scholarly journals Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer’s disease in metabolically stressed APPswe/PS1dE9 mice

2021 ◽  
Author(s):  
Miren Ettcheto ◽  
Elena Sánchez-Lopez ◽  
Amanda Cano ◽  
Marina Carrasco ◽  
Katherine Herrera ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Combined Therapy ◽  
Chronic Administration ◽  
Transgenic Animals ◽  
Amyloid Plaque ◽  
Tolerance Test ◽  
Metabolic Effects ◽  
Metabolic Disturbances ◽  
Insulin Tolerance

Abstract Background: Several studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20mg·kg-1·d-1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD. Results: Our studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other pathways associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response.Conclusions: Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.

scholarly journals Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer’s disease in metabolically stressed APPswe/PS1dE9 mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Miren Ettcheto ◽  
Elena Sánchez-Lopez ◽  
Amanda Cano ◽  
Marina Carrasco ◽  
Katherine Herrera ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Combined Therapy ◽  
Chronic Administration ◽  
Transgenic Animals ◽  
Amyloid Plaque ◽  
Tolerance Test ◽  
Metabolic Effects ◽  
Metabolic Disturbances ◽  
Insulin Tolerance

Abstract Background Several studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20 mg kg−1 d−1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD. Results Our studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other alterations associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response. Conclusions Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.

scholarly journals Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0249239
Author(s):  
Jason A. West ◽  
Anastasia Tsakmaki ◽  
Soumitra S. Ghosh ◽  
David G. Parkes ◽  
Rikke V. Grønlund ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Fasting Blood Glucose ◽  
Chronic Administration ◽  
Dual Therapy ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Beneficial Effects ◽  
Gut Hormone ◽  
Gip Receptor

Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3–30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5–42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.

scholarly journals CYP2J2 attenuates metabolic dysfunction in diabetic mice by reducing hepatic inflammation via the PPARγ

2015 ◽  
Vol 308 (4) ◽  
pp. E270-E282 ◽  
Author(s):  
Rui Li ◽  
Xizhen Xu ◽  
Chen Chen ◽  
Yan Wang ◽  
Artiom Gruzdev ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Biological Effects ◽  
Tolerance Test ◽  
Mapk Signaling ◽  
Metabolic Dysfunction ◽  
Glucose Levels ◽  
Hepatic Cells ◽  
Insulin Tolerance

Epoxyeicosatrienoic acids (EETs) and arachidonic acid-derived cytochrome P450 (CYP) epoxygenase metabolites have diverse biological effects, including anti-inflammatory properties in the vasculature. Increasing evidence suggests that inflammation in type 2 diabetes is a key component in the development of insulin resistance. In this study, we investigated whether CYP epoxygenase expression and exogenous EETs can attenuate insulin resistance in diabetic db/db mice and in cultured hepatic cells (HepG2). In vivo, CYP2J2 expression and the accompanying increase in EETs attenuated insulin resistance, as determined by plasma glucose levels, glucose tolerance test, insulin tolerance test, and hyperinsulinemic euglycemic clamp studies. CYP2J2 expression reduced the production of proinflammatory cytokines in liver, including CRP, IL-6, IL-1β, and TNFα, and decreased the infiltration of macrophages in liver. CYP2J2 expression also decreased activation of proinflammatory signaling cascades by decreasing NF-κB and MAPK activation in hepatocytes. Interestingly, CYP2J2 expression and exogenous EET treatment increased glucose uptake and activated the insulin-signaling cascade both in vivo and in vitro, suggesting that CYP2J2 metabolites play a role in glucose homeostasis. Furthermore, CYP2J2 expression upregulated PPARγ, which has been shown to induce adipogenesis, which attenuates dyslipidemias observed in diabetes. All of the findings suggest that CYP2J2 expression attenuates the diabetic phenotype and insulin resistance via inhibition of NF-κB and MAPK signaling pathways and activation of PPARγ.

scholarly journals Deciphering the Hypoglycemic Glucagon Response: Development of a Graded Hyperinsulinemic Hypoglycemic Clamp Technique in Female Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3866-3871 ◽  
Author(s):  
Siri Malmgren ◽  
Bo Ahrén
Keyword(s):  
Blood Glucose ◽  
Defense Mechanisms ◽  
Tolerance Test ◽  
Glucose Lowering ◽  
Insulin Tolerance ◽  
Hyperbolic Curve ◽  
Glucose Lowering Therapy

Glucose lowering therapy in type 1 and type 2 diabetes is often associated with hypoglycemic events. To avoid this, glucose lowering therapies need to be developed that support the hypoglycemic defense mechanisms. Such development needs a tool for evaluating counterregulatory mechanisms in vivo. A sustained glucagon release during hypoglycemia is of most importance to hypoglycemic defense mechanisms. We have therefore developed a graded hyperinsulinemic hypoglycemic clamp in mice and used it to evaluate counterregulatory glucagon dynamics. Glucose was clamped at narrow intervals aiming at 2.5, 3.5, 4.5, and 6.0 mmol/L. Glucagon levels were increased during hypoglycemia in a glucose-dependent way with a glucagon counterregulatory threshold between 3.5 and 4.0 mmol/L. Modelling the glucose-glucagon relationship using a hyperbolic curve with the equation: plasma glucagon = −4.20 + 90.79/blood glucose showed high correlation. When comparing this method to the insulin tolerance test as an approach to study glucagon dynamics in vivo, we found that the graded clamp more efficiently evoked a robust, predictable, glucagon response with considerably less variation in blood glucose. In conclusion, we have developed a tool for the study of in vivo glucagon dynamics during hypoglycemia in mice and demonstrated a hyperbolic glucose-counterregulatory glucagon relationship.

scholarly journals Increased thromboxane mediates the adverse renal effects of interleukin-2 in rats.

1994 ◽  
Vol 4 (9) ◽  
pp. 1701-1710
Author(s):  
D Rubinger ◽  
E Cohen ◽  
Y Haviv ◽  
J Bernheim ◽  
E Shiloni ◽  
...  
Keyword(s):  
Body Weight ◽  
Urinary Excretion ◽  
Low Dose ◽  
Combined Therapy ◽  
Interleukin 2 ◽  
Chronic Administration ◽  
Urinary Sodium Excretion ◽  
Metabolic Effects ◽  
High Dose ◽  
Sodium And Potassium

The capillary leak syndrome with decreased GFR and renal water and sodium retention after recombinant interleukin-2 (IL-2) administration may arise from endothelial activation via an increase in prostaglandin synthesis. This study was undertaken to better define the role of the prostaglandin system in the renal and metabolic effects of IL-2 administration in rats. The chronic administration of IL-2 (100,000 U/kg, thrice daily, ip) resulted in a significant increase in body weight, a decrease in GFR and in the urinary excretion of sodium and potassium, and an increase in the urinary excretion of thromboxane (TXB2). After combined IL-2 and low-dose indomethacin (1.7 mg/kg per day po), a significant decrease in body weight with normalization of GFR, of the urinary excretion of Na, and of urinary TXB2 was noted in animals receiving combined therapy as compared with those receiving IL-2 alone. In contrast, high-dose indomethacin administration (33.3 mg/kg po for the last 3 days of the study) was associated with a further decrease in GFR, enhancement of the sodium and potassium retention, and suppression of prostaglandin E2 excretion. The administration of the thromboxane receptor antagonist SQ 29548 in IL-2-treated rats led to a reversal of the fall in GFR induced by the lymphokine without significant changes in urinary sodium excretion. These results support the hypothesis that thromboxane is an important mediator of the renal and systemic effects of IL-2. These effects are reversed at least partly by low-dose indomethacin, which selectively suppresses thromboxane A2 (TXA2) synthesis, or by TXA2 receptor antagonism.

scholarly journals p50α/p55α Phosphoinositide 3-Kinase Knockout Mice Exhibit Enhanced Insulin Sensitivity

2004 ◽  
Vol 24 (1) ◽  
pp. 320-329 ◽  
Author(s):  
Dong Chen ◽  
Franck Mauvais-Jarvis ◽  
Matthias Bluher ◽  
Simon J. Fisher ◽  
Alison Jozsi ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Knockout Mice ◽  
Splice Variants ◽  
Tolerance Test ◽  
Glucose Levels ◽  
Gold Thioglucose ◽  
Insulin Tolerance ◽  
Altered Glucose ◽  
Phosphoinositide 3 Kinase

ABSTRACT Class Ia phosphoinositide (PI) 3-kinases are heterodimers composed of a regulatory and a catalytic subunit and are essential for the metabolic actions of insulin. In addition to p85α and p85β, insulin-sensitive tissues such as fat, muscle, and liver express the splice variants of the pik3r1 gene, p50α and p55α. Το define the role of these variants, we have created mice with a deletion of p50α and p55α by using homologous recombination. These mice are viable, grow normally, and maintain normal blood glucose levels but have lower fasting insulin levels. Results of an insulin tolerance test indicate that p50α/p55α knockout mice have enhanced insulin sensitivity in vivo, and there is an increase in insulin-stimulated glucose transport in isolated extensor digitorum longus muscle tissues and adipocytes. In muscle, loss of p50α/p55α results in reduced levels of insulin-stimulated insulin receptor substrate 1 (IRS-1) and phosphotyrosine-associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation, whereas in adipocytes levels of both insulin-stimulated PI 3-kinase and Akt are unchanged. Despite this, adipocytes of the knockout mice are smaller and have increased glucose uptake with altered glucose metabolic pathways. When treated with gold thioglucose, p50α/p55α knockout mice become hyperphagic like their wild-type littermates. However, they accumulate less fat and become mildly less hyperglycemic and markedly less hyperinsulinemic. Taken together, these data indicate that p50α and p55α play an important role in insulin signaling and action, especially in lipid and glucose metabolism.

scholarly journals EFFECT OF CALORIC RESTRICTION AND RAPAMYCIN ON OVARIAN AGING IN MICE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S103-S103
Author(s):  
Driele Garcia ◽  
Tatiana Saccon ◽  
Joao Rincon ◽  
Jorgea Pradiee ◽  
Rafael Mondadori ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Caloric Restriction ◽  
Primordial Follicle ◽  
Tolerance Test ◽  
Metabolic Effects ◽  
Primordial Follicles ◽  
Female Mice ◽  
Insulin Tolerance ◽  
Follicular Reserve

Abstract The ovarian follicular reserve of primordial follicle declines with aging in female mammals. Caloric restriction (CR) has been shown to increase the preservation of the ovarian follicular reserve. Likewise, rapamycin has similar effects to CR on the ovarian reserve. Therefore, the aim of our study was to evaluate the effects of rapamycin and CR on the metabolism and ovarian follicular reserve and gene expression in mice. Thirty-six female mice were used, and allocated into 3 groups: control, rapamycin (4mg/kg body weight every other day) and 30% CR. At 85 days of treatment, an insulin tolerance test (ITT) and glucose tolerance test (GTT) was performed. At 93 days ovaries were collected for analysis. CR females had lower body weight (P<0.05) and were more insulin sensitive (P=0.003), while rapamycin treated females did not change body weight (P>0.05) and were more resistant to insulin (P<0.05). Females from the CR and rapamycin groups had a twice higher number of primordial follicles (P=0.02 and 0.04) and half the number of primary, secondary and tertiary follicles (P<0.05). Both CR and rapamycin females had increased ovarian gene expression of Foxo3a mRNA (P<0.05). In conclusion, female mice from rapamycin and CR groups had an increased ovarian follicular reserve associated to higher expression of Foxo3a mRNA, despite divergent metabolic effects of the treatments.

scholarly journals Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period

2012 ◽  
Vol 303 (7) ◽  
pp. R700-R709 ◽  
Author(s):  
Alba Carreras ◽  
Foaz Kayali ◽  
Jing Zhang ◽  
Camila Hirotsu ◽  
Yang Wang ◽  
...  
Keyword(s):  
High Frequency ◽  
Intermittent Hypoxia ◽  
Low Frequency ◽  
Rest Period ◽  
Tolerance Test ◽  
Metabolic Effects ◽  
Metabolic Dysfunction ◽  
Reduced Body ◽  
Insulin Tolerance ◽  
Plasma Leptin

Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IHL) have not been extensively examined, it would appear that IHL and high-frequency intermittent hypoxia (IHH) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IHH (cycles of 90 s 6.4% O2 and 90 s 21% O2 during daylight), IHL (8% O2 during daylight hours), or control (CTL) for 5 wk. At the end of exposures, some of the mice were subjected to a glucose tolerance test (GTT; after intraperitoneal injection of 2 mg glucose/g body wt), and others were subjected to an insulin tolerance test (ITT; 0.25 units Humulin/kg body wt), with plasma leptin and insulin levels being measured in fasting conditions. Skeletal muscles were harvested for GLUT4 and proliferator-activated receptor gamma coactivator 1-α (PGC1-α) expression. Both IHH and IHL displayed reduced body weight increases compared with CTL. CTL mice had higher basal glycemic levels, but GTT kinetics revealed marked differences between IHL and IHH, with IHL manifesting the lowest insulin sensitivity compared with either IHH or CTL, and such findings were further confirmed by ITT. No differences emerged in PGC1-α expression across the three experimental groups. However, while cytosolic GLUT4 protein expression remained similar in IHL, IHH, and CTL, significant decreases in GLUT4 membrane fraction occurred in hypoxia and were most pronounced in IHL-exposed mice. Thus IHH and IHL elicit differential glucose homeostatic responses despite similar cumulative hypoxic profiles.

scholarly journals Hormonal and metabolic disturbances and their correction in children with obesity

2003 ◽  
Vol 49 (4) ◽  
pp. 22-26
Author(s):  
N. V. Bolotova ◽  
A. P. Averyanov ◽  
S. V. Lazebnikova ◽  
Ye. G. Dronova
Keyword(s):  
Total Cholesterol ◽  
Combined Therapy ◽  
Glycemic Load ◽  
Tolerance Test ◽  
The Body ◽  
Obese Children ◽  
Metabolic Disturbances ◽  
The Metabolic Syndrome ◽  
Low Calorie Diet ◽  
Calorie Diet

The paper deals with the prevalence and specific features of the metabolic syndrome (MS) in children with different forms of obesity and with the capacities of its correction. Ninety-eight children aged 9-17years, including 44 children with exogenous constitutional obesity and 54 with pubertal juvenile dyspituitarism, were examined. For the diagnosis of MS, clinical exami­nations methods were used. These included: estimation of the body mass index, circumferences of the waist and hips, their ra­tio, the levels of total cholesterol, triglycerides, coagulogram, fasting insulin, the routine glucose tolerance test, and fasting glucose/insulin ratio. The incidence of MS in obese children was 42.9%. A combination of 5 components of MS, such as in­sulin resistence, abdominal obesity, hyperlipidemia, hyperco- agulative changes, and aterial hypertension, was noted in 23.8% of the children and that of 4 and 3 (incomplete MS) components in different combinations was in 52.4 and 23.8%, respectively. The combined therapy low-calorie diet and metformin (Siofor, Berlin-Chemie) was used to correct the metabolic disturbances detected in 28 children aged above 13 years. The use of Siofor in children with MS, unlike dietary monotherapy, substantially improved the values of total cholesterol, fibrinogen, and blood pressure and normalized a response to glycemic load in most patients

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