Natural Alkaloids Intervening the Insulin Pathway: New Hopes for Anti-Diabetic Agents?

2019 ◽  
Vol 26 (32) ◽  
pp. 5982-6015 ◽  
Author(s):  
Maria-Ioanna Christodoulou ◽  
Job Tchoumtchoua ◽  
Alexios-Leandros Skaltsounis ◽  
Andreas Scorilas ◽  
Maria Halabalaki
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Signal Transduction Pathway ◽  
Insulin Signal Transduction ◽  
Risk Of Death ◽  
Increased Risk ◽  
Expression Activity ◽  
Insulin Signal Transduction Pathway

Background: Accumulating experimental data supports the capacity of natural compounds to intervene in complicated molecular pathways underlying the pathogenesis of certain human morbidities. Among them, diabetes is now a world’s epidemic associated with increased risk of death; thus, the detection of novel anti-diabetic agents and/or adjuvants is of vital importance. Alkaloids represent a diverse group of natural products with a range of therapeutic properties; during the last 20 years, published research on their anti-diabetic capacity has been tremendously increased. Purpose: To discuss current concepts on the anti-diabetic impact of certain alkaloids, with special reference to their molecular targets throughout the insulin-signaling pathway. Methodology: Upon in-depth search in the SCOPUS and PUBMED databases, the literature on alkaloids with insulin secretion/sensitization properties was critically reviewed. Results: In-vitro and in-vivo evidence supports the effect of berberine, trigonelline, piperine, oxymatrine, vindoneline, evodiamine and neferine on insulin-signaling and related cascades in beta-cells, myocytes, adipocytes, hepatocytes and other cells. Associated receptors, kinases, hormones and cytokines, are affected in terms of gene transcription, protein expression, activity and/or phosphorylation. Pathophysiological processes associated with insulin resistance, beta-cell failure, oxidative stress and inflammation, as well as clinical phenotype are also influenced. Discussion: Growing evidence suggests the ability of specific alkaloids to intervene in the insulin-signal transduction pathway, reverse molecular defects resulting in insulin resistance and glucose intolerance and improve disease complications, in-vitro and in-vivo. Future indepth molecular studies are expected to elucidate their exact mechanism of action, while large clinical trials are urgently needed to assess their potential as anti-diabetic agents.

scholarly journals Shen-Zhi-Ling oral liquid ameliorates cerebral glucose metabolism disorder in early AD via insulin signal transduction pathway in vivo and in vitro

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Gaofeng Qin ◽  
Yunfang Dong ◽  
Zhenhong Liu ◽  
Zhuoyan Gong ◽  
Chenyan Gao ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Insulin Signal Transduction ◽  
Insulin Signal ◽  
Insulin Signal Transduction Pathway

Abstract Background Shen-Zhi-Ling oral liquid (SZL) is an herbal formula known for its efficacy of nourishing “heart and spleen”, and is used for the treatment and prevention of middle- and early-stage dementia. This study investigated the effects of SZL on amelioration of AD, and examined whether the underlying mechanisms from the perspective of neuroprotection are related to brain glucose metabolism. Methods Firstly, LC–MS/MS was used to analysis the SZL mainly enters the blood component. Then, the effects of SZL on cognitive and behavioral ability of APP/PS1 double transgenic mice and amyloid protein characteristic pathological changes were investigated by behavioral study and morphological observation. The effects of SZL on the ultrastructure of mitochondria, astrocytes, and micrangium related to cerebral glucose metabolism were observed using transmission electron microscopy. Then, micro-PET was also used to observe the effects of SZL on glucose uptake. Furthermore, the effects of SZL on insulin signaling pathway InR/PI3K/Akt and glucose transporters (GLUT1 and GLUT3) were observed by immunohistochemistry, Western-blot and RT-qPCR. Finally, the effects of SZL on brain glucose metabolism and key enzyme were observed. In vitro, the use of PI3K and/or GSK3β inhibitor to observe the effects of SZL drug-containing serum on GLUT1 and GLUT3. Results In vivo, SZL could significantly ameliorate cognitive deficits, retarded the pathological damage, including neuronal degeneration, Aβ peptide aggregation, and ultrastructural damage of hippocampal neurons, improve the glucose uptake, transporters and glucolysis. Beyond that, SZL regulates the insulin signal transduction pathway the insulin signal transduction pathway InR/PI3K/Akt. Furthermore, 15% SZL drug-containing serum increased Aβ42-induced insulin signal transduction-pathway related indicators and GLUT1 and GLUT3 expression in SH-SY5Y cells. The improvement of GLUT1 and GLUT3 in the downstream PI3K/Akt/GSK3β signaling pathway was reversed by the use of PI3K and/or GSK3β inhibitor. Conclusions In summary, our results demonstrated that improving glucose uptake, transport, and glycolysis in the brain may underlie the neuroprotective effects of SZL, and its potential molecular mechanism may be related to regulate the insulin signal transduction pathway.

scholarly journals Studies of insulin resistance in patients with clinical and subclinical hypothyroidism

2009 ◽  
Vol 160 (5) ◽  
pp. 785-790 ◽  
Author(s):  
Eirini Maratou ◽  
Dimitrios J Hadjidakis ◽  
Anastasios Kollias ◽  
Katerina Tsegka ◽  
Melpomeni Peppa ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Plasma Membrane ◽  
Glucose Transport ◽  
Subclinical Hypothyroidism ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Model Assessment ◽  
Increased Risk

ObjectiveAlthough clinical hypothyroidism (HO) is associated with insulin resistance, there is no information on insulin action in subclinical hypothyroidism (SHO).Design and methodsTo investigate this, we assessed the sensitivity of glucose metabolism to insulin both in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes with flow cytometry) in 21 euthyroid subjects (EU), 12 patients with HO, and 13 patients with SHO.ResultsAll three groups had comparable plasma glucose levels, with the HO and SHO having higher plasma insulin than the EU (P<0.05). Homeostasis model assessment index was increased in HO (1.97±0.22) and SHO (1.99±0.13) versus EU (1.27±0.16, P<0.05), while Matsuda index was decreased in HO (3.89±0.36) and SHO (4.26±0.48) versus EU (7.76±0.87, P<0.001), suggesting insulin resistance in both fasting and post-glucose state. At 100 μU/ml insulin: i) GLUT4 levels on the monocyte plasma membrane were decreased in both HO (215±19 mean fluorescence intensity, MFI) and SHO (218±24 MFI) versus EU (270±25 MFI, P=0.03 and 0.04 respectively), and ii) glucose transport rates in monocytes from HO (481±30 MFI) and SHO (462±19 MFI) were decreased versus EU (571±15 MFI, P=0.04 and 0.004 respectively).ConclusionsIn patients with HO and SHO: i) insulin resistance was comparable; ii) insulin-stimulated rates of glucose transport in isolated monocytes were decreased due to impaired translocation of GLUT4 glucose transporters on the plasma membrane; iii) these findings could justify the increased risk for insulin resistance-associated disorders, such as cardiovascular disease, observed in patients with HO or SHO.

scholarly journals Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance

Reproduction ◽  
2008 ◽  
Vol 136 (3) ◽  
pp. 335-344 ◽  
Author(s):  
Erica Louden ◽  
Maggie M Chi ◽  
Kelle H Moley
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Kinase Activity ◽  
Pi3 Kinase ◽  
Ampk Activation ◽  
Embryonic Cells ◽  
Insulin Resistant

Maternal insulin resistance results in poor pregnancy outcomes. In vivo and in vitro exposure of the murine blastocyst to high insulin or IGF1 results in the down-regulation of the IGF1 receptor (IGF1R). This in turn leads to decreased glucose uptake, increased apoptosis, as well as pregnancy resorption and growth restriction. Recent studies have shown that blastocyst activation of AMP-activated protein kinase (AMPK) reverses these detrimental effects; however, the mechanism was not clear. The objective of this study was to determine how AMPK activation rescues the insulin-resistant blastocyst. Using trophoblast stem (TS) cells derived from the blastocyst, insulin resistance was recreated by transfecting with siRNA to Igf1r and down-regulating expression of the protein. These cells were then exposed to AMPK activators 5-aminoimidazole-4-carboxamide riboside and phenformin, and evaluated for apoptosis, insulin-stimulated 2-deoxyglucose uptake, PI3-kinase activity, and levels of phospho-AKT, phospho-mTor, and phospho-70S6K. Surprisingly, disrupted insulin signaling led to decreased AMPK activity in TS cells. Activators reversed these effects by increasing the AMP/ATP ratio. Moreover, this treatment increased insulin-stimulated 2-deoxyglucose transport and cell survival, and led to an increase in PI3-kinase activity, as well as increased P-mTOR and p70S6K levels. This study is the first to demonstrate significant crosstalk between the AMPK and insulin signaling pathways in embryonic cells, specifically the enhanced response of PI3K/AKT/mTOR to AMPK activation. Decreased insulin signaling also resulted in decreased AMPK activation. These findings provide mechanistic targets in the AMPK signaling pathway that may be essential for improved pregnancy success in insulin-resistant states.

scholarly journals The emerging role of iron in heart failure and vascular calcification in CKD

2020 ◽  
Author(s):  
Paola Ciceri ◽  
Mario Cozzolino
Keyword(s):  
Heart Failure ◽  
Iron Deficiency ◽  
Vascular Calcification ◽  
Strong Association ◽  
In Vivo Models ◽  
Risk Of Death ◽  
Increased Risk ◽  
Cv Disease

Abstract Iron deficiency is a frequent comorbidity of cardiovascular (CV) diseases and nearly 50% of patients with heart failure (HF) with or without anaemia have low levels of available iron. There is a strong association between anaemia and the increase in mortality and hospitalizations in patients with CV disease and HF. Moreover, anaemia and chronic kidney disease (CKD) often coexist in patients with HF, with anaemia increasing the risk of death in these subjects and with a further increased risk in CKD population. The evidence that the treatment of iron deficiency and the increase in haemoglobin are associated with a better prognosis in HF patients has elicited new interest in the utilization of iron in HF and CKD patients. One of the central players in CV disease is vascular calcification (VC), which has been recognized as a major independent risk factor for incident CV disease and overall mortality in chronic disease patients. In this review, we summarize the evidences generated by clinical trials aimed to study the effect of iron deficiency correction, the effect of iron-based phosphate binder in in vivo models of kidney failure and the effect of iron in in vitro models of VC, trying to give an overview of the present knowledge on iron effect and its mechanisms of action.

scholarly journals Antenatal corticosteroids alter insulin signaling pathways in fetal baboon skeletal muscle

2014 ◽  
Vol 221 (2) ◽  
pp. 253-260 ◽  
Author(s):  
Cynthia L Blanco ◽  
Alvaro G Moreira ◽  
Lisa L McGill-Vargas ◽  
Diana G Anzueto ◽  
Peter Nathanielsz ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Content ◽  
Insulin Signaling ◽  
Vastus Lateralis ◽  
Signal Transduction Pathway ◽  
Vastus Lateralis Muscle ◽  
Fetal Life ◽  
Antenatal Corticosteroids ◽  
Insulin Signal Transduction ◽  
Insulin Signal Transduction Pathway

We hypothesize that prenatal exposure to glucocorticoids (GCs) negatively alters the insulin signal transduction pathway and has differing effects on the fetus according to gestational age (GA) at exposure. Twenty-three fetal baboons were delivered from 23 healthy, nondiabetic mothers. Twelve preterm (0.67 GA) and 11 near-term (0.95 GA) baboons were killed immediately after delivery. Half of the pregnant baboons at each gestation received two doses of i.m. betamethasone 24 h apart (170 μg/kg) before delivery, while the other half received no intervention. Vastus lateralis muscle was obtained from postnatal animals to measure the protein content and gene expression of insulin receptor β (IRβ; INSR), IRβ Tyr 1361 phosphorylation (pIRβ), IR substrate 1 (IRS1), IRS1 tyrosine phosphorylation (pIRS1), p85 subunit of PI3-kinase, AKT (protein kinase B), phospho-AKT Ser473 (pAKT), AKT1, AKT2, and glucose transporters (GLUT1 and GLUT4). Skeletal muscle from preterm baboons exposed to GCs had markedly reduced protein content of AKT and AKT1 (respectively, 73 and 72% from 0.67 GA control, P<0.001); IRβ and pIRβ were also decreased (respectively, 94 and 85%, P<0.01) in the muscle of premature GC-exposed fetuses but not in term fetuses. GLUT1 and GLUT4 tended to increase with GC exposure in preterm animals (P=0.09), while GLUT4 increased sixfold in term animals after exposure to GC (P<0.05). In conclusion, exposure to a single course of antenatal GCs during fetal life alters the insulin signaling pathway in fetal muscle in a manner dependent on the stage of gestation.

scholarly journals Flavonoids and Insulin-Resistance: From Molecular Evidences to Clinical Trials

2019 ◽  
Vol 20 (9) ◽  
pp. 2061 ◽  
Author(s):  
Benedetta Russo ◽  
Fabiana Picconi ◽  
Ilaria Malandrucco ◽  
Simona Frontoni
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Clinical Trials ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Food Sources ◽  
Main Factors

Insulin-resistance is one of the main factors responsible for the onset and progression of Metabolic Syndrome (MetS). Among all polyphenols, the effects of flavonoids and their main food sources on insulin sensitivity have been widely evaluated in molecular and clinical studies. The aim of this review is to analyse the data observed in vitro, in vivo and in clinical trials concerning the effects of flavonoids on insulin resistance and to determine the molecular mechanisms with which flavonoids interact with insulin signaling.

scholarly journals Exploring mechanistic links between extracellular branched-chain amino acids and muscle insulin resistance: an in vitro approach

2020 ◽  
Vol 319 (6) ◽  
pp. C1151-C1157
Author(s):  
Hannah Crossland ◽  
Kenneth Smith ◽  
Iskandar Idris ◽  
Bethan E. Phillips ◽  
Philip J. Atherton ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Insulin Signaling ◽  
Prolonged Exposure ◽  
Glycogen Synthesis ◽  
Branched Chain Amino Acids ◽  
Increased Risk ◽  
Impaired Insulin ◽  
Branched Chain

Branched-chain amino acids (BCAAs) are essential for critical metabolic processes; however, recent studies have associated elevated plasma BCAA levels with increased risk of insulin resistance. Using skeletal muscle cells, we aimed to determine whether continued exposure of high extracellular BCAA would result in impaired insulin signaling and whether the compound sodium phenylbutyrate (PB), which induces BCAA metabolism, would lower extracellular BCAA, thereby alleviating their potentially inhibitory effects on insulin-mediated signaling. Prolonged exposure of elevated BCAA to cells resulted in impaired insulin receptor substrate 1/AKT signaling and insulin-stimulated glycogen synthesis. PB significantly reduced media BCAA and branched-chain keto acid concentrations and increased phosphorylation of AKT [+2.0 ± 0.1-fold; P < 0.001 versus without (−)PB] and AS160 (+3.2 ± 0.2-fold; P < 0.001 versus −PB); however, insulin-stimulated glycogen synthesis was further reduced upon PB treatment. Continued exposure of high BCAA resulted in impaired intracellular insulin signaling and glycogen synthesis, and while forcing BCAA catabolism using PB resulted in increases in proteins important for regulating glucose uptake, PB did not prevent the impairments in glycogen synthesis with BCAA exposure.

scholarly journals OR14-04 A Novel ERRα-Dependent Insulin Signaling Pathway

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hui Xia ◽  
Vincent Giguere
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Energy Homeostasis ◽  
Glycogen Synthase ◽  
Orphan Nuclear Receptor ◽  
Alcoholic Fatty Liver ◽  
Altered Expression ◽  
Kinase Substrate ◽  
Insulin Signal Transduction

Abstract Insulin resistance, a condition in which a cell, tissue, or organism fails to respond appropriately to insulin, is a hallmark for the development of type 2 diabetes and a major contributor to the pathogenesis of non-alcoholic fatty liver disease. In addition to altered insulin signaling transduction, more and more research highlights dysregulated gene expression as nuclear mechanisms underlying insulin resistance. ERRα is an orphan nuclear receptor that plays a central role in the regulation of energy homeostasis. Here, we present evidence to support ERRα as a novel and potent transcriptional regulator of insulin action. By using a high-throughput insulin-based phospho-proteomic database of the mouse liver and bioinformatics analysis based on conserved kinase substrate motif, we first identified ERRα as a direct substrate of glycogen synthase kinase 3β (GSK3β). Our data demonstrate that under basal conditions, GSK3β phosphorylates ERRα at residues S19, S22, and S26. Phosphorylated ERRα is then recognized and ubiquitynated by the SCF-FBXW7 E3 ligase complex, resulting in its degradation by the proteasome. Indeed, pharmacological inhibition of GSK3β in vivo as well as liver-specific knockout of Fbxw7 both lead to the accumulation of ERRα in the liver. Insulin, by inhibiting GSK3β, leads to the stabilization of ERRα in the nucleus, resulting in the altered expression of insulin-responsive genes involved in gluconeogenesis and insulin signal transduction. Genome-wide analysis reveals that more than 40% of the insulin-regulated genes in the liver are direct ERRα targets, indicating a prominent role of ERRα in the regulation of insulin signaling. Together, our findings underscore a novel ERRα-dependent mechanism for insulin’s effects in physiology and disease, implicating the therapeutic value of targeting the GSK3β/FBXW7/ERRα axis in vivo.

Fat distribution and storage: how much, where, and how?

2007 ◽  
Vol 157 (suppl_1) ◽  
pp. S39-S45 ◽  
Author(s):  
Ram Weiss
Keyword(s):  
Insulin Resistance ◽  
Signal Transduction Pathway ◽  
Insulin Resistance Syndrome ◽  
Fat Distribution ◽  
Good Health ◽  
Lipid Deposition ◽  
Insulin Signal Transduction ◽  
Underlying Mechanisms ◽  
Insulin Signal Transduction Pathway ◽  
Inflammatory Milieu

Obesity does not necessarily imply disease and similarly obese individuals may manifest obesity-related morbidity or seemingly be in reasonably good health. Recent studies have shown that patterns of lipid partitioning are a major determinant of the metabolic profile and not just obesity per se. The underlying mechanisms and clinical relevance of lipid deposition in the visceral compartment and in insulin-sensitive tissues are described. Increased intramyocellular lipid deposition impairs the insulin signal transduction pathway and is associated with insulin resistance. Increased hepatic lipid deposition is similarly associated with the majority of the components of the insulin resistance syndrome. The roles of increased circulating fatty acids in conditions of insulin resistance and the typical pro-inflammatory milieu of specific obesity patterns are provided. Insights into the patterns of lipid storage within the cell are provided along with their relation to changes in insulin sensitivity and weight loss.

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