Improvement In Insulin Signaling Research Articles

Korean Red Ginseng Improves Oxidative Stress-Induced Hepatic Insulin Resistance via Enhancing Mitophagy.

This study explored the potential of saponins from Korean Red Ginseng to target the PINK1/Parkin mitophagy pathway, aiming to enhance insulin sensitivity in hepatocytes-a key factor in metabolic disorders like metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. Results from both in vitro and in vivo experiments showed increased expression of PINK1 and Parkin, activating mitophagy and reducing oxidative stress through reduction in mitochondrial and total reactive oxygen species. Additionally, improvements in insulin signaling were observed, including the upregulation of phosphorylated IRS and AKT, and downregulation of gluconeogenic enzymes, underscoring the saponins' efficacy in boosting insulin sensitivity. The findings highlighted Korean Red Ginseng-derived saponins as potential treatments for insulin resistance and related metabolic conditions.

Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes.

Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and lactation. Less clear is the role of dopamine in the pathophysiology of type 2 diabetes mellitus (T2D) and chronic complications and conditions frequently associated with it. This review summarizes recent evidence on the role of dopamine in regulating insular metabolism and activity, the pathophysiology of traditional chronic complications associated with T2D, the pathophysiological interconnection between T2D and chronic neurological and psychiatric disorders characterized by impaired dopamine activity/metabolism, and therapeutic implications. Reinforcing dopamine signaling is therapeutic in T2D, especially in patients with dopamine-related disorders, such as Parkinson's and Huntington's diseases, addictions, and attention-deficit/hyperactivity disorder. On the other hand, although specific trials are probably needed, certain medications approved for T2D (e.g., metformin, pioglitazone, incretin-based therapy, and gliflozins) may have a therapeutic role in such dopamine-related disorders due to anti-inflammatory and anti-oxidative effects, improvement in insulin signaling, neuroinflammation, mitochondrial dysfunction, autophagy, and apoptosis, restoration of striatal dopamine synthesis, and modulation of dopamine signaling associated with reward and hedonic eating. Last, targeting dopamine metabolism could have the potential for diagnostic and therapeutic purposes in chronic diabetes-related complications, such as diabetic retinopathy.

Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet

BackgroundEsaxerenone is a novel, non-steroidal selective mineralocorticoid receptor (MR) blocker. MR activation plays a crucial role in the development of cardiovascular and metabolic diseases. In this study, we investigated the effects of esaxerenone on various metabolic parameters in mice. Materials and methodsEsaxerenone (3 mg/kg/day) was orally administered to high-fat diet (HFD)-fed male C57BL/6 mice. Mice fed a normal diet (ND) served as controls. Glucose and insulin tolerance, plasma lipid levels, and transaminase levels were assessed as metabolic parameters. Macrophage accumulation in the adipose tissue was evaluated using histological analysis. 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes were used for in vitro experiments. Gene expression and insulin signaling were examined using quantitative RT-PCR and western blotting, respectively. ResultsHFD successfully induced insulin resistance compared with that in ND. Esaxerenone ameliorated insulin resistance (P < 0.05) without altering other metabolic parameters, such as the lipid profile. Esaxerenone administration tended to decrease plasma transaminase levels compared with those in the non-treated group. In the adipose tissue, esaxerenone decreased macrophage accumulation (P < 0.05) and increased the expression levels of adiponectin and PPARγ. Aldosterone significantly decreased the expression levels of PPARγ and adiponectin in 3T3-L1 adipocytes. Furthermore, aldosterone attenuated insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes in a dose-dependent manner (P < 0.01). These effects were ameliorated by pretreatment with esaxerenone. ConclusionEsaxerenone ameliorated insulin resistance in HFD-fed mice. Reduction of inflammation and improvement in insulin signaling may underlie the beneficial effects of esaxerenone.

Novel soybean peptide iglycin ameliorates insulin resistance of high-fat diet fed C57BL/6J mice and differentiated 3T3L1 adipocytes with improvement of insulin signaling and mitochondrial function

Soy consumption has been associated with potential health benefits in reducing chronic diseases. These physiological functions have been attributed to soy proteins or more commonly to bioactive peptides. Thus, more studies are required to identify these bioactive peptides, and elucidate their biological mechanisms of action. In the present study, a novel peptide iglycin was purified from soybean seeds with a molecular mass of 3.88 kDa. Thereafter, iglycin reduced fasting blood glucose and restored insulin sensitivity of C57BL/6J mice on a high-fat diet with increased phosphorylation of insulin receptor substrate 1 (IRS1) and AKT in adipose tissue. Furthermore, it improved glucose uptake, induced translocation of intracellular GLUT4 to plasma membrane and activation of insulin signaling in adipocytes under insulin-resistant condition. In addition, it decreased reactive oxygen species production, lipid peroxidation and inhibited adipocyte apoptosis with improved mitochondrial function as evidenced by up-regulation of succinate dehydrogenase activity, mitochondrial membrane potential and intracellular ATP store. These data suggested that iglycin ameliorated insulin resistance via activation of insulin signaling, which was associated with inhibition of oxidative stress, adipocyte apoptosis, and improvement of mitochondrial function.

Combined effects of yacon flour and probiotic yogurt on the metabolic parameters and inflammatory and insulin signaling proteins in high-fat-diet-induced obese mice.

Prebiotics and probiotics may be effective dietary components that can alter the gut microbiota of the host and, consequently, overcome imbalances associated with obesity. This work aimed to evaluate the synergistic and isolated effects and mechanisms by which probiotic yogurt containing Bifidobacterium animalis and/or Lactobacillus acidophilus and yacon flour alter metabolic parameters and inflammatory and insulin signaling proteins in diet-induced obese mice. Swiss mice were fed a high-fat diet (n=48) or a standard diet (control; n=6) for 56 days. The 42 mice that gained the most weight were selected and divided into seven groups that received different combinations of probiotic yogurt and yacon flour. After 30 days, biochemical parameters (blood glucose, serum total cholesterol, and triacylglycerols), crude fat excretion in feces, and periepididymal fat were assessed and an immunoblotting analysis of insulin signaling proteins and interleukin-1β was conducted. The combination of yacon flour and a yogurt with two strains of probiotics exerted positive effects on the parameters evaluated, such as decreased body weight (-6.5%; P < 0.05), fasting glucose (-23.1%; P < 0.05), and triacylglycerol levels (-21.4%; P < 0.05) and decreased periepididymal fat accumulation (-44.2%; P < 0.05). There was a decrease in inflammatory markers (P < 0.001) and an improvement in insulin signaling (P < 0.001). The combination of a prebiotic with two strains of probiotics in a food matrix may exert a protective effect against obesity-associated inflammation, improving insulin resistance, even in the short term. © 2022 Society of Chemical Industry.

Exercise with 40-Hz light flicker improves hippocampal insulin signaling in Alzheimer disease mice.

We examined whether exercise is associated with hippocampus-mediated improvement in insulin signaling and cell differentiation in the triple transgenic mouse model of Alzheimer disease (3xTg AD) murine model following exposure to 40-Hz light flickering and exercise. We subjected 12-month-old 3xTg AD mice to exercise and 40-Hz light flickering for 3 months. The exercise session was proceeded for 12 consecutive weeks with gradual increase of intensity. To investigate insulin signaling proteins, western blot was conducted to detect the ratio of phosphorylated insulin receptor β (p-IRβ)/total IRβ (t-IRβ), phosphorylated insulin receptor substrate 1 (p-IRS-1)/total IRS-1 (t-IRS-1), phosphorylated phosphatidylinositide-3-kinase (p-PI3K)/total PI3K (t-PI3K), phosphorylated 3-phosphoinositide dependent protein kinase-1 (p-PDK1)/total PDK-1 (t-PDK1), phosphorylated protein kinase B (p-Akt)/total-Akt (t-Akt), and phosphorylated glycogen synthase kinase 3 beta (p-GSK3β)/total GSK3β (t-GSK3β). Doublecortin immunohistochemistry was performed for assessing cell differentiation in the hippocampus. Treatments exerted a positive effect. The combination of exercise and 40-Hz light flickering exposure was the most effective treatment enhancing insulin signaling. Increased ratio of p-IRβ/t-IRβ, p-IRS-1/t-IRS-1, p-PI3K/t-PI3K, p-PDK1/t-PDK1, p-Akt/t-Akt, and p-GSK3β/t-GSK3β and enhanced cell differentiation were observed in the 3xTg AD with exercise under 40-Hz light flickering group. Our results indicate that exercise under 40-Hz light flickering most potently improved insulin signaling, thereby promoted cell differentiation.

Nano Chromium Picolinate Improves Gene Expression Associated with Insulin Signaling in Porcine Skeletal Muscle and Adipose Tissue

Simple SummaryDietary chromium has been shown to reduce fat deposition and improve insulin action whereas dietary fat can increase fat deposition and cause insulin resistance. This study found that dietary nanoparticles of chromium picolinate, an organic form of chromium, caused changes in the genes involved in insulin action in both muscle and fat tissue that indicated improved insulin action. Conversely, a moderate increase in dietary fat caused changes consistent with increased fat deposition and reduced insulin action. In conclusion, nanoparticles of chromium picolinate offer a means of supplementing pigs diets to improve growth performance and carcass composition.The aim of this study was to investigate the interactive effects of dietary nano chromium picolinate (nCrPic) and dietary fat on genes involved in insulin signaling in skeletal muscle and subcutaneous adipose tissue of pigs. Forty-eight gilts were stratified on body weight into four blocks of four pens of three pigs and then within each block each pen was randomly allocated to four treatment groups in a 2 × 2 factorial design. The respective factors were dietary fat (22 or 57 g/kg) and dietary nCrPic (0 or 400 ppb nCrPic) fed for six weeks. Skeletal muscle samples were collected from the Longissimus thoracis and subcutaneous adipose tissue collected from above this muscle. Dietary nCrPic increased adiponectin, uncoupling protein 3 (UCP3) and serine/threonine protein kinase (AKT) mRNA expression, whereas dietary fat decreased adiponectin and increased leptin, tumor necrosis factor-α (TNF-α), peroxisome proliferator-activated receptors γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) mRNA expression in adipose tissue. In skeletal muscle, dietary nCrPic increased phosphatidylinositol 3 kinase (PI3K), AKT, UCP3 and interleukin-15 (IL-15), as well as decreased suppressor of cytokine signaling 3 (SOCS3) mRNA expression. The improvement in insulin signaling and muscle mass and the reduction in carcass fatness by dietary nCrPic may be via decreased SOCS3 and increased UCP3 and IL-15 in skeletal muscle and increased adiponectin in subcutaneous adipose tissue.

Interlink Between Insulin Resistance and Neurodegeneration with an Update on Current Therapeutic Approaches.

The interlink between diabetes mellitus and neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD) has been identified by several researchers. Patients with Type-2 Diabetes Mellitus (T2DM) are found to be affected with cognitive impairments leading to learning and memory deficit, while patients with Type-1 Diabetes Mellitus (T1DM) showed less severe levels of these impairments in the brain. This review aimed to discuss the connection between insulin with the pathophysiology of neurodegenerative diseases (AD and PD) and the current therapeutic approached mediated through insulin for management of neurodegenerative diseases. An extensive literature search was conducted using keywords "insulin"; "insulin resistance"; "Alzheimer's disease"; "Parkinson's disease" in public domains of Google scholar, PubMed, and ScienceDirect. Selected articles were used to construct this review. Studies have shown that impaired insulin signaling contributes to the accumulation of amyloid-β, neurofibrillary tangles, tau proteins and α-synuclein in the brain. Whereas, improvement in insulin signaling slows down the progression of cognitive decline. Various therapeutic approaches for altering the insulin function in the brain have been researched. Besides intranasal insulin, other therapeutics like PPAR-γ agonists, neurotrophins, stem cell therapy and insulin-like growth factor-1 are under investigation. Research has shown that insulin insensitivity in T2DM leads to neurodegeneration through mechanisms involving a variety of extracellular, membrane receptor, and intracellular signaling pathway disruptions. Some therapeutics, such as intranasal administration of insulin and neuroactive substances have shown promise but face problems related to genetic background, accessibility to the brain, and invasiveness of the procedures.

Eicosapentaenoic and Docosahexaenoic Acids Differentially Alter Gut Microbiome and Reverse High-Fat Diet-Induced Insulin Resistance.

To assess the individual effects of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on insulin resistance (IR), gut microbiome, and gut metabolites in high-fat-diet-induced obese (DIO) mice. DIO mice are fed an either high-fat diet (HFD), EPA (1%w/w) enriched HFD, or DHA (1%wt/wt) enriched HFD for 15 weeks. Both EPA and DHA supplements reverse hyperglycemia and IR but do not affect body weight in DIO mice while DHA exhibits a more pronounced ameliorative effect in male mice. Both EPA- and DHA-enriched Lactobacillus and short-chain fatty acids (SCFAs)-producing species from Lachnospiraceae while reduced lipopolysaccharide (LPS)-producing Bilophila and Escherichia/Shigella. Compared with EPA, DHA-supplemented mice have more abundant propionic/butyric acid-producing bacteria, including Coprococcus, Butyricimonas synergistica, Bacteroides acidifaciens, and Intestinimonas, and less-abundant LPS-correlated species Streptococcus and p-75-a5. The shifts in gut microbiome co-occurred with the changes in levels of propionic/butyric acid, circulating LPS, and serotonin. Additionally, EPA/DHA supplementation attenuates adipose inflammation with upregulated glucose transporter 4 and Akt phosphorylation, indicating the improvement of insulin signaling. EPA and DHA differentially reverse IR and relieve adipose inflammation while modulating gut microbiome and SCFAs/LPS production, underscoring the gut-adipose axis as a primary target of EPA/DHA.

Chromium picolinate attenuates cognitive deficit in ICV-STZ rat paradigm of sporadic Alzheimer’s-like dementia via targeting neuroinflammatory and IRS-1/PI3K/AKT/GSK-3β pathway

Alzheimer's disease (AD) is prevalent in old age people and is one of the most common brain diseases. Brain insulin resistance, neuroinflammation, oxidative stress, and mitochondrial and cholinergic dysfunction are key features of the disease. In our study, streptozotocin (STZ) in a dose of 3mg/kg was injected in male Wistar rats bilaterally through the intracerebroventricular (ICV) route on stereotaxic apparatus. Chromium picolinate (CrPic) was tested at doses of 1mg/kg, 2mg/kg, and 4mg/kg, while rivastigmine (2mg/kg) was used as reference standard drug. Cognitive dysfunction induced by STZ was assessed by behavioral tests like Morris water maze and novel object recognition test. Treatment with CrPic revealed attenuation of cognitive deficit. This was confirmed by behavioral tests, biochemical estimations of antioxidant enzymes, oxidative stress, nitrosative stress, and cholinergic and mitochondrial activity. CrPic did not change AchE activity significantly. STZ-induced neuroinflammation evident by increased TNF-α, IL-6, and CRP levels was also significantly decreased by CrPic. Dysfunctional insulin signaling after ICV-STZ was demonstrated by reduced IRS-1, PI3K, AKT, BDNF gene expression, and increased GSK-3β,NF-κB gene expression with the help of qRT-PCR. CrPic treatment produced an improvement in insulin signaling revealed by increased gene expression of IRS-1, PI3-K, AKT, BDNF, and decreased gene expression of GSK-3βandNF-κB. It was concluded that CrPic reversed AD pathology revealed by improved memory, reduced oxidative stress, neuroinflammation, mitochondrial dysfunction, and upregulated insulin signaling.

Potential Role for Osteocalcin in the Development of Atherosclerosis and Blood Vessel Disease.

There is increasing evidence for the involvement of the skeleton in the regulation of atherosclerotic vascular disease. Osteocalcin, an osteoblast derived protein, exists in two forms, carboxylated and undercarboxylated osteocalcin. Undercarboxylated osteocalcin has been linked to the regulation of metabolic functions, including glucose and lipid metabolism. Features of atherosclerosis have been associated with circulating osteocalcin; however, this association is often conflicting and unclear. Therefore, the aim of this review is to examine the evidence for a role of osteocalcin in atherosclerosis development and progression, and in particular endothelial dysfunction and vascular calcification. The current literature suggests that undercarboxylated osteocalcin stimulates the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway to upregulate nitric oxide and nuclear factor kappa β (NF-кβ) in vascular cells, possibly protecting endothelial function and preventing atherogenesis. However, this effect may be mediated by metabolic factors, such as improvements in insulin signaling, rather than through a direct effect on the vasculature. Total osteocalcin is frequently associated with vascular calcification, an association that may occur as a result of vascular cells eliciting an osteogenic phenotype. Whether osteocalcin acts as a mediator or a marker of vascular calcification is currently unclear. As such, further studies that examine each form of osteocalcin are required to elucidate if it is a mediator of atherogenesis, and whether it functions independently of metabolic factors.

The effects of phenolic glycosides from Betula platyphylla var. japonica on adipocyte differentiation and mature adipocyte metabolism

Betula platyphylla var. japonica (Betulaceae) has been used traditionally in Asian countries for the treatment of inflammatory diseases. A recent study has reported a phenolic compound, platyphylloside from B. platyphylla, that shows inhibition on adipocyte differentiation and induces lipolysis in 3T3-L1 cells. Based on this finding, we conducted phytochemical analysis of the EtOH extract of the bark of B. platyphylla var. japonica, which resulted in the isolation of phenolic glycosides (1–4). Treatment of the isolated compounds (1–4) during adipocyte differentiation of 3T3-L1 mouse adipocytes resulted in dose-dependent inhibition of adipogenesis. In mature adipocytes, arylbutanoid glycosides (2–4) induced lipolysis related genes HSL and ATGL, whereas catechin glycoside (1) had no effect. Additionally, arylbutanoid glycosides (2–4) also induced GLUT4 and adiponectin mRNA expression, indicating improvement in insulin signaling. This suggests that the isolates from B. platyphylla var. japonica exert benefial effects in regulation of adipocyte differentiation as well as adipocyte metabolism.

Preventive effect of oleate on palmitate-induced insulin resistance in skeletal muscle and its mechanism of action.

Insulin resistance in skeletal muscle is a feature associated with exposure to an excess of saturated fatty acids such as palmitate. Oleic acid has been shown to blunt palmitate-induced insulin resistance in muscle cells. However, there is no literature available regarding the effect of oleic acid on palmitate-induced insulin resistance in intact muscle. Therefore, this study investigated the effect of oleic acid on palmitate-induced insulin resistance in rat soleus muscle and its underlying mechanisms. For these purposes, oleic acid (1mM) was administered for 12h in the absence or presence of palmitate (2mM). At the end of the experiment, plasmalemmal GLUT4, the phosphorylation of AS160 and Akt-2, and the total expression of these signaling proteins were examined. We found that treatment with palmitate for 12h reduced insulin-stimulated GLUT4 translocation and the phosphorylation of AS160 and Akt-2. However, the administration of oleic acid fully restored insulin-stimulated GLUT4 translocation (P<0.05), as well as AS160 and Akt-2 phosphorylation (P<0.05) despite the continuous presence of palmitate. Wortmannin, an inhibitor of PI3-K, only slightly prevented the oleic acid-induced improvements in insulin-stimulated GLUT4 translocation, and AS160 phosphorylation. However, this treatment completely inhibited the oleic acid-induced improvement in insulin-stimulated Akt-2 phosphorylation. In contrast, the oleic acid-induced improvement in insulin signaling was not affected by compound C, an AMPK specific inhibitor. In conclusion, the results clearly indicate that oleic acid administration alleviates palmitate-induced insulin resistance by promoting GLUT4 translocation in muscle, at least in part, by activating the PI3K pathway.

Banxia-houpu decoction restores glucose intolerance in CUMS rats through improvement of insulin signaling and suppression of NLRP3 inflammasome activation in liver and brain

Ethnopharmacological relevanceBanxia-houpu decoction is a famous formula in traditional Chinese medicine (TCM) with the powerful anti-depressant activity. Aim of the studyThis study aimed to investigate the effect of Banxia-houpu decoction on glucose intolerance associated with anhedonia in chronic unpredictable mild stress (CUMS) rats, then to explore its underlying pharmacological mechanisms. Materials and methodsAfter 6-week CUMS procedure, male Wistar rats were given Banxia-houpu decoction (3.29 and 6.58g/kg, intragastrically) for 6 weeks. Sucrose solution consumption test was employed to evaluate the anhedonia behavior. Oral glucose tolerance test (OGTT) was used to determine glucose tolerance. Serum levels of corticosterone, corticotropin-releasing factor (CRF), insulin and interleukin-1 beta (IL-1β) were measured by commercial enzyme-linked immunosorbent assay kits, respectively. Furthermore, the key proteins for insulin signaling, as well as nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, were analyzed by Western blot in periphery liver and brain regions hypothalamus, hippocampus and prefrontal cortex, respectively. ResultsBanxia-houpu decoction significantly increased sucrose solution consumption and decreased serum corticosterone and CRF levels in CUMS rats, further demonstrating its antidepressant activity. More importantly, Banxia-houpu decoction improved glucose tolerance in OGTT in this animal model. Furthermore, it protected against CUMS-induced insulin signaling impairment in the liver, as well as hypothalamus and prefrontal cortex in rats. Although without significant effect on serum IL-1β levels, Banxia-houpu decoction inhibited NLRP3 inflammasome activation in the liver, hypothalamus, hippocampus and prefrontal cortex of CUMS rats, respectively. ConclusionsThe present study demonstrates that Banxia-houpu decoction suppresses NLRP3 inflammasome activation and improves insulin signaling impairment in both periphery liver and brain regions in CUMS rats, possibly contributing to its anti-depressive effect with glucose tolerance improvement. These results may provide the evidence that Banxia-houpu decoction is a potential antidepressant with the advantage to reduce the risk of comorbid depression with type 2 diabetes mellitus.

Hippocampal insulin signaling and neuroprotection mediated by physical exercise in Alzheimer´s Disease

Abstract — Epidemiological studies indicate continuous increases in the prevalence of Alzheimer’s Disease (AD) in the next few decades. The key feature of this disease is hippocampal neurodegeneration. This structure has an important role in learning and memory. Intense research efforts have sought to elucidate neuroprotective mechanisms responsible for hippocampal integrity. Insulin signaling seems to be a very promising pathway for the prevention and treatment of AD. This hormone has been described as a powerful activator of neuronal survival. Recent research showed that reduced insulin sensitivity leads to low-grade inflammation, and both phenomena are closely related to AD genesis. Concomitantly, exercise has been shown to exert anti-inflammatory effects and to promote improvement in insulin signaling in the hippocampus, which supports neuronal survival and constitutes an interesting non-pharmacological alternative for the prevention and treatment of AD. This review examines recent advances in understanding the molecular mechanisms involved in hippocampal neuroprotection mediated by exercise.Keywords: insulin, hippocampus, inflammation, physical exercise.

Evaluation of fish oil-rich in MUFAs for anti-diabetic and anti-inflammation potential in experimental type 2 diabetic rats.

The advantages of monounsaturated fatty acids (MUFAs) on insulin resistance and type 2 diabetes mellitus (T2DM) have been well established. However, the molecular mechanisms of the anti-diabetic action of MUFAs remain unclear. This study examined the anti-hyperglycemic effect and explored the molecular mechanisms involved in the actions of fish oil- rich in MUFAs that had been acquired from hybrid catfish (Pangasius larnaudii×Pangasianodon hypophthalmus) among experimental type 2 diabetic rats. Diabetic rats that were fed with fish oil (500 and 1,000 mg/kg BW) for 12 weeks significantly reduced the fasting plasma glucose levels without increasing the plasma insulin levels. The diminishing levels of plasma lipids and the muscle triglyceride accumulation as well as the plasma leptin levels were identified in T2DM rats, which had been administrated with fish oil. Notably, the plasma adiponectin levels increased among these rats. The fish oil supplementation also improved glucose tolerance, insulin sensitivity and pancreatic histological changes. Moreover, the supplementation of fish oil improved insulin signaling (p-AktSer473 and p-PKC-ζ/λThr410/403), p-AMPKThr172 and membrane GLUT4 protein expressions, whereas the protein expressions of pro-inflammatory cytokines (TNF-α and nuclear NF-κB) as well as p-PKC-θThr538 were down regulated in the skeletal muscle. These data indicate that the effects of fish oil-rich in MUFAs in these T2DM rats were partly due to the attenuation of insulin resistance and an improvement in the adipokine imbalance. The mechanisms of the anti-hyperglycemic effect are involved in the improvement of insulin signaling, AMPK activation, GLUT4 translocation and suppression of pro-inflammatory cytokine protein expressions.

Oleanolic acid: a promising neuroprotective agent for cerebral ischemia.

Oleanolic acid: a promising neuroprotective agent for cerebral ischemia.

Tyrosine isomers and hormonal signaling: A possible role for the hydroxyl free radical in insulin resistance.

Oxidative stress processes play a major role in the development of the complications associated with diabetes and other diseases via non-enzymatic glycation, the hexosamine pathway, the polyol pathway and diacylglycerol-protein kinase C. Oxidative stress may lead to the production of hydroxyl free radicals, which can attack macromolecules, such as lipids, nucleic acids or amino acids. Phenylalanine (Phe) can be enzymatically converted to the physiological para-tyrosine (p-Tyr); however, a hydroxyl free radical attack on Phe may yield meta- and ortho-tyrosine (m- and o-Tyr, respectively) in addition to p-Tyr. Hence, m- and o-Tyr may be regarded as markers of hydroxyl free radical-induced damage. Their accumulation has been described; e.g., this accumulation has been found in the urine of patients with diabetes mellitus (DM) and/or chronic kidney disease, in cataract lenses, in vessel walls, in irradiated food and in amniotic fluid, and it may serve as an indicator of oxidative stress. The use of resveratrol to treat patients with type 2 DM led to a decrease in the urinary excretion of o-Tyr and concomitantly led to an improvement in insulin signaling and insulin sensitivity. Literature data also suggest that m- and o-Tyr may interfere with intracellular signaling. Our group has shown that erythropoietin (EPO) has insulin-like metabolic effects on fat cells in addition to its ability to promote the proliferation of erythroid precursor cells. We have shown that the supplementation of cell culture medium with m- and o-Tyr inhibits erythroblast cell proliferation, which could be ameliorated by p-Tyr. Additionally, in vivo, the o-Tyr/p-Tyr ratio is higher in patients with renal replacement therapy and a greater need for EPO. However, the o-Tyr/p-Tyr ratio was an independent determinant of EPO-resistance indices in our human study. The o-Tyr content of blood vessel walls inversely correlates with insulin- and acetylcholine-induced vasodilation, which could be further impaired by artificial oxidative stress and improved by the use of antioxidants. In rats that receive o-Tyr supplements, decreased vasorelaxation is detected in response to insulin. Additionally, o-Tyr supplementation led to the incorporation of the unnatural amino acid into cellular proteins and caused a decrease in the insulin-induced phosphorylation of endothelial nitric oxide synthase. Our data suggest that m- and o-Tyr may not only be markers of oxidative stress; instead, they may also be incorporated into cellular proteins, leading to resistance to insulin, EPO and acetylcholine.

Improvement of insulin signaling in myoblast cells by an addition of SKIP-binding peptide within Pak1 kinase domain

Abnormalities in insulin-induced glucose incorporation in skeletal muscle were observed in Type 2 diabetes. Our previous studies revealed that the binding between skeletal muscle and kidney-enriched inositol polyphosphate phosphatase (SKIP) and p21-activated protein kinase (Pak1) at the plasma membrane is induced insulin-dependently and that this binding mediated a rapid and efficient termination of insulin signaling and a subsequent glucose uptake into skeletal muscle cells. Here, we identified 11-amino-acids peptide within kinase domain of Pak1, necessary and sufficient for SKIP binding. Expression of this region in C2C12 cells resulted in an increase in insulin signaling. Supplementation of a synthetic peptide of this sequence increased insulin signaling and insulin-induced glucose uptake into skeletal muscle cell lines. These findings suggest the physiological role of Pak1–SKIP binding in the regulation of insulin signaling in skeletal muscle.

Rapamycin impacts positively on longevity, despite glucose intolerance induction

Rapamycin impacts positively on longevity, despite glucose intolerance induction