Insulin Receptor Concentration Research Articles

Effect of Tithonia diversifolia Leaf Extract on Leptin, Adiponectin, and Insulin Receptor Levels in Diabetic Rats

This study aimed to evaluate the effect of Tithonia diversifolia extract (TDE) on leptin, adiponectin, and insulin receptor (IR) concentrations in diabetic rats. Twenty-four Wistar rats were divided into a control and treatment groups (n=6 per group). The control group received normal saline, and the treatment groups received 0.25% sodium carboxymethyl cellulose, TDE at 100 mg/kg body weight (bw), and catechin at 10 mg/kg bw for 7 days. On day 8, the rats were sacrificed, blood samples were obtained, and leptin, adiponectin, and insulin concentrations were measured using avidinhorseradish peroxidase sandwich-enzyme-linked immunosorbent assay. A calorimetric method was used to measure blood glucose (BG) and total serum cholesterol concentrations. The pancreas and kidneys were collected for the measurement of renal IR and macrophage cluster of differentiation (CD)14 levels using immunohistochemical staining. Acute type 2 diabetes mellitus (T2DM) with elevated BG and total serum cholesterol concentrations was observed in the treatment groups administered streptozotocin. The administration of TDE at 100 mg/kg bw significantly decreased leptin and increased adiponectin concentrations (P≤0.05). Furthermore, TDE treatment significantly increased renal IR and decreased macrophage CD14 levels (P<0.05). Therefore, TDE decreased leptin and BG concentrations by increasing IR levels. TDE also suppressed the necrosis of pancreatic tissues by inhibiting macrophage CD14 expression in diabetic rats. However, further research is necessary to determine the effect of TDE on interleukin and IR levels in the related tissues of patients with T2DM.

Hyperglycemia and Hyperlipidemia Induced Inflammation and Oxidative Stress in Human T Lymphocytes and Salutary Effects of ω- 3 Fatty Acid.

Abstract Type 2 Diabetes conditions are associated with hyperglycemia and hyperlipidemia; however, the role of Saturated Fatty Acids (SFA) vs. Unsaturated Fatty Acids (UFA) and high glucose on human T lymphocytes (T cells) is not known. We investigated the salutary effect of the UFA ω-3 fatty acid, α- linolenic acid, on glucose and SFA, palmitic acid, induced activation on T cells as a cause of the inflammatory process with high glucose and SFA foods. These cells in the presence of palmitic acid and/or high glucose but not linolenic acid exhibited a concentration and time-dependent emergence of insulin receptors (INSR), expression, generation of ROS, lipid peroxidation, cytokines and NF-kB p65 translocation to the nucleus. Whereas, activation of the cells by elevated levels of glucose and palmitic acid were additive, addition of linolenic acid in a dose-related manner inhibited activation of cells by glucose and palmitic acid and reduced markers of oxidative stress, lipid peroxidation and cytokines. We propose that UFAs such as α-linolenic acid may serve as a protective mechanism against the deleterious effects of hyperglycemia and hyperlipidemia of high sugar and SFA foods as in diabetes.

Hyperlipidimia, Hyperleptinemia and Insulin Resistance Intercorrelation with Obesity

The present study has shown a parallel increase of triacylglycerol, cholesterol, and low density lipoprotein (LDL) along with an increase in body mass and BMI of human obese subjects. Conversely a fall in HDL concentration was observed. Plasma leptin level increased proportionately with increase of body weight as obesity advanced from obese to morbid type. A positive correlation was observed between leptin and insulin concentrations in obese subjects. A parallel increase of plasma glucose concentration was followed with decreased expression of insulin receptor, measured in adipose tissue, with the progress of obesity. The decreased insulin receptor concentration might be the reason for seen insulin resistance and increased insulin level which marked the positive correlation with associated liptin level in obese subjects.

Acute Insulin Resistance and Rapid Alterations in Neuronal Derived Blood Exosome Concentration After Branched Endovascular Aortic Aneurysm Repair

Hyperglycaemia following branched endovascular repair (BEVAR) of extensive aortic aneurysms is associated with post-operative lower extremity weakness (LEW). Insulin administration to maintain euglycaemia appears to decrease LEW rates. The purpose of this study was to examine changes in insulin receptor content of neuron derived blood exosomes (NDEs) after BEVAR. Ten patients with a range of post-operative lower extremity neurological deficits after elective BEVAR were included in the study. Blood samples were collected pre-operatively, immediately after aneurysm repair, and on post-operative day 1. NDE insulin receptor substrate proteins were quantified by enzymevlinked immunosorbent assays. NDE levels of phosopho-serine312-type 1 insulin receptor substrate ([P-Ser312-IRS1], an inhibitor of insulin signalling) increased sevenfold in the immediate post-operative period (from 7.90±0.89 to 58.54±6.77pg/mL; p<.001), whereas those of pan-tyrosine-phospho insulin receptor substrate ([P-panTyr-IRS1], which facilitates insulin signalling), rose only 50% (from 0.41±0.07 to 0.63±0.10pg/mL; p=.03). As a result, the mean ratio of P-Ser312-IRS1 to P-panTyr-IRS1, which reflects the level of insulin resistance, increased fivefold immediately post-operatively (from 22.31±3.28 to 106.33±11.83; p<.001) and returned to normal levels by the next day (18.72±1.87). BEVAR is associated with an acute state of insulin resistance within neuronal tissue. Further studies in a larger cohort of patients are needed to understand the potential interconnected processes of insulin resistance, hyperglycaemia, and spinal cord ischaemia after extensive endovascular aortic procedures.

Restoration of insulin receptor improves diabetic phenotype in T2DM mice.

Type 2 diabetes mellitus (T2DM), also known as adult-onset diabetes, is characterized by ineffective insulin action due to insulin resistance in key metabolic tissues. Insulin receptor (IR) plays an important role in insulin signal transduction, defect of which has been considered the fundamental cause of T2DM. IR content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation has not been considered as a treatment option because it is limited by uncontrollable expression level, tissue selectivity, or developmental defects. In the current study, we demonstrated that single-dose adeno-associated virus (AAV) vector delivered expression of human IR (hIR) in the liver of inducible IR-knockout mice and significantly improved the diabetic phenotype caused by IR deletion during adulthood. Such an approach was also applied, for the first time to our knowledge, to treating ob/ob mice, a model of severe T2DM attributed to superfluous calorie intake and insulin resistance. Interestingly, similar treatment with AAV-hIR had no obvious effect in healthy animals, indicative of low hypoglycemic risk as a consequence of potential excessive insulin action. The results described here support restoration of IR expression as a safe and effective T2DM therapeutic with a long-lasting profile.

NCS-1 Deficiency Is Associated With Obesity and Diabetes Type 2 in Mice.

Neuronal calcium sensor-1 (NCS-1) knockout (KO) in mice (NCS-1−/− mice) evokes behavioral phenotypes ranging from learning deficits to avolition and depressive-like behaviors. Here, we showed that with the onset of adulthood NCS-1−/− mice gain considerable weight. Adult NCS-1−/− mice are obese, especially when fed a high-fat diet (HFD), are hyperglycemic and hyperinsulinemic and thus develop a diabetes type 2 phenotype. In comparison to wild type (WT) NCS-1−/− mice display a significant increase in adipose tissue mass. NCS-1−/− adipocytes produce insufficient serum concentrations of resistin and adiponectin. In contrast to WT littermates, adipocytes of NCS-1−/− mice are incapable of up-regulating insulin receptor (IR) concentration in response to HFD. Thus, HFD-fed NCS-1−/− mice exhibit in comparison to WT littermates a significantly reduced IR expression, which may explain the pronounced insulin resistance observed especially with HFD-fed NCS-1−/− mice. We observed a direct correlation between NCS-1 and IR concentrations in the adipocyte membrane and that NCS-1 can be co-immunoprecipitated with IR indicating a direct interplay between NCS-1 and IR. We propose that NCS-1 plays an important role in adipocyte function and that NCS-1 deficiency gives rise to obesity and diabetes type 2 in adult mice. Given the association of altered NCS-1 expression with behaviorial abnormalities, NCS-1−/− mice may offer an interesting perspective for studying in a mouse model a potential genetic link between some psychiatric disorders and the risk of being obese.

Effects of Dietary Chromium Methionine on Growth Performance, Hematological Characteristics and Carbohydrate Metabolic Enzyme Activities of Common Carp (Cyprinus carpio)

A 60-day feeding trial was conducted to evaluate the effects of dietary chromium methionine (Cr-Met) supplementation on growth performance, digestive enzymes, hematological characteristics, and carbohydrate metabolic key enzyme activities in juvenile common carp (Cyprinus carpio). Seven diets (32.2% crude protein, 6% crude lipids of dry matter) were formulated to contain graded levels of Cr3+ (0.31, 0.43, 0.57, 0.73, 1.13, 1.90 and 3.64 mg/kg, respectively). Each diet was randomly assigned to triplicate groups of 60 juvenile common carp (approximately 40.95±4.80 g), which were stocked in plastic tanks. The results indicated that the highest weight gain (WG), specific growth rate (SGR), feed efficiency (FE), and protein efficiency ratio (PER), were observed in fish fed the diet containing 1.13 mg/kg Cr3+. There were no significant differences in the wholebody compositions; however the glycogen levels in the muscle and hepatopancreas in fish fed the basal diet were lower than those fed the other diets. The insulin (INS) and glycogen (GC) concentrations in the serum were not significantly influenced by the dietary Cr-Met levels. However, fish fed the basal diet had higher glucose and cortisol concentrations, and lower insulin receptor (ISR) and LDH concentrations in the serum than those fed diets supplemented with Cr-Met. Fish fed the 1.13 mg/kg Cr3+ diet had significantly higher hexokinase (HK), 6-phosphofructo-1-kinase (6-PFK1), glucose-6-phosphate dehydrogenase (G6PDH), glycogen synthase (GS), and lower phosphoenolpyruvate carboxykinase (PEPCK) activities than those fed the basal diet. Based on the two-slope broken line model analysis between SGR and dietary Cr3+ levels, the optimal dietary Cr3+ supplement level was estimated to be 1.09 mg/kg for juvenile common carp.

Alteraciones en la exhibición de receptor de insulina en linfocitos tumorales humanos impuestas por la diabetes

Obese and diabetic population present higher frequencies of certain types of cancer. This justifies the need for early-stage tumoral markers. The aim of this study was to test the effects of diabetic metabolic conditions on insulin receptor (IR) protein levels and exhibition in human tumoral T cells (Jurkat) by Western-blot and flow cytometry, respectively. Our results indicate that hyperglicemia doubles the total protein levels of the beta subunit of the receptor, while lowering the levels of the alpha subunit. High free fatty acids levels (FFA) reduces the levels of both subunits in hyperglicemia, but not in normoglicemia. Hyperglicemia lowers the exhibition of IR but high FFA concentrations in hyperglicemic conditions increases it by 60%. We conclude that diabetic metabolic conditions alter the functionality of the IR in Jurkat cells. This could link diabetes to tumoral proliferation.

Distribution of Adiponectin Receptors 1 and 2 in the Rat Olfactory Bulb and the Effect of Adiponectin Injection on Insulin Receptor Expression.

Background Adiponectin (APN) is an adipocyte-derived hormone that has peripheral beneficial effects. Although its receptors AdipoR1 and AdipoR2 are expressed in the brain, their function in neurons is poorly understood. The aims of this work were to describe the distribution of APN receptors in the olfactory bulb (OB) as well as the possible effects of APN injection on the insulin receptor (InsR) content and Akt kinase. Method We performed the double immunofluorescence technique to describe the distribution of AdipoRs and the cellular type they were expressing. mRNA transcript and protein content were assessed by RT-PCR and Western blot, respectively. APN injection was performed to analyze its possible effect on the insulin pathway. Results We found that AdipoRs were localized in all cell layers and in both neurons and astrocytes. We observed the presence of mRNA transcripts and immunoblot analysis confirmed the protein on the intact OB; APN injection in the OB resulted in a slight decrease of the total InsR and Akt phosphorylation and a reduction of phopho-InsR content. Conclusions These data demonstrated that AdipoRs are expressed in OB regions, and APN injection could act as an insulin pathway modulator in the OB and thus possibly contribute to olfaction physiology.

Targeting Insulin Receptor with a Novel Internalizing Aptamer

Nucleic acid-based aptamers are emerging as therapeutic antagonists of disease-associated proteins such as receptor tyrosine kinases. They are selected by an in vitro combinatorial chemistry approach, named Systematic Evolution of Ligands by Exponential enrichment (SELEX), and thanks to their small size and unique chemical characteristics, they possess several advantages over antibodies as diagnostics and therapeutics. In addition, aptamers that rapidly internalize into target cells hold as well great potential for their in vivo use as delivery tools of secondary therapeutic agents. Here, we describe a nuclease resistant RNA aptamer, named GL56, which specifically recognizes the insulin receptor (IR). Isolated by a cell-based SELEX method that allows enrichment for internalizing aptamers, GL56 rapidly internalizes into target cells and is able to discriminate IR from the highly homologous insulin-like growth factor receptor 1. Notably, when applied to IR expressing cancer cells, the aptamer inhibits IR dependent signaling. Given the growing interest in the insulin receptor as target for cancer treatment, GL56 reveals a novel molecule with great translational potential as inhibitor and delivery tool for IR-dependent cancers.

Effects of high glucose on caveolin-1 and insulin signaling in 3T3-L1 adipocytes

ABSTRACTAdipocytes exposed to high glucose concentrations exhibit impaired metabolic function, including an increase of oxidative and proinflammatory factors that might favor the development of insulin resistance. Caveolin-1 (Cav-1) is a key mediator of the insulin transduction pathway whose expression is significantly enhanced during adipocyte differentiation. In this work, we studied the effects of high glucose concentration on the regulation of Cav-1 expression and activation and its relation to the insulin signaling pathway during the adipogenic process and in long-term differentiated adipocytes. Both, long-term high glucose exposure during adipogenesis and short-term glucose incubation of mature adipocytes, promoted triglyceride accumulation in 3T3-L1 cells. The short-term exposure of mature adipocytes to high glucose significantly reduced the sensitivity to insulin of Cav-1, insulin receptor (IR) and potein kinase B (AKT-2) phosphorylation, as well as insulin-induced deoxyglucose uptake. Adipocytes differentiated in the presence of high glucose lost Cav-1 and IR response to insulin-stimulated phosphorylation, but maintained the insulin sensitivity of AKT-2 phosphorylation and deoxyglucose uptake. Although long-term high glucose exposure increased DNA methylation in Cav-1 promoter, Cav-1 expression was not affected. Moreover, these cells showed an increase of Cav-1, IR and AKT-2 protein content, pointing to an adaptive response induced by the long-term high glucose exposure.

Insulin-related signaling pathways elicited by light in photoreceptor nuclei from bovine retina

Retina light stimulation triggers phototransduction events as well as different signaling mechanisms in outer segments (sensorial portion) of photoreceptor cells. We have recently reported a novel light-dependent activation of diacylglycerol kinase (DAGK) and protein kinase C (PKC) at the nuclear level of photoreceptor cells. The aim of the present study was to analyze whether ex-vivo light exposure of bovine retinas also modulates insulin-related signaling pathways in nuclei from photoreceptor cells. To this end, a nuclear fraction enriched in small nuclei from photoreceptor cells (PNF) was obtained using a modified nuclear isolation protocol. In PNF obtained from bovine retinas exposed to light or darkness, the presence of insulin receptor (IR) and phosphorylated insulin receptor (pIR), the activation of Akt, p38 and extracellular signal-regulated kinase (ERK1/2) and the local action of insulin on lipid kinases were studied.Immunofluorescence (IF) and Western blot (WB) studies revealed the presence of IR in photoreceptor nuclei. In PNF a light-dependent increase in IR total content was observed. The presence of activated IR (pIR) was also observed in PNF by WB, being its content higher in PNF from light than in to darkness. Light exposure also produced a significant increase in the content of p-Akt (3 fold) and p-p38 (60%) without changes in total Akt and p38. In addition, an increase in the content of total ERK1/2 (2 fold) was found without changes in p-ERK/total ERK ratio, indicating that light induces translocation of p-ERK to the nucleus.Polyphosphoinositide kinase and diacylglycerol kinase (DAGK) activities were measured in isolated nuclei from light-activated or darkness-adapted retinas through the formation of polyphosphoinositides (PPIs) and phosphatidic acid (PA) using nuclear lipid substrates and [γ-32P]ATP as radioactive substrate. A light-dependent increase in PPIs and PA formation was detected when isolated nuclei were exposed to 0.8 μM insulin plus 0.2 mM vanadate.WB studies revealed that retina's exposure to insulin under light condition increased nuclear IR content. In addition, PNF exposure to insulin increased ERK1/2 phosphorylation with no changes in total ERK1/2.Our results demonstrate the presence and the functional state of IR in the nucleus from photoreceptor cells. They also show that molecular signaling components linked to tyrosine kinase receptors and MAPK pathways, such as Akt and ERK1/2, respectively, are present in photoreceptor nuclei and are regulated by insulin and light.

Role of Islet Glucokinase, Glucose Metabolism, and Insulin Pathway in the Enhancing Effect of Islet Neogenesis-Associated Protein on Glucose-Induced Insulin Secretion.

To demonstrate the role of islet glucokinase, glucose metabolism, and intracellular insulin mediators in the enhancing effect of islet neogenesis-associated protein pentadecapeptide (INGAP-PP) on glucose-induced insulin secretion. Islets from normal rats were cultured for 4 days in the absence or presence of 10 μg/mL INGAP-PP, with/without Wortmannin or LY294002. Islets were incubated with different glucose concentrations to measure insulin secretion and content, hexokinase and glucokinase activity, glucose oxidation and utilization, glucokinase, insulin receptor, insulin receptor substrate (IRS)-1/2, and PI3K concentration and phosphorylation. The INGAP-PP significantly increased insulin release at high but not at low glucose concentration, glucokinase activity, glucose metabolism, glucokinase, insulin receptor, IRS-2 and PI3K protein concentration, insulin receptor and IRS-1/2 tyrosine phosphorylation, and the association of p85 with IRS-1. Wortmannin and LY294002 blocked INGAP-PP effect on insulin secretion and glucokinase protein levels in a dose-dependent manner. The enhancing effect of INGAP-PP on glucose-induced insulin release could be partly ascribed to its effect on glucokinase activity and glucose metabolism and is mainly mediated by the PI3K/AKT pathway. These results, together with the low hypoglycemia risk associated with the use of INGAP-PP, offer a new alternative for diabetes prevention and treatment.

Influence of diet on serum glucose and insulin concentrations, insulin receptor concentration in adipose and muscle tissues, and oxygen consumption in liver and muscle in gilts

Raw samples of 14 muscles: Mm. biceps femoris (BF), quadriceps femoris (CF), diaphragm (DI), flexor digitorum (FD), gluteus medius (GM), infraspinatus (IE), longissimus lumborum (LL), longissimus thoracis (LT), psoas major (PM), pectoralis profundus (PP), semimembranosus (SM), semitendinosus (ST), sternomandibularis (STER) and triceps brachii (TB) from four Swiss Brown (485±15 days old) young bull carcasses and weighing approximately 300 kg were evaluated for some chemical and physical properties. PM (2.11 kg) and DI (2.24 kg) were the muscles which had the lowest Warner–Bratzler shear force values, while PP (6.66 kg) had the greatest shear force (P<0.05). FD and IE muscles had the highest concentration of total collagen content while PM and DI had the lowest (P<0.05) contents, TB and IE muscles presented the highest insoluble collagen concentration while PM and LT had the lowest (P<0.05) contents. High positive correlation between total collagen content and Warner–Bratzler shear force of raw samples was found (r=0.723; P<0.01) and between insoluble collagen content and Warner–Bratzler shear force was (r=0.661; P<0.01). Significant differences (P<0.05) were observed among muscles for differential scanning calorimetry, sarcomere length, pH and colour parameters.

Trans and interesterified fat and palm oil during the pregnancy and lactation period inhibit the central anorexigenic action of insulin in adult male rat offspring.

Palm oil and interesterified fat have been used to replace partially hydrogenated fats, rich in trans isomers, in processed foods. This study investigated whether the maternal consumption of normolipidic diets containing these lipids affects the insulin receptor and Akt/protein kinase B (PKB) contents in the hypothalamus and the hypophagic effect of centrally administered insulin in 3-month-old male offspring. At 90 days, the intracerebroventricular injection of insulin decreased 24-h feeding in control rats but not in the palm, interesterified or trans groups. The palm group exhibited increases in the insulin receptor content of 64 and 69 % compared to the control and trans groups, respectively. However, the quantifications of PKB did not differ significantly across groups. We conclude that the intake of trans fatty acid substitutes during the early perinatal period affects food intake regulation in response to centrally administered insulin in the young adult offspring; however, the underlying mechanisms remain unclear.

Genetic obesity alters recruitment of TANK-binding kinase 1 and AKT into hypothalamic lipid rafts domains

Lipid rafts (LRs) are membrane subdomains enriched in cholesterol, glycosphingolipids and sphingolipids containing saturated fatty acid. Signaling proteins become concentrated in these microdomains mainly by saturated fatty acid modification, thus facilitating formation of protein complexes and activation of specific signaling pathways. High intake of saturated fatty acids promotes inflammation and insulin resistance, in part by disrupting insulin signaling pathway. Here we investigate whether lipid-induced toxicity in obesity correlates with altered composition of insulin signaling proteins in LRs in the brain. Our results showed that insulin receptor (IR) is highly concentrated in LRs fraction in comparison with soluble or postsynaptic density (PSD) fractions. Analysis of LRs domains from hippocampus of obese mouse showed a significant decrease of IR and its downstream signaling protein AKT, while in the PSD fraction we detected partial decrease of AKT and no changes in the IR concentration. No changes were shown in the soluble extract. In hypothalamus, genetic obesity also decreases interaction of AKT, but we did not detect changes in the IR distribution. However, in this structure genetic obesity increases recruitment of the IR negative regulator TANK-binding kinase 1 (TBK1) into LRs and PSD fraction. No changes of AKT, IR and TBK1 were found in soluble fractions of obese in comparison with lean mice. In vitro studies showed that incubation with saturated palmitic acid but not with unsaturated docosahexaenoic acid (DHA) or palmitoleic acid decreases association of IR and AKT and increases TBK1 recruitment into LRs and PSD domains, emulating what happens in the obese mice. TBK1 recruitment to insoluble domains correlates with decreases of IR tyrosine phosphorylation and ser473 AKT phosphorylation, markers of insulin resistance. These data support the hypothesis that hyperlipidemia associated with genetic obesity alters targeting of TBK1 and insulin signaling proteins into insoluble LRs domains.

Low-protein, high-carbohydrate diet increases glucose uptake and fatty acid synthesis in brown adipose tissue of rats

ObjectiveThe aim of this study was to evaluate glucose uptake and the contribution of glucose to fatty acid (FA) synthesis and the glycerol-3-phosphate (G3P) of triacylglycerol synthesis by interscapular brown adipose tissue (IBAT) of low-protein, high-carbohydrate (LPHC) diet-fed rats. MethodsLPHC (6% protein; 74% carbohydrate) or control (17% protein; 63% carbohydrate) diets were administered to rats (∼100 g) for 15 d. Total FA and G3P synthesis and the synthesis of FA and G3P from glucose were evaluated in vivo by 3H2O and 14C-glucose. Sympathetic neural contribution for FA synthesis was evaluated by comparing the synthesis in denervated (7 d before) IBAT with that of the contralateral innervated side. The insulin signaling and β3 adrenergic receptor (β3-AR) contents, as well as others, were determined by Western blot (Student's t test or analysis of variance; P ≤ 0.05). ResultsTotal FA synthesis in IBAT was 133% higher in the LPHC group and was reduced 85% and 70% by denervation for the LPHC and control groups, respectively. Glucose uptake was 3.5-fold higher in the IBAT of LPHC rats than in that of the control rats, and the contribution of glucose to the total FA synthesis increased by 12% in control rats compared with 18% in LPHC rats. The LPHC diet increased the G3P generation from glucose by 270% and the insulin receptor content and the p-AKT insulin stimulation in IBAT by 120% and reduced the β3-AR content by 50%. ConclusionsThe LPHC diet stimulated glucose uptake, both the total rates and the rates derived from glucose-dependent FA and G3P synthesis, by increasing the insulin sensitivity and the sympathetic flux, despite a reduction in the β3-AR content.

Експресія інсулінового рецептора у субклітинних фракціях м’язової та жирової тканин як фактор розвитку тканинної інсулінорезистентності у щурів за умов висококалорійної дієти

Nowadays the problem of insulin resistance, which has close cause-effect relations with obesity, diabetes mellitus type 2, metabolic syndrome, etc., is of urgent importance in medicine. We have revealed bidirectional changes of the IR content in crude membrane and cytosol of the adipose tissue cells in rats under conditions of the long-term high-energy diet. It is possible that reduction of the IR content in the adipose tissue cells has been predetermined by the disruption of lipid bilayer of adipocytes as a result of peroxidation processes activation. Increase in the IR content in the cytosol of cells of this tissue may indicate the activation of synthesis of this protein; however, it is possible that the IR translocation process disorder occurs due to the damage of plasma membrane, preventing the transfer of newly synthesized molecules of the receptor to the membrane and causing their accumulation in cytosol. The obtained results show that the tissues react to the long-term consumption of high-energy food in different ways. Thus, the content of insulin receptors in the plasma membrane of the muscle tissue cells increases, and, on the contrary, it decreases in adipose tissue cells. Such results may indicate that IR development at the late period of the experiment is likely the result of the adipose tissue cells disfunction. The obtained data may be of high significance in understanding the mechanism of the IR development under conditions of the long-term consumption of the high-energy food.

Vitis vinifera L. grape skin extract activates the insulin-signalling cascade and reduces hyperglycaemia in alloxan-induced diabetic mice

This study examined the effect of Vitis vinifera grape skin extract (ACH09) on hyperglycaemia and the insulin-signalling cascade in alloxan-treated mice. Glycaemia, serum insulin and Western blot analysis of insulin cascade proteins were evaluated in the gastrocnemius muscles of four groups of adult mice: control, ACH09 (200 mg/kg per day, p.o.), alloxan (300 mg/kg, i.p.) and alloxan + ACH09. Insulin secretion in isolated pancreatic islets was also studied. Glycaemia values in the alloxan + ACH09 and ACH09 groups were significantly lower than in the alloxan-treated and control groups, respectively. Increased insulin resistance (HOMA index) was observed in the alloxan-treated group but not in the alloxan + ACH09 group. Insulin receptor content and Akt phosphorylation were significantly greater in the alloxan + ACH09 group compared with the alloxan-treated group. The glucose transporter (GLUT-4) content was reduced in alloxan-treated mice compared with the control group, while alloxan + ACH09 and ACH09-treated mice showed a significant increase in GLUT-4 content. ACH09 treatment did not change glucose-induced insulin secretion in isolated pancreatic islets. The results suggest that ACH09 has hypoglycaemic and antihyperglycaemic effects that are independent of an increase in insulin release but are probably dependent on an increase in insulin sensitivity resulting from an activation of the insulin-signalling cascade in skeletal muscle.

Increased insulin sensitivity and insulin signaling protein content following regular exercise in T1‐diabetic rats

Type 1 diabetic (T1D) patients can develop insulin insensitivity due to the daily requirement of exogenous insulin. Regular exercise has been shown to improve insulin sensitivity (IS) through the increased expression of muscle Glut4 and insulin receptor (IR) content. This study examined the role of exercise on IS and Glut4 and IR expression in T1D rats. Thirty animals were randomly divided into 3 groups; control (C), diabetic sedentary (D), and diabetic exercised (DE). D and DE were injected with STZ and implanted with insulin pellets to maintain blood glucose levels between 9 and 15 mM. DE ran on a treadmill at 27m/min, 1hr/day, 5days/wk for 10wks. Compared to C, D demonstrate a significant decrease in Glut4 and IR protein content in the red (RV) and white (WV) vastus muscles (p<0.05), and a significant reduction in blood glucose clearance following an intravenous glucose challenge (p<0.05). DE demonstrated a significant increase in Glut4 protein in RV and WV (p<0.05), while IR protein content was elevated in the WV only (p<0.05). Also, blood glucose clearance rates were significantly increased in DE compared to D (p<0.05). To conclude, STZ-diabetic rodents exhibit insulin insensitivity which can be alleviated through regular exercise. These improvements in IS though exercise are concomitant with changes in Glut4 and IR protein content in a muscle-specific fashion. Supported by CIHR Grant #CCT- 83029.