in the postprandial state. Individuals with type 2 DM frequently develop fasting and postprandial hyperglucagonemia, showing a 50 to 100% increase in glucagon levels in the fasting state, which leads to increased hepatic production of glucose, and the consequent development of hyperglycemia. In addition, the administration of exogenous insulin is not enough to normalize glucagon levels in individuals with type 1 and type 2 DM.⁵⁰ In fact, it was demonstrated that postprandial hyperglucagonemia is responsible for 50% of the increments in plasma glucose in type 2 DM patients.⁴⁹ Hence, addressing the dysfunctions associated with glucagon has emerged as a new therapeutic avenue. Specifically, targeting the glucagon receptor may be a promising approach to reduce the hepatic glucose production and lower plasma glucose levels.³

In the hepatocyte, glucagon binds to its seven-transmembrane receptor, a G protein-coupled receptor that can be also found in pancreatic β cells, activating adenylate cyclase to increase intracellular levels of cyclic adenosine monophosphate (cAMP), which in turn stimulates protein kinase A (PKA) signaling. PKA activation subsequently induces cAMP-response element-binding protein (CREB) and its coactivators CREB-regulated transcriptional coactivator 2 (CRTC2) and CREB-binding protein (CBP), thereby activating gluconeogenic enzymes. The binding of glucagon also activates the phospholipase C (PLC)/inositol triphosphate (IP₃)/Ca²⁺ pathway, responsible for increasing the intracellular Ca²⁺ levels. Both pathways mediate the hyperglycemic effects of glucagon (Fig. 4).^30,51,52

Fig. 4 Glucagon receptor signaling. cAMP: cyclic adenosine monophosphate; CREB: cAMP-response element-binding protein; CBP: CREB-binding protein; CRTC2: CREB-regulated transcriptional coactivator 2; GLUT2: glucose transporter 2; IP₃: inositol triphosphate; PIP₂: phosphatidylinositol (4,5)-bisphosphate; PKA: protein kinase A; PLC: phospholipase C.

Targeting the glucagon receptor represents a promising approach under investigation to reduce hepatic glucose production. Research findings have demonstrated that mice lacking glucagon receptors in the liver exhibit improved glucose tolerance, elevated plasma glucagon levels and higher insulin sensitivity. Some evidence demonstrates that the hepatic glucagon receptor is linked to the development of pancreatic α cells, where α cell hyperplasia was observed in mice lacking the glucagon receptor. In addition, besides the glucose regulatory effect, pharmacological inhibition of the glucagon receptor also plays a role in lipid metabolism. However, inconsistent results have been observed, with both elevations and reductions in blood cholesterol levels.⁵³ It remains unclear if this effect is translated to humans, highlighting the need for additional studies on this subject.³⁰

Bay 27-9955, MK-0893 and LY2409021 are three glucagon receptor antagonists already studied in human clinical trials.³⁰ Bay 27-9955 decreased fasting glucose levels in humans, but the trials were discontinued. MK-0893 is a selective and reversible competitive glucagon receptor antagonist compound that showed improvements in hyperglycemia. However, it has been observed to cause increases in plasma cholesterol levels. LY2409021 showed a promising reduction in glucose levels in phase I and phase II clinical trials, and clinical development is ongoing.^3,30 Recent studies with LY2409021 showed that this glucagon receptor antagonist was able to decrease fasting plasma glucose concentrations, with no improvements in postprandial glucose tolerance in type 2 DM patients.⁵⁴ While results with glucagon receptor antagonists suggest that this target could be a promising strategy in DM, further research is needed.

3.3 Glucokinase

GK, also known as hexokinase IV or hexokinase D, belongs to the hexokinase family. In mammals and other vertebrates, four hexokinases have been discovered and identified as hexokinase I–IV, or as hexokinase A–D. Hexokinases I, II and III possess a molecular weight of near 100 kDa, while hexokinase IV, GK, displays a molecular weight of near 50 kDa, and is composed of 465 amino acids.⁵⁵

In the human body, GK is mainly expressed in the pancreatic β cells and liver cells. This enzyme is responsible for the first step of glucose metabolism, catalyzing the phosphorylation of D-glucose to glucose 6-phosphate.⁵⁶ In pancreatic β cells, GK acts as a glucose sensor, controlling the threshold for glucose-stimulated insulin secretion. In type 2 DM individuals, insulin secretion is impaired in part due to the reduced activity of GK. Therefore, increased levels of glucose are required to initiate insulin secretion. In hepatocytes, this enzyme plays a key role in glucose uptake and hepatic glucose regulation,⁵⁷ and its activity is regulated through an interaction with the GK regulatory protein (GKRP), which binds and inactivates GK in the nucleus. In the postprandial state, GK is released to the cytoplasm following GKRP–GK complex disruption, stimulating glycolysis, glycogen production and storage and de novo lipogenesis (Fig. 5). In the fasting state, GKRP inactivates the enzyme, and glycogenolysis and gluconeogenesis pathways are activated to produce glucose.⁵⁸ In type 2 DM individuals, it is described an impairment of near 50% of the GK activity during the progression of the disease, contributing to the reduction of glycogen storage and improper glucose regulation.⁵⁷

Fig. 5 Molecular regulation of GK in hepatic cells. GK: glucokinase; GKRP: GK regulatory protein; GLUT2: glucose transporter 2.

GK activation is a potential intervention for glucose homeostasis. GK activation targeting the liver stimulates hepatic glucose uptake and glycogen production and storage, inhibiting glycogenolysis. The activation of GK in pancreatic β cells stimulates the secretion of insulin. The net effect of GK actions in the liver and β cells, in addition to its reduced activity in type 2 DM individuals, has led to the development of dual activators targeting both the liver and pancreas, or only selective activators targeting only one tissue.^35,59 However, GK activators have not reached clinical use due to adverse side effects, including hypoglycemia, toxicity, and increased plasma concentration of triglycerides. Still, these effects might be preventable with patient selection and liver-selective GK activators.⁵⁹ The liver-selective GK activator PF-04991532 has shown favorable effects on glucose regulation in diabetic rats. However, additional studies need to be conducted due to the occurrence of oxidative metabolites of the compound found in the human plasma. Additional clinical studies are underway with another liver-selective GK activator, TTP399.³ Recent clinical studies with TTP399 have demonstrated promising effects.^60,61 These clinical investigations aim to assess whether glycemic control is improved in patients with type 1 DM, without increasing hypoglycemia or ketoacidosis. The findings indicate enhanced glycemic control without elevating the incidence of hypoglycemia, and reduced occurrence of diabetic ketoacidosis.^60,61

A different approach for GK activators is to inhibit the binding to GKRP. This approach could be beneficial since liver-selective GKRP inhibition decreases glucose levels without the risk of hypoglycemia. The compound AMG-3969, which can dissociate GK and its receptor, showed promising results in a diabetic mice model, decreasing blood glucose levels, with no effect in normal mice.³ These effects with liver-selective GK activators or liver-selective GKRP inhibitors have been demonstrating encouraging results as a novel alternative to be used as antidiabetic agents.

3.4 Glycogen phosphorylase

Glycogen stored in the liver serves as a crucial source of glucose, particularly valuable during periods of reduced food intake. GP is a key enzyme involved in the glycogenolysis pathway. This enzyme catalyzes the degradation of glycogen at the α-1,4-glycosidic linkage, to produce glycogen 1-phosphate.⁶² This product can be converted into glucose 6-phosphate by phosphoglucomutase (PGM), and glucose 6-phosphate can be further transformed into glucose by glucose 6-phosphatase (G6Pase). Glucose can then be transported from the hepatocyte into the bloodstream (Fig. 6).²⁹

Fig. 6 Representation of the hepatic glycogenolysis process. cAMP: cyclic adenosine monophosphate; G6Pase: glucose 6-phosphatase; GLUT2: glucose transporter 2; GP: glycogen phosphorylase; PGM: phosphoglucomutase; PhK: phosphorylase kinase; PKA: protein kinase A.

GP exists in two interconvertible forms, the active phosphorylated GPa form, and the inactive dephosphorylated GPb form.⁶³ GP activation requires a cascade mechanism in the hepatocyte, which starts with the binding of glucagon to its receptor, activating the cAMP/PKA signaling pathway, already mentioned in section 3.2. PKA phosphorylates phosphorylase kinase (PhK), which in turn activates GP by serine-14 phosphorylation (Fig. 6).^29,62

Three different isoforms of GP have been identified, involving different tissue locations and physiological functions, namely in the brain (bGP), liver (lGP), and muscle (mGP). bGP provides an energy supply of glucose for periods of hypoglycemia, mGP delivers energy during muscle contraction, and lGP ensures glucose release from hepatic glycogen to other parts of the body.^64,65 Therefore, as a key isoform involved in glucose regulation, lGP is a target for new possible pharmaceutical interventions. The inhibition of lGP may reduce plasma glucose levels by increasing glucose storage in the form of glycogen, reducing hyperglycemia.⁶² In addition, as glucose is a physiological regulator of lGP, inhibitors of lGP offer an appealing advantage. They demonstrated the ability to inhibit the enzyme at elevated blood glucose levels, but their potency diminishes when blood glucose levels decrease, thereby reducing the risk of hypoglycemia.³ However, there is a sequence homology among brain, muscle and liver isoforms of around 80%, and around 100% homology in the catalytic site of the enzyme.⁶⁶ This high homology among isoforms is posing challenges in the search for a selective inhibitor of lGP. mGP inhibition is associated with serious adverse side effects in muscle due to the accumulation of glycogen in the tissues. Hence, it is essential to find selective and safe GP inhibitors.⁶²

CP-368962 is a GP inhibitor that has been studied in clinical trials, showing hypoglycemic effects in type 2 DM individuals. However, after 4 weeks of treatment with CP-368962, the hypoglycemic effect was lost, indicating reduced durability of the effect.³ Therefore, additional studies are needed to identify novel GP inhibitors.

3.5 Fructose 1,6-bisphosphatase

The inhibition of gluconeogenesis is a promising strategy for type 2 DM management. However, so far, drugs targeting directly gluconeogenesis have not been approved for medical use.⁶⁷ FBPase is a cytosolic enzyme that catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate, being a key regulatory enzyme of gluconeogenesis (Fig. 7).⁶⁸ Human FBPase consists of four identical polypeptide chains with 337 amino acid residues and nearly 37 kDa per submit. Two isoforms have been reported, the liver FBPase (FBP1), expressed in liver and kidney tissues, and the muscle FBPase (FBP2), found in the muscle tissue. FBP1 and FBP2 display nearly 77% homology, with almost complete identity at the active site.⁶⁹ FBP1 is recognized as a regulatory enzyme of gluconeogenesis with a crucial role in the regulation of glucose levels, whereas the physiological role of FBP2 is not yet elucidated. Considering its central role in endogenous glucose production, it has been recognized as a potential target for the management of type 2 DM.^69,70 Phosphoenolpyruvate carboxykinase (PEPCK), which converts oxaloacetate to phosphoenolpyruvate (PEP), and glucose 6-phosphatase (G6Pase), which catalyzes the conversion of glucose 6-phosphate to glucose, were the primary targets studied in gluconeogenesis for type 2 DM treatment. However, the inhibition of these enzymes is associated with several limitations and adverse effects. Moreover, the levels of PEPCK and G6Pase are not elevated in patients with type 2 DM.^3,69 The presence of side effects has limited the research on inhibitors targeting these enzymes. Thus, FBPase represents a valid molecular target for gluconeogenesis inhibition.^3,69 Furthermore, in the liver, FBPase is elevated in insulin-resistant and insulin-deficient animal models of DM, emphasizing the importance of this enzyme in the control of glucose levels of DM patients.⁶⁷

Fig. 7 Representation of the hepatic gluconeogenesis process. FBPase: fructose 1,6-bisphosphatase; GLUT2: glucose transporter 2; PEP: phosphoenolpyruvate; TCA: tricarboxylic acid.

MB07803 is a FBPase inhibitor already studied in clinical trials in type 2 DM patients. This inhibitor leads to the reduction of blood glucose levels. However, some patients experienced nausea and vomiting at higher doses, highlighting the need for additional studies with this compound. Furthermore, exploring the potential of novel FBPase inhibitors is essential.³

4. Polyphenols

Natural products are recognized for their great value in human health. Historically, plants have been traditionally used as medicines to treat several diseases. Hence, some medications are obtained from natural sources or derived from natural compounds. Acarbose (α-glucosidase inhibitor class) and metformin (biguanides class) are examples of antidiabetic medications derived from natural compounds. Studies with natural products have been increasing over the last few years, providing unique resources for drug discovery.⁷¹

Polyphenols are naturally occurring compounds found in plants, comprising more than 8000 structures discovered to date in several plant species, including vegetables, fruits, grains, and beverages.^2,72 Polyphenols comprise an essential part of the human diet, being responsible for some sensory and nutritional aspects of plant foods, including astringency, color and odor. As natural compounds synthesized by plants, these secondary metabolites are mainly involved in the attraction of pollinators, defense against ultraviolet radiation and protection against pathogens.⁷³

Polyphenols consist of one or more phenolic groups in a molecule, varying from a single phenolic structure to a complex polymer with a high molecular mass.^2,72 Polyphenols can be categorized in diverse forms due to the high diversity and distribution. The most common polyphenols can be classified according to the number of phenol rings and the structural elements that bind these rings into phenolic acids [benzoic acid derivatives (C1–C6) and cinnamic acid derivatives (C3–C6)], stilbenes (C6–C2–C6), flavonoids (C6–C3–C6, flavanones, flavones, flavanols, flavonols, isoflavones and anthocyanidins) and lignans (C6–C4–C6) (Fig. 8). Flavonoids are the most common and abundant group among polyphenols, with phenolic acids being the second most abundant group.^2,74,75

Fig. 8 Schematic representation of the general backbone structures illustrating phenolic acids, stilbenes, flavonoids, and lignans. R=OH.

Polyphenols have been recognized for numerous pharmacological activities, including antioxidant, cardioprotection, anticancer, anti-inflammatory, antimicrobial, anti-ageing, anti-obesity, and antidiabetic activities, among others, as reviewed by various authors.^5–9 Increasing attention has been dedicated to the study of the antidiabetic activity of polyphenols, which can act on several different targets, including α-amylase and α-glucosidase,⁷⁶ dipeptidyl peptidase-4,⁷⁷ sodium-glucose cotransporter 2,⁷⁸ and proliferator-activated receptor γ,⁷⁹ among others. However, the studies with isolated polyphenols in clinical trials are still limited and often controversial, and therefore further studies are required to better understand the potential of these compounds as antidiabetic agents in humans.⁸⁰ The limited bioavailability and extensive metabolism of these compounds have constrained their potential in vivo effects, making this a key topic of growing scientific interest that has been extensively addressed in several reviews.^2,81–84 In their natural form, dietary polyphenols are often present as glycosides, esters, or complex polymers, which are poorly absorbed in the human gastrointestinal tract.⁸⁴ Upon ingestion, these compounds undergo extensive transformation by intestinal enzymes and/or by colonic microflora before absorption, resulting in metabolites with substantial structural modifications. Following absorption, these metabolites reach the liver via the portal circulation, where they are further processed. The resulting hepatic metabolites then enter systemic circulation and are distributed to the peripheral tissues, where they may exert biological effects.^2,82 The chemical structure of each polyphenol largely determines its absorption, distribution, metabolism, and excretion (ADME).⁸⁴ These metabolic complexities contribute to the challenges of translating promising in vitro findings into consistent clinical outcomes. Despite the growing body of research, clear conclusions on polyphenol bioavailability remain limited. Reported plasma concentrations following normal dietary intake rarely exceed nanomolar to low micromolar levels,^85,86 which contrasts with the higher concentrations commonly used in in vitro studies. Therefore, in clinical settings, it is essential to consider the most effective forms of polyphenol administration to enhance their therapeutic potential. Numerous strategies are currently being explored to improve their bioavailability, with nanotechnology showing promising results in increasing their efficacy and stability in vivo.²

Finding new alternatives to the current antidiabetic medications is required to manage type 2 DM with reduced side effects, and several polyphenols have been demonstrated to be promising compounds. As such, the main purpose of the present review is to highlight the effect of polyphenols on liver targets currently investigated in the clinic for the treatment of type 2 DM, including PTP1B, glucagon receptor, GK, GP, and FBPase.

4.1 Polyphenols as modulators of liver targets for diabetes mellitus treatment

A search on the PubMed database was conducted, using as keywords “polyphenols OR polyphenol OR phenolic acids OR phenolic acid OR stilbenes OR stilbene OR flavonoids OR flavonoid OR lignans OR lignan”, with each one of the following liver targets: “protein tyrosine phosphatase 1B” (186 results), “glucagon receptor” (92 results), “glucokinase” (57 results), “glycogen phosphorylase” (44 results), and “fructose 1,6-bisphosphatase” (18 results). Data were collected and articles from the last 10 years, from 2014 to February 2024, were included in the revision. Eligibility criteria included papers focused solely on polyphenols targeting PTP1B, glucagon receptor, GK, GP, and FBPase, in in vitro and in vivo studies. Studies performed with plant extracts and in silico studies were excluded from this review.

4.1.1 Polyphenols as protein tyrosine phosphatase 1B inhibitors. Promising evidence suggests that PTP1B inhibitors could enhance the phosphorylation levels of IR and its substrates in hepatocytes, thereby improving insulin sensitivity. However, a significant hurdle in this pursuit has been the structural similarity between PTP1B and other phosphatases. Thus far, the quest for highly selective compounds with optimal bioavailability and cell permeability has posed a persistent challenge.⁴² Numerous studies, both in vitro and in vivo (as outlined in Table 1), have explored the potential of polyphenols as inhibitors of PTP1B, showing interesting outcomes. Within this scope, various polyphenol subclasses such as flavonoids, stilbenes, and phenolic acids have been investigated, with a particular emphasis on the extensive exploration of flavonoids. In some studies, an extensive panel of polyphenol derivatives underwent screening, wherein only the most potent compound(s) are delineated within Table 1. In particular, Jing Xu et al.⁸⁷ investigated a group of 26 polyphenolic compounds, encompassing flavonoids and phenolic acid derivatives. Notably, ellagic acid, a derivative of gallic acid, emerged as the most potent compound. Subsequently, the two most active compounds identified were the flavonoids kaempferol and myricetin. The authors noted that flavonoid aglycones exhibited higher activity levels compared with flavonoid glycosides. However, in certain studies, the most active compounds were flavonoid glycosides.^88–91 The discrepant conclusions among the articles may stem from experimental variations such as differences in the incubation time of the enzyme with the compounds, the enzyme–substrate ratio, or the purity of the compounds. In addition, as illustrated in Table 1, several flavonoid glycosides showed the potential to reduce the expression of PTP1B in cellular models, particularly in insulin-resistant hepatic models, including breviscapine,⁹² prunin,⁹³ didymin⁹⁴ and cyanidin-3-arabinoside.⁹⁵ Furthermore, Jing Xu et al.⁸⁷ concluded that the correlation between structure and activity might be linked to the presence of hydroxy groups. Compounds containing hydroxy groups exhibited heightened activity when compared with those containing methoxy groups, while the inhibitory activity diminished upon substitution of the hydroxy groups with sugars.⁸⁷ Examining Table 1, it appears that the presence of hydroxy groups is crucial for the inhibitory activity of PTP1B.

Table 1 Polyphenols as protein tyrosine phosphatase 1B inhibitors. Description of the most active compound(s) identified in each study

Chemical structure	Compound source	Model	Effect	Ref.
↑ means “increase”, ↓ means “reduction”. IC50: half-maximal inhibitory concentration, IRS2: insulin receptor substrate 2, PTP1B: protein tyrosine phosphatase 1B, STZ: streptozotocin, DM: diabetes mellitus.
In vitro studies
	Commercial	Non-cellular enzymatic study (human PTP1B)	IC50 = 0.18 ± 0.02 mg mL^−1	100
	Commercial	Non-cellular enzymatic study	IC50 = 7.62 ± 0.21 μM	89
	Commercial	Non-cellular enzymatic study (human PTP1B)	IC50 = 37.14 ± 0.07 μM	88
	Isolated from Anoectochilus chapaensis	Non-cellular enzymatic study (human PTP1B)	Isorhamnetin: IC50 = 1.75 ± 0.02 μM	102
			Isorhamnetin-3-O-β-D-glucoside: IC50 = 1.16 ± 0.03 μM
			Isorhamnetin-3-O-β-D-rutinoside: IC50 = 1.20 ± 0.05 μM
	Isolated from Epimedium koreanum	Non-cellular enzymatic study (human PTP1B)	IC50 = 9.94 ± 0.15 μM	103
	Isolated from Xanthium strumarium	Non-cellular enzymatic study	IC50 = 8.9 ± 0.7 μM	104
	Isolated from Artemisia capillaris	Non-cellular enzymatic study (human PTP1B)	IC50 = 139.75 ± 2.97 μM	105
	Commercial	Non-cellular enzymatic study (human PTP1B)	IC50 = 7.76 ± 0.21 μM	106
	Isolated from Smilax china L.	Non-cellular enzymatic study (human PTP1B)	IC50 = 0.92 ± 0.19 μM	90
	Not mentioned	Non-cellular enzymatic study	IC50 = 17.5 ± 2.6 μM	91
	Isolated from Acer ginnala Maxim.	Non-cellular enzymatic study (human PTP1B)	IC50 = 3.46 ± 0.05 μM	107
	Synthesis	Non-cellular enzymatic study (human PTP1B)	1: IC50 = 16 ± 2 μM	96
			2: IC50 = 10 ± 1 μM
	Isolated from Quercus liaotungensis	Non-cellular enzymatic study (human PTP1B)	IC50 = 1.03 ± 0.12 μM	87
	Isolated from Agrimonia pilosa	Non-cellular enzymatic study (human PTP1B)	Ellagic acid: IC50 = 7.14 ± 1.75 μM	108
			Apigenin 7-O-β-D-glucuronide: IC50 = 7.73 ± 0.24 μM
	Isolated from Angelica keiskei	Non-cellular enzymatic study	IC50 = 0.82 ± 0.09 μg mL^−1	109
	Synthesis	Non-cellular enzymatic study (human PTP1B)	IC50 = 0.57 ± 0.2 μM	101
	Synthesis	Non-cellular enzymatic study	96.31 ± 1.76% at 20 μg mL^−1	110
	Isolated from Glycyrrhiza glabra	Non-cellular enzymatic study	IC50 = 6.0 ± 1.4 μM	97
	Isolated from Salvia amarissima Ortega	Non-cellular enzymatic study (human PTP1B)	IC50 = 62.0 ± 4.1 μM	111
	Isolated from Hypericum scabrum	Non-cellular enzymatic study	IC50 = 2.19 ± 0.2 μM	112
	Isolated from Silybum marianum	Non-cellular enzymatic study (human PTP1B)	IC50 = 6.79 ± 0.22 μM	113
	Isolated from Eremophila denticulata	Non-cellular enzymatic study (human PTP1B)	76.1 ± 12.4% at 100 μM	114
	Commercial	Non-cellular enzymatic study (human PTP1B)	IC50 = 6.70 ± 0.03 μM	115
	Isolated from Geranium collinum	Non-cellular enzymatic study	IC50 = 0.23 ± 0.04 μg mL^−1	116
	Isolated from Coreopsis tinctoria Nutt.	Non-cellular enzymatic study	IC50 = 7.73 ± 0.48 μg mL^−1	117
	Isolated from Amomum tsao-ko	Non-cellular enzymatic study	IC50 = 56.4 ± 5.0 μM	118
	Isolated from Eremophila bignoniiflora	Non-cellular enzymatic study (human PTP1B)	IC50 = 41.4 ± 1.4 μM	119
	Synthesis	Non-cellular enzymatic study	IC50 = 2.37 ± 0.37 μM	120
	Isolated from Livistona chinensis	Non-cellular enzymatic study (human PTP1B)	IC50 = 9.41 ± 0.08 μM	121
	Isolated from Helminthostachys zeylanica	Non-cellular enzymatic study (human PTP1B)	IC50 = 0.6 ± 0.2 μM	122
	Isolated from Euonymus alatus	Non-cellular enzymatic study (human PTP1B)	IC50 = 13.7 ± 0.2 μM	123
	Isolated from Ficus tikoua	Non-cellular enzymatic study	IC50 = 11.16 ± 1.88 μM	124
	Isolated from Psoralea corylifolia	Non-cellular enzymatic study	IC50 = 10.3 ± 0.9 μM	125
	Synthesis	Non-cellular enzymatic study	IC50 = 1.6 ± 0.9 μM	126
	Isolated from Flemingia philippinensis	Non-cellular enzymatic study (human PTP1B)	IC50 = 2.4 ± 0.3 μM	127
	Isolated from the roots of Sophora flavescens	Non-cellular enzymatic study	IC50 = 5.26 ± 0.24 μM	128
	Isolated from Paulownia tomentosa	Non-cellular enzymatic study	IC50 = 1.9 ± 0.1 μM	98
	Isolated from Macaranga denticulata	Non-cellular enzymatic study	IC50 = 14.0 ± 1.2 μM	99
	Isolated from Erythrina subumbrans	Non-cellular enzymatic study	IC50 = 3.21 ± 0.24 μM	129
	Isolated from Dodonaea viscosa	Non-cellular enzymatic study	IC50 = 13.5 ± 0.3 μM	130
	Isolated from Sophora alopecuroides L.	Non-cellular enzymatic study (human PTP1B)	Inhibition = 95.22% at 0.1 μg mL^−1	131
	Isolated from Selaginella uncinata	Non-cellular enzymatic study	IC50 = 4.6 ± 0.5 μM	132
	Isolated from Ficus racemosa	Non-cellular enzymatic study (human PTP1B)	IC50 = 2.5 ± 0.2 μM	133
	Isolated from Selaginella tamariscina	Non-cellular enzymatic study (human PTP1B)	IC50 = 4.5 ± 0.1 μM	134
	Isolated from Silybum marianum	Non-cellular enzymatic study (human PTP1B)	Silybin A: IC50 = 1.54 ± 0.22 μM	135
			Isosilybin B: IC50 = 1.37 ± 0.22 μM
	Isolated from Cudrania tricuspidata	Non-cellular enzymatic study (human PTP1B)	Cudratricusxanthone N: IC50 = 2.0 ± 0.4 μM	136
			Cudracuspixanthone A: IC50 = 1.9 ± 0.4 μM
	Isolated from Polygonum multiflorum	Non-cellular enzymatic study (human PTP1B)	1: IC50 = 2.1 ± 0.08 μM	137
			2: IC 50 = 1.9 ± 0.04 μM
	Isolated from Morus laevigata	Non-cellular enzymatic study	IC50 = 0.87 ± 0.09 μM	138
	Isolated from Morus nigra	Non-cellular enzymatic study	Morunigrines A: IC50 = 1.8 ± 0.2 μM	139
			Morunigrines B: IC50 = 1.3 ± 0.3 μM
	Isolated from Morus alba L.	Non-cellular enzymatic study (human PTP1B)	IC50 = 1.90 ± 0.12 μM	140
	Isolated from Allium cepa	Non-cellular enzymatic study	1: IC50 = 1.68 ± 0.02 μM	141
			2: IC50 = 1.13 ± 0.01 μM
	Synthesis	Non-cellular enzymatic study	IC50 = 0.91 ± 0.33 μM	142
	Isolated from Morus alba	Non-cellular enzymatic study	IC50 = 2.85 ± 0.30 μM	143
	Isolated from Rheum undulatum	Non-cellular enzymatic study (human PTP1B)	Piceatannol: IC50 = 4.81 ± 0.21 μM	144
			δ-Viniferin: IC50 = 4.25 ± 0.02 μM
	Isolated from Cajanus cajan	Cellular study with HepG2 cells overexpressing PTP1B	No differences in PTP1B mRNA expression	145
			↓ PTP1B protein expression
	Isolated from Juniperus chinensis	Non-cellular enzymatic study (human PTP1B)	IC50 = 25.27 ± 0.14 μM	146
		Cellular study with insulin-resistant HepG2 cells	↓ PTP1B protein expression
	Isolated from Chrysanthemum morifolium	Non-cellular enzymatic study (human PTP1B)	Diosmetin 7-glucoside: 27.74 ± 2.10% at 1 μM	147
			Diosmin: 36.26 ± 1.62% at 1 μM
			Diosmetin: 22.81 ± 2.07% at 1 μM
			Luteolin: 19.80 ± 2.18% at 1 μM
			Apigenin: 29.77 ± 1.48% at 1 μM
			Acacetin: 38.17 ± 1.62% at 1 μM
		Cellular study with CHO-K1 cells	↓ PTP1B protein expression
	Isolated from mulberry leaves	Non-cellular enzymatic study	1: IC 50 = 4.53 ± 0.31 μM	148
			2: IC50 = 10.53 ± 1.76 μM
		Cellular study with insulin-resistant HepG2 cells	1: ↓ PTP1B protein expression
	Isolated from blueberry fruits	Non-cellular enzymatic study (human PTP1B)	Procyanidin B1: IC 50 = 0.60 ± 0.042 μM	149
			Procyanidin B2: IC50 = 4.79 ± 0.023 μM
		Cellular study with insulin-resistant HepG2 cells	↓ PTP1B protein expression
	Commercial	Cellular study with insulin-resistant HepG2 cells	↓ PTP1B protein expression	92
	Commercial	Cellular study with insulin-resistant HepG2 cells	↓ PTP1B protein expression	150
	Synthesis	Non-cellular enzymatic study (human PTP1B)	Inhibition = 18.09 ± 3.39% at 1 μM	151
		In vitro cellular study with CHO-K1 cells	↓ PTP1B protein expression
	Isolated from Prunus davidiana	Non-cellular enzymatic study (human PTP1B)	IC50 = 5.5 ± 0.29 μM	93
		Cellular study with insulin-resistant HepG2 cells	↓ PTP1B protein expression
	Commercial	Non-cellular enzymatic study (human PTP1B)	IC50 = 1.23 ± 0.11 μM	94
		Cellular study with insulin-resistant HepG2 cells	↓ PTP1B protein expression
	Isolated from blueberry fruits	Non-cellular enzymatic study (human PTP1B)	Cyanidin-3-arabinoside: IC50 = 8.91 ± 0.63 μM	95
		Cellular study with HepG2 cells overexpressing PTP1B	↓ PTP1B protein expression
In vivo studies
	Synthesis	DM high-fat diet/streptozotocin-induced using C57BL/6J mice (50 and 100 mg kg^−1 of compound, administration for 6 weeks)	↓ PTP1B protein expression	152
	Synthesis	High-fat diet using C57BL/6J mice (10 mg kg^−1 day^−1 of compound, gastric gavage for 10 weeks, 5 days a week)	↓ PTP1B protein expression	153
	Not mentioned	DM induced by STZ using Wistar rats (50 mg kg^−1 of compound, administration daily by gavage daily for 8 weeks)	↓ PTP1B gene expression	154
	Commercial	High-fat diet using C57BL/6J mice (20 mg kg^−1 of compound, administration by dietary supplementation for 15 weeks)	↓ PTP1B protein expression	155
	Commercial	IRS2-deficient using C57BL/6 and 129/Sv mice (2.5 mg kg^−1 day^−1 of compound, orally administered for 8 weeks via drinking water)	↓ PTP1B gene expression and activity	156
	Commercial	High-fat and high-fructose diet using C57BL/6 mice (2 g L^−1 of compound, treatment through drinking water for 16 weeks)	↓ PTP1B protein expression	150
	Synthesis	Goto-Kakizaki rats (1, 5 and 10 mg kg^−1 of compound, subcutaneously daily for 14 days)	=PTP1B protein expression on liver	157

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Proença et al.⁹⁶ studied the in vitro inhibitory activity of a panel of 36 structurally related flavonoids. The authors concluded that the presence of both 7- and 8-OBn groups in the A ring, together with the presence of both 3′- and 4′-OMe groups in the B ring and the 3-OH group in the C ring, are essential for the inhibitory activity of PTP1B. The authors highlight that the presence of methoxy groups, together with hydroxy groups, are determinant for the intended activity,⁹⁶ contrasting with Jing Xu et al.⁸⁷ Although both studies investigate the human enzyme, using identical methodologies, the discrepant conclusions may stem from variations in enzyme–substrate ratios, as well as the additional factor of NaOH addition to stop the reaction in the study by Jing Xu et al.⁸⁷

Upon examination of Table 1, it is evident that the presence of functional groups containing hydrocarbon chains, such as the prenyl and geranyl groups, is significant for the inhibition of the enzyme PTP1B. Particularly, Wei Li et al.⁹⁷ studied 42 polyphenol derivatives, comprising different groups, including chalcones and flavonoids. Among the compounds investigated, flavonoid glycosides exhibited negligible inhibitory activity, diverging from other studies represented in Table 1. Nevertheless, prenylated compounds demonstrated noteworthy effectiveness. The authors emphasized the critical role of prenyl groups and hydroxy moieties in ortho-position for facilitating the activity of these compounds, eliciting inhibition of PTP1B through diverse modes.⁹⁷ Geranylated flavonoids also demonstrated promising inhibitory activities, indicating that geranyl is an important substitution for the inhibition of PTP1B.^98,99

Among the selected studies of Table 1, it is worth highlighting that only two specifically addressed the issue of polyphenol bioavailability [Rampadarath et al.,¹⁰⁰, Zhao et al.,¹⁰¹]. Rampadarath et al.¹⁰⁰ conducted an in silico pharmacokinetic analysis of orientin, assessing its ADME properties and drug-likeness using the SwissADME platform. The authors report that a potential therapeutic compound should ideally exhibit at least 10% oral bioavailability, a criterion that favors orientin, which showed a predicted value of 17%. While these computational results are promising and suggest orientin as a potentially bioavailable compound, no in vivo validation of these predictions was performed, thus limiting conclusions regarding its actual pharmacokinetic behavior. On the other hand, Zhao et al.¹⁰¹ carried out a more comprehensive pharmacokinetic profiling of the most active compound identified in their study in Sprague-Dawley rats. After intravenous administration at 2 mg kg⁻¹, the polyphenol showed a long half-life (≈21 h). When given orally at a higher dose (20 mg kg⁻¹), the compound reached a moderate level in the bloodstream over time, with a shorter half-life (≈9 h). These findings underscore the importance of pharmacokinetic characterization in evaluating the therapeutic viability of polyphenolic compounds. However, such studies remain scarce, and further investigations are essential.

Despite the substantial number of in vitro studies on polyphenols in the inhibition of PTP1B, relatively few in vivo studies have been published in the past decade. Notably, overall, all compounds exhibit hydroxy groups, belonging to different groups, including flavonoids, stilbenes, and phenolic acids. In the published in vivo studies, all tested polyphenols have shown the capability to decrease the expression of PTP1B.

4.1.2 Polyphenols as glucagon receptor antagonists. In the search conducted utilizing the specified keywords “polyphenols OR polyphenol OR phenolic acids OR phenolic acid OR stilbenes OR stilbene OR flavonoids OR flavonoid OR lignans OR lignan” and “glucagon receptor”, a total of 92 articles were retrieved from PubMed. However, upon thorough examination, it was found that none of these articles pertained to polyphenols acting as glucagon receptor antagonists in studies related to diabetes. The retrieved articles predominantly focused on other receptors, especially GLP-1 receptors, or the evaluation of glucagon levels. Therefore, it is evident from the literature that no relevant studies are found due to the emphasis on different receptors and pathways. This absence of relevant findings suggests a potential area for future investigation, highlighting the need for further research into the potential role of polyphenols as glucagon receptor antagonists in the context of DM, with no published studies identified to date.

4.1.3 Polyphenols as glucokinase activators. Polyphenols have been already investigated as GK activators in several in vitro, ex vivo and in vivo studies (Table 2), demonstrating encouraging effects. Polyphenols belonging to diverse groups have been studied, including flavonoids, stilbenes, and phenolic acids, with flavonoids being the most explored compounds.

Table 2 Polyphenols as glucokinase activators. Description of the most active compound(s) identified in each study

Chemical structure	Compound source	Study method	Effect	Ref.
↑ means “increase”, ↓ means “reduction”. GK: glucokinase, IC50: half-maximal inhibitory concentration, STZ: streptozotocin, DM: diabetes mellitus.
In vitro studies
	Commercial	Cellular assay with HepG2	Resveratrol: ↓ the GK activity	158
			Oxyresveratrol: no effect
			Cyanidin-3-glucoside: ↑ GK activity
			Cyanidin-3-rutinoside: ↑ GK activity
			Resveratrol: ↓ GK protein expression
			Oxyresveratrol: ↓ GK protein expression
			Cyanidin-3-glucoside: ↑ GK protein expression
			Cyanidin-3-rutinoside: ↑ GK protein expression
		Cellular assay with MIN6	Resveratrol: ↓ GK protein expression	159
			Oxyresveratrol: ↓ GK protein expression
			Cyanidin-3-glucoside: ↑ GK protein expression
			Cyanidin-3-rutinoside: ↑ GK protein expression
	Isolated from Selaginella tamariscina	Cellular assay with HepG2	1: ↑ GK protein expression	165
			2: ↑ GK protein expression
			3: ↑ GK protein expression
	Not mentioned	Cellular assay with HepG2	↑ GK protein expression	162
	Commercial	Cellular assay with INS-1E	Caffeic acid: no differences in GK mRNA expression	160
			Naringenin: ↑ GK mRNA expression under normoglycaemic and glucotoxic conditions
			Quercetin: ↑ GK mRNA expression under glucotoxic conditions
	Commercial	Cellular assay with L6	↑ GK activity	166
	Isolated from Selaginella tamariscina	Cellular assay with HepG2	↑ GK activity	167
	Commercial	Cellular assay with HepG2	↑ GK activity	168
	Commercial	Cellular assay with HepG2	↑ GK protein expression	169
Ex vivo studies
	Commercial	Study with isolated perfused rat liver using Wistar rats	Hesperetin: ↓ liver GK activity	170
			Naringen: ↓ liver GK activity
			Hesperidin: no effect
In vivo studies
	Commercial	DM induced by NA/STZ using Wistar rats (50 mg kg^−1 of compound, daily administration by gastric intubation for 4 weeks)	↑ mRNA expression of liver GK levels on NA/STZ-induced rats	163
	Not mentioned	DM induced by high fat and sugar diet, and STZ, using Sprague-Dawley rats (75 and 150 mg kg^−1 of compound, administration by gavage, 6 days weeks, for 8 weeks)	↑ liver GK protein expression on high fat and sugar diet, and STZ-induced rats	162
	Not mentioned	DM induced by high-fat diet and fructose using Wistar rats (50 mg kg^−1 of compound, administration by intubation for 30 days)	↑ liver GK levels on STZ-induced rats. No effect on normal rats	171
	Commercial	STZ-induced Wistar rats (4, 8 and 16 mg kg^−1 of compound, administration by intubation for 45 days)	↑ liver GK levels on STZ-induced rats. No effect on normal rats	172
	Isolated from Selaginella tamariscina	STZ-induced CD-1 mice (20 and 40 mg kg^−1 of compound, for 8 weeks, type of administration not mentioned)	↑ liver GK levels on STZ-induced rats.	173
	Commercial	Megalobrama amblycephala fish fed with high-fat diet (0.04%, 0.36%, 1.08% of compound, administration hand-fed, 3 times a day, for 10 weeks)	↓ mRNA expression of liver GK levels on fish fed with high-fat diet	161
	Commercial	DM induced by high-fat diet and STZ using C57BL/6J mice (0.005% w/w of compound, administration orally for 5 weeks)	↑ liver GK activity and mRNA expression levels on high-fat diet- and STZ-induced mice	174
	Commercial	DM induced by alloxan using Kunming mice (5, 10, 20 mg kg^−1 of compound, administration intragastrically, once a day for 28 days)	↑ liver GK mRNA expression and protein levels on alloxan-induced mice.	175
	Synthesis	Wistar rats treated with obesogenic diet, high in sucrose and fat (15, 30 mg kg^−1 day^−1 of compound, administration orally once a day, for 6 weeks)	↑ liver GK levels on obesogenic rats, with the lower concentration of pterostilbene	164
	Isolated	DM induced by alloxan and glucose, using Danio rerio zebrafish (2, 4, 10 μg mL^−1 of compound, treatment with incubation for 24 h)	↑ GK protein expression on alloxan- and glucose-induced zebrafish	176

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In two different in vitro studies using different cellular models,^158,159 the same group studied the effects of two stilbenes, resveratrol and oxyresveratrol, and two flavonoids, cyanidin-3-glucoside and cyanidin-3-rutinoside, against the enzyme GK. The findings indicate that flavonoids exhibit greater promise in activating GK compared with stilbenes. Stilbenes either demonstrated no effect or led to a reduction in GK activity at higher concentrations.^158,159 Bhattacharya et al.¹⁶⁰ analyzed the effects of caffeic acid, naringenin and quercetin in the expression levels of GK. Remarkably, both flavonoids, naringenin and quercetin, were able to increase the levels of GK. Caffeic acid showed no effects in this study. It is also possible to verify that flavonoids proved to be more favourable, compared with the studied phenolic acid.¹⁶⁰ One ex vivo study was performed with hesperidin, hesperetin and naringenin, using isolated perfused rat liver. Contrasting with the other studies, these flavonoids were not able to increase GK activity, showing no effect or even reduction in its levels.

Regarding the in vivo studies, several polyphenols were explored, including polydatin, ferulic acid, galangin, amentoflavone, resveratrol, myricitrin, formononetin, pterostilbene and theaflavin-3,3′-digallate, as represented in Table 2. Almost all compounds display only hydroxy groups in their backbones, except ferulic acid, formononetin and pterostilbene, which hold hydroxy and methoxy groups. In general, all compounds, including those with hydroxy and methoxy groups in their backbone, exhibited an increase in GK levels.

Interestingly, the stilbene resveratrol was also studied in vivo,¹⁶¹ showing a reduction in the mRNA expression of liver GK, consistent with the findings of in vitro cellular studies.^158,159 However, other stilbenes, polydatin and pterostilbene, were also studied in in vivo models, and showed a capacity to increase GK levels.^162–164 Particularly, the stilbene polydatin was studied in two different in vivo studies, revealing promising activity for the activation of GK.^162,163 Additionally, Hao et al.¹⁶² investigated the activity of polydatin in an insulin-resistant HepG2 cell model, which also demonstrated an ability to increase the GK protein expression.

4.1.4 Polyphenols as glycogen phosphorylase inhibitors. lGP has been considered an important target for DM management. lGP inhibition leads to the reduction of plasma glucose levels by the increase of glycogen storage in the liver. However, these inhibitors have not reached the clinic.⁶² Various natural and synthetic inhibitors have been described to bind diverse sites of the enzyme.^63,177,178 Polyphenols have been reported, in vitro and in vivo, as potent inhibitors of GP, as represented in Table 3. A high diversity of polyphenol structures has been studied in vitro, including flavonoids, stilbenes, and phenolic acids. Regarding in vivo studies, flavonoids are the most studied compounds.

Table 3 Polyphenols as glycogen phosphorylase inhibitors. Description of the most active compound(s) identified in each study

Chemical structure	Compound source	Study method	Effect	Ref.
↑ means “increase”, ↓ means “reduction”. GP: glycogen phosphorylase, IC50: half-maximal inhibitory concentration, STZ: streptozotocin, DM: diabetes mellitus.
In vitro studies
	Commercial and synthesis	Non-cellular enzymatic study (rabbit muscle GPa)	Norwogonin (IC50 = 13.2 ± 1.4 μM)	62
			Baicalein (IC50 = 23.5 ± 2.9 μM)
			Baicalin (IC50 = 20.5 ± 2.5 μM)
			Baicalein-7-methylether
			(IC50 = 22.6 ± 0.4 μM)
	Commercial	Non-cellular enzymatic study (rabbit muscle GPb)	Chrysin (Ki = 19 μM)	179
			Flavopiridol (Ki = 1.24 μM)
	Resveratrol glucoside isolated from Paeonia clusii and tachioside isolated from Dorycnium pentaphyllum	Non-cellular enzymatic study (rabbit muscle GPb)	Resveratrol glucoside (IC50 = 258.4 ± 0.6 μM)	185
			Tachioside (IC50 = 571.1 ± 45.5 μM)
	Isolated from Seriphidium stenocephalum	Non-cellular enzymatic study (rabbit muscle GP)	Stenocephol (IC50 = 8.794 μM)	186
	Commercial	Non-cellular enzymatic study (rabbit muscle GPa and GPb)	Ellagic acid (Ki = 13.4 ± 1.2 μM for GPb and 7.52 ± 0.36 μM for GPa)	187
			Gallic acid (Ki = 1.73 ± 0.16 mM for GPb and 3.86 ± 0.27 mM for GPa)
	Synthesis	Non-cellular enzymatic study (rabbit muscle GPa and GPb, and human liver GPa)	Quercetin (Ki = 43.52 ± 1.65 μM for human GP)	180
			Chrysin (Ki = 7.28 ± 0.09 μM for human GP)
			1 (Ki = 7.39 ± 0.09 μM for human GP)
			2 (Ki = 3.39 ± 0.22 μM for human GP)
			3 (Ki = 3.89 ± 0.08 μM for human GP)
			4 (Ki = 2.23 ± 0.08 μM for human GP)
			5 (Ki = 21.36 ± 0.98 μM for human GP)
		Cellular study with HepG2	Flavonoid 4 ↓ glycogenolysis in hepatocytes (IC50 = 70 μM)
In vivo studies
	Not mentioned	DM induced by high-fat diet and fructose using Wistar rats (50 mg kg^−1 of compound, with administration by intubation for 30 days)	↓ liver GP levels on STZ-induced rats. No effect on normal rats	171
	Commercial	DM induced by NA/STZ using Wistar rats (100 mg kg^−1 day^−1 of compounds, administration by oral gavage for 4 weeks)	↓ liver GP levels with the same effect in hesperidin- and quercetin-treated rats	181
	Commercial	DM induced by high-fat diet and STZ using Wistar rats (100 mg kg^−1 day^−1 of compound, administration orally for 30 days)	↓ liver GP levels on DM rats. No effect on normal rats	188
	Commercial	DM induced by STZ using Wistar rats (20, 40, 80 mg kg^−1 of compound, administration intragastrically for 30 days)	↓ liver GP levels on DM rats. No effect on normal rats	184
	Commercial	STZ–cadmium-induced diabetic nephrotoxic Wistar rats (1 mg kg^−1 of compound, administered intraperitoneally once a day for 12 weeks)	↓ liver GP levels on STZ–cadmium-induced rats. No effect on normal rats	189
	Commercial	DM induced by nicotineamide/STZ using rats (100 mg kg^−1 day^−1 of compounds, by oral gavage for 4 weeks)	↓ liver GP levels on nicotineamide/STZ-induced rats, with the same effect for naringenin and naringin.	183
	Commercial	STZ-induced Wistar rats (25, 50, 100 mg kg^−1 of compound, administered orally using an intragastric tube for 30 days)	↓ liver GP levels on STZ-induced rats. No effect on normal rats.	182
	Commercial	STZ induced Wistar rats (100 mg kg^−1 of compound, administered orally daily for 30 days)	↓ liver GP levels on STZ-induced rats. No effect on normal rats.	190
	Isolated from Semecarpus anacardium	DM induced by high-fat diet and STZ using Wistar rats (20, 40, 80 mg kg^−1 of compound, administration intragastrically for 30 days)	↓ liver GP levels on high-fat diet and STZ-induced rats. No effect on normal rats.	191
	Commercial	STZ-induced Wistar rats (20 mg kg^−1 of compound, administered orally daily for 6 weeks)	↓ liver GP levels on STZ-induced rats.	192

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Rocha et al.⁶² explored the activity of 17 polyphenols in vitro against the enzyme rabbit muscle GPa. The authors concluded that the hydroxylation of the A ring is determinant for the inhibitory activity, whereas methoxy substituents were disadvantageous for GPa inhibitory activity. The flavonoid norwogonin (Table 3) was the most promising compound among the panel of polyphenols tested, showcasing heightened inhibitory activity in the presence of glucose. This characteristic suggests a potential for reducing the risk of hypoglycemia, particularly relevant in diabetic contexts marked by elevated plasma glucose levels. The authors also studied the flavonoid chrysin (Table 3), one of the most active compounds of the study. This flavonoid was studied by other authors,^179,180 being recognized as a potent GP inhibitor.

Chetter et al.¹⁸⁰ studied the inhibitory potential of 10 flavonoids against rabbit muscle GPa and GPb, and human liver GPa. The flavonoid, which contains hydroxy groups at the C-5 and C-7 positions and a methyl at the C-3′ position (Table 3), was the most active compound of the group. This compound was also studied using hepatocarcinoma HepG2 cells, where it effectively inhibited endogenous GP activity.¹⁸⁰ In this study, the flavonoid quercetin (Table 3) showed the highest IC₅₀ among all the tested compounds. Comparably, Rocha et al.⁶² also studied quercetin, which showed no inhibitory activity.

Polyphenols were already studied using in vivo models for testing the inhibition of GP (Table 3), including ferulic acid, hesperidin, quercetin, theaflavin, naringin, myricetin, naringenin, naringin, hesperidin, tangeretin, a biflavonoid and hesperetin. In general, these polyphenols are hydroxylated, except ferulic acid, hesperidin, tangeretin and hesperetin. The flavonoid hesperidin was already explored in 2 different studies and demonstrated a significant reduction of the GP levels in both studies.^181,182 Quercetin, explored in two in vitro studies,^62,180 was also studied in vivo by Ali et al.,¹⁸¹ demonstrating its ability to reduce lGP levels in treated animals, exhibiting a similar effect to hesperidin.

Ahmed et al.¹⁸³ explored the antidiabetic effects of two flavonoids, naringin and naringenin, using nicotineamide- and streptozotocin-induced diabetic rats. Both flavonoids reduced lGP levels, showing that the presence of the disaccharide at the C-7 of the A ring, when compared with naringin, was not valuable for the reduction of lGP levels.¹⁸³ Naringin was also investigated by Pari and Chandramohan¹⁸⁴ using diabetic rats induced with streptozotocin. The results are in accordance with Ahmed et al.,¹⁸³ illustrating the ability of naringin to reduce lGP levels.

4.1.5 Polyphenols as fructose 1,6-bisphosphatase inhibitors. As of now, a clinically used drug acting through the inhibition of FBPase has not been established. The highly hydrophilic nature of the active site of this enzyme restricts the discovery of novel potential inhibitors, highlighting the importance of designing and studying novel inhibitors.⁶⁹ Having in mind the importance of finding novel FBPase inhibitors, the identification and recognition of the current studied compounds is essential.

There are few reports on the literature in the last 10 years exploring the inhibitory potential of polyphenols, as represented in Table 4. Considering the studies using polyphenols as FBPase inhibitors, flavonoids are the most explored compounds. Pterostilbene, a stilbene, is the only compound studied as an FBPase inhibitor that does not belong to the flavonoid family.

Table 4 Polyphenols as fructose 1,6-bisphosphatase inhibitors. Description of the most active compound(s) identified in each study

Chemical structure	Compound source	Study method	Effect	Ref.
↑ means “increase”, ↓ means “reduction”. FBPase: fructose 1,6-bisphosphatase, IC50: half-maximal inhibitory concentration, STZ: streptozotocin, DM: diabetes mellitus.
In vitro studies
	Commercial	Non-cellular enzymatic study (human FBPase)	Baicalein (IC50 = 29 ± 3 μM)	68
			Scutellarein (IC50 = 38.2 ± 0.4 μM)
			Herbacetin (IC50 = 8.7 ± 0.7 μM)
			Gossypetin (IC50 = 24 ± 2 μM)
	Isolated from Desmodium caudatum	Non-cellular enzymatic study (human FBPase)	8-Prenylquercetin (IC50 = 3.62 ± 0.37 μM)	193
In vivo studies
	Commercial	STZ-induced Wistar rats (4, 8 and 16 mg kg^−1 of compound, with administration by intubation for 45 days)	↓ liver FBPase levels on STZ-induced rats. No effect on normal rats	172
	Not mentioned	STZ-induced Swiss Albino mice (5 and 10 mg kg^−1 of compound, intraperitoneal administration for 5 weeks)	↓ liver FBPase levels on STZ-induced mice. No effect on normal rats	194
	Commercial	DM induced by STZ using Wistar rats (20, 40, 80 mg kg^−1 of compound, administered orally by intragastric intubation, daily for a period of 30 days)	↓ liver FBPase levels on STZ-induced rats. No effect on normal rats	184
	Commercial	STZ–cadmium-induced diabetic nephrotoxic Wistar rats (1 mg kg^−1 of compound, administered intraperitoneally once a day for 12 weeks)	↓ liver FBPase levels on STZ–cadmium-induced rats.	189
			↓ FBPase levels of normal rats
	Commercial	STZ-induced Wistar rats (25 and 50 mg kg^−1 of compound, administered orally to for 30 days)	↓ liver FBPase levels on STZ-induced rats. No effect on normal rats	195
	Commercial	STZ-induced Wistar rats (25, 50, 100 mg kg^−1 of compound, administered orally using an intragastric tube for 30 days)	↓ liver FBPase levels on STZ-induced rats. No effect on normal rats	182
	Commercial	STZ-induced Wistar rats (100 mg kg^−1 of compound, administered orally daily for 30 days)	↓ liver FBPase levels on STZ-induced rats. No effect on normal rats	190
	Isolated from Semecarpus anacardium	DM induced by high-fat diet and STZ using Wistar rats (20, 40, 80 mg kg^−1 of compound, administration intragastrically for 30 days)	↓ liver FBPase levels on high-fat diet and STZ-induced rats. No effect on normal rats	191

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Proença et al.⁶⁸ investigated the effect of 55 structurally related flavonoids, using an in vitro non-cellular assay with isolated human FBPase. The results showed that herbacetin (Table 4), was the most potent inhibitor of the study, with similar potency to the positive control AMP. The authors concluded that, in general, the addition of hydroxy substituents increased the inhibitory effect of the flavonoids, and methoxy substituents are disadvantageous for the intended effect. In particular, the authors reported that hydroxy groups at the C-3, C-4′, C-5, C-7, and C-8 positions, as well as the double bond between C-2 and C-3 and the 4-oxo function at the pyrone ring, are determinant for the inhibitory potential of the compounds. For example, the flavonoid quercetin was not able to inhibit the enzyme.⁶⁸ Similarly, Zhang et al.¹⁹³ studied the effect of hydroxylated flavonoids in an in vitro non-cellular assay, and verified that the existence of hydroxy groups together with a prenyl group were essential for the inhibitory activity of the flavonoids. In accordance with Proença et al.,⁶⁸ the flavonoid quercetin was not able to inhibit the enzyme. However, when comparing quercetin with 8-prenylquercetin, the addition of the prenyl group at the C-8 position was essential for the effect.¹⁹³ Proença et al.⁶⁸ and Zhang et al.¹⁹³ also studied in common the flavonoids apigenin and naringenin, showing no effect on both studies.

Some authors have already studied polyphenols in in vivo studies, including galangin, pterostilbene, naringin, myricetin, morin, hesperidin, tangeretin and a biflavonoid, as represented in Table 4. These polyphenols were able to reduce the levels of FBPase in streptozotocin-induced animals. In general, these polyphenols are hydroxylated, except pterostilbene and hesperidin, holding methoxy and hydroxy groups, and tangeretin, bearing only methoxy groups. Proença et al.⁶⁸ studied the flavonoids galangin, myricetin, and morin, revealing their lack of inhibitory activity against the human enzyme. The different results observed are possibly due to the distinct complexity associated with both in vitro and in vivo experiments.

5. Conclusions

Polyphenols have emerged as promising compounds for therapeutic research, demonstrating significant potential across multiple targeted pathways.

Polyphenols as PTP1B inhibitors emerge as the most extensively studied category among the reviewed targets. In contrast, research on the other targets, including glucagon receptor antagonists, GK activators, GP inhibitors, and FBPase inhibitors, remains relatively limited. Notably, studies investigating polyphenols as glucagon receptor antagonists are virtually absent, highlighting a critical gap in the literature. Flavonoids have garnered particular interest across various targeted pathways, with the presence of hydroxyl groups playing a key role in their activities. However, despite the significant number of studies, cellular-based investigations remain scarce for all targets, limiting mechanistic insights into their efficacy and specificity. The development of in vitro mechanistic studies, particularly using cellular models, 3D cultures, and co-cultures, would be valuable in addressing this gap, as no such studies were identified within our search criteria over the past decade.

Additionally, it is important to acknowledge that in vitro enzymatic studies are conducted under varying conditions, with differences in enzyme concentrations and buffer compositions, while in vivo studies are performed in distinct models with variations in study duration, dosing regimens, and administration routes. These factors introduce challenges in making direct comparisons between studies. Moreover, polyphenols are subject to extensive metabolism and rapid elimination in the human body, which may limit their therapeutic potential in vivo despite promising in vitro results. Despite the increasing research on polyphenols, pharmacokinetic studies remain scarce, making it difficult to fully understand their ADME profiles. To address these challenges, future research should prioritize pharmacokinetic characterization and explore novel delivery systems aimed at enhancing bioefficacy and stability. In this context, approaches using nano-based delivery systems are gaining attention and may significantly improve the clinical translation of polyphenol-based therapies.

Overall, while considerable progress has been made in the last decade in elucidating the potential of polyphenols as inhibitors across various targets, there exists a pressing need for further investigation, particularly in cellular and in vivo models, to comprehensively understand their mechanisms of action, bioavailability, safety and therapeutic efficacy.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work received financial support from the PT national funds (FCT/MECI, Fundação para a Ciência e Tecnologia and Ministério da Educação, Ciência e Inovação) through the project UID/50006 -Laboratório Associado para a Química Verde - Tecnologias e Processos Limpos. S. Rocha acknowledges the Fundação para a Ciência e a Tecnologia (FCT), the financial support for the PhD grant (PD/BD/145169/2019 and COVID/BD/153305/2023), through the PhD Programme in Medicines and Pharmaceutical Innovation (i3DU). M. Freitas acknowledges her CEEC contract-2020.04126.CEECIND/CP1596/CT0006 and LAQV-REQUIMTE for her contract under the reference LA/P/0008/2020: https://doi.org/10.54499/LA/P/0008/2020.

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