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1.
Behav Brain Res ; 437: 114130, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36179806

RESUMO

This study examined the impact of Type 1 Diabetes Mellitus (T1DM) on executive function using a series of operant conditioning-based tasks in rats. Sprague Dawley rats were randomized to either non-diabetic (n = 12; 6 male) or diabetic (n = 14; 6 male) groups. Diabetes was induced using multiple low-dose streptozotocin injections. All diabetic rodents were insulin-treated using subcutaneous insulin pellet implants (9-15 mM). At week 14 of the study, rats were placed on a food restricted diet to induce 5-10 % weight loss. Rodents were familiarized and their set-shifting ability was tested on a series of tasks that required continuous adjustments to novel stimulus-reward paradigms in order to receive food rewards. Results showed no differences in the number of trials, nor number and type of errors made to successfully complete each task between groups. Therefore, we report no differences in executive function, or more specifically set-shifting abilities between non-diabetic and diabetic rodents that receive insulin.


Assuntos
Diabetes Mellitus Tipo 1 , Função Executiva , Ratos , Animais , Masculino , Diabetes Mellitus Tipo 1/induzido quimicamente , Ratos Sprague-Dawley , Roedores , Insulina/farmacologia
2.
Behav Brain Res ; 437: 114146, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36202146

RESUMO

Some diabetes patients develop depression, the main treatment for which is antidepressants. Pharmacological interactions between insulin and antidepressants (e.g., fluoxetine) are controversial in the literature. Some authors reported hypoglycemic actions of fluoxetine, whereas others reported antidepressant-like actions. In healthy rats, insulin produces an antidespair-like action in rats through an increase in locomotor and exploratory activity, but differences in actions of insulin and fluoxetine on neuronal activity are unknown. The present study evaluated Wistar healthy rats that were treated with saline, insulin, fluoxetine, or fluoxetine + insulin for 3 days (short-term) or 21 days (long-term). The model consisted of electrical stimulation of the lateral septal nucleus (LSN) while we performed single-unit extracellular response recordings in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Stimulation of the LSN produced an initial brief excitatory paucisynaptic response and then a long-lasting inhibitory afterdischarge in the PL and IL. Treatment with saline and fluoxetine, but not insulin, minimally affected the paucisynaptic response. Differences were found in LSN-IL responsivity. The inhibitory afterdischarge was clearly enhanced in the long-term fluoxetine group but not by insulin alone or fluoxetine + insulin. These findings suggest that insulin produces some actions that are opposite to fluoxetine on LSN-mPFC connection responsivity, with no synergistic actions between the actions of insulin and fluoxetine.


Assuntos
Núcleos Septais , Animais , Ratos , Fluoxetina/farmacologia , Insulina/farmacologia , Ratos Wistar , Córtex Pré-Frontal/fisiologia , Antidepressivos/farmacologia
3.
Commun Biol ; 5(1): 1183, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333465

RESUMO

The relaxin/insulin-like family peptide receptor 2 (RXFP2) belongs to the family of class A G-protein coupled receptors (GPCRs) and it is the only known target for the insulin-like factor 3 peptide (INSL3). The importance of this ligand-receptor pair in the development of the gubernacular ligament during the transabdominal phase of testicular descent is well established. More recently, RXFP2 has been implicated in maintaining healthy bone formation. In this report, we describe the discovery of a small molecule series of RXFP2 agonists. These compounds are highly potent, efficacious, and selective RXFP2 allosteric agonists that induce gubernacular invagination in mouse embryos, increase mineralization activity in human osteoblasts in vitro, and improve bone trabecular parameters in adult mice. The described RXFP2 agonists are orally bioavailable and display favorable pharmacokinetic properties, which allow for future evaluation of the therapeutic benefits of modulating RXFP2 activation in disease models.


Assuntos
Relaxina , Masculino , Adulto , Humanos , Camundongos , Animais , Relaxina/farmacologia , Insulina/farmacologia , Receptores Acoplados a Proteínas G/fisiologia , Testículo , Hormônios Esteroides Gonadais , Receptores de Peptídeos
4.
ACS Biomater Sci Eng ; 8(11): 4873-4885, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-36317822

RESUMO

Stimuli-responsive hydrogels are an area of active discovery for approaches to deliver therapeutics in response to disease-specific indicators. Glucose-responsive delivery of insulin is of particular interest in better managing diabetes. Accordingly, hydrogels have been explored as platforms that enable both a rate and dose of insulin release aligning with the real-time physiological disease state; materials often include glucose sensing by dynamic-covalent cross-linking between phenylboronic acids (PBAs) and diols, with competition from ambient glucose reducing cross-link density of the material and accelerating release of encapsulated insulin. Yet, these materials historically have challenges with insulin leakage, offer limited glucose-responsive release of the insulin payload, and require unreasonably high injection pressures for syringe administration. Here, a thermogel platform prepared from temperature-induced micelles formed into a network by PBA-Diol cross-linking is optimized using a formulation-centered approach to maximize glucose-responsive insulin delivery. Importantly, the dual-responsive nature of this platform enables a low-viscosity sol at ambient temperature for facile injection, solidifying into a stable viscoelastic hydrogel network once in the body. The final optimized formulation affords acceleration in insulin release in response to glucose and enables single dose blood glucose control in diabetic rodents when subjected to multiple glucose challenges.


Assuntos
Micelas , Poloxâmero , Glucose , Hidrogéis , Insulina/farmacologia
5.
Front Immunol ; 13: 1019248, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389828

RESUMO

The inflammatory response plays critical important role in tissue hemostasis. Our previous study showed insulin-binding protein-5 (IGFBP5) could enhance the regeneration of tissue defect under inflammation condition, but the function of IGFBP5 in controlling inflammation and regulating immune responses remains unclear. In present study, we studied the regulatory effect of IGFBP5 on T cell immune response in vitro, and the maintenance of Th17/Treg balance in vivo by using dextran sulfate sodium salt (DSS)-induced colitis in mice. The results showed that IGFBP5 inhibited the differentiation of CD4+ T cells into Th17 subset while promoted its differentiation into Treg subsets. Further results of animal experiments demonstrated that recombinant IGFBP5 reversed the imbalance of Th17/Treg and alleviated the severity of DSS-induced colitis. The percentage of Th17 cells decreased and the percentage of Treg cells increased in the inflamed colon tissue and mesenteric lymph nodes of mice with colitis after IGFBP5 treatment. Besides, pro-inflammatory cytokines such as TNF-α, IL-1ß and IFN-γ in serum were suppressed after the treatment of IGFBP5. Moreover, the function of IGFBP5 in regulating Th17/Treg balance could be inhibited by the inhibitors of ERK or JNK pathway. In conclusion, all these data showed that IGFBP5 could regulate Th17/Treg balance via ERK or JNK pathways. The findings of our study provide a theoretical basis for the application of IGFBP5 in inflammatory diseases.


Assuntos
Colite , Células Th17 , Animais , Camundongos , Proteínas de Transporte/farmacologia , Sulfato de Dextrana , Inflamação , Insulina/farmacologia , Linfócitos T Reguladores
6.
Biomolecules ; 12(11)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36358934

RESUMO

Hypothermic (cold) preservation is a limiting factor for successful cell and tissue transplantation where cell swelling (edema) usually develops, impairing cell function. University of Wisconsin (UW) solution, a standard cold preservation solution, contains effective components to suppress hypothermia-induced cell swelling. Antifreeze proteins (AFPs) found in many cold-adapted organisms can prevent cold injury of the organisms. Here, the effects of a beetle AFP from Dendroides canadensis (DAFP-1) on pancreatic ß-cells preservation were first investigated. As low as 500 µg/mL, DAFP-1 significantly minimized INS-1 cell swelling and subsequent cell death during 4 °C preservation in UW solution for up to three days. However, such significant cytoprotection was not observed by an AFP from Tenebrio molitor (TmAFP), a structural homologue to DAFP-1 but lacking arginine, at the same levels. The cytoprotective effect of DAFP-1 was further validated with the primary ß-cells in the isolated rat pancreatic islets in UW solution. The submilligram level supplement of DAFP-1 to UW solution significantly increased the islet mass recovery after three days of cold preservation followed by rewarming. The protective effects of DAFP-1 in UW solution were discussed at a molecular level. The results indicate the potential of DAFP-1 to enhance cell survival during extended cold preservation.


Assuntos
Besouros , Animais , Ratos , Besouros/química , Besouros/metabolismo , Sobrevivência Celular , alfa-Fetoproteínas/farmacologia , Proteínas Anticongelantes/química , Glutationa/farmacologia , Insulina/farmacologia , Edema
7.
Front Immunol ; 13: 1029759, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389775

RESUMO

The function of intracellular trafficking in immune-complex triggered inflammation remains poorly understood. Here, we investigated the role of Insulin-Regulated Amino Peptidase (IRAP)-positive endosomal compartments in Fc receptor (FcR)-induced inflammation. Less severe FcγR-triggered arthritis, active systemic anaphylaxis and FcεRI-triggered passive systemic anaphylaxis were observed in IRAP-deficient versus wild-type mice. In mast cells FcεRI stimulation induced rapid plasma membrane recruitment of IRAP-positive endosomes. IRAP-deficient cells exhibited reduced secretory responses, calcium signaling and activating SykY519/520 phosphorylation albeit receptor tyrosine phosphorylation on ß and γ subunits was not different. By contrast, in the absence of IRAP, SHP1-inactivating phosphorylation on Ser591 that controls Syk activity was decreased. Ex-vivo cell profiling after FcγR-triggered anaphylaxis confirmed decreased phosphorylation of both SykY519/520 and SHP-1S591 in IRAP-deficient neutrophils and monocytes. Thus, IRAP-positive endosomal compartments, in promoting inhibition of SHP-1 during FcR signaling, control the extent of phosphorylation events at the plasma membrane and contribute to setting the intensity of immune-complex triggered inflammatory diseases.


Assuntos
Anafilaxia , Insulina , Animais , Camundongos , Insulina/farmacologia , Aminopeptidases/metabolismo , Cistinil Aminopeptidase , Receptores Fc , Receptores de IgG/genética , Receptores de IgE , Complexo Antígeno-Anticorpo , Inflamação
8.
Cell Commun Signal ; 20(1): 179, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376971

RESUMO

BACKGROUND: The aim of the present study was to determine the role of individual PHLPP isoforms in insulin signaling and insulin resistance in neuronal cells. METHODS: PHLPP isoforms were either silenced or overexpressed individually, and the effects were observed on individual Akt isoforms, AS160 and on neuronal glucose uptake, under insulin sensitive and resistant conditions. To determine PHLPP regulation itself, we tested effect of scaffold protein, Scribble, on PHLPP isoforms and neuronal glucose uptake. RESULTS: We observed elevated expression of both PHLPP1 and PHLPP2 in insulin resistant neuronal cells (Neuro-2A, mouse neuroblastoma; SHSY-5Y, human neuroblastoma) as well as in the whole brain lysates of high-fat-diet mediated diabetic mice. In insulin sensitive condition, PHLPP isoforms differentially affected activation of all Akt isoforms, wherein PHLPP1 regulated serine phosphorylation of Akt2 and Akt3, while PHLPP2 regulated Akt1 and Akt3. This PHLPP mediated Akt isoform specific regulation activated AS160 affecting glucose uptake. Under insulin resistant condition, a similar trend of results were observed in Akt isoforms, AS160 and glucose uptake. Over-expressed PHLPP isoforms combined with elevated endogenous expression under insulin resistant condition drastically affected downstream signaling, reducing neuronal glucose uptake. No compensation was observed amongst PHLPP isoforms under all conditions tested, indicating independent roles and pointing towards possible scaffolding interactions behind isoform specificity. Silencing of Scribble, a scaffolding protein known to interact with PHLPP, affected cellular localization of both PHLPP1 and PHLPP2, and caused increase in glucose uptake. CONCLUSIONS: PHLPP isoforms play independent roles via Scribble in regulating Akt isoforms differentially, affecting AS160 and neuronal glucose uptake. Video abstract.


Assuntos
Diabetes Mellitus Experimental , Resistência à Insulina , Neuroblastoma , Animais , Humanos , Camundongos , Glucose , Insulina/farmacologia , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
9.
Am J Physiol Heart Circ Physiol ; 323(6): H1231-H1238, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36331555

RESUMO

Insulin resistance in the vasculature is a hallmark of type 2 diabetes (T2D), and blunting of insulin-induced vasodilation is its primary consequence. Individuals with T2D exhibit a marked impairment in insulin-induced dilation in resistance arteries across vascular beds. Importantly, reduced insulin-stimulated vasodilation and blood flow to skeletal muscle limits glucose uptake and contributes to impaired glucose control in T2D. The study of mechanisms responsible for the suppressed vasodilatory effects of insulin has been a growing topic of interest for not only its association with glucose control and extension to T2D but also its relationship with cardiovascular disease development and progression. In this mini-review, we integrate findings from recent studies by our group with the existing literature focused on the mechanisms underlying endothelial insulin resistance in T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Resistência à Insulina/fisiologia , Glicemia , Insulina/farmacologia , Vasodilatação , Músculo Esquelético
10.
Sci Rep ; 12(1): 16765, 2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36202918

RESUMO

Congenital hyperinsulinism (CHI) is a rare genetic condition characterized by uncontrolled insulin secretion, resulting in hypoglycemia. Although glucagon has lately been regarded as a therapeutic option for CHI, its use is severely hampered by its poor solubility and stability at physiological pH, as well as its short duration of action. To address these constraints, we developed HM15136, a novel long-acting glucagon analog composed of a glucagon analog conjugated to the Fc fragment of human immunoglobulin G4 via a polyethylene glycol linker. In this study, we established that HM15136 was more soluble than natural glucagon (≥ 150 mg/mL vs 0.03 mg/mL). Next, we confirmed that HM15136 activated glucagon receptor in vitro and induced glycogenolysis and gluconeogenesis in rat primary hepatocytes. Pharmacokinetics (PK)/Pharmacodynamics (PD) analysis of HM15136 shows that HM15136 has a markedly longer half-life (36 h vs. < 5 min) and increased bioavailability (90%) compared to native glucagon in mice. Further, HM15136 could effectively reverse acute hypoglycemia induced by insulin challenge, and multiple doses of HM15136 could sustain increased blood glucose levels in CHI rats. In conclusion, our findings indicate that HM15136 promotes sustained elevation of blood glucose, demonstrating the potential for development as a once-weekly therapy for CHI.


Assuntos
Hiperinsulinismo Congênito , Hiperinsulinismo , Animais , Glicemia/análise , Hiperinsulinismo Congênito/tratamento farmacológico , Glucagon , Meia-Vida , Humanos , Hiperinsulinismo/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas , Insulina/farmacologia , Camundongos , Polietilenoglicóis/farmacologia , Ratos , Receptores de Glucagon , Roedores
11.
Can J Physiol Pharmacol ; 100(12): 1106-1114, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36223651

RESUMO

In this study, we wanted to verify whether the effect of insulin on calcium homeostasis depends on the heart's development stage. Using a quantitative 3D confocal microscopy, we tested the effect of a high insulin concentration (100 µU) in freshly cultured ventricular cardiomyocytes from newborn and adult rats. Our results showed that the cytosolic basal level of calcium was higher in newborn cardiomyocytes with no change in the nuclear basal calcium level compared with the adult cardiomyocytes; in addition, insulin induced a slow increase of cytosolic and nuclear calcium in newborn ventricular cardiomyocytes, followed by two phases. However, the first phase of slow cytosolic and nuclear calcium increase was absent in adult rat ventricular cardiomyocytes. Furthermore, the time to the onset of increase of cytosolic and nuclear calcium was longer in newborn cardiomyocytes compared with adults. Moreover, the time to peak of the calcium transient was shorter in newborns than in adult cardiomyocytes. These results demonstrate that insulin differently regulates calcium homeostasis in newborns than in adult cardiomyocytes. Thus, newborn rat cardiomyocytes, commonly used in research as a model for adult cardiomyocytes, should be used with caution when dealing with insulin in normal and disease conditions.


Assuntos
Cálcio , Miócitos Cardíacos , Ratos , Animais , Cálcio/farmacologia , Insulina/farmacologia , Células Cultivadas , Ventrículos do Coração
12.
Int J Mol Sci ; 23(19)2022 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-36233271

RESUMO

Ranolazine (Rn) is a drug used to treat persistent chronic coronary ischemia. It has also been shown to have therapeutic benefits on the central nervous system and an anti-diabetic effect by lowering blood glucose levels; however, no effects of Rn on cellular sensitivity to insulin (Ins) have been demonstrated yet. The present study aimed to investigate the permissive effects of Rn on the actions of Ins in astrocytes in primary culture. Ins (10-8 M), Rn (10-6 M), and Ins + Rn (10-8 M and 10-6 M, respectively) were added to astrocytes for 24 h. In comparison to control cells, Rn and/or Ins caused modifications in cell viability and proliferation. Rn increased protein expression of Cu/Zn-SOD and the pro-inflammatory protein COX-2 was upregulated by Ins. On the contrary, no significant changes were found in the protein expression of NF-κB and IκB. The presence of Rn produced an increase in p-ERK protein and a significant decrease in COX-2 protein expression. Furthermore, Rn significantly increased the effects of Ins on the expression of p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ. In addition, Rn + Ins produced a significant decrease in COX-2 expression. In conclusion, Rn facilitated the effects of insulin on the p-AKT, p-eNOS, p-ERK, Mn-SOD, and PPAR-γ signaling pathways, as well as on the anti-inflammatory and antioxidant effects of the hormone.


Assuntos
Astrócitos , Insulina , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Astrócitos/metabolismo , Glicemia/metabolismo , Ciclo-Oxigenase 2/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Insulina Regular Humana , NF-kappa B/metabolismo , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ranolazina/farmacologia , Superóxido Dismutase/metabolismo
13.
Sci Rep ; 12(1): 17659, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271244

RESUMO

Modelling insulin-glucose homeostasis may provide novel functional insights. In particular, simple models are clinically useful if they yield diagnostic methods. Examples include the homeostasis model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI). However, limitations of these approaches have been criticised. Moreover, recent advances in physiological and biochemical research prompt further refinement in this area. We have developed a nonlinear model based on fundamental physiological motifs, including saturation kinetics, non-competitive inhibition, and pharmacokinetics. This model explains the evolution of insulin and glucose concentrations from perturbation to steady-state. Additionally, it lays the foundation of a structure parameter inference approach (SPINA), providing novel biomarkers of carbohydrate homeostasis, namely the secretory capacity of beta-cells (SPINA-GBeta) and insulin receptor gain (SPINA-GR). These markers correlate with central parameters of glucose metabolism, including average glucose infusion rate in hyperinsulinemic glucose clamp studies, response to oral glucose tolerance testing and HbA1c. Moreover, they mirror multiple measures of body composition. Compared to normal controls, SPINA-GR is significantly reduced in subjects with diabetes and prediabetes. The new model explains important physiological phenomena of insulin-glucose homeostasis. Clinical validation suggests that it may provide an efficient biomarker panel for screening purposes and clinical research.


Assuntos
Resistência à Insulina , Humanos , Resistência à Insulina/fisiologia , Receptor de Insulina , Glicemia/metabolismo , Hemoglobina A Glicada , Insulina/farmacologia , Biomarcadores , Modelos Teóricos
14.
Biochem J ; 479(21): 2279-2296, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36256829

RESUMO

Certain metabolic intermediates produced during metabolism are known to regulate a wide range of cellular processes. Methylglyoxal (MG), a natural metabolite derived from glycolysis, has been shown to negatively influence systemic metabolism by inducing glucose intolerance, insulin resistance, and diabetic complications. MG plays a functional role as a signaling molecule that initiates signal transduction. However, the specific relationship between MG-induced activation of signal transduction and its negative effects on metabolism remains unclear. Here, we found that MG activated mammalian target of rapamycin complex 1 (mTORC1) signaling via p38 mitogen-activated protein kinase in adipocytes, and that the transforming growth factor-ß-activated kinase 1 (TAK1) is needed to activate p38-mTORC1 signaling following treatment with MG. We also found that MG increased the phosphorylation levels of serine residues in insulin receptor substrate (IRS)-1, which is involved in its negative regulation, thereby attenuating insulin-stimulated tyrosine phosphorylation in IRS-1. The negative effect of MG on insulin-stimulated IRS-1 tyrosine phosphorylation was exerted due to the MG-induced activation of the TAK1-p38-mTORC1 signaling axis. The involvement of the TAK1-p38-mTORC1 signaling axis in the induction of IRS-1 multiple serine phosphorylation was not unique to MG, as the proinflammatory cytokine, tumor necrosis factor-α, also activated the same signaling axis. Therefore, our findings suggest that MG-induced activation of the TAK1-p38-mTORC1 signaling axis caused multiple serine phosphorylation on IRS-1, potentially contributing to insulin resistance.


Assuntos
Resistência à Insulina , Aldeído Pirúvico , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Aldeído Pirúvico/farmacologia , Aldeído Pirúvico/metabolismo , Resistência à Insulina/fisiologia , Serina/metabolismo , Transdução de Sinais/fisiologia , Adipócitos/metabolismo , Insulina/farmacologia , Insulina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Tirosina/metabolismo , Fosfoproteínas/metabolismo
15.
Sci Transl Med ; 14(668): eabh1316, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36288279

RESUMO

Circadian rhythms play a critical role in regulating metabolism, including daily cycles of feeding/fasting. Glucokinase (GCK) is central for whole-body glucose homeostasis and oscillates according to a circadian clock. GCK activators (GKAs) effectively reduce hyperglycemia, but their use is also associated with hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of GCK, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. Acute treatment of obese Zucker rats with the GKA AZD1656 robustly increased flux into all major metabolic pathways of glucose disposal, enhancing glucose elimination. Four weeks of continuous AZD1656 treatment of obese Zucker rats improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, timing AZD1656 to feeding periods robustly reduced hepatic steatosis and inflammation in addition to improving glycemia, whereas treatment timed to fasting periods caused overall detrimental metabolic effects. Mechanistically, timing AZD1656 to feeding periods diverted newly synthesized lipid toward direct VLDL secretion rather than intrahepatic storage. In line with increased hepatic insulin signaling, timing AZD1656 to feeding resulted in robust activation of AKT, mTOR, and SREBP-1C after glucose loading, pathways known to regulate VLDL secretion and hepatic de novo lipogenesis. In conclusion, intermittent AZD1656 treatment timed to feeding periods promotes glucose disposal when needed the most, restores metabolic flexibility and hepatic insulin sensitivity, and thereby avoids hepatic steatosis. Thus, chronotherapeutic approaches may benefit the development of GKAs and other drugs acting on metabolic targets.


Assuntos
Fígado Gorduroso , Glucoquinase , Ratos , Animais , Ratos Zucker , Glucoquinase/metabolismo , Hipoglicemiantes/uso terapêutico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Insulina/farmacologia , Glucose/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Fígado/metabolismo , Cronoterapia , Inflamação/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Lipídeos
16.
FASEB J ; 36(11): e22594, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36250347

RESUMO

Neurite outgrowth is a fundamental process in neurons that produces extensions and, consequently, neural connectivity. Neurite damage and atrophy are observed in various brain injuries and disorders. Understanding the intrinsic pathways of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration. Insulin is a pivotal hormone in the regulation of glucose homeostasis. There is increasing evidence for the neurotrophic functions of insulin, including the induction of neurite outgrowth. However, the associated mechanism remains elusive. Here, we demonstrate that insulin potentiates neurite outgrowth mediated by the small GTPases ADP-ribosylation factor 6 (ARF6) and Ras-related C3 botulinum toxin substrate 1 (Rac1) through the neuronal adaptor FE65. Moreover, insulin enhances atypical protein kinase Cι/λ (PKCι/λ) activation and FE65 phosphorylation at serine 459 (S459) in neurons and mouse brains. In vitro and cellular assays show that PKCι/λ phosphorylated FE65 at S459. Consistently, insulin potentiates FE65 S459 phosphorylation only in the presence of PKCι/λ. Phosphomimetic studies show that an FE65 S459E mutant potently activates ARF6, Rac1, and neurite outgrowth. Notably, this phosphomimetic mutation enhances the FE65-ARF6 interaction, a process that promotes ARF6-Rac1-mediated neurite outgrowth. Likewise, insulin treatment and PKCι/λ overexpression potentiate the FE65-ARF6 interaction. Conversely, PKCι/λ knockdown suppresses the stimulatory effect of FE65 on ARF6-Rac1-mediated neurite outgrowth. The effect of insulin on neurite outgrowth is also markedly attenuated in PKCι/λ knockdown neurons, in the presence and absence of FE65. Our findings reveal a novel mechanism linking insulin with ARF6-Rac1-dependent neurite extension through the PKCι/λ-mediated phosphorylation of FE65.


Assuntos
Insulina , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Proteínas rac1 de Ligação ao GTP , Fator 6 de Ribosilação do ADP , Animais , Glucose/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Camundongos , Neuritos/metabolismo , Crescimento Neuronal/fisiologia , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Serina/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo
17.
J Gastrointestin Liver Dis ; 31(3): 344-354, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36112705

RESUMO

Obesity is a systemic disease and represents one of the leading causes of death worldwide by constituting the main risk factor for a series of non-communicable diseases such as type 2 diabetes mellitus (T2DM), cardiovascular diseases and dyslipidemia. Lifestyle interventions have been attempting to prevent T2DM and obesity but are difficult to maintain by most patients. However, the recent focus on the intestinal microbiota and its important role in the host's metabolism provides a new key for improving metabolic health. Modulating the composition of the gut microbiota was proposed as a method to manage these metabolic diseases and most frequently this is undertaken by using probiotics, prebiotics or synbiotics. Furthermore, the action of metformin, the most commonly prescribed drug for treating T2DM, is mediated in part by the gut microbiota, although this interplay may also be responsible for the frequent gastrointestinal adverse effects of metformin. Thus, adding a gut microbiota modulator (GMM), such as probiotics or prebiotics, to metformin therapy could amplify its anti-diabetic effects, while decreasing its adverse reactions. This review summarizes the various therapies that are used to shift the composition of the microbiome and their efficacy in alleviating metabolic parameters, it assesses the interaction between metformin and the gut microbiota, and it evaluates the existing clinical and preclinical studies that analyze the potential synergy of a combined metformin-GMM therapy.


Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Metformina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Insulina/farmacologia , Insulina/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Obesidade/tratamento farmacológico , Prebióticos
18.
Nutrients ; 14(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36079898

RESUMO

Saturated free fatty acids (FFAs) such as palmitate in the circulation are known to cause endoplasmic reticulum (ER) stress and insulin resistance in peripheral tissues. In addition to protein kinase B (AKT) signaling, extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance. However, there are conflicting data regarding role of ERK signaling in ER stress-induced insulin resistance. In this study, we investigated the effects of ER stress on insulin resistance and ERK phosphorylation in Huh-7 cells and evaluated how oleate prevents palmitate-mediated ER stress. Treatment with insulin resulted in an increase of 38-45% in the uptake of glucose in control cells compared to non-insulin-treated control cells, along with an increase in the phosphorylation of AKT and ERK. We found that treatment with palmitate increased the expression of ER stress genes, including the splicing of X box binding protein 1 (XBP1) mRNA. At the same time, we observed a decrease in insulin-mediated uptake of glucose and ERK phosphorylation in Huh-7 cells, without any change in AKT phosphorylation. Supplementation of oleate along with palmitate mitigated the palmitate-induced ER stress but did not affect insulin-mediated glucose uptake or ERK phosphorylation. The findings of this study suggest that palmitate reduces insulin-mediated ERK phosphorylation in liver cells and this effect is independent of fatty-acid-induced ER stress.


Assuntos
Resistência à Insulina , Insulina , Estresse do Retículo Endoplasmático , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ácidos Graxos/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Insulina/farmacologia , Fígado/metabolismo , Ácido Oleico/metabolismo , Ácido Oleico/farmacologia , Palmitatos/metabolismo , Palmitatos/farmacologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
19.
Front Endocrinol (Lausanne) ; 13: 986616, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093068

RESUMO

Background: Type 2 diabetes (T2D) is characterized by a decreased insulin sensitivity. Magnesium (Mg2+) deficiency is common in people with T2D. However, the molecular consequences of low Mg2+ levels on insulin sensitivity and glucose handling have not been determined in adipocytes. The aim of this study is to determine the role of Mg2+ in the insulin-dependent glucose uptake. Methods: First, the association of low plasma Mg2+ with markers of insulin resistance was assessed in a cohort of 395 people with T2D. Secondly, the molecular role of Mg2+ in insulin-dependent glucose uptake was studied by incubating 3T3-L1 adipocytes with 0 or 1 mmol/L Mg2+ for 24 hours followed by insulin stimulation. Radioactive-glucose labelling, enzymatic assays, immunocytochemistry and live microscopy imaging were used to analyze the insulin receptor phosphoinositide 3-kinases/Akt pathway. Energy metabolism was assessed by the Seahorse Extracellular Flux Analyzer. Results: In people with T2D, plasma Mg2+ concentration was inversely associated with markers of insulin resistance; i.e., the lower Mg2+, the more insulin resistant. In Mg2+-deficient adipocytes, insulin-dependent glucose uptake was decreased by approximately 50% compared to control Mg2+condition. Insulin receptor phosphorylation Tyr1150/1151 and PIP3 mass were not decreased in Mg2+-deficient adipocytes. Live imaging microscopy of adipocytes transduced with an Akt sensor (FoxO1-Clover) demonstrated that FoxO1 translocation from the nucleus to the cytosol was reduced, indicting less Akt activation in Mg2+-deficient adipocytes. Immunocytochemistry using a Lectin membrane marker and at the membrane located Myc epitope-tagged glucose transporter 4 (GLUT4) demonstrated that GLUT4 translocation was diminished in insulin-stimulated Mg2+-deficient adipocytes compared to control conditions. Energy metabolism in Mg2+ deficient adipocytes was characterized by decreased glycolysis, upon insulin stimulation. Conclusions: Mg2+ increases insulin-dependent glucose uptake in adipocytes and suggests that Mg2+ deficiency may contribute to insulin resistance in people with T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adipócitos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Insulina/farmacologia , Magnésio , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/metabolismo
20.
Adv Food Nutr Res ; 102: 181-231, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36064293

RESUMO

Food proteins, depending on their origin, possess unique characteristics that regulate blood glucose via multiple physiological mechanisms, including the insulinotropic effects of amino acids, the activation of incretins, and slowing gastric emptying rate. The strategies aimed at curbing high blood glucose are important in preventing impaired blood glucose control, including insulin resistance, prediabetes and diabetes. The effect of proteins on blood glucose control can be achieved with high-protein foods short-term, and high-protein diets long-term using foods that are naturally high in protein, such as dairy, meat, soy and pulses, or by formulating high-protein functional food products using protein concentrates and isolates, or blended mixtures of proteins from different sources. Commercial sources of protein powders are represented by proteins and hydrolysates of caseins, whey proteins and their fractions, egg whites, soy, yellow pea and hemp which will be reviewed in this chapter. The effective doses of food protein that are capable of reducing postprandial glycemia start from 7 to 10g and higher per serving; however, the origin of protein, and macronutrient composition of a meal will determine the magnitude and duration of their effect on glycemia. The theoretical and methodological framework to evaluate the effect of foods, including food proteins, on postprandial glycemia for substantiation of health claims on food has been proposed in Canada and is discussed in the context of global efforts to harmonize the international food regulation and labeling.


Assuntos
Glicemia , Controle Glicêmico , Glicemia/metabolismo , Esvaziamento Gástrico , Insulina/farmacologia , Período Pós-Prandial
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