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Therapeutic Mechanisms of Nature Products against Insulin Resistance

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (28 April 2023) | Viewed by 10826

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Prof. Dr. Anne-Dominique Lajoix

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Guest Editor

Biocommunication in Cardio-Metabolism (BC2M), Faculty of Pharmacy, University of Montpellier, Montpellier, France
Interests: type 2 diabetes; obesity; pancreatic β-cells; insulin resistance; nitric oxide; oxidative stress; inflammation
Special Issues, Collections and Topics in MDPI journals

Dr. Didier Tousch

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Qualisud, Faculty of Sciences, University of Montpellier, CIRAD, SupAgro, Montpellier, France
Interests: natural compounds; asteracea; caffeic acid derivatives; metabolic syndrome; type 2 diabetes; insulin resistance; antioxidant; inflammation
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Insulin resistance corresponds to a reduced responsiveness of insulin-sensitive tissues to physiological levels of insulin. This disorder is present in several diseases, such as metabolic syndrome, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases. Insulin resistance is often recognized as the primary defect leading to type 2 diabetes. During early phases of diabetes, a compensatory insulin hypersecretion allows insulin resistance to be counteracted and normoglycemia to be maintained. Thereafter, a progressive pancreatic β-cell failure is responsible for a decrease in insulin secretion, leading to chronic hyperglycemia. The main drivers of insulin resistance are related to obesity, decreased exercise practices, and the overconsumption of high-fat and high-carbohydrate food. To improve metabolic disorders, such as type 2 diabetes, pharmacological strategies include insulin sensitisers (biguanides, thiazolidinediones), insulin secretagogues (e.g., sulphonylureas), alphaglucosidase inhibitors, and sodium–glucose co-transporter 2 inhibitors. Natural products are also a source of active compounds that could be useful tools to improve metabolic disorders in combination with pharmacological drugs. They can originate from plants, animals, fungus, algae, microorganisms, food ingredients, and traditional medicine, and can act directly on insulin resistance to improve glucose homeostasis. They can target insulin-sensitive tissues, such as skeletal muscle, adipose tissues, liver, or the cardiovascular system. Their mechanisms of action can identify molecular targets in order to use them in combination with other pharmacological drugs.We thus invite investigators to provide studies investigating the therapeutic mechanisms of natural products at cellular and molecular levels on the target tissues that contribute to insulin resistance.

Prof. Dr. Anne-Dominique Lajoix
Dr. Didier Tousch
Guest Editors

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Keywords

insulin resistance
signaling pathways
liver
skeletal muscle
adipose tissues
traditional medicine
plants
fungus
algae
food ingredients

Published Papers (5 papers)

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15 pages, 4905 KiB

Open AccessArticle

Glucose Uptake Is Increased by Estradiol Dipropionate in L6 Skeletal Muscle Cells

by Yanhong Yao, Xinzhou Yang, Jinhua Shen and Ping Zhao

Pharmaceuticals 2023, 16(1), 25; https://doi.org/10.3390/ph16010025 - 25 Dec 2022

Cited by 1 | Viewed by 1984

Abstract

GLUT4 is an important glucose transporter, which is closely related to insulin resistance and type 2 diabetes. In this study, we investigated the mechanism of Estradiol Dipropionate (EDP) on uptake of glucose in L6 skeletal muscle cells. In our study, we confirmed that EDP promoted uptake of glucose in L6 skeletal muscle cells in both normal and insulin resistant models. Western blot indicated that EDP accelerated GLUT4 expression and significantly activated AMPK and PKC phosphorylation; the expression of GLUT4 was significantly inhibited by AMPK inhibitor compound C and PKC inhibitor Gö6983, but not by Wortmannin (Akt inhibitor). Meanwhile, EDP boosted GLUT4 expression, and also increased intracellular Ca²⁺ levels. In the presence of 2 mM, 0 mM extracellular Ca²⁺ and 0 mM extracellular Ca²⁺ + BAPTA-AM, the involvement of intracellular Ca²⁺ levels contribute to EDP-induced GLUT4 expression and fusion with plasma membrane. Therefore, this study investigated whether EDP promoted GLUT4 expression through AMPK and PKC signaling pathways, thereby enhancing GLUT4 uptake of glucose and fusion into plasma membrane in L6 skeletal muscle cells. In addition, both EDP induced GLUT4 translocation and uptake of glucose were Ca²⁺ dependent. These findings suggested that EDP may be potential drug for the treatment of type 2 diabetes. Full article

(This article belongs to the Special Issue Therapeutic Mechanisms of Nature Products against Insulin Resistance)

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17 pages, 3414 KiB

Open AccessArticle

Serpentine Enhances Insulin Regulation of Blood Glucose through Insulin Receptor Signaling Pathway

by Yinghao Wang, Guanfu Liu, Xutao Liu, Minhua Chen, Yuping Zeng, Yuyan Li, Xiaoyun Wu, Xuanjun Wang and Jun Sheng

Pharmaceuticals 2023, 16(1), 16; https://doi.org/10.3390/ph16010016 - 22 Dec 2022

Viewed by 2100

Abstract

Insulin sensitizers targeting insulin receptors (IR) are a potential drug for the treatment of diabetes. Serpentine is an alkaloid component in the root of Catharanthus roseus (L.) G. Don. Serpentine screened by surface plasmon resonance (SPR) technology has the ability to target IR. The objective of this study was to investigate whether serpentine could modulate the role of insulin in regulating blood glucose through insulin receptors in cells and in animal models of diabetes. SPR technology was used to detect the affinity of different concentrations of serpentine with insulin receptors. The Western blotting method was used to detect the expression levels of key proteins of the insulin signaling pathway in C2C12 cells and 3T3-L1 cells as well as in muscle and subcutaneous adipose tissue of diabetic mice after serpentine and insulin treatment. Diabetic mice were divided into four groups and simultaneously injected with insulin or serpentine, and the blood glucose concentration and serum levels of insulin, glucagon, and C-peptide were measured 150 min later. mRNA levels of genes related to lipid metabolism and glucose metabolism in liver, muscle, and subcutaneous adipose tissue were detected by RT-PCR. Serpentine was able to bind to the extracellular domain of IR with an affinity of 2.883 × 10⁻⁶ M. Serpentine combined with insulin significantly enhanced the ability of insulin to activate the insulin signaling pathway and significantly enhanced the glucose uptake capacity of C2C12 cells. Serpentine enhanced the ability of low-dose insulin (1 nM) and normal-dose insulin (100 nM) to activate the insulin signaling pathway. Serpentine also independently activated AMPK phosphorylation, thus stimulating glucose uptake by C2C12 cells. In high-fat-diet/streptozotocin (HFD/STZ)-induced diabetic mice, serpentine significantly prolonged the hypoglycemic time of insulin, significantly reduced the use of exogenous insulin, and inhibited endogenous insulin secretion. In addition, serpentine alone significantly increased the expression of GSK-3β mRNA in muscle tissue, thus enhancing glucose uptake, and at the same time, serpentine significantly increased glucagon secretion and liver gluconeogenesis. Serpentine enhances the ability of insulin to regulate blood glucose through the insulin receptor, and can also regulate blood glucose alone, but it has a negative regulation mechanism and cannot produce a hypoglycemic effect. Therefore, serpentine may be useful as an insulin sensitizer to assist insulin to lower blood glucose. Full article

(This article belongs to the Special Issue Therapeutic Mechanisms of Nature Products against Insulin Resistance)

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17 pages, 4512 KiB

Open AccessArticle

Andrographolide Promotes Uptake of Glucose and GLUT4 Transport through the PKC Pathway in L6 Cells

by Jingya Liao, Ziwei Yang, Yanhong Yao, Xinzhou Yang, Jinhua Shen and Ping Zhao

Pharmaceuticals 2022, 15(11), 1346; https://doi.org/10.3390/ph15111346 - 31 Oct 2022

Cited by 1 | Viewed by 1722

Abstract

Glucose transporter 4 (GLUT4) is a membrane protein that regulates blood glucose balance and is closely related to type 2 diabetes. Andrographolide (AND) is a diterpene lactone extracted from herbal medicine Andrographis paniculata, which has a variety of biological activities. In this study, the antidiabetic effect of AND in L6 cells and its mechanism were investigated. The uptake of glucose of L6 cells was detected by a glucose assay kit. The expression of GLUT4 and phosphorylation of protein kinase B (PKB/Akt), AMP-dependent protein kinase (AMPK), and protein kinase C (PKC) were detected by Western blot. At the same time, the intracellular Ca²⁺ levels and GLUT4 translocation in myc-GLUT4-mOrange-L6 cells were detected by confocal laser scanning microscopy. The results showed that AND enhanced the uptake of glucose, GLUT4 expression and fusion with plasma membrane in L6 cells. Meanwhile, AND also significantly activated the phosphorylation of AMPK and PKC and increased the concentration of intracellular Ca²⁺. AND-induced GLUT4 expression was significantly inhibited by a PKC inhibitor (Gö6983). In addition, in the case of 0 mM extracellular Ca²⁺ and 0 mM extracellular Ca²⁺ + 10 μM BAPTA-AM (intracellular Ca²⁺ chelator), AND induced the translocation of GLUT4, and the uptake of glucose was significantly inhibited. Therefore, we concluded that AND promoted the expression of GLUT4 and its fusion with plasma membrane in L6 cells through PKC pathways in a Ca²⁺—dependent manner, thereby increasing the uptake of glucose. Full article

(This article belongs to the Special Issue Therapeutic Mechanisms of Nature Products against Insulin Resistance)

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24 pages, 3517 KiB

Open AccessEditor’s ChoiceArticle

Steviol Glycoside, L-Arginine, and Chromium(III) Supplementation Attenuates Abnormalities in Glucose Metabolism in Streptozotocin-Induced Mildly Diabetic Rats Fed a High-Fat Diet

by Jakub Michał Kurek, Ewelina Król, Halina Staniek and Zbigniew Krejpcio

Pharmaceuticals 2022, 15(10), 1200; https://doi.org/10.3390/ph15101200 - 28 Sep 2022

Cited by 4 | Viewed by 2579

Abstract

Stevia rebaudiana Bertoni and its glycosides are believed to exhibit several health-promoting properties. Recently, the mechanisms of the anti-diabetic effects of steviol glycosides (SG) have been the subject of intense research. The following study aims to evaluate the results of SG (stevioside (ST) and rebaudioside A (RA)) combined with L-arginine (L-Arg) and chromium(III) (CrIII) supplementation in streptozotocin- (STZ) induced mild type 2 diabetic rats fed a high-fat diet (HFD), with particular emphasis on carbohydrate and lipid metabolisms. The experiment was carried out on 110 male Wistar rats, 100 of which were fed an HFD to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin to induce mild type 2 diabetes. After confirmation of hyperglycemia, the rats were divided into groups. Three groups served as controls: diabetic untreated, diabetic treated with metformin (300 mg/kg BW), and healthy group. Eight groups were fed an HFD enriched with stevioside or rebaudioside A (2500 mg/kg BW) combined with L-arginine (2000 or 4000 mg/kg BW) and Cr(III) (1 or 5 mg/kg BW) for six weeks. The results showed that supplementation with SG (ST and RA) combined with L-arg and Cr(III) could improve blood glucose levels in rats with mild type 2 diabetes. Furthermore, ST was more effective in improving blood glucose levels, insulin resistance indices, and very low-density lipoprotein cholesterol (VLDL-C) concentrations than RA. Although L-arg and Cr(III) supplementation did not independently affect most blood carbohydrate and lipid indices, it further improved some biomarkers when combined, particularly with ST. Notably, the beneficial impact of ST on the homeostatic model assessment–insulin resistance (HOMA-IR) and on the quantitative insulin-sensitivity check index (QUICKI) was strengthened when mixed with a high dose of L-arg, while its impact on antioxidant status was improved when combined with a high dose of Cr(III) in rats with mild type 2 diabetes. In conclusion, these results suggest that supplementary stevioside combined with L-arginine and Cr(III) has therapeutic potential for mild type 2 diabetes. However, further studies are warranted to confirm these effects in other experimental models and humans. Full article

(This article belongs to the Special Issue Therapeutic Mechanisms of Nature Products against Insulin Resistance)

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13 pages, 3171 KiB

Open AccessBrief Report

Irisin Preserves Cardiac Performance and Insulin Sensitivity in Response to Hemorrhage

by Supaporn Kulthinee, Lijiang Wang, Naohiro Yano, Patrycja M. Dubielecka, Ling X. Zhang, Shougang Zhuang, Gangjian Qin, Yu Tina Zhao, Yue Eugene Chin and Ting C. Zhao

Pharmaceuticals 2022, 15(10), 1193; https://doi.org/10.3390/ph15101193 - 27 Sep 2022

Cited by 2 | Viewed by 1466

Abstract

Irisin, a cleaved product of the fibronectin type III domain containing protein-5, is produced in the muscle tissue, which plays an important role in modulating insulin resistance. However, it remains unknown if irisin provides a protective effect against the detrimental outcomes of hemorrhage. Hemorrhages were simulated in male CD-1 mice to achieve a mean arterial blood pressure of 35–45 mmHg, followed by resuscitation. Irisin (50 ng/kg) and the vehicle (saline) were administrated at the start of resuscitation. Cardiac function was assessed by echocardiography, and hemodynamics were measured through femoral artery catheterization. A glucose tolerance test was used to evaluate insulin sensitivity. An enzyme-linked immunosorbent assay was performed to detect inflammatory factors in the muscles and blood serum. Western blot was carried out to assess the irisin production in skeletal muscles. Histological analyses were used to determine tissue damage and active-caspase 3 apoptotic signals. The hemorrhage suppressed cardiac performance, as indicated by a reduced ejection fraction and fractional shortening, which was accompanied by enhanced insulin resistance and hyperinsulinemia. Furthermore, the hemorrhage resulted in a marked decrease in irisin and an increase in the production of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). Additionally, the hemorrhage caused marked edema, inflammatory cell infiltration and active-caspase 3 positive signals in skeletal muscles and cardiac muscles. Irisin treatment led to a significant improvement in the cardiac function of animals exposed to a hemorrhage. In addition, irisin treatment improved insulin sensitivity, which is consistent with the suppressed inflammatory cytokine secretion elicited by hemorrhages. Furthermore, hemorrhage-induced tissue edema, inflammatory cell infiltration, and active-caspase 3 positive signaling were attenuated by irisin treatment. The results suggest that irisin protects against damage from a hemorrhage through the modulation of insulin sensitivity. Full article

(This article belongs to the Special Issue Therapeutic Mechanisms of Nature Products against Insulin Resistance)

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