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1.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673206

RESUMO

Type 2 diabetes (T2D) is one of the prominent causes of morbidity and mortality in the United States and beyond, reaching global pandemic proportions. One hallmark of T2D is dysfunctional glucose-stimulated insulin secretion from the pancreatic ß-cell. Insulin is secreted via the recruitment of insulin secretory granules to the plasma membrane, where the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and SNARE regulators work together to dock the secretory granules and release insulin into the circulation. SNARE proteins and their regulators include the Syntaxins, SNAPs, Sec1/Munc18, VAMPs, and double C2-domain proteins. Recent studies using genomics, proteomics, and biochemical approaches have linked deficiencies of exocytosis proteins with the onset and progression of T2D. Promising results are also emerging wherein restoration or enhancement of certain exocytosis proteins to ß-cells improves whole-body glucose homeostasis, enhances ß-cell function, and surprisingly, protection of ß-cell mass. Intriguingly, overexpression and knockout studies have revealed novel functions of certain exocytosis proteins, like Syntaxin 4, suggesting that exocytosis proteins can impact a variety of pathways, including inflammatory signaling and aging. In this review, we present the conventional and unconventional functions of ß-cell exocytosis proteins in normal physiology and T2D and describe how these insights might improve clinical care for T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Exocitose , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Proteínas SNARE/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/genética , Células Secretoras de Insulina/patologia , Proteínas SNARE/genética , Transdução de Sinais
2.
Ars pharm ; 62(1): 52-65, ene.-mar. 2021. tab, graf
Artigo em Inglês | IBECS | ID: ibc-199700

RESUMO

INTRODUCTION: The prevalence of diabetes type 2 is increasing worldwide, thus the search of novel alternative ther¬apies is needed. According to their traditional use, we selected five Bolivian plants Chenopodium quinoa (CQ) Ama¬ranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) and Smallanthus sonchifolius (SS) that are traditionally used to control glycemia. METHODS: The effect of a single oral administration of Ethanolic (EtOH), hydro-ethanolic (EtOH70) and aqueous (Aq) extracts from all plant species were tested for their effect on blood glucose in non-fasted mice and during the oral glucose tolerance test (OGTT). The effect on insulin secretion was evaluated in mice pancreatic islets. RESULTS: EtOH70 extracts of all the plants showed glucose-reducing effect at the highest dose evaluated (2000 mg/ kg b.w.). EtOH70 extracts improved the glucose tolerance evaluated by the OGTT in mice fasted for 12 hours. The extracts have different effects on glucose homeostasis since just extracts of AC, LM and CQ but not CP and SS in¬creased insulin secretion as shown on mice pancreatic islets. The phytochemical qualitative characterization of EtOH70 extracts detected phenolic acids and flavonoids in AC, CP and CQ; alkaloids in LM and anthocyanidins in SS. None of EtOH70 extracts tested showed in vitro or in vivo acute toxicity at concentrations where they exhibit glucose lowering effects. CONCLUSIONS: We report here that extracts from AC, CQ, CP, LM and SS exhibit glucose lowering effect while just AC, CQ and LM stimulate directly the insulin secretion


INTRODUCCIÓN: La prevalencia de diabetes tipo 2 está aumentando en todo el mundo, por lo que se necesita la búsqueda de nuevas terapias alternativas. Según su uso tradicional, seleccionamos cinco plantas bolivianas Chenopodium quinoa (CQ) Amaranthus caudatus (AC), Chenopodium pallidicaule (CP), Lupinus mutabilis (LM) y Smallanthus sonchifolius (SS) que se usan tradicionalmente para controlar la glucemia. MÉTODOS: Se evaluó el efecto de la administración oral única de extractos etanólicos (EtOH), hidroetanólicos (EtOH70) y acuosos (Aq) de las plantas mencionadas para determinar su efecto sobre la glucosa en sangre en ratones en o sin ayunas y durante la prueba de tolerancia a la glucosa oral (PTGO). El efecto sobre la secreción de insulina se evaluó en islotes pancreáticos de ratones. RESULTADOS: Los extractos de EtOH70 de todas las plantas disminuyeron la glucemia a la dosis más alta evaluada (2000 mg / kg b.w.). Los extractos de EtOH70 mejoraron la tolerancia a la glucosa evaluada mediante la PTGO en ratones con ayuno de 12 horas. Los extractos tienen diferentes efectos sobre la homeostasis de la glucosa, ya que solo los extractos de AC, LM y CQ pero no CP y SS aumentaron la secreción de insulina como se muestra en los islotes pancreáticos de los ratones. La caracterización cualitativa fitoquímica de extractos de EtOH70 detectó ácidos fenólicos y flavonoides en AC, CP y CQ, alcaloides en LM y antocianidinas en SS. Ninguno de los extractos de EtOH70 probados mostró toxicidad aguda in vitro o in vivo a concentraciones en las que exhiben efectos reductores de glucosa. CONCLUSIÓN: Los extractos de AC, CQ, CP, LM y SS exhiben un efecto reductor de la glucosa, mientras que solo AC, CQ y LM estimulan directamente la secreción de insulina


Assuntos
Animais , Masculino , Camundongos , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Secreção de Insulina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Suplementos Nutricionais , Chenopodium quinoa/química , Amaranthus/química , Chenopodium/química , Lupinus/química , Ilhotas Pancreáticas/efeitos dos fármacos , Fatores de Tempo , Valores de Referência , Reprodutibilidade dos Testes , Bolívia , Teste de Tolerância a Glucose
3.
Molecules ; 26(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572808

RESUMO

Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic ß-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Polifenóis/uso terapêutico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Hormônios Gastrointestinais/genética , Peptídeo 1 Semelhante ao Glucagon/genética , Humanos , Secreção de Insulina/genética , Células Secretoras de Insulina/patologia
4.
Medicine (Baltimore) ; 100(5): e24061, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592858

RESUMO

ABSTRACT: Irisin, a novel myokine, is believed to be the crucial factor in converting white adipose tissue to beige adipose tissue. For this paper, we studied the relationship among irisin and components of metabolic syndrome (MetS), and insulin secretion and resistance in schoolchildren of Taiwan.Subjects receiving routine annual health examination at elementary school were enrolled. Demographic data, anthropometry, MetS components, irisin, and insulin secretion and resistance were collected. Subjects were divided into normal, overweight, and obese groups for evaluation of irisin in obesity. Finally, the relationship between irisin and MetS was analyzed.There were 376 children (179 boys and 197 girls), aged 10.3 ±â€Š1.5 years, were enrolled. In boys, irisin levels were not associated with body mass index percentile, body fat, blood pressure, lipid profiles, insulin secretion or resistance. After adjusting for age, the irisin level in boys was negatively related to fasting plasma glucose (FPG) (r = -0.21, P = .006). In girls, after adjusting for age, the irisin levels were positively related only to FPG (r = 1.49, P = .038). In both genders, irisin levels were similar among normal, overweight, and obese groups, and between subjects with and without MetS.The irisin levels were not associated with MetS in either boys or girls. In girls, circulating irisin levels have a nonsignificant declining trend in overweight and obese girls. However, irisin levels were negatively related to FPG in boys and positively related to FPG in girls. The contrary relationship between irisin and FPG in boys and girls needs further exploration.


Assuntos
Tecido Adiposo/metabolismo , Fibronectinas , Secreção de Insulina/fisiologia , Insulina , Síndrome Metabólica , Sobrepeso , Antropometria/métodos , Determinação da Pressão Arterial/métodos , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Fibronectinas/sangue , Fibronectinas/metabolismo , Humanos , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/metabolismo , Sobrepeso/diagnóstico , Sobrepeso/epidemiologia , Sobrepeso/metabolismo , Serviços de Saúde Escolar/estatística & dados numéricos , Taiwan/epidemiologia
5.
Nat Commun ; 12(1): 1064, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594056

RESUMO

Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment.


Assuntos
Síndrome do Ovário Policístico/patologia , Adiposidade , Animais , Animais Recém-Nascidos , Peso Corporal , Análise Discriminante , Modelos Animais de Doenças , Dislipidemias/patologia , Sistema Endócrino/patologia , Ciclo Estral , Feminino , Teste de Tolerância a Glucose , Gonadotropinas/farmacologia , Hormônios/sangue , Humanos , Secreção de Insulina , Análise dos Mínimos Quadrados , Lipídeos/química , Masculino , Troca Materno-Fetal , Análise Multivariada , Ovário/patologia , Ovário/fisiopatologia , Fenótipo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Ratos Wistar , Reprodução , Maturidade Sexual
6.
Adv Exp Med Biol ; 1275: 195-227, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33539017

RESUMO

Type 2 diabetes (T2D) is a worldwide serious public health problem. Insulin resistance and ß-cell failure are the two major components of T2D pathology. In addition to defective endoplasmic reticulum (ER) stress signaling due to glucolipotoxicity, ß-cell dysfunction or ß-cell death initiates the deleterious vicious cycle observed in T2D. Although the primary cause is still unknown, overnutrition that contributes to the induction of the state of low-grade inflammation, and the activation of various protein kinases-related metabolic pathways are main factors leading to T2D. In this chapter following subjects, which have critical checkpoints regarding ß-cell fate and protein kinases pathways are discussed; hyperglycemia-induced ß-cell failure, chronic accumulation of unfolded protein in ß-cells, the effect of intracellular reactive oxygen species (ROS) signaling to insulin secretion, excessive saturated free fatty acid-induced ß-cell apoptosis, mitophagy dysfunction, proinflammatory responses and insulin resistance, and the reprogramming of ß-cell for differentiation or dedifferentiation in T2D. There is much debate about selecting proposed therapeutic strategies to maintain or enhance optimal ß-cell viability for adequate insulin secretion in T2D. However, in order to achieve an effective solution in the treatment of T2D, more intensive clinical trials are required on newer therapeutic options based on protein kinases signaling pathways.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Estresse Oxidativo , Proteínas Quinases/metabolismo
7.
Adv Clin Exp Med ; 30(1): 35-40, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33529505

RESUMO

BACKGROUND: Type 2 diabetes (T2D) is known to be one of the most prevalent diseases, and its prevalence is significantly associated with age and metabolic syndrome (MetS). Few studies have been conducted on liver function, MetS and insulin secretion among young adults. OBJECTIVES: In the present study, we explored the relationship between the liver function enzyme - alanine aminotransferase (ALT) - and first-phase insulin secretion (FPIS) among young adults. MATERIAL AND METHODS: There were 22,971 men and 28,740 women, aged 18-27 years, assigned to subgroups according to the presence of MetS and quartiles of ALT values. Simple correlation was applied to evaluate their relationship. The difference between the slopes of these relationships and FPIS were statistically analyzed with Chris's calculator. RESULTS: Most values for metabolic parameters, including ALT and FPIS, were determined to be relatively high in individuals with MetS. By contrast, individuals with MetS had lower high-density-lipoprotein cholesterol (HDL-C) counts and FPIS. Similar results were observed in the quartiles of ALT. Significant positive results were also found in the linear model. Depending on the ALT level, the slope change of FPIS still demonstrated a positive correlation between ALT and FPIS. This correlation was stronger for men than for women. CONCLUSIONS: A positive correlation between ALT and FPIS exists among young adults. Moreover, this correlation was stronger for men than for women. Both the cause and the effect require further investigation.


Assuntos
Resistência à Insulina , Secreção de Insulina , Síndrome Metabólica , Adolescente , Adulto , Alanina Transaminase , HDL-Colesterol , Feminino , Humanos , Masculino , Síndrome Metabólica/diagnóstico , Adulto Jovem
8.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498234

RESUMO

Diabetes mellitus now affects more than 400 million individuals worldwide, with significant impacts on the lives of those affected and associated socio-economic costs. Although defects in insulin secretion underlie all forms of the disease, the molecular mechanisms which drive them are still poorly understood. Subsets of specialised beta cells have, in recent years, been suggested to play critical roles in "pacing" overall islet activity. The molecular nature of these cells, the means through which their identity is established and the changes which may contribute to their functional demise and "loss of influence" in both type 1 and type 2 diabetes are largely unknown. Genomic imprinting involves the selective silencing of one of the two parental alleles through DNA methylation and modified imprinted gene expression is involved in a number of diseases. Loss of expression, or loss of imprinting, can be shown in mouse models to lead to defects in beta cell function and abnormal insulin secretion. In the present review we survey the evidence that altered expression of imprinted genes contribute to loss of beta cell function, the importance of beta cell heterogeneity in normal and disease states, and hypothesise whether there is a direct link between the two.


Assuntos
Diabetes Mellitus/genética , Impressão Genômica , Células Secretoras de Insulina/metabolismo , Animais , Diabetes Mellitus/metabolismo , Humanos , Secreção de Insulina , Análise de Célula Única , Transcriptoma
9.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466949

RESUMO

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic ß cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving ß cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of ß cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica , Células Secretoras de Insulina/metabolismo , MicroRNAs/genética , Animais , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Secreção de Insulina/genética , Células Secretoras de Insulina/citologia , Fenótipo
10.
Nat Commun ; 12(1): 674, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514698

RESUMO

Transcriptionally mature and immature ß-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in ß-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH ß-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH ß-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the ß-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in ß-cell maturity, might be important for the maintenance of islet function.


Assuntos
Secreção de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Técnicas de Introdução de Genes , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Fatores de Transcrição Maf Maior/genética , Fatores de Transcrição Maf Maior/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Cultura Primária de Células , Transativadores/genética , Transativadores/metabolismo
11.
J Med Chem ; 64(2): 1127-1138, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33449689

RESUMO

There is a critical unmet need for therapeutics to treat the epidemic of comorbidities associated with obesity and type 2 diabetes, ideally devoid of nausea/emesis. This study developed monomeric peptide agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y2 receptor (Y2-R) based on exendin-4 (Ex-4) and PYY3-36. A novel peptide, GEP44, was obtained via in vitro receptor screens, insulin secretion in islets, stability assays, and in vivo rat and shrew studies of glucoregulation, weight loss, nausea, and emesis. GEP44 in lean and diet-induced obese rats produced greater reduction in body weight compared to Ex-4 without triggering nausea associated behavior. Studies in the shrew demonstrated a near absence of emesis for GEP44 in contrast to Ex-4. Collectively, these data demonstrate that targeting GLP-1R and Y2-R with chimeric single peptides offers a route to new glucoregulatory treatments that are well-tolerated and have improved weight loss when compared directly to Ex-4.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose/metabolismo , Náusea/tratamento farmacológico , Receptores de Neuropeptídeo Y/agonistas , Vômito/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Animais , Ligação Competitiva , Glicemia/metabolismo , Exenatida/química , Humanos , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Peptídeo YY/química , Ratos , Ratos Sprague-Dawley , Musaranhos , Relação Estrutura-Atividade
12.
Int J Mol Sci ; 22(1)2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33401592

RESUMO

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic ß-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and ß-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on ß-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human ß-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on ß-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited ß-cell glucose-stimulated insulin secretion in vitro, stimulation of ß-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, ß-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress ß-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on ß-cell function or cell mass and, instead, early metformin treatment may help protect ß-cells from exhaustion and decompensation.


Assuntos
Glucose/farmacologia , Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Metformina/farmacologia , Estado Pré-Diabético/tratamento farmacológico , Animais , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Ratos
13.
Nat Rev Mol Cell Biol ; 22(2): 142-158, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33398164

RESUMO

Metabolic homeostasis in mammals is tightly regulated by the complementary actions of insulin and glucagon. The secretion of these hormones from pancreatic ß-cells and α-cells, respectively, is controlled by metabolic, endocrine, and paracrine regulatory mechanisms and is essential for the control of blood levels of glucose. The deregulation of these mechanisms leads to various pathologies, most notably type 2 diabetes, which is driven by the combined lesions of impaired insulin action and a loss of the normal insulin secretion response to glucose. Glucose stimulates insulin secretion from ß-cells in a bi-modal fashion, and new insights about the underlying mechanisms, particularly relating to the second or amplifying phase of this secretory response, have been recently gained. Other recent work highlights the importance of α-cell-produced proglucagon-derived peptides, incretin hormones from the gastrointestinal tract and other dietary components, including certain amino acids and fatty acids, in priming and potentiation of the ß-cell glucose response. These advances provide a new perspective for the understanding of the ß-cell failure that triggers type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Glucose/metabolismo , Homeostase , Secreção de Insulina , Células Secretoras de Insulina/fisiologia , Animais , Humanos , Células Secretoras de Insulina/citologia
14.
J Diabetes Res ; 2021: 8822702, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33490287

RESUMO

Aims: The current study aims to explore if a family history of diabetes can influence the efficiency of lifestyle intervention on insulin secretion and study the insulin resistance in Chinese men and women with metabolic syndrome in a cohort with a 2-year follow-up. Methods: 151 individuals (90 individuals did not have a family history of diabetes (DMFH (-)) and 61 with a family history of diabetes (DMFH (+)) with metabolic syndrome participated in the lifestyle intervention program at baseline and finished with 1-year follow-up. 124 individuals have two-year follow-up data. A family history of diabetes was ascertained by self-report. Lifestyle interventions were individual sessions on lifestyle changes. Results: During the 1-year follow-up, Ln Insulinogenic index (Δbaseline-1year = 0.29 ± 0.65, P = 0.001) and 30-min glucose (Δbaseline-1year = -0.41 ± 1.71, P = 0.024) changed significantly in the DMFH(-) group; in the DMFH(+) group, Ln ISIm (Δbaseline-1year = -0.22 ± 0.60, P = 0.022) and 30-min glucose (Δbaseline-1year = 0.53 ± 1.89, P = 0.032) changed significantly, and there was no significant change of other parameters. The change of 30 min glucose during a 1-year intervention has shown a significant difference between the two groups (P = 0.002). During the 2 years intervention, Ln Insulinogenic index changed significantly in the DMFH(-) group (Δbaseline-1year = 0.33 ± 0.66, P < 0.001 and Δbaseline-2year = 0.43 ± 1.17, P = 0.034). Fasting insulin (Δbaseline-2year = 2.95 ± 8.69, P = 0.034), 2 h insulin (Δbaseline-2year = 23.75 ± 44.89, P = 0.002), Ln HOMA-B (Δbaseline-2year = 0.43 ± 1.02, P = 0.009), Ln HOMA-IR (Δbaseline-2year = 0.53 ± 1.04, P = 0.002), Ln ISIm (Δbaseline-2year = 0.52 ± 0.95, P = 0.004), and Ln Insulinogenic index (Δbaseline-2year = 0.66 ± 1.18, P = 0.047) changed significantly after 2 years of intervention, compared to the baseline in the DMFH(+) group. The change of Ln ISIm (P = 0.023), fasting (P = 0.030), and 2 h insulin (P = 0.007) during the 2-year intervention has shown a significant difference between the two groups. Family history of diabetes was related with a 0.500 unit increase in 2-year ISIm (P = 0.020) modified by lifestyle intervention adjusted for age, baseline BMI, sex, and baseline waist circumference and a 0.476 unit increase in 2-year ISIm (P = 0.027) with extra adjustment for weight change. Conclusions: Patients with a family history of diabetes benefit more from lifestyle intervention in regard to insulin resistance than those without a family history of diabetes adjusting for age, baseline BMI, sex, baseline waist circumference, and weight change.


Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Insulina/metabolismo , Anamnese , Síndrome Metabólica/terapia , Comportamento de Redução do Risco , Adulto , Idoso , China/epidemiologia , Feminino , Seguimentos , Humanos , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Estilo de Vida , Masculino , Anamnese/estatística & dados numéricos , Síndrome Metabólica/etnologia , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Life Sci ; 269: 119029, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33450256

RESUMO

AIMS: The present study aimed to disclose a potent and selective GPR120 agonist LXT34 and its anti-diabetic effects. MAIN METHODS: Calcium mobilization assay was used to measure the agonistic potency and selectivity of LXT34 in GPR120 or GPR40-overexpression Chinese hamster ovary (CHO) cells. Glucagon-like peptide-1 (GLP-1) release and glucose-stimulated insulin secretion (GSIS) were evaluated in human colonic epithelial cell line NCI-H716 and mouse insulinoma cell line MIN6 by enzyme-linked immunosorbent assay (ELISA), respectively. The anti-inflammatory effect was determined in lipopolysaccharide (LPS)-induced murine macrophage cell line RAW264.7. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed to assess the anti-diabetic effects of LXT34 in db/db mice, and chronic inflammation in liver and adipose tissues were investigated using histomorphology, immunoblot and gene expression analysis. KEY FINDINGS: LXT34 was a potent GPR120 agonist with negligible activity toward human and mouse GPR40. LXT34 could potentiate GSIS and suppress LPS-induced inflammation in macrophages. LXT34 not only markedly improved glucose tolerance and insulin resistance, but also distinctly reduced macrophages infiltration, pro-inflammatory cytokines expression and JNK phosphorylation of both liver and adipose tissues in db/db mice. SIGNIFICANCE: LXT34, a novel and potent GPR120-selective agonist, showed beneficial effects on improving glucose homeostasis in obesity-related type 2 diabetes.


Assuntos
Inflamação/patologia , Secreção de Insulina , Receptores Acoplados a Proteínas-G/agonistas , Tecido Adiposo/patologia , Animais , Doença Crônica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/farmacologia , Inflamação/sangue , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Receptores Acoplados a Proteínas-G/metabolismo
17.
Diabetes Res Clin Pract ; 172: 108627, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33333205

RESUMO

AIM: To compare zinc (Zn) and copper (Cu) levels in US adults with normoglycemia, prediabetes and diabetes, and study the association of serum Zn and Cu levels with pancreatic ß cell insulin secretion, pancreatic dysfunction and insulin resistance in US adults with normoglycemia and prediabetes. METHOD: Homeostatic Model Assessment (HOMA2) calculator was used to compute estimates of steady state ß cell insulin secretion (HOMA2-B), peripheral insulin sensitivity (HOMA2-S), insulin resistance (HOMA-IR), and disposition index (HOMA-DI) in 804 adult individuals from the National Health and Nutrition Examination Survey (NHANES 2011-2012). RESULTS: There was no significant difference between serum Zn and Cu levels among subjects with normoglycemia, prediabetes, and diabetes. After adjusting for multiple possible confounders, higher serum Zn concentrations were associated with lower ß cell insulin secretion (HOMA2-B; p = 0.01) and lower insulin resistance (HOMA-IR; p = 0.04) in the prediabetic subjects. In normoglycemic group, higher serum Zn levels were associated with improved pancreatic function (HOMA-DI; P = 0.02). On the other hand, higher serum Cu levels were associated with increased ß cell insulin secretion (HOMA2-B, P = 0.03) only in the subjects with prediabetes. CONCLUSION: These findings support the need for further studies to investigate the role of trace elements in diabetes pathogenesis.


Assuntos
Cobre/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina/fisiologia , Zinco/metabolismo , Adulto , Feminino , História do Século XXI , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Resultado do Tratamento , Estados Unidos
18.
J Ethnopharmacol ; 264: 113075, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32829055

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally plant-based remedies such as Commiphora myrrha (CM) have been used as an ayurvedic medicine to treat diabetes mellitus in some region of Arabia and Africa. Previous reports have shown that CM reduced blood glucose levels and increased insulin concentrations in animal models of diabetes in vivo. However, the exact mechanisms by which CM improved glycemic control in these animals are not fully understood. We hypothesized that CM may have a direct insulinotropic activity on ß-cells to increase insulin secretion. AIM OF THE STUDY: The direct effects of CM were investigated using MIN6 ß-cells and isolated mouse and human islets in static and perifusion insulin secretion experiments. Isolated mouse and human islets were used to investigate the rate and pattern of CM-induced insulin secretion. MATERIALS AND METHODS: The effect of CM on insulin secretion was assessed by static and perifusion experiments using MIN6 cells, a mouse-derived ß-cell line, and primary mouse and human islets. The effects of CM on cell viability and membrane integrity of MIN6 cells and mouse islets were assessed using an ATP viability assay and a trypan blue exclusion test. The mRNA expression profiles of preproinsulin and Pdx1, a major ß-cell transcription factor, were determined by quantitative RT-PCR following chronic exposure to CM. RESULTS: Exposing MIN6 cells to a CM resin solution (0.5-10 mg/ml) caused a concentration-dependent increase in insulin secretion in a static setting. Similarly, incubating mouse islets to CM (0.1-10 mg/ml) resulted in stimulation of insulin secretion in a concentration-dependent manner. CM concentrations at ≤ 2 mg/ml were not associated with reduction in cell viability nor with reduction in cell membrane integrity. However, higher concentrations of CM were accompanied with marked uptake of trypan blue dye and cell death. In a perifusion setting, CM (2 mg/ml) caused rapid and reversible increases in insulin secretion from both mouse and human islets at both sub-stimulatory and stimulatory glucose levels. The stimulatory effect of CM on insulin secretion did not change the total insulin content of ß-cells nor the mRNA expression of preproinsulin and Pdx1. CONCLUSIONS: These data indicate that aqueous CM resin solution has a direct stimulatory effect on ß-cells without compromising plasma membrane integrity. CM stimulates insulin secretion from MIN6 cells, a mouse-derived ß-cell line, and isolated primary mouse and human islets in vitro at both sub-stimulatory and stimulatory glucose concentrations. The mechanism by which CM may induce insulin secretion is most likely due to a stimulation of insulin granules release rather than insulin synthesis.


Assuntos
Commiphora , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Extratos Vegetais/farmacologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/isolamento & purificação
19.
Methods Mol Biol ; 2233: 131-138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33222132

RESUMO

The application of forward chemical genetics to insulin secretion in high-throughput has been uncommon because of high costs and technical challenges. However, with the advancement of secreted luciferase tools, it has become feasible for small laboratories to screen large numbers of compounds for effects on insulin secretion. The purpose of this chapter is to outline the methods involved in high-throughput screening for small molecules that chronically impact pancreatic beta cell function. Attention is given to specific points in the protocol that help to improve the dynamic range and reduce variability in the assay. Using this approach in 384-well format, at least 48 and as many as 144 plates can theoretically be processed per week. This protocol serves as a guideline and can be modified as required for alternate stimulation paradigms and improved upon as new technologies become available.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Antagonistas da Insulina/química , Insulina/metabolismo , Bibliotecas de Moléculas Pequenas/química , Linhagem Celular , Humanos , Insulina/isolamento & purificação , Antagonistas da Insulina/classificação , Antagonistas da Insulina/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos
20.
J Agric Food Chem ; 69(1): 212-222, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33353303

RESUMO

ι-Carrageenan performs diversified biological activities but has low bioavailability. ι-Carrageenan tetrasaccharide (ιCTs), a novel marine oligosaccharide prepared by the marine enzyme Cgi82A, was investigated for its effects on insulin resistance in high-fat and high-sucrose diet mice. Oral administration of ιCTs (ιCTs-L 30.0 mg/kg·bw, ιCTs-H 90.0 mg/kg·bw) decreased fasting blood glucose by 35.1% ± 1.41 (P < 0.01) and 27.4% ± 0.420 (P < 0.05), and enhanced glucose tolerance. Besides, ιCTs-L ameliorated islet vacuolization, decreased the ß cell apoptosis by 21.8% ± 0.200 (P < 0.05), and promoted insulin secretion by 5.41% ± 0.0173 (P < 0.01) through pancreatic hematoxylin and eosin (H&E) staining, TUNEL staining, and insulin-glucagon immunostaining analysis. Interestingly, ιCTs-L and ιCTs-H treatment increased the incretin GLP-1 content in serum by 22.1% ± 0.402 (P < 0.01) and 10.7% ± 0.0935 (P < 0.05) respectively, through regulating the bile acid levels, which contributed to the inhibition of ß cell apoptosis. Mechanically, ιCTs upregulated the expression of the GLP-1 receptor (GLP-1R) and protein kinase A (PKA) in the GLP-1/cAMP/PKA signaling pathway, and further inhibited the expression of cytochrome C and caspase 3 in the mitochondrial apoptotic pathway. In conclusion, this study suggested that ιCTs alleviated insulin resistance by GLP-1-mediated inhibition of ß cell apoptosis and proposed a new strategy for developing potential functional foods that prevent insulin resistance.


Assuntos
Apoptose/efeitos dos fármacos , Carragenina/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células Secretoras de Insulina/citologia , Mitocôndrias/efeitos dos fármacos , Oligossacarídeos/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Glicemia/metabolismo , Carragenina/química , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Oligossacarídeos/análise , Extratos Vegetais/análise , Transdução de Sinais/efeitos dos fármacos
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