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1.
Life Sci ; 257: 118073, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663574

RESUMO

AIMS: The preservation of pancreatic beta-cell function is crucial for the treatment of type 2 diabetes. Inhibition of class I histone deacetylase (HDAC) has been proved to protect beta-cells from palmitate- or cytokine-induced apoptosis and increase insulin secretion. However, the underlying molecular mechanism is unclear. MAIN METHODS: Rat islets were isolated for insulin secretion, real-time PCR, RNA- sequencing, ChIP-PCR, and oxygen consumption rate analysis after treated with the HDAC1 and HDAC3 inhibitor MS-275. KEY FINDINGS: MS-275 pretreatment significantly potentiated insulin secretion from rat islets. RNA-sequencing revealed that multiple signaling pathways were involved in MS-275-regulated islet function. Cacna1g and Adcy1 in calcium and cAMP signaling pathways were up-regulated in MS-275-treated islets, which was validated by real-time PCR. The expressions of the two genes displayed a similar increase in islets isolated from mice treated with MS-275. Knockdown of HDAC1 elevated Cacna1g and Adcy1 expressions in islets. ChIP-sequencing analysis showed that the pan-HDAC inhibitor sodium butyrate increased H3K27 acetylation level in the upstream region of Adcy1 and the promoter region of Cacna1g. ChIP-PCR revealed a similar result in MS-275-treated rat islets. However, MS-275 had minor effect on glucose-induced oxygen consumption rate in rat islets. Unlike glucose, MS-275 did not alter the expressions of glucose-sensitive genes such as Glut2 and Gck, but elevated intracellular Ca2+ concentration in beta-cells. SIGNIFICANCE: Our findings support the notion that MS-275-potentiated insulin secretion is involved in calcium and cAMP signaling-mediated gene expressions independent of glucose oxidation. Therefore, HDAC inhibition may serve as a therapeutic strategy for type 2 diabetes.


Assuntos
Benzamidas/farmacologia , Glucose/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Secreção de Insulina/efeitos dos fármacos , Piridinas/farmacologia , Animais , Cálcio/metabolismo , AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Técnicas de Silenciamento de Genes , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilases/efeitos dos fármacos , Células Secretoras de Insulina , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
2.
PLoS One ; 15(6): e0233364, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530969

RESUMO

Type 2 diabetes mellitus (T2DM) is among the most prevalent diseases in the world, affecting over 420 million people. The disease is marked by a poor metabolic effect of insulin leading to chronic hyperglycaemia, which can result in microvascular complications. It is widely known that postprandial glycaemia is reliant on the total carbohydrate content of a meal. However, the importance of the amount and the source of these carbohydrates remains controversial due to mechanisms other than insulin secretion. Oxidative stress, inflammation, pyruvate production and the quality of the intestinal microbiota, resulting in plasma lipopolysaccharides and short-chain fatty acids production, play an important role in blood sugar control and consequently in type 2 diabetes. Thus, we systematically reviewed the preclinical evidences on the impact of the amount and type of carbohydrate found in different diets and its influence on blood glucose levels in diabetic animals. We used a comprehensive and structured search in biomedical databases Medline (PubMed), Scopus and Web of Science, recovering and analyzing 27 original studies. Results showed that sucrose-rich diets deteriorated diabetic condition in animal models regardless of the total dietary carbohydrate content. On the other hand, fiber, particularly resistant starch, improved blood glucose parameters through direct and indirect mechanisms, such as delayed gastric emptying and improved gut microbiota. All studies used rodents as animal models and male animals were preferred over females. Improvements in T2DM parameters in animal models were more closely related to the type of dietary carbohydrate than to its content on a diet, i. e., resistant starch seems to be the most beneficial source for maintaining normoglycemia. Results show that current literature is at high risk of bias due to neglecting experimental methods.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Carboidratos da Dieta/análise , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Dieta/métodos , Carboidratos da Dieta/metabolismo , Fibras na Dieta/metabolismo , Sacarose na Dieta/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Masculino , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue
3.
Life Sci ; 256: 117969, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553926

RESUMO

AIMS: Cannabinoids are the chemical compounds with a high affinity for cannabinoid receptors affecting the central nervous system through the release of neurotransmitters. However, the current knowledge related to the role of such compounds in the regulation of cellular aging is limited. This study aimed to investigate the effect of cannabidiol and tetrahydrocannabinol on the function of aged pancreatic islets. MAIN METHODS: The expression of p53, p38, p21, p16, and Glut2 genes and ß-galactosidase activity were measured as hallmarks of cell aging applying real-time PCR, ELISA, and immunocytochemistry techniques. Pdx1 protein expression, insulin release, and oxidative stress markers were compared between young and aged rat pancreatic islet cells. KEY FINDINGS: Upon the treatment of aged pancreatic islets cells with cannabidiol and tetrahydrocannabinol, the expression of p53, p38, p21 and the activity of ß-galactosidase were reduced. Cannabidiol and tetrahydrocannabinol increase insulin release, Pdx1, Glut2, and thiol molecules expression, while the oxidative stress parameters were decreased. The enhanced expression of Pdx1 and insulin release in aged pancreatic islet cells reflects the extension of cell healthy aging due to the significant reduction of ROS. SIGNIFICANCE: This study provides evidence for the involvement of cannabidiol and tetrahydrocannabinol in the oxidation process of cellular aging.


Assuntos
Canabinoides/farmacologia , Senescência Celular , Ilhotas Pancreáticas/citologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Biomarcadores/metabolismo , Canabidiol/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Dronabinol/farmacologia , Proteínas de Homeodomínio/metabolismo , Secreção de Insulina/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transativadores/metabolismo
4.
Diabetes Metab Syndr ; 14(4): 519-520, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32388332

RESUMO

BACKGROUND AND AIMS: Administration of corticosteroids is common in obstetric practice. In this concise review we queried on the effects of corticosteroids in pregnancies complicated by SARS-CoV-2. METHODS: We performed a literature search on PubMed, regarding the use of corticosteroids in patients with SARS-CoV-2 infection, in pregnancies complicated by SARS-CoV-2, as well as their impact on glycemia in pregnant women with or without diabetes. Furthermore, we searched for effects of SARS-CoV-2 and of other coronaviridae on insulin secretion and glycemia. RESULTS: SARS-CoV-2 infection appears to be a risk factor for complications in pregnancy. Corticosteroids may not be recommended for treating SARS-CoV-2 pneumonia but they may be needed for at-risk pregnancies. Corticosteroids in pregnancy have a diabetogenic potential. SARS-CoV-2 and other coronaviridae may have effects on glycemia. CONCLUSIONS: Caution should be exercised while using corticosteroids in pregnant women with COVID-19 requiring preterm delivery.


Assuntos
Corticosteroides/farmacologia , Infecções por Coronavirus/complicações , Diabetes Mellitus/fisiopatologia , Hiperglicemia/patologia , Hipoglicemia/patologia , Pneumonia Viral/complicações , Complicações Infecciosas na Gravidez/patologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Feminino , Homeostase , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hipoglicemia/etiologia , Hipoglicemia/metabolismo , Secreção de Insulina/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/etiologia , Complicações Infecciosas na Gravidez/metabolismo
5.
Gene ; 746: 144649, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32251702

RESUMO

BACKGROUND: Studies have shown that vitamin D can enhance glucose-stimulated insulin secretion (GSIS) and change the expression of genes in pancreatic ß-cells. Still the mechanisms linking vitamin D and GSIS are unknown. MATERIAL AND METHODS: We used an established ß-cell line, INS1E. INS1E cells were pre-treated with 10 nM 1,25(OH)2vitamin D or 10 nM 25(OH)vitamin D for 72 h and stimulated with 22 mM glucose for 60 min. RNA was extracted for gene expression analysis. RESULTS: Expression of genes affecting viability, apoptosis and GSIS changed after pre-treatment with both 1,25(OH)2vitamin D and 25(OH)vitamin D in INS1E cells. Stimulation with glucose after pre-treatment of INS1E cells with 1,25(OH)2vitamin D resulted in 181 differentially expressed genes, whereas 526 genes were differentially expressed after pre-treatment with 25(OH)vitamin D. CONCLUSION: Vitamin D metabolites may affect pancreatic ß-cells and GSIS through changed gene expression for genes involved in ß-cell function and viability.


Assuntos
Apoptose , Regulação da Expressão Gênica/efeitos dos fármacos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Vitamina D/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Ratos , Vitamina D/farmacocinética , Vitamina D/farmacologia
6.
Am J Chin Med ; 48(3): 615-629, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329641

RESUMO

Mitochondrial metabolism plays a crucial role in insulin resistance and insulin secretion in type 2 diabetes mellitus (T2D). Some studies have focused on how Cassia tora extracts affect insulin resistance and hyperglycemia. However, the effects of Cassia tora extracts on mitochondrial dysfunction associated with insulin secretion have not been well explained. In this study, well-known effective compounds extracted from Cassia tora using 70% ethanol were administered to a high-fat diet (HFD) fed mouse to examine the effects of Cassia tora ethanolic extracts (CSEE) on mitochondrial dysfunction in the pancreas. Furthermore, we examined how CSEE regulates the basal mechanism of insulin secretion through mitochondrial functions. Our experimental data suggest that pancreatic mitochondrial metabolism in HFD mice is enhanced to compensate for constrained glucose consumption. HFD-fed mice treated with CSEE showed improved pancreatic mitochondrial functions resulting in alleviation of insulin resistance at target tissue as well as basal hyperinsulinemia.


Assuntos
Cassia/química , Glucose/metabolismo , Mitocôndrias/metabolismo , Pâncreas , Extratos Vegetais/farmacologia , Animais , Dieta Hiperlipídica , Hiperglicemia/tratamento farmacológico , Hiperinsulinismo/tratamento farmacológico , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Camundongos , Fitoterapia , Extratos Vegetais/uso terapêutico
7.
PLoS One ; 15(3): e0224344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176701

RESUMO

A key event in the development of both major forms of diabetes is the loss of functional pancreatic islet ß-cell mass. Strategies aimed at enhancing ß-cell regeneration have long been pursued, but methods for reliably inducing human ß-cell proliferation with full retention of key functions such as glucose-stimulated insulin secretion (GSIS) are still very limited. We have previously reported that overexpression of the homeobox transcription factor NKX6.1 stimulates ß-cell proliferation, while also enhancing GSIS and providing protection against ß-cell cytotoxicity through induction of the VGF prohormone. We developed an NKX6.1 pathway screen by stably transfecting 832/13 rat insulinoma cells with a VGF promoter-luciferase reporter construct, using the resultant cell line to screen a 630,000 compound chemical library. We isolated three compounds with consistent effects to stimulate human islet cell proliferation, but not expression of NKX6.1 or VGF, suggesting an alternative mechanism of action. Further studies of the most potent of these compounds, GNF-9228, revealed that it selectively activates human ß-cell relative to α-cell proliferation and has no effect on δ-cell replication. In addition, pre-treatment, but not short term exposure of human islets to GNF-9228 enhances GSIS. GNF-9228 also protects 832/13 insulinoma cells against ER stress- and inflammatory cytokine-induced cytotoxicity. GNF-9228 stimulates proliferation via a mechanism distinct from recently emergent DYRK1A inhibitors, as it is unaffected by DYRK1A overexpression and does not activate NFAT translocation. In conclusion, we have identified a small molecule with pleiotropic positive effects on islet biology, including stimulation of human ß-cell proliferation and insulin secretion, and protection against multiple agents of cytotoxic stress.


Assuntos
Proliferação de Células/efeitos dos fármacos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulinoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Glucose/farmacologia , Proteínas de Homeodomínio/metabolismo , Humanos , Células Secretoras de Insulina/patologia , Insulinoma/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Ratos
8.
Oxid Med Cell Longev ; 2020: 8565760, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32148658

RESUMO

Catharanthus roseus (C. roseus) and ursolic acid (UA) are ayurvedic medicines with multiple pharmacological activities including antidiabetic activity, but till date, no study is available on their combination. This study documented the antidiabetic efficacy of the combination of C. roseus and UA in rats. Rats were divided into six groups. All groups were given a single dose of Streptozotocin (STZ) at a dose of 50 mg/kg by intraperitoneal route for induction of diabetes, except the normal control group. Group 1 was treated as a normal control (NC) group and fed with saline water, Group 2 as a Diabetes Control group, Group 3 as a STZ+C. roseus ethanolic extract (CREE) group at 50 mg/kg p.o., Group 4 as a STZ+UA group orally at 50 mg/kg, Group 5 as a STZ+CREE (25 mg/kg p.o.)+UA (25 mg/kg p.o.) group, and Group 6 as a STZ+Glimepiride (0.1 mg/kg) group. Diabetes was confirmed after 72 hours by estimation of blood glucose level, and then treatment was given for the next 28 days. During the course of treatment, plasma insulin and blood glucose were measured regularly at the interval of 7 days. At the end of the protocol, blood was collected and animals were sacrificed. The glucose level, insulin level, liver glycogen storage level, and antioxidant enzymes (LPO, CAT, SOD, GPx, GST) were measured. The blood glucose level in Group 5 significantly (P < 0.001) reduced to 98.35 ± 2.45 mg/dl in comparison with that in Group 2 (321.75 ± 5.46 mg/dl). The level of plasma insulin in Group 5 increased (13.65 ± 0.10 µU/ml) significantly (P < 0.01) as compared with that in Group 2 (05.93 ± 0.31 µU/ml). In Group 5, the level of glycogen in liver was significantly (P < 0.01) increased as compared with that in Group 2 rats. The level of antioxidant enzymes in Group 5 restored toward normal values significantly (P < 0.01; P < 0.001) as compared with that in Group 2 animals. These findings suggest that low-dose combination of CREE and UA is effective in the treatment of diabetes.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Catharanthus/química , Diabetes Mellitus Experimental/tratamento farmacológico , Flores/química , Glicogênio/metabolismo , Secreção de Insulina/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Humanos , Masculino , Ratos , Ratos Wistar , Triterpenos/farmacologia
9.
Nat Biomed Eng ; 4(5): 499-506, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32015407

RESUMO

Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced ß-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm2). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose-boronate complexes that-owing to their increased negative charge-induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery.


Assuntos
Glicemia/metabolismo , Insulina/farmacologia , Adesivo Transdérmico , Animais , Diabetes Mellitus Experimental/sangue , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Humanos , Secreção de Insulina/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Agulhas , Suínos , Porco Miniatura
10.
J Med Chem ; 63(6): 2958-2973, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32077280

RESUMO

Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).


Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Indóis/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Compostos Aza/farmacocinética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Indóis/farmacocinética , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
11.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 13-17, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31950783

RESUMO

Objective: To investigate the effects of Akkermansia muciniphila ( A. muciniphila) on the proliferation, apoptosis and insulin secretion of rat pancreatic islet cell tumor cells (INS-1). Methods: INS-1 cells were divided into three groups, normal, repair, and protect groups, and subsequently every group was subjected with A. muciniphila metabolites, live A. muciniphilaorpasteurized A. muciniphila for 48 h. A group that did not treat with anything was set as blank control. After intervention, the cell viability was determined by MTT method, the insulin secretion level stimulated by glucose was determined by ELISA, the expressions of the genes involved in insulin secretion and apoptosis were tested by qRT-PCR, and the expression of apoptosis related protein Bax was evaluated by Western blot. Results: There was no significant change in INS-1 cell morphology after co-incubation with 3 types of A. Muciniphila interventions for 48 h. The proliferative activity of INS-1 cells was decreased in the repair group that treated with live A. muciniphila than that of control ( P<0.005). A. muciniphila intervention had no effect on insulin secretion in INS-1 cells in normal, repair or protection group ( P>0.05). A. muciniphila secretions promoted the expression of glucose transporter 2 ( Glut2) in 3 groups and the expression of glucokinase ( GCK) in repair group ( P<0.05). The expression of Baxof the INS-1 cell in the normal group was decreased after intervented with 3 kinds of A. muciniphila intervention materials ( P<0.001).The expression of Bax gene of the INS-1 cell in the repair group that treated with dead A. muciniphilawas decreased ( P<0.05). The expression of Bax protein of INS-1 cells that treated with A. muciniphila interventions was decreased. Conclusion: A. muciniphila can promote the expression of insulin secretion-related genes in INS-1 cells, inhibit the expression of apoptotic genes and apoptosis protein Bax.This research provides a new direction for applying A. muciniphila in improving type 2 diabetes.


Assuntos
Adenoma de Células das Ilhotas Pancreáticas , Apoptose , Diabetes Mellitus Tipo 2 , Secreção de Insulina , Probióticos , Verrucomicrobia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Ratos , Verrucomicrobia/fisiologia
12.
Am J Physiol Endocrinol Metab ; 318(3): E430-E439, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961705

RESUMO

Chronic exposure to high concentrations of stearic acid (C18:0) can result in ß-cell dysfunction, leading to development of type 2 diabetes. However, the molecular mechanisms underlying the destructive effects of stearic acid on ß-cells remain largely unknown. In this study, we aimed to investigate the role of miR-297b-5p on stearic acid-induced ß-cell apoptosis. Differential expression of microRNAs (miRNAs) was assessed in a ß-TC6 cell line exposed to stearic acid, palmitic acid, or a normal culture medium by high-throughput sequencing. The apoptosis rate was measured by flow cytometry after miR-297b-5p mimic/inhibitor transfection, and large-tumor suppressor kinase 2 (LATS2) was identified as a target of miR-297b-5p using a luciferase activity assay. In vivo, C57BL/6 mice were fed with normal and high-stearic-acid diet, respectively. Mouse islets were used for similar identification of miR-297b-5p and Lats2 in ß-TC6 cell. We selected two differentially expressed miRNAs in stearic acid compared with those in the palmitic acid and control groups. miR-297b-5p expression was significantly lower in ß-TC6 cells and mouse islets in stearic acid than in control group. Upregulation of miR-297b-5p alleviated the stearic acid-induced cell apoptosis and reduction in insulin secretion by inhibiting Lats2 expression in vitro. Meanwhile, silencing Lats2 significantly reversed the stearic acid-stimulated ß-cell dysfunction in both ß-TC6 cells and islets. Our findings indicate a suppressive role for miR-297b-5p in stearic acid-induced ß-cell apoptosis, which may reveal a potential target for the treatment of ß-cell dysfunction in the pathogenesis of type 2 diabetes.


Assuntos
Apoptose/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/genética , Ácidos Esteáricos/farmacologia , Proteínas Supressoras de Tumor/genética , Animais , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/sangue , Citometria de Fluxo , Humanos , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido Palmítico/metabolismo , Regulação para Cima/efeitos dos fármacos
13.
Am J Physiol Endocrinol Metab ; 318(3): E392-E404, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31910030

RESUMO

In adipose, insulin functions to suppress intracellular lipolysis and secretion of nonesterified fatty acid (NEFA) into plasma. We applied glucose and NEFA minimal models (MM) following a frequently sampled intravenous glucose tolerance test (FSIVGTT) to assess glucose-specific and NEFA-specific insulin resistance. We used total NEFA and individual fatty acids in the NEFA MM, comparing the model parameters in metabolic syndrome (MetSyn) subjects (n = 52) with optimally healthy controls (OptHC; n = 14). Results are reported as mean difference (95% confidence interval). Using the glucose MM, MetSyn subjects had lower [-73% (-82, -57)] sensitivity to insulin (Si) and higher [138% (44, 293)] acute insulin response to glucose (AIRg). Using the NEFA MM, MetSyn subjects had lower [-24% (-35, -13)] percent suppression, higher [32% (15, 52)] threshold glucose (gs), and a higher [81% (12, 192)] affinity constant altering NEFA secretion (ϕ). Comparing fatty acids, percent suppression was lower in myristic acid (MA) than in all other fatty acids, and the stearic acid (SA) response was so unique that it did not fit the NEFA MM. MA and SA percent of total were increased at 50 min after glucose injection, whereas oleic acid (OA) and palmitic acid (PA) were decreased (P < 0.05). We conclude that the NEFA MM, as well as the response of individual NEFA fatty acids after a FSIVGTT, differ between OptHC and MetSyn subjects and that the NEFA MM parameters differ between individual fatty acids.


Assuntos
Ácidos Graxos não Esterificados/metabolismo , Hiperglicemia/metabolismo , Hipoglicemia/metabolismo , Resistência à Insulina , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Feminino , Glucose/farmacologia , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina/efeitos dos fármacos , Lipídeos/sangue , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade
14.
Environ Health Perspect ; 128(1): 16001, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31898917

RESUMO

BACKGROUND: The prevalence of type 2 diabetes (T2D) has more than doubled since 1980. Poor nutrition, sedentary lifestyle, and obesity are among the primary risk factors. While an estimated 70% of cases are attributed to excess adiposity, there is an increased interest in understanding the contribution of environmental agents to diabetes causation and severity. Arsenic is one of these environmental chemicals, with multiple epidemiology studies supporting its association with T2D. Despite extensive research, the molecular mechanism by which arsenic exerts its diabetogenic effects remains unclear. OBJECTIVES: We conducted a literature search focused on arsenite exposure in vivo and in vitro, using relevant end points to elucidate potential mechanisms of oral arsenic exposure and diabetes development. METHODS: We explored experimental results for potential mechanisms and elucidated the distinct effects that occur at high vs. low exposure. We also performed network analyses relying on publicly available data, which supported our key findings. RESULTS: While several mechanisms may be involved, our findings support that arsenite has effects on whole-body glucose homeostasis, insulin-stimulated glucose uptake, glucose-stimulated insulin secretion, hepatic glucose metabolism, and both adipose and pancreatic ß-cell dysfunction. DISCUSSION: This review applies state-of-the-science approaches to identify the current knowledge gaps in our understanding of arsenite on diabetes development. https://doi.org/10.1289/EHP4517.


Assuntos
Arsênico/toxicidade , Glicemia/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Homeostase/efeitos dos fármacos , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/epidemiologia , Exposição Ambiental , Humanos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos
15.
Int J Mol Med ; 45(1): 23-32, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31939616

RESUMO

Insulin secretion from pancreatic ß­cells regulates glucose metabolism and is related to various diseases including diabetes. The late endosomal/lysosomal adaptor MAPK and mTOR activator 1 (LAMTOR1) is one of the subunits of the 'Ragulator' complex and plays an important role in energy metabolism including glucose metabolism. The present study was designed to explore the role of LAMTOR1 in murine pancreatic ß­cell function. A murine model with ß cell­specific deficiency (ßLamtor1­KO) was generated to assess ß­cell function (insulin sensitivity paired with ß­cell responses) by hyperglycemic clamp in vivo. Islet perfusion and mitochondrial functional analyses were performed to investigate the individual steps in the insulin secretion pathway. Results showed that glucose tolerance in vivo as well as glucose­stimulated insulin secretion in the hyperglycemic clamp and islet perfusion were higher in ßLamtor1­KO mice compared to the control models. Although mitochondrial dysfunction was present, the deletion of Lamtor1 increased glutamate content in the mouse insulin granules as well as acetyl­CoA carboxylase 1 (ACC1) activity thus enhancing insulin secretion. Together, our data indicate that LAMTOR1 is important for maintaining mitochondrial function in mouse pancreatic ß­cells, however deletion of Lamtor1 increases the amplification pathway induced by glutamate and ACC1, ultimately leading to increased insulin secretion. These findings suggest that knockout of Lamtor1 is a potential technique for improving pancreatic ß­cell function and treating diabetes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Glucose/farmacologia , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Acetil-CoA Carboxilase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Deleção de Genes , Teste de Tolerância a Glucose , Glutamatos/metabolismo , Insulina/biossíntese , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Modelos Biológicos
16.
J Endocrinol ; 245(1): 1-12, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31977312

RESUMO

The well-documented hormonal disturbance in a general obese population is characterised by an increase in insulin secretion and a decrease in growth hormone (GH) secretion. Such hormonal disturbance promotes an increase in fat mass, which deteriorates obesity and accelerates the development of insulin resistance and type 2 diabetes. While the pathological consequence is alarming, the pharmaceutical approach attempting to correct such hormonal disturbance remains limited. By applying an emerging anti-diabetic drug, the sodium-glucose cotransporter 2 inhibitor, dapagliflozin (1 mg/kg/day for 10 weeks), to a hyperphagic obese mouse model, we observed a significant improvement in insulin and GH secretion as early as 4 weeks after the initiation of the treatment. Restoration of pathological disturbance of insulin and GH secretion reduced fat accumulation and preserved lean body mass in the obese animal model. Such phenotypic improvement followed with concurrent improvements in glucose and lipid metabolism, insulin sensitivity, as well as the expression of metabolic genes that were regulated by insulin and GH. In conclusion, 10 weeks of treatment with dapagliflozin effectively reduces hyperinsulinemia and restores pulsatile GH secretion in the hyperphagic obese mice with considerable improvement in lipid and glucose metabolism. Promising outcomes from this study may provide insights into drug intervention to correct hormonal disturbance in obesity to delay the diabetes progression.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Hormônio do Crescimento/metabolismo , Secreção de Insulina/efeitos dos fármacos , Insulina/metabolismo , Obesidade/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Resistência à Insulina , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
17.
Biochem Biophys Res Commun ; 524(1): 22-27, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31980171

RESUMO

The occurrence of type 2 diabetes(T2D) increases with age. The platelet-derived growth factor (PDGF) is one of the key factors regulating ß cell proliferation and function, but the contribution of PDGF signaling in ß cells aging and senescence remains unexplored. Here, we showed that the level of both serum and tissue PDGF-AA decreased with age, and the serum PDGF-AA level was positively correlated with ß cell proliferation and function in aging. The decline of PDGF-AA level in aging was partly due to decreased number as well as secretion of osteoblast lineage cells in bone tissue. Conditioned medium from osteoblast lineage cells induced insulinoma ß cells proliferation and insulin secretion in vitro, while addition of PDGF-AA neutralizing antibody attenuated this effect. Transplantation of juvenile osteoblast lineage cells increased serum PDGF-AA level and promoted ß cell proliferation and function in aging mice, which eventually resulted in better glucose tolerance. Taken together, these findings revealed the role of decreased bone-derived PDGF-AA in mediating the disrupted proliferation and function of ß cells in aging.


Assuntos
Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores Etários , Animais , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Osteoblastos/citologia , Osteoblastos/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Transplantes
18.
Expert Opin Ther Pat ; 30(1): 27-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31771391

RESUMO

Introduction: The activation of free fatty acid receptor 1 (FFAR1) induces insulin secretion in a glucose-dependent manner, and thereby is considered as an attractive anti-diabetic target. The clinical studies provided a lot of evidence that FFAR1 agonists improved glucose control in T2DM without the risk of hypoglycemia. The field of FFAR1 agonists is extremely competitive with many patent applications filed in recent years identifying potent candidates.Area covered: The present review summarizes patent applications (2016-2019) filing for FFAR1 modulators, including FFAR1 partial/full agonists, atypical agonists, and multiple target agonists, along with in vitro and in vivo evaluation.Expert opinion: The clinical studies of FFAR1 agonists have proved their potential for the improvement of glucose control. However, there are a few issues still to be solved in this field since TAK-875 terminated in Phase III studies due to liver toxicity. The biggest challenge on the development of FFAR1 agonists may not be the identification of a highly potent compound, but finding out the exact mechanisms of hepatotoxicity and avoid it. Moreover, the further exploration of chemical spaces on FFAR1 full agonists and multi-targeted agonists, as well as corresponding clinical studies, will be expected and might open up new directions in this field.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Benzofuranos/efeitos adversos , Benzofuranos/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Patentes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Sulfonas/efeitos adversos , Sulfonas/farmacologia
19.
Am J Physiol Endocrinol Metab ; 318(2): E189-E197, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31743041

RESUMO

Glucagon-like peptide-1 (GLP-1) is an enteral peptide that contributes to the incretin effect. GLP-1 action is typically described as endocrine, but this mechanism has been questioned because rapid inactivation in the circulation by dipeptidylpeptidase 4 (DPP4) results in a short half-life, limiting the amount of the hormone that can reach the pancreatic islet. An alternative mechanism for GLP-1 to regulate insulin secretion through neuroendocrine signaling originating from sensors in the portal vein has been proposed. We hypothesized that portal infusion of GLP-1 would cause greater glucose-stimulated insulin secretion than equimolar administration into the jugular vein. To test this, hyperglycemic clamps with superimposed graded infusions of GLP-1 into the jugular or portal veins of male rats were performed. These experiments were repeated with pharmacologic DPP4 inhibition to determine the effect of GLP-1 metabolism in the jugular and portal venous beds. Contrary to our hypothesis, we found a higher insulinotropic effect with jugular compared with portal GLP-1, which was associated with higher plasma concentrations of intact GLP-1. The greater insulinotropic effect of jugular venous GLP-1 persisted even with pharmacological DPP4 inhibition. These findings do not support an important role of portal vein GLP-1 signaling for the incretin effect but highlight the hepatoportal bed as a major site of GLP-1 degradation that persists even with pharmacological inhibition. Together, these results support rapid inactivation of enterally released GLP-1 in the liver as limiting endocrine actions on the ß-cell and raise questions about the conventional endocrine model of pharmacologic effects of DPP4 inhibitors.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/farmacologia , Fígado/metabolismo , Animais , Dipeptidil Peptidase 4/metabolismo , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucose/farmacologia , Técnica Clamp de Glucose , Injeções Intravenosas , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Veias Jugulares , Masculino , Veia Porta , Ratos , Ratos Long-Evans
20.
Phytochemistry ; 170: 112213, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31786408

RESUMO

Clutia lanceolata Forssk. (C. lanceolata) is a medicinal plant native to sub-Saharan Africa and the Arabian Peninsula. Phytochemical investigation of the aerial parts of C. lanceolata yielded twenty-one coumarins including methylthio and methylsulfinyl-coumarins. Thirteen of these compounds are reported here for the first time, named as cluteolin A to M. The remaining eight compounds are known but have not been associated previously with C. lanceolata. The structures of the undescribed compounds were elucidated from their 2D NMR and MS spectra. Single crystal X-ray analyses confirmed the structures of eleven compounds. As, in Saudi Arabian tradition, C. lanceolata has been reported to have anti-diabetic and anti-fungal properties, the coumarins were examined for their biological activity. Seven compounds strongly enhanced the glucose-triggered release of insulin by murine pancreatic islets, with two compounds showing more than two-fold enhancement of insulin secretion, compared with the standard drug glimepiride.


Assuntos
Cumarínicos/farmacologia , Euphorbiaceae/química , Secreção de Insulina/efeitos dos fármacos , Insulina/metabolismo , Compostos Fitoquímicos/farmacologia , Enxofre/farmacologia , Animais , Cumarínicos/química , Cumarínicos/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Arábia Saudita , Enxofre/química , Enxofre/isolamento & purificação
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