Insulin resistance: Review of the underlying molecular mechanisms.
Yaribeygi Habib,Farrokhi Farin Rashid,Butler Alexandra E,Sahebkar Amirhossein
Journal of cellular physiology
Most human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for these tissues. However, decrease in insulin sensitivity due to the disruption of various molecular pathways causes insulin resistance (IR). IR underpins many metabolic disorders such as type 2 diabetes and metabolic syndrome, impairments in insulin signaling disrupting entry of glucose into the adipocytes, and skeletal muscle cells. Although the exact underlying cause of IR has not been fully elucidated, a number of major mechanisms, including oxidative stress, inflammation, insulin receptor mutations, endoplasmic reticulum stress, and mitochondrial dysfunction have been suggested. In this review, we consider the role these cellular mechanisms play in the development of IR.
10.1002/jcp.27603
Mechanisms of Insulin Action and Insulin Resistance.
Physiological reviews
The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.
10.1152/physrev.00063.2017
Catalpol ameliorates hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway.
Yan Jiting,Wang Changyuan,Jin Yue,Meng Qiang,Liu Qi,Liu Zhihao,Liu Kexin,Sun Huijun
Pharmacological research
Type 2 diabetes is characterized by insulin resistance in target tissues and hyperglycemia. Catalpol is a natural product isolated from the root of Rehmannia glutinosa, which has been reported to produce the effect of anti-diabetes in recent reports. The goal of the current study is to investigate the therapeutic effects of catalpol on hepatic insulin resistance in type 2 diabetes and elucidate the underlying cellular mechanisms. Type 2 diabetes in vivo was induced by combined high-fat diet (HFD) and streptozotocin (STZ) injection in C57BL/6J mice. Insulin resistance in vitro was induced by glucosamine administration in HepG2 cells. Catalpol exhibited the effects decreasing hepatic gluconeogenesis and increasing hepatic glycogen synthesis both in vivo and in vitro. Additionally, catalpol improved hepatic NADPH oxidase type 4 (NOX4)-mediated oxidative stress and activated hepatic AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathway in vivo and in vitro. The effects of catalpol on preventing gluconeogenesis and increasing glycogen synthesis in glucosamine-induced HepG2 cells were prevented by pretreatment with LY294002, the inhibitor of PI3K. Furthermore, the effect of catalpol on depriving glucosamine-induced insulin resistance was prevented by knockdown of NOX4 or AMPK with short interfering RNA (siRNA) in HepG2 cells. Moreover, the suppressive effect of catalpol on glucosamine-induced NOX4 over-expression was weakened by knockdown of AMPK with siRNA. Taken together, these findings suggested that catalpol ameliorated hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway.
10.1016/j.phrs.2017.12.026
Small-Molecule Inhibition of Glucose Transporters GLUT-1-4.
Chembiochem : a European journal of chemical biology
Glucose addiction is observed in cancer and other diseases that are associated with hyperproliferation. The development of compounds that restrict glucose supply and decrease glycolysis has great potential for the development of new therapeutic approaches. Addressing facilitative glucose transporters (GLUTs), which are often upregulated in glucose-dependent cells, is therefore of particular interest. This article reviews a selection of potent, isoform-selective GLUT inhibitors and their biological characterization. Potential therapeutic applications of GLUT inhibitors in oncology and other diseases that are linked to glucose addiction are discussed.
10.1002/cbic.201900544
Antioxidant activity of vasoactive intestinal peptide in HK2 human renal cells.
Vacas Eva,Bajo Ana M,Schally Andrew V,Sánchez-Chapado Manuel,Prieto Juan C,Carmena María J
Peptides
Oxidative stress is a major mediator of tissue and cell injuries. The injury in chronic nephrotic syndrome, acute renal failure, myeloma kidney injury and other kidney diseases is initiated by oxidative stress. We have previously demonstrated that vasoactive intestinal peptide (VIP) acts as an antiproliferative agent in renal cancer cells. This study was designed to evaluate the renoprotective activity of VIP against H(2)O(2)-induced oxidative damage in a proximal tubule kidney cell line (human, non-tumor, HK2 cells) in order to investigate the potential usefulness of this peptide in the treatment of oxidative-stress related kidney diseases. HK2 cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Propidium iodide was used to identify cells undergoing apoptosis. Western blotting was performed with anti-Bcl-2, anti-Bax and anti-formyl peptide receptor (low-affinity variant FPRL-1) monoclonal antibodies whereas 2,7-dichlorofluorescein diacetate was used for measurement of levels of intracellular reactive oxygen species (ROS). HK2 cells were injured with H(2)O(2) in order to induce apoptosis: the effect was time- and dose-dependent. VIP increased the levels of the antiapoptotic protein Bcl-2 and decreased those of the proapoptotic protein Bax. VIP decreased the intracellular ROS levels reached by H(2)O(2)-induced oxidative stress. VIP effect on ROS levels involved FPLR-1 but not VPAC(1,2) receptors as evidenced by the use of the respective antagonists WRW4 and JV-1-53. Thus, VIP protects HK2 cells from apoptosis by increasing Bcl-2 levels and this effect is initiated through FPLR1 receptor. In conclusion, VIP might exert a renoprotective effect by the suppression of oxidative stress.
10.1016/j.peptides.2012.09.011
Hsa-miR-494-3p attenuates gene HtrA3 transcription to increase inflammatory response in hypoxia/reoxygenation HK2 Cells.
Gong Qian,Shen Zhi-Ming,Sheng Zhe,Jiang Shi,Ge Sheng-Lin
Scientific reports
The occurrence of cardiac surgery-associated acute kidney injury (CSA-AKI) increases hospital stay and mortality. MicroRNAs has a crucial role in AKI. This objective of the current study is to explore the function of hsa-miR-494-3p in inflammatory response in human kidney tubular epithelial (HK2) cells with hypoxia/reoxygenation. According to KDIGO standard, patients after cardiac surgery with cardiopulmonary bypass were divided into two groups: AKI (n = 10) and non-AKI patients (n = 8). HK2 were raised in the normal and hypoxia/reoxygenation circumstances and mainly treated by overexpression ofmiR-494-3p and HtrA3. The relationship between miR-494-3p and HtrA3 was determined by dual-luciferase reporter assay. Our result showed that Hsa-miR-494-3p was elevated in the serum of patients with CSA-AKI, and also induced in hypoxic reoxygenated HK2 cells. Hsa-miR-494-3p also increased a hypoxia-reoxygenation induced inflammatory response in HK2 cells. Moreover, as a target gene of miR-494-3p, overexpression of HtrA3 downregulated the hypoxia-reoxygenation induced inflammatory response in HK2 cells. Overexpression of hsa-miR-494-3p-induced inflammatory response was inhibited by overexpression of HtrA3. Collectively, we identified that hsa-miR-494-3p, a miRNA induced in both circulation of AKI patients and hypoxia-reoxygenation-treated HK2 cells, enhanced renal inflammation by targeting HtrA3, which may suggest a possible role as a new therapeutic target for CSA-AKI.
10.1038/s41598-021-81113-x
Antihepatotoxic properties of picroliv: an active fraction from rhizomes of Picrorhiza kurrooa.
Ansari R A,Tripathi S C,Patnaik G K,Dhawan B N
Journal of ethnopharmacology
The hepatoprotective activity of picroliv, the irridoid glycoside mixture from Picrorhiza kurrooa, was determined in adult male albino rats. Pretreatment with picroliv prevented the hepatotoxic effects of paracetamol and galactosamine as evidenced by various biochemical and histopathological observations. Maximum hepatoprotective effect was observed with daily oral doses of 6 and 12 mg/kg for 7 or 8 days. The antihepatotoxic action of picroliv seems likely due to an alteration in the biotransformation of the toxic substances resulting in decreased formation of reactive metabolites.
Studies on inhibitors of skin tumor promotion. XI. Inhibitory effects of flavonoids from Scutellaria baicalensis on Epstein-Barr virus activation and their anti-tumor-promoting activities.
Konoshima T,Kokumai M,Kozuka M,Iinuma M,Mizuno M,Tanaka T,Tokuda H,Nishino H,Iwashima A
Chemical & pharmaceutical bulletin
To search for possible anti-tumor-promoters, fourteen flavones obtained from the root of Scutellaria baicalensis were examined for their inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Among these flavones, 5,7,2'-trihydroxy- and 5,7,2',3'-tetrahydroxyflavone showed remarkable inhibitory effects on the EBV-EA activation, and the effect of the latter on Raji cell cycle was also examined by flow cytometer. These two flavones exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.
10.1248/cpb.40.531
Protective effect of picroliv against lipopolysaccharide-induced cognitive dysfunction and neuroinflammation by attenuating TLR4/NFκB pathway.
Li Lihong,Jin Xiaoqing,Zhang Haifeng,Yin Jiangyan
Folia neuropathologica
INTRODUCTION:Present investigation determines the beneficial effect of picroliv against lipopolysaccharide (LPS)-induced neuronal inflammation and injury. MATERIAL AND METHODS:Neuronal injury was induced by LPS 250 µg/kg, i.p. for the period of one week, and picroliv 12.5 and 25 mg/kg was given i.p. 30 min prior to the administration of LPS for the duration of 12 days. The effect of picroliv was determined on the cognitive function by Morris water maze (MWM). Mediators of inflammation were estimated by using enzyme-linked immunosorbent assay (ELISA) and western blot, reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical analysis was done to determine the expressions of several proteins. RESULTS:Data of the study reveal that picroliv ameliorates the reduced memory impairment and cognitive dysfunction in LPS-induced mice. Moreover, expressions of inflammatory protein and -amyloid protein and level of inflammatory mediators were found to be reduced in the picroliv-treated group as compared to the negative control group. Data of RT-PCR reveal that the gene of Toll-like receptor 4 (TLR-4), -synuclein, neurotrophic factor (BDNF) and interleukin-1 (IL-1) protein were also decreased in the picroliv-treated group as compared to the negative control group. In addition picroliv attenuates the altered level of nuclear factor-kB(p-NF-kB), amyloid- (A), -synuclein and glial fibrillary acidic protein (GFAP) positive cells in the brain of LPS-induced mice. CONCLUSIONS:The report concludes that picroliv protects the neuroinflammation and injury in LPS-induced mice by regulating the inflammatory pathway.
10.5114/fn.2018.80867
Comparative Study on the Biochemical Profile and Antioxidant Activity of Rolye ex Benth. Obtained from Uttarakhand.
Evidence-based complementary and alternative medicine : eCAM
Royle ex Benth. is one of the well-established herbal plants with an exceptional therapeutic potential. It belongs to the Scrophulariaceae family and is commonly called as kutki. The drug obtained from the plant is a bitter tonic due to the presence of kutkin in it. Over 61 secondary metabolites from the plants have been identified, including iridoid glycosides, flavonoids, cucurbitacins, and phenolic chemicals. However, picrosides are the major phytochemicals in this species that are responsible for its well-known hepatoprotective properties. The present study was conducted to compare (dried rhizomes) obtained from local traders from the markets of three different districts of Uttarakhand, i.e., the Dewal block of Chamoli, Ukhimath block of Rudraprayag, and Dharchula block of Pithoragarh. Biochemical analysis was conducted on the powder of dried rhizomes for alkaloids, phenolics, tannins, flavonoids, and antioxidant activity. Based on analysis, it was found that the total phenolic content, total flavonoid content, total alkaloid content, and radical scavenging activity of . rhizomes purchased from Darma valley, Pithoragarh district of Uttarakhand, were the highest, followed by rhizomes collected from the Dewal block of Chamoli district and the least were found in rhizomes obtained from the Ukhimath block of Rudraprayag district of Uttarakhand. The maximum tannin content was found in rhizomes obtained from the Dewal block of Chamoli, while total reducing power was observed the highest in rhizomes from the Ukhimath block of Rudraprayag. The results provided evidence that obtained from Darma valley, Pithoragarh, are the potential source of phenolics, flavonoids, and tannins and have the highest DPPH-scavenging activity and therefore could be served as the basis for future drugs and food materials.
10.1155/2023/8792414
Long term effect of aflatoxin B(1) on lipid peroxidation in rat liver and kidney: effect of picroliv and silymarin.
Rastogi R,Srivastava A K,Rastogi A K
Phytotherapy research : PTR
Aflatoxin B(1) (AFB(1)) is a potent hepatotoxic and hepatocarcinogenic mycotoxin. The mechanism of cellular damage caused by AFB(1) has not been fully elucidated. Lipid peroxidation is one of the main manifestations of oxidative damage and has been found to play an important role in the toxicity and carcinogenesis of many carcinogens. The present investigation aims at assessing the comparative antioxidant effect of picroliv, a standardized iridoid glycoside fraction of Picrorhiza kurroa and silymarin, a well known standard hepatoprotective, on aflatoxin B(1) induced lipid-peroxidation in rat liver and kidney. Marked increases in lipid peroxide levels and a concomitant decrease in enzymic antioxidant levels were observed in aflatoxin B(1) (2 mg/kg, i.p) -toxicated rats, while drug (picroliv and silymarin both) treatment reversed the condition to near normal levels. The effects of picroliv and silymarin were comparable.
10.1002/ptr.722
Picroliv protects against alcohol-induced chronic hepatotoxicity in rats.
Rastogi R,Saksena S,Garg N K,Kapoor N K,Agarwal D P,Dhawan B N
Planta medica
Daily administration of ethyl alcohol (3.76 g/kg, p.o.) for 45 days resulted in significant changes in several biochemical parameters of the liver and serum of albino rats. After exposure to alcohol for 30 days when Picroliv (12 mg/kg, p.o.), an iridoid glycoside fraction of Picrorhiza kurroa, was administered for 15 days along with alcohol, the degree of change in most of the parameters was reduced.
10.1055/s-2006-957882
Effects of some iridoids from plant origin on arachidonic acid metabolism in cellular systems.
Bermejo Benito P,Díaz Lanza A M,Silván Sen A M,De Santos Galindez J,Fernandez Matellano L,Sanz Gómez A,Abad Martínez M J
Planta medica
Seven iridoid glycosides isolated from different extracts of Scrophularia scorodonia L., namely bartsioside, aucubin, harpagide, harpagoside, 8-acetylharpagide, scorodioside and scropolioside B, had been evaluated for their in vitro anti-inflammatory activity in cellular systems generating COX and LOX metabolites. Structure-activity relationships obtained from in vitro screening results were discussed. Most compounds assayed did not exhibit any significant effect on PGE2- and LTC4-release from calcium ionophore-stimulated mouse peritoneal macrophages. In the LTC4-assay, only aucubin showed a significant effect, with an IC50 value of 72 microM. Harpagoside and harpagide also inhibited release of LTC4, but neither effect reached statistical significance. The release of PGE2 by mouse peritoneal macrophages stimulated with calcium ionophore was inhibited by harpagoside and 8-acetylharpagide, but this effect is not statistically significant. However, most iridoids assayed showed a significant effect on TXB2-release from calcium ionophorestimulated human platelets, with inhibition percentages slightly lower than the reference drug ibuprofen. Only harpagide, scorodioside and scropolioside B had no significant effect on TXB2-release. Our results indicate that selective inhibition of the TX-synthase enzyme may be the primary target of action of most of these iridoids, and one of the mechanisms through which they exert their anti-inflammatory effects.
10.1055/s-2000-8549
Protective effects of iridoid glycosides on acute colitis via inhibition of the inflammatory response mediated by the STAT3/NF-кB pathway.
Yuan Jiahui,Cheng Weipeng,Zhang Gongye,Ma Qiujuan,Li Xiaomei,Zhang Bing,Hu Tianhui,Song Gang
International immunopharmacology
Morroniside and loganin are iridoid glycosides extracted from Cornus officinalis, a plant species widely used in traditional Chinese medicine. However, the anti-inflammatory effects of morroniside and loganin in colitis are barely understood. The aim of the present study was to explore the effects of morroniside and loganin on the dextran sodium sulfate (DSS)-induced murine model of colitis and an LPS-induced colorectal cancer (CRC) cell inflammation model, and to clarify the underlying mechanisms. We found that morroniside and loganin were able to ameliorate clinical features, including disease activity index (DAI), histological inflammation score and periodic acid-Schiff staining (PAS). In the mouse model, morroniside and loganin treatment increased expression of tight junction proteins (TJs) and decreased pro-inflammatory cytokine production. Moreover, our findings showed that the expression of p-STAT3 and p-p65 were suppressed compared to the disease group. In in vitro experiments, treatment with morroniside and loganin had no obvious effects on proliferative activity in HCT116 cells and HIEC-6 cells. Expression of pro-inflammatory cytokines was inhibited by morroniside and loganin treatment in comparison with the LPS-treated group. Taken together, morroniside and loganin have beneficial effects on colitis in vivo and are anti-inflammatory in vitro. Possible mechanisms of the anti-inflammatory response may include blockade of the STAT3/NF-κB pathway.
10.1016/j.intimp.2020.106240
Hypoglycemic, hypolipidemic and antioxidant effects of iridoid glycosides extracted from : possible involvement of the PI3K-Akt/PKB signaling pathway.
RSC advances
Iridoid glycosides (CIG) are the major component of . In this work, we researched the antioxidative, hypoglycemic and lowering blood lipids effects of CIG on diabetic mice induced by a high-fat diet (HFD) and streptozotocin (STZ). Furthermore, to investigate the molecular mechanism of action, the phosphorylation and protein expression of phosphoinositide 3-kinase (PI3K) and its downstream proteins, such as insulin receptor (INSR), protein kinase B (Akt/PKB) and glucose transporter 4 (GLUT4) have been detected. The results showed that CIG significantly improved oral glucose tolerance in diabetic mice. Biochemical indices also revealed that CIG had a positive effect on lipid metabolism and oxidative stress. In addition, CIG can significantly enhance the expression level of the PI3K-Akt/PKB pathway related proteins in skeletal muscle, which is the key pathway of insulin metabolism. These findings show that CIG can improve the hyperglycemia and hyperlipidemia of HFD-STZ-induced diabetic mice through the PI3K-Akt/PKB signaling pathway, and CIG might be a potential medicine or functional food for type 2 diabetes mellitus remedies.
10.1039/c8ra06045b
Geniposide and Gentiopicroside Suppress Hepatic Gluconeogenesis via Regulation of AKT-FOXO1 Pathway.
Yang Shao-Qing,Chen Ye-Dan,Li Heng,Hui Xian,Gao Wen-Yun
Archives of medical research
BACKGROUND:Hepatic gluconeogenesis plays an important role in regulating fasting plasma glucose levels and is a target of anti-diabetic drugs. Several kinds of iridoid glucosides exhibit hypoglycemic effect, whereas the mechanism was not clear. AIM OF THE STUDY:In this study, the effects of geniposide and gentiopicroside, two natural iridoid glucosides, on hepatic gluconeogenesis were investigated. METHODS:Glucose uptake assay, MTT assay, q-PCR, luciferase assay and western blot assay were performed to investigate the pharmacological effect of geniposide and gentiopicroside on human liver cell line L02. Thereby the fast blood glucose and intraperitoneal glucose tolerance were measured in high fat diet induced hyperglycemic mice after geniposide or gentiopicroside administration. RESULTS:The results showed that geniposide and gentiopicroside inhibited the transcription of G6PC and PEPCK in L02 cells and in mice. Additional experimental data indicated that these two compounds were able to inhibit the transcriptional activity of FOXO1 by inducing phosphorylation of AKT at Ser473. Furthermore, we found that these two compounds alleviated high fat diet induced hyperglycemia in mice. CONCLUSIONS:Geniposide and gentiopicroside might reduce blood glucose and suppress hepatic gluconeogenesis by regulating the AKT-FOXO1 pathway, and the potential use of these two iridoid glucosides as anti-diabetic agents merits further in-depth exploration.
10.1016/j.arcmed.2018.10.005
Effects of boschnaloside from Boschniakia rossica on dysglycemia and islet dysfunction in severely diabetic mice through modulating the action of glucagon-like peptide-1.
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Boschniakia rossica is a well-known traditional Chinese medicine for tonifying kidney and improving impotence. Boschnaloside is the major iridoid glycoside in this herb but therapeutic benefits for diabetes remained to be evaluated. HYPOTHESIS/PURPOSE:The current investigation aims to study the antidiabetic effect and the underlying pharmacological mechanisms. STUDY DESIGN AND METHODS:Receptor binding, cAMP production, Ins secretion, glucagon-like peptide 1 (GLP-1) secretion, and dipeptidyl peptidase-4 activity assays were performed. Therapeutic benefits of orally administrated boschnaloside (150 and 300 mg/kg/day) were evaluated using severely 12-week old female diabetic db/db mice (Hemoglobin A1c >10%). RESULTS:Oral treatment of boschnaloside for 4 weeks improved diabetic symptoms including fasting blood sugar, hemoglobin A1c, glucose intolerance, and Homeostatic Model Assessment of Ins Resistance, accompanied by circulating GLP-1 and adiponectin levels. In addition, bochnaloside treatment improved islet/β cell function associated with an alteration of the pancreatic and duodenal homeobox 1 level. It was shown that boschnaloside interacted with the extracellular domain of GLP-1 receptor and enhanced glucose stimulated Ins secretion. Boschnaloside also augmented the insulinotropic effect of GLP-1. Finally, the presence of boschnaloside caused a reduction of dipeptidyl peptidase-4 activity while enhanced GLP-1 secretion from STC-1 cells. CONCLUSION:It appears that bochnaloside at oral dosage greater than 150 mg/kg/day exerts antidiabetic effects in vivo through modulating the action of GLP-1.
10.1016/j.phymed.2019.152946
A Story of Serendipities: From Phlorizin to Gliflozins.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation
Diabetes has been acknowledged since ancient times. However, it was only during the late 1800s that we realized that the primary organ for blood glucose regulation was the pancreas. The 20th century witnessed insulin purification, which revolutionized the treatment of diabetes maigre; this was followed by the development of oral antidiabetic drugs. The sodium-glucose cotransporter 2 inhibitors or gliflozins are the latest class. Unique cardio- and renoprotective effects separate them from other oral antidiabetic drugs. Here, we present the history behind the development of these inhibitors, arguably the hottest and the most pleasant topic in nephrology. The first serendipity was Koninck and Stas (assistants to Prof. Van Mons, a renowned pomology expert); these researchers isolated a crystalline glycoside called phloridzin (phlorizin) from the bark of apple trees while working at their boss's nursery. Their discovery was published in German in 1835. The second serendipity, after a half century, was from Prof. von Mering, who decided to administer phlorizin to dogs. Oskar Minkowski initially observed polyuria than glucosuria. Insightfully, von Mering postulated that phlorizin affects kidneys. In 1887, they reported that phlorizin induced glucosuria in people with diabetes. The third serendipity was that phlorizin causes several gastrointestinal side effects and has poor oral bioavailability. The first phlorizin-based drug to enter trials was T-1095. The first clinically available gliflozin was dapagliflozin, receiving approval in Europe and the United States in 2012 and 2014, respectively. The 2015 EMPA-REG Outcome trial reported extremely satisfying results that no one expected. Subsequent trials and real-world data have resulted in changes in all impactful guidelines. The impact of these agents on heart failure and chronic kidney disease seems independent of their antidiabetic properties. More than 100 years after von Mering's original discovery, descendants of phlorizin are fast becoming the most inspiring medicine for the 21st century physician.
10.6002/ect.IAHNCongress.25
Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter.
Nature
Human sodium-glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney. Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes. Here we determined the cryogenic electron microscopy structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to an overall resolution of 2.95 Å. Our structure shows eukaryotic SGLT-specific structural features. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle. Our work provides a framework for understanding the mechanism of SLC5A family glucose transporters and also develops a foundation for the future rational design and optimization of new inhibitors targeting these transporters.
10.1038/s41586-021-04212-9
Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus.
Scheen André J
Drugs
Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment, and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population. The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebo-controlled trials with cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy also deserve more attention. SGLT2 inhibitors are generally well-tolerated. The most frequently reported adverse events are female genital mycotic infections, while urinary tract infections are less commonly observed and generally benign. In conclusion, with their unique mechanism of action that is independent of insulin secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease. Although SGLT2 inhibitors have already been extensively investigated, further studies should even better delineate the best place of these new glucose-lowering agents in the already rich armamentarium for the management of T2DM.
10.1007/s40265-014-0337-y
Sodium-glucose cotransporter 2 inhibition attenuates protein overload in renal proximal tubule via suppression of megalin O-GlcNacylation in progressive diabetic nephropathy.
Otomo Hitomi,Nara Mitsuhiko,Kato Shunsuke,Shimizu Tatsunori,Suganuma Yumi,Sato Takehiro,Morii Tsukasa,Yamada Yuichiro,Fujita Hiroki
Metabolism: clinical and experimental
AIMS:The crosstalk between sodium-glucose cotransporter 2 (SGLT2) inhibition and a membrane-associated endocytic receptor megalin function involved in renal proximal tubular protein overload in progressive diabetic nephropathy (DN) is uncertain. Here, we determined whether SGLT2 inhibition affects megalin endocytic function through suppressing its O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) and protects the diabetic kidney from protein overload. MATERIALS AND METHOD:We treated 8-week-old male non-obese and hypoinsulinemic KK/Ta-Ins2 (KK/Ta-Akita) mice which develop progressive DN with an SGLT2 inhibitor ipragliflozin or insulin for 6 weeks, and investigated the endocytic function (proximal tubular protein reabsorption), renal expression and O-GlcNAcylation of megalin along with their effects on renal phenotypes including histology and biochemical markers. RESULTS:The treatment with ipragliflozin, but not insulin, suppressed megalin O-GlcNAcylation and accelerated its internalization, resulting in reduction in proximal tubular reabsorption of the highly filtered plasma proteins such as albumin and neutrophil gelatinase-associated lipocalin. These alterations following the ipragliflozin treatment contributed to amelioration of proximal tubular protein overload, mitochondrial morphological abnormality, and renal oxidative stress and tubulointerstitial fibrosis. CONCLUSIONS:The present study provides a novel crosstalk mechanism between SGLT2 inhibition and megalin underlying the potential renal benefits of SGLT2 inhibition in DN.
10.1016/j.metabol.2020.154405
Critical Role of Dipeptidyl Peptidase IV: A Therapeutic Target for Diabetes and Cancer.
De Sourav,Banerjee Subhasis,Kumar S K Ashok,Paira Priyankar
Mini reviews in medicinal chemistry
Diabetes mellitus is an emerging predator and affecting around 422 million adults worldwide. Higher levels of circulating insulin and increased pressure on the pancreas to produce insulin have been inferred as possible etiology for diabetes leading to a higher risk of pancreatic cancer. Out of several drug targets in hypoglycemic discovery, Dipeptidyl peptidase-IV (DPP-IV) has been considered an emerging target. It is a protease enzyme which inactivates incretin hormones i.e., Glucagonlike peptide 1 (GLP-1) and glucose-dependent insulin tropic polypeptide (GIP). Inhibition of DPP-4 results in the longer action of GLP-1 and GIP, therefore, DPP-4 inhibitors play an important role in maintaining glucose homeostasis. In comparison to early oral hypoglycemic, DPP-IV inhibitors are well tolerated and provide a better glycemic control over a longer period. These enzymes are expressed in a dimeric form on the surface of different cells such as prostate, liver and small intestinal epithelium cells. Disruption of the local signaling environment is an emerging factor in cancer development. Till date, not even a single DPP-IV inhibitor as anticancer has been developed. This review focuses on various features of the enzyme and their suitable inhibitors for target disease.
10.2174/1389557518666180423112154
Alpha-Glucosidase Inhibitory Peptides: Sources, Preparations, Identifications, and Action Mechanisms.
Nutrients
With the change in people's lifestyle, diabetes has emerged as a chronic disease that poses a serious threat to human health, alongside tumor, cardiovascular, and cerebrovascular diseases. α-glucosidase inhibitors, which are oral drugs, have proven effective in preventing and managing this disease. Studies have suggested that bioactive peptides could serve as a potential source of α-glucosidase inhibitors. These peptides possess certain hypoglycemic activity and can effectively regulate postprandial blood glucose levels by inhibiting α-glucosidase activity, thus intervening and regulating diabetes. This paper provides a systematic summary of the sources, isolation, purification, bioavailability, and possible mechanisms of α-glucosidase inhibitory peptides. The sources of the α-glucosidase inhibitory peptides were introduced with emphasis on animals, plants, and microorganisms. This paper also points out the problems in the research process of α-glucosidase inhibitory peptide, with a view to providing certain theoretical support for the further study of this peptide.
10.3390/nu15194267
Thiazolidinediones: the Forgotten Diabetes Medications.
Lebovitz Harold E
Current diabetes reports
PURPOSE OF REVIEW:Thiazolidinediones (TZDs) are the only pharmacologic agents that specifically treat insulin resistance. The beneficial effects of TZDs on the cardiovascular risk factors associated with insulin resistance have been well documented. TZD use has been limited because of concern about safety issues and side effects. RECENT FINDINGS:Recent studies indicate that cardiovascular toxicity with rosiglitazone and increase in bladder cancer with pioglitazone are no longer significant issues. There are new data which show that pioglitazone treatment reduces myocardial infarctions and ischemic strokes. New data concerning TZD-mediated edema, congestive heart failure, and bone fractures improves the clinician's ability to select patients that will have minimal significant side effects. Thiazolidinediones are now generic and less costly than pharmaceutical company-promoted therapies. Better understanding of the side effects coupled with clear benefits on the components of the insulin resistance syndrome should promote TZD use in treating patients with type 2 diabetes.
10.1007/s11892-019-1270-y
Metformin: clinical use in type 2 diabetes.
Sanchez-Rangel Elizabeth,Inzucchi Silvio E
Diabetologia
Metformin is one of the most popular oral glucose-lowering medications, widely considered to be the optimal initial therapy for patients with type 2 diabetes mellitus. Interestingly, there still remains controversy regarding the drug's precise mechanism of action, which is thought to involve a reduction in hepatic glucose production. It is now recommended as first-line treatment in various guidelines, including that of the EASD and ADA. Its favoured status lies in its efficacy, low cost, weight neutrality and good safety profile. Other benefits have also been described, including improvements in certain lipids, inflammatory markers, and a reduction in cardiovascular events, apparently independent from the drug's glucose-lowering effect. Data have emerged questioning the previous reluctance to use this agent in those with mild to moderate chronic kidney disease. Regulations guiding its use in patients with stable, modest renal dysfunction have, as a result, become more lenient in recent years. With no long-term studies comparing it against newer glucose-lowering drugs, some of which have more robust evidence for cardioprotection, metformin's established role as 'foundation therapy' in type 2 diabetes may justifiably be challenged.
10.1007/s00125-017-4336-x
Mechanisms and Characteristics of Sulfonylureas and Glinides.
Lv Wei,Wang Xianqing,Xu Qian,Lu Wencong
Current topics in medicinal chemistry
BACKGROUND:Type 2 diabetes mellitus is a complex progressive endocrine disease characterized by hyperglycemia and life-threatening complications. It is the most common disorder of pancreatic cell function that causes insulin deficiency. Sulfonylurea is a class of oral hypoglycemic drugs. Over the past half century, these drugs, together with the subsequent non-sulfonylureas (glinides), have been the main oral drugs for insulin secretion. OBJECTIVE:Through in-depth study, the medical profession considers it as an important drug for improving blood sugar control. METHODS:The mechanism, characteristics, efficacy and side effects of sulfonylureas and glinides were reviewed in detail. RESULTS:Sulfonylureas and glinides not only stimulated the release of insulin from pancreatic cells, but also had many extrapanular hypoglycemic effect, such as reducing the clearance rate of insulin in liver, reducing the secretion of glucagon, and enhancing the sensitivity of peripheral tissues to insulin in type 2 diabetes mellitus. CONCLUSION:Sulfonylureas and glinides are effective first-line drugs for the treatment of diabetes mellitus. Although they have the risk of hypoglycemia, weight gain and cardiovascular disease, their clinical practicability and safety can be guaranteed as long as they are reasonably used.
10.2174/1568026620666191224141617
Pharmacological treatment of hyperglycemia in type 2 diabetes.
The Journal of clinical investigation
Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA's recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.
10.1172/JCI142243
Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance.
Kojta Iwona,Chacińska Marta,Błachnio-Zabielska Agnieszka
Nutrients
Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. The exact mechanism by which adipose tissue induces insulin resistance is still unclear. It has been demonstrated that obesity is associated with the adipocyte dysfunction, macrophage infiltration, and low-grade inflammation, which probably contributes to the induction of insulin resistance. Adipose tissue synthesizes and secretes numerous bioactive molecules, namely adipokines and cytokines, which affect the metabolism of both lipids and glucose. Disorders in the synthesis of adipokines and cytokines that occur in obesity lead to changes in lipid and carbohydrates metabolism and, as a consequence, may lead to insulin resistance and type 2 diabetes. Obesity is also associated with the accumulation of lipids. A special group of lipids that are able to regulate the activity of intracellular enzymes are biologically active lipids: long-chain acyl-CoAs, ceramides, and diacylglycerols. According to the latest data, the accumulation of these lipids in adipocytes is probably related to the development of insulin resistance. Recent studies indicate that the accumulation of biologically active lipids in adipose tissue may regulate the synthesis/secretion of adipokines and proinflammatory cytokines. Although studies have revealed that inflammation caused by excessive fat accumulation and abnormalities in lipid metabolism can contribute to the development of obesity-related insulin resistance, further research is needed to determine the exact mechanism by which obesity-related insulin resistance is induced.
10.3390/nu12051305
Disordered lipid metabolism and the pathogenesis of insulin resistance.
Savage David B,Petersen Kitt Falk,Shulman Gerald I
Physiological reviews
Although abnormal glucose metabolism defines type 2 diabetes mellitus (T2DM) and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of T2DM are increasingly focused on disordered lipid metabolism. Here we review recent human studies exploring the mechanistic links between disorders of fatty acid/lipid metabolism and insulin resistance. As "mouse models of insulin resistance" were comprehensively reviewed in Physiological Reviews by Nandi et al. in 2004, we will concentrate on human studies involving the use of isotopes and/or magnetic resonance spectroscopy, occasionally drawing on mouse models which provide additional mechanistic insight.
10.1152/physrev.00024.2006
Insulin Signal Transduction Perturbations in Insulin Resistance.
Khalid Mariyam,Alkaabi Juma,Khan Moien A B,Adem Abdu
International journal of molecular sciences
Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic β-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to β-cell decline through the IAPP-RAGE induced β-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus.
10.3390/ijms22168590
The aetiology and molecular landscape of insulin resistance.
Nature reviews. Molecular cell biology
Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues - prominently in muscle, fat and liver - is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia and hyperlipidaemia. Insulin resistance is caused by a combination of genetic and environmental factors. Recent genetic and biochemical studies suggest a key role for adipose tissue in the development of insulin resistance, potentially by releasing lipids and other circulating factors that promote insulin resistance in other organs. These extracellular factors perturb the intracellular concentration of a range of intermediates, including ceramide and other lipids, leading to defects in responsiveness of cells to insulin. Such intermediates may cause insulin resistance by inhibiting one or more of the proximal components in the signalling cascade downstream of insulin (insulin receptor, insulin receptor substrate (IRS) proteins or AKT). However, there is now evidence to support the view that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway that is more closely linked to the terminal biological response. Identifying these targets is of major importance, as it will reveal potential new targets for treatments of diseases associated with insulin resistance.
10.1038/s41580-021-00390-6
The changing face of diabetes complications.
Gregg Edward W,Sattar Naveed,Ali Mohammed K
The lancet. Diabetes & endocrinology
The global increase in type 2 diabetes prevalence is well documented, but international trends in complications of type 2 diabetes are less clear. The available data suggest large reductions in classic complications of type 2 diabetes in high-income countries over the past 20 years, predominantly reductions in myocardial infarction, stroke, amputations, and mortality. These trends might be accompanied by less obvious, but still important, changes in the character of morbidity in people with diabetes. In the USA, for example, substantial reductions in macrovascular complications in adults aged 65 years or older mean that a large proportion of total complications now occur among adults aged 45-64 years instead, rates of renal disease could persist more than other complications, and obesity-related type 2 diabetes could have increasing effect in youth and adults under 45 years of age. Additionally, the combination of decreasing mortality and increasing diabetes prevalence has increased the overall mean years lived with diabetes and could lead to a diversification of diabetes morbidity, including continued high rates of renal disease, ageing-related disability, and cancers. Unfortunately, data on trends in diabetes-related complications are limited to only about a dozen countries, most of which are high income, leaving the changing character for countries of low and middle income ambiguous.
10.1016/S2213-8587(16)30010-9
Treatment of Diabetic Kidney Disease: Current and Future.
Yamazaki Tomotaka,Mimura Imari,Tanaka Tetsuhiro,Nangaku Masaomi
Diabetes & metabolism journal
Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. However, only renin-angiotensin system inhibitor with multidisciplinary treatments is effective for DKD. In 2019, sodium-glucose cotransporter 2 (SGLT2) inhibitor showed efficacy against DKD in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, adding a new treatment option. However, the progression of DKD has not been completely controlled. The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Furthermore, NF-E2-related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treatment: Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) trial. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights.
10.4093/dmj.2020.0217
Diabetes and global ageing among 65-99-year-old adults: Findings from the International Diabetes Federation Diabetes Atlas, 9 edition.
Sinclair Alan,Saeedi Pouya,Kaundal Abha,Karuranga Suvi,Malanda Belma,Williams Rhys
Diabetes research and clinical practice
AIMS:The main aims are: (a) to draw attention to the nature and pattern of recent global and regional prevalence estimates and projections of diabetes in older adults (65-99 years), and (b) to describe the societal health implications of these changes on a global scale. METHODS:Diabetes prevalences and projections were estimated using a logistic regression method to generate smoothed age- and sex-specific prevalence estimates for 5-year age groups. RESULTS:In 2019, it is estimated that 19.3% of people aged 65-99 years (135.6 million, 95% CI: 107.6-170.6 million) live with diabetes. It is projected that the number of people older than 65 years (65-99 years) with diabetes will reach 195.2 million by 2030 and 276.2 million by 2045. For the regional distribution, the highest prevalence in 2019 being the North America and Caribbean Region at 27.0%. Countries with the highest number of people older than 65 years with diabetes are China, the United States of America and India. CONCLUSIONS:There is a need for more data from national and regional sources on those aged 65 years and over, but the prevailing evidence points to diabetes being a considerable global chronic illness burden in ageing societies.
10.1016/j.diabres.2020.108078