RESUMO
AIM: In previous studies, the researchers observed an increase in insulin secretion in STZ-treated diabetic rats following treatment with the hydroalcoholic extract of Securigera securidaca (HESS) seeds. This study focuses on the relationship between the antioxidant properties of HESS with changes in diabetic pancreatic tissue and the gene expression of factors that impact insulin secretion. METHODS: In this controlled experimental study, three varying doses of HESS were administered to three groups of diabetic rats induced by STZ. Oxidative stress indicators like total antioxidant capacity (TAC), total oxidant status (TOS) and malondialdehyde were assessed in both pancreatic and liver tissues. Pancreatic histology was studied post-haematoxylin staining. Insulin and FGF21 levels in the blood were measured using the ELISA method. The expression of Nrf2 and FGF21 genes in the pancreas and liver, along with MafA and PDX-1 genes in the pancreas, was quantified using real-time PCR. RESULTS: The administration of HESS in varying doses led to a dose-dependent rise in blood insulin levels and a decrease in blood glucose levels and oxidative stress. By reducing oxidative stress, HESS treatment lowered the heightened levels of NRF2 and FGF21 in the liver and pancreas of diabetic rats, improving pancreatic tissue health. As oxidative stress decreased, the expression of MafA and PDX1 genes in the pancreas approached levels seen in healthy rats. CONCLUSION: HESS elicits an increase in insulin secretion through the mitigation of oxidative stress and tissue damage, as well as the modulation of gene expression related to the insulin transcription factors PDX-1 and MafA.
Assuntos
Diabetes Mellitus Experimental , Secreção de Insulina , Insulina , Extratos Vegetais , Sementes , Regulação para Cima , Animais , Extratos Vegetais/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos , Sementes/química , Secreção de Insulina/efeitos dos fármacos , Insulina/metabolismo , Masculino , Securidaca , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Fator 2 Relacionado a NF-E2/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Antioxidantes/farmacologia , Fígado/metabolismo , Transativadores , Proteínas de HomeodomínioRESUMO
Insulin resistance (IR) is a well-recognized covariate of Polycystic Ovarian Syndrome (PCOS) with varying burden and risk factors among populations. The relationship of insulin secretory defect or ISD with PCOS is less understood. The presence of IR and ISD as well as their covariates have been explored in the present case-control study among young adult to early middle-aged, normal weight to obese, Bangalee women with PCOS. A number of 158 PCOS [age 23 (15-34) years, Median (Range)] and 126 Non-PCOS [24 (19-34) years] females were recruited purposively with PCOS diagnosed following Modified Rotterdam Criteria 2003. Hormones were measured by CLIA method and lower abdominal ultrasonography was done by trained personnel. IR and ISD were assessed by homeostasis model assessment with 75th percentile values of HOMA-IR (2.4) and HOMA%B (143) in Non-PCOS group considered as the cut-off values. Hyperandrogenism (HA) was measured by calculating Fasting Androgen Index (FAI). HOMA-IR was high among 52% of PCOS and 28% of Non-PCOS women. Body Mass Index (BMI) and HA were independently associated covariates of IR (p < 0.001). HOMA%B was compromised among 48% of PCOS subjects and the deficiency showed independent association (p < 0.001) with 2 h glycemia on OGTT in Non-PCOS and HA in PCOS groups. The data suggest insulin resistance as a major risk factor for PCOS among Bangalee women with obesity and hyperandrogenemia as its major covariates. The findings also indicate that presence of impaired insulin secretion is a major determinant of hyperglycemia and, consequently, of higher T2DM risk among young women in this population.
Assuntos
Resistência à Insulina , Síndrome do Ovário Policístico , Humanos , Feminino , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Estudos de Casos e Controles , Adulto , Adulto Jovem , Adolescente , Insulina/sangue , Índice de Massa Corporal , Hiperandrogenismo , Índia/epidemiologia , Secreção de Insulina , Fatores de Risco , Glicemia/análise , Glicemia/metabolismoRESUMO
The existence of functionally diverse and plastic ß cells in islets of Langerhans has been reported since the 1980s. Recently, high-resolution technologies have advanced our understanding of ß-cell heterogeneity and plasticity. Here, we define plasticity broadly as dynamic changes in cellular phenotypes and heterogeneity as differences in cellular behaviors. Individual ß cells react differently to environmental challenges and act together to maintain ß-cell mass and glucose homeostasis within a narrow range of 70-140 mg/dL. During the progress of diabetes, this elaborate balance is disrupted, and a lack of ß-cell compensation leads to dysregulated blood glucose. In this chapter, we assess ß-cell stress that instigates increased ß-cell heterogeneity and adaptive ß-cell responses such as proliferation, dedifferentiation, maturity, and insulin secretion. We also discuss the maturity, electrical activity, and insulin secretion of well-characterized ß-cell subgroups. Finally, we touch upon the plasticity of other non-ß pancreatic cells and their cooperation with ß cells to maintain homeostasis.
Assuntos
Plasticidade Celular , Células Secretoras de Insulina , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Humanos , Animais , Secreção de Insulina , Insulina/metabolismo , HomeostaseRESUMO
The pancreatic ß cells are at the hub of myriad signals to regulate the secretion of an adequate amount of insulin needed to re-establish postprandial euglycemia. The ß cell possesses sophisticated metabolic enzymes and a variety of extracellular receptors and channels that amplify insulin secretion in response to autocrine, paracrine, and neurohormonal signals. Considerable research has been undertaken to decipher the mechanisms regulating insulin secretion. While the triggering pathway induced by glucose is needed to initiate the exocytosis process, multiple other stimuli modulate the insulin secretion response. This chapter will discuss the recent advances in understanding the role of the diverse glucose- and fatty acid-metabolic coupling factors in amplifying insulin secretion. It will also highlight the intracellular events linking the extracellular receptors and channels to insulin secretion amplification. Understanding these mechanisms provides new insights into learning more about the etiology of ß-cell failure and paves the way for developing new therapeutic strategies for type 2 diabetes.
Assuntos
Secreção de Insulina , Células Secretoras de Insulina , Insulina , Humanos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Animais , Glucose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Transdução de Sinais , Ácidos Graxos/metabolismoRESUMO
Dysfunction or loss of pancreatic ß cells can cause insulin deficiency and impaired glucose regulation, resulting in conditions like type 2 diabetes. The ATP-binding cassette transporter A1 (ABCA1) plays a key role in the reverse cholesterol transport system, and its decreased expression is associated with pancreatic ß cell lipotoxicity, resulting in abnormal insulin synthesis and secretion. Increased glutamate release can cause glucotoxicity in ß cells, though the detailed mechanisms remain unclear. This study investigated the effect of N-methyl-D-aspartic acid (NMDA) on ABCA1 expression in INS-1 cells and primary pancreatic islets to elucidate the signaling mechanisms that suppress insulin secretion. Using Western blotting, microscopy, and biochemical analyses, we found that NMDA activated the mitogen-activated protein kinase (MEK)-dependent pathway, suppressing ABCA1 protein and mRNA expression. The MEK-specific inhibitor PD98059 restored ABCA1 promoter activity, indicating the involvement of the extracellular signal-regulated kinase (MEK/ERK) pathway. Furthermore, we identified the liver X receptor (LXR) as an effector transcription factor in NMDA regulation of ABCA1 transcription. NMDA treatment increased cholesterol and triglyceride levels while decreasing insulin secretion, even under high-glucose conditions. These effects were abrogated by treatment with PD98059. This study reveals that NMDA suppresses ABCA1 expression via the MEK/ERK/LXR pathway, providing new insights into the pathological suppression of insulin secretion in pancreatic ß cells and emphasizing the importance of investigating the role of NMDA in ß cell dysfunction.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Células Secretoras de Insulina , Receptores X do Fígado , Sistema de Sinalização das MAP Quinases , N-Metilaspartato , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , N-Metilaspartato/farmacologia , Ratos , Receptores X do Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Colesterol/metabolismo , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Masculino , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Linhagem CelularRESUMO
Numerous studies have established associations between vitamin D and diabetes. The vitamin D receptor is widely distributed throughout the human body, including in pancreatic beta cells (ß-cells), hepatocytes, and immune cells. Therefore, vitamin D's effect on the risk, progression, or complications of diabetes may be mediated through various mechanisms. These include the regulation of insulin secretion or sensitivity and modulation of ß-cell function and its immunomodulatory and anti-inflammatory effects. This review extensively explores the relationship between vitamin D status and diabetes, as well as the preventive or therapeutic effects of vitamin D supplementation on diabetes from human studies. Additionally, it examines in detail the impact of vitamin D on immune and inflammatory responses in the diabetic milieux and ß-cell function to better understand the underlying mechanisms through which vitamin D influences diabetes.
Assuntos
Células Secretoras de Insulina , Vitamina D , Humanos , Vitamina D/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Suplementos Nutricionais , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/imunologia , Receptores de Calcitriol/metabolismo , Diabetes Mellitus , Secreção de Insulina/efeitos dos fármacos , Diabetes Mellitus Tipo 2 , Imunomodulação , AnimaisRESUMO
BACKGROUND: This case report explores the long-term dynamics of insulin secretion and glycemic control in two patients with diabetes mellitus type 2 over 20 years. The observations underscore the impact of lifestyle interventions, including weight loss and calorie restriction, on insulin secretion patterns and glucose levels during 75 g oral glucose tolerance tests. Additionally, the role of hemoglobin A1c fluctuations, influenced by various factors such as body weight, exercise, and pharmacological interventions, is investigated. CASE PRESENTATION: Case 1 involves a Japanese woman now in her late 70s who successfully maintained her hemoglobin A1c below 7% for over two decades through sustained weight loss and lifestyle changes. Despite a gradual decline in the homeostasis model assessment of ß cell function, the patient exhibited remarkable preservation of insulin secretion patterns over the 20-year follow-up. In case 2, a Japanese woman, now in her early 70s, experienced an improvement in hemoglobin A1c to 6.3% after a period of calorie limitation due to a wrist fracture in 2018. This incident seemed to trigger a temporary rescue of pancreatic ß cell function, emphasizing the dynamic nature of insulin secretion. Both cases highlight the potential for pancreatic ß cell rescue and underscore the persistence of insulin secretion over the 20-year follow-up. Additionally, we have briefly discussed three additional cases with follow-ups ranging from 10 to 17 years, demonstrating similar trends in glucose and insulin ratios. CONCLUSIONS: Long-term lifestyle interventions, such as weight loss and calorie restriction, can preserve pancreatic ß cell function and maintain glycemic control in type 2 diabetes patients over 20 years. Two patients showed stable or improved insulin secretion and favorable hemoglobin A1c levels, challenging the traditional view of irreversible ß cell decline. The findings highlight the importance of personalized, nonpharmacological approaches, suggesting that sustained lifestyle changes can significantly impact diabetes management and potentially rescue ß cell function.
Assuntos
Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Células Secretoras de Insulina , Insulina , Redução de Peso , Humanos , Feminino , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas/metabolismo , Insulina/metabolismo , Insulina/sangue , Idoso , Células Secretoras de Insulina/metabolismo , Glicemia/metabolismo , Restrição Calórica , Secreção de Insulina , Teste de Tolerância a Glucose , Hipoglicemiantes/uso terapêutico , Controle GlicêmicoRESUMO
This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D.
Assuntos
Biomarcadores , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Secreção de Insulina , Insulina , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Feminino , Masculino , Pessoa de Meia-Idade , Insulina/metabolismo , Insulina/sangue , Peptídeo C/sangue , Peptídeo C/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Adulto , Glicemia/metabolismo , Dieta , Índice de Massa Corporal , Obesidade/metabolismo , Obesidade/dietoterapia , Composição Corporal , Sobrepeso/metabolismo , Sobrepeso/dietoterapiaRESUMO
BACKGROUND: Islet or ß-cell transplantation is a therapeutical approach to substitute the insulin-producing cells which are abolished in type 1 diabetes mellitus. The shortage of human islets as well as the complicated and costly isolation process limit the application of these techniques in daily clinical practice. EndoC-ßH is a human ß-cell line that readily forms aggregates termed pseudoislets, providing an alternative to primary human islets or ß-cells. METHODS: EndoC-ßH3 cells were seeded and incubated to form pseudoislets. Their insulin secretion was analyzed by ELISA and compared with cell monolayers. Pseudoislets were transplanted into streptozotocin-treated NMRi nu/nu mice. Blood glucose was monitored before and after transplantation and compared with wild types. Grafts were analyzed by immunohistology. RESULTS: This study shows that EndoC-ßH cells are able to form pseudoislets by aggregation, leading to an enhanced glucose stimulated insulin secretion in vitro. These pseudoislets were then successfully transplanted into the livers of diabetic mice and produced insulin in vitro. Blood glucose levels of the streptozocin-treated recipient mice were significantly decreased when compared to pre-transplantation and matched the levels found in control mice. CONCLUSION: We suggest pseudoislets aggregated from EndoC-ßH cells as a valuable and promising model for islet transplantation research.
Assuntos
Glicemia , Diabetes Mellitus Experimental , Células Secretoras de Insulina , Insulina , Transplante das Ilhotas Pancreáticas , Animais , Diabetes Mellitus Experimental/terapia , Camundongos , Transplante das Ilhotas Pancreáticas/métodos , Humanos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Glicemia/metabolismo , Secreção de Insulina , Linhagem Celular , Camundongos Nus , Masculino , Agregação Celular , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/cirurgia , Diabetes Mellitus Tipo 1/metabolismoRESUMO
AIM: The relative contributions of insulin secretory defects and possible additional contribution of insulin resistance for the development of cystic fibrosis (CF)-related diabetes (CFRD) are poorly understood. We aimed to (a) determine which indices of insulin resistance predict progression to CFRD, and (b) to model the relative contributions of insulin secretory function and insulin resistance to predict the risk of CFRD. MATERIALS AND METHODS: Three hundred and three individuals living with CF underwent a 2-h oral glucose tolerance test with blood sampling every 30 min at 12-24-month intervals until they developed CFRD or until the end of follow-up (up to 15 years). Indices of insulin resistance (e.g. Stumvoll) and insulin secretion were calculated from oral glucose tolerance test glucose and insulin measurements. CFRD-free survival was assessed by survival analysis. RESULTS: Estimated insulin resistance showed associations with glucose homeostasis and risk of progression to CFRD. The CFRD-free survival was significantly different between quartiles of insulin resistance (p < 0.0001). When patients were subdivided according to both insulin resistance and insulin secretion (insulinogenic index), CFRD-free survival was significantly lower in those with combined lowest insulin secretion and highest insulin resistance (Stumvoll) indices (hazard ratio: 11.2; p < 0.0001). There was no significant difference when the same analysis was performed for the nine other indices. CONCLUSIONS: Insulin resistance is correlated with glucose homeostasis and the risk of progression to CFRD. Patients combining low insulin secretion and high insulin resistance had the greatest odds of developing CFRD over a 15-year period.
Assuntos
Fibrose Cística , Progressão da Doença , Teste de Tolerância a Glucose , Resistência à Insulina , Secreção de Insulina , Insulina , Humanos , Fibrose Cística/complicações , Fibrose Cística/sangue , Masculino , Feminino , Insulina/metabolismo , Insulina/sangue , Adulto , Adolescente , Diabetes Mellitus/metabolismo , Glicemia/metabolismo , Adulto Jovem , CriançaRESUMO
Ras-related Rap1A GTPase is implicated in pancreas ß-cell insulin secretion and is stimulated by the cAMP sensor Epac2, a guanine exchange factor and activator of Rap1 GTPase. In this study, we examined the differential proteomic profiles of pancreata from C57BL/6 Rap1A-deficient (Null) and control wild-type (WT) mice with nanoLC-ESI-MS/MS to assess targets of Rap1A potentially involved in insulin regulation. We identified 77 overlapping identifier proteins in both groups, with 8 distinct identifier proteins in Null versus 56 distinct identifier proteins in WT mice pancreata. Functional enrichment analysis showed four of the eight Null unique proteins, ERO1-like protein ß (Ero1lß), triosephosphate isomerase (TP1), 14-3-3 protein γ, and kallikrein-1, were exclusively involved in insulin biogenesis, with roles in insulin metabolism. Specifically, the mRNA expression of Ero1lß and TP1 was significantly (p < 0.05) increased in Null versus WT pancreata. Rap1A deficiency significantly affected glucose tolerance during the first 15-30 min of glucose challenge but showed no impact on insulin sensitivity. Ex vivo glucose-stimulated insulin secretion (GSIS) studies on isolated Null islets showed significantly impaired GSIS. Furthermore, in GSIS-impaired islets, the cAMP-Epac2-Rap1A pathway was significantly compromised compared to the WT. Altogether, these studies underscore an essential role of Rap1A GTPase in pancreas physiological function.
Assuntos
Insulina , Camundongos Endogâmicos C57BL , Pâncreas , Proteômica , Transdução de Sinais , Proteínas rap1 de Ligação ao GTP , Animais , Proteínas rap1 de Ligação ao GTP/metabolismo , Proteínas rap1 de Ligação ao GTP/genética , Camundongos , Proteômica/métodos , Insulina/metabolismo , Pâncreas/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos Knockout , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Secreção de Insulina , Masculino , Glucose/metabolismoRESUMO
AIMS/HYPOTHESIS: The aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency. METHODS: In a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity. RESULTS: Among 61 participants (NGT 21%, EGI 33%, IGT 16%, CFRD 30%), insulin secretion indices (Φ total, dynamic and static) were significantly lower in the CFRD group compared with the other groups. Insulin sensitivity declined with worsening in glucose tolerance (p value for trend <0.001) and the disposition index declined between NGT and EGI and between IGT and CFRD. Those with CFRD had elevated insulin clearance compared with NGT (p=0.019) and low insulin secretion (Φ total) was also associated with high insulin clearance (p<0.001). CONCLUSIONS/INTERPRETATION: In individuals with PI-CF, disposition index declined with incremental impairment in glucose tolerance due to a reduction in both insulin secretion and insulin sensitivity. Moreover in CF, reduced insulin secretion was associated with higher insulin clearance.
Assuntos
Fibrose Cística , Intolerância à Glucose , Teste de Tolerância a Glucose , Resistência à Insulina , Secreção de Insulina , Insulina , Humanos , Fibrose Cística/metabolismo , Fibrose Cística/sangue , Estudos Transversais , Masculino , Resistência à Insulina/fisiologia , Feminino , Insulina/metabolismo , Insulina/sangue , Adulto , Intolerância à Glucose/metabolismo , Intolerância à Glucose/sangue , Secreção de Insulina/fisiologia , Adulto Jovem , Glicemia/metabolismo , Insuficiência Pancreática Exócrina/metabolismo , AdolescenteRESUMO
BACKGROUND: Insulin resistance is a frequent precursor of typical obesity and metabolic syndrome complications. However, accurate diagnosis remains elusive because of its pathophysiological complexity and heterogeneity. Herein, we have explored the utility of insulin secretion dynamics in response to an oral glucose tolerance test as a surrogate marker to identify distinct metabotypes of disease severity. METHODS: The study population consisted of children with obesity and insulin resistance, stratified according to the post-challenge insulin peak timing (i.e., early, middle, and late peak), from whom fasting and postprandial plasma and erythrocytes were collected for metabolomics analysis. RESULTS: Children with late insulin peak manifested worse cardiometabolic health (i.e., higher blood pressure, glycemia, and HOMA-IR scores) than early responders. These subjects also showed more pronounced changes in metabolites mirroring failures in energy homeostasis, oxidative stress, metabolism of cholesterol and phospholipids, and adherence to unhealthy dietary habits. Furthermore, delayed insulin peak was associated with impaired metabolic flexibility, as reflected in compromised capacity to regulate mitochondrial energy pathways and the antioxidant defense in response to glucose overload. CONCLUSIONS: Altogether, these findings suggest that insulin resistance could encompass several phenotypic subtypes characterized by graded disturbances in distinctive metabolic derangements occurring in childhood obesity, which serve as severity predictive markers.
Assuntos
Biomarcadores , Glicemia , Teste de Tolerância a Glucose , Resistência à Insulina , Insulina , Síndrome Metabólica , Metabolômica , Obesidade Infantil , Índice de Gravidade de Doença , Humanos , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/sangue , Síndrome Metabólica/fisiopatologia , Síndrome Metabólica/epidemiologia , Criança , Masculino , Feminino , Obesidade Infantil/diagnóstico , Obesidade Infantil/sangue , Obesidade Infantil/fisiopatologia , Obesidade Infantil/epidemiologia , Adolescente , Insulina/sangue , Glicemia/metabolismo , Biomarcadores/sangue , Fenótipo , Fatores Etários , Fatores de Tempo , Valor Preditivo dos Testes , Secreção de Insulina , Período Pós-Prandial , Metabolismo EnergéticoRESUMO
The present study investigated the associations of serum gamma-glutamyl transferase (GGT), a marker of fatty liver and oxidative stress, and ALT/AST, a marker of fatty liver, with percentage trunk fat and postload glucose, insulin resistance, and ß-cell function in middle-aged Japanese individuals, whose BMI averaged < 23.0 kg/m2. Pancreatic ß-cell function was assessed using the disposition index calculated by a product of the insulinogenic index (IGI) and Matsuda insulin sensitivity index, a biomarker of early-phase glucose-stimulated insulin secretion and whole-body insulin sensitivity, respectively. Multivariate linear regression analyses revealed that the disposition index was associated inversely with GGT independently of percentage trunk fat, homeostasis model assessment insulin resistance (HOMA-IR), a marker of insulin resistance, and Matsuda index. When IGI was included instead of the disposition index, IGI (inversely) and HOMA-IR were associated with GGT independently of percentage trunk fat and Matsuda index. When the area under the glucose concentration curve (AUCg) during an oral glucose tolerance test was included instead of the disposition index, AUCg and HOMA-IR emerged as independent determinants of GGT. ALT/AST was associated with HOMA-IR alone. Results suggest a different pathophysiologic basis between GGT and ALT/AST in predicting diabetic risk in non-obese Japanese.
Assuntos
Alanina Transaminase , Resistência à Insulina , Secreção de Insulina , Células Secretoras de Insulina , gama-Glutamiltransferase , Humanos , gama-Glutamiltransferase/sangue , gama-Glutamiltransferase/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Alanina Transaminase/sangue , Alanina Transaminase/metabolismo , Feminino , Pessoa de Meia-Idade , Japão , Insulina/sangue , Insulina/metabolismo , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Glicemia/análise , Teste de Tolerância a Glucose , População do Leste AsiáticoRESUMO
Insulin-producing ß-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing 'non-ß-cells' (namely α-cells, δ-cells and γ-cells). Yet whether the non-ß-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of ß-cells and human pseudoislets containing only primary ß-cells. Mice lacking non-ß-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only ß-cells was comparable to that in intact islets. Similarly, human ß-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-ß-cells are dispensable for blood glucose homeostasis and ß-cell function. These results support efforts aimed at developing diabetes treatments by generating ß-like clusters devoid of non-ß-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-ß-cells into insulin producers in situ.
Assuntos
Secreção de Insulina , Células Secretoras de Insulina , Insulina , Ilhotas Pancreáticas , Animais , Células Secretoras de Insulina/metabolismo , Camundongos , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Glicemia/metabolismo , Dieta Hiperlipídica , Resistência à InsulinaRESUMO
AIM: To investigate the effect of G protein-coupled receptor 55 (GPR55) deletion on glucose homeostasis and islet function following diet-induced obesity. METHODS: GPR55-/- and wild-type (WT) mice were fed ad libitum either standard chow (SC) or a high-fat diet (HFD) for 20 weeks. Glucose and insulin tolerance tests were performed at 9/10 and 19/20 weeks of dietary intervention. Insulin secretion in vivo and dynamic insulin secretion following perifusion of isolated islets were also determined, as were islet caspase-3/7 activities and ß-cell 5-bromo-20-deoxyuridine (BrdU) incorporation. RESULTS: GPR55-/- mice fed a HFD were more susceptible to diet-induced obesity and were more glucose intolerant and insulin resistant than WT mice maintained on a HFD. Islets isolated from HFD-fed GPR55-/- mice showed impaired glucose- and pcacahorbol 12-myristate 13-acetate-stimulated insulin secretion, and they also displayed increased cytokine-induced apoptosis. While there was a 5.6 ± 1.6-fold increase in ß-cell BrdU incorporation in the pancreases of WT mice fed a HFD, this compensatory increase in ß-cell proliferation in response to the HFD was attenuated in GPR55-/- mice. CONCLUSIONS: Under conditions of diet-induced obesity, GPR55-/- mice show impaired glucose handling, which is associated with reduced insulin secretory capacity, increased islet cell apoptosis and insufficient compensatory increases in ß-cell proliferation. These observations support that GPR55 plays an important role in positively regulating islet function.
Assuntos
Dieta Hiperlipídica , Homeostase , Secreção de Insulina , Células Secretoras de Insulina , Insulina , Camundongos Knockout , Obesidade , Receptores de Canabinoides , Animais , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Obesidade/metabolismo , Obesidade/genética , Camundongos , Dieta Hiperlipídica/efeitos adversos , Receptores de Canabinoides/metabolismo , Receptores de Canabinoides/genética , Resistência à Insulina/genética , Masculino , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Apoptose , Camundongos Endogâmicos C57BL , Teste de Tolerância a Glucose , Glicemia/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismoRESUMO
Aim: Type II diabetes (T2D) stems from insulin resistance, with ß-cell dysfunction as a hallmark in its progression. Studies reveal that ß cells undergo apoptosis or dedifferentiation during T2D development. The transcription factor PAX4 is vital for ß differentiation and survival, thus may be a potential enhancer of ß-cell function in T2D islets. Materials & methods: Human PAX4 cDNA was delivered into T2D human islets with an adenoviral vector, and its effects on ß cells were examined. Results: PAX4 gene delivery significantly improved ß-cell survival, and increased ß-cell composition in the T2D human islets. Basal insulin and glucose-stimulated insulin secretion in PAX4-expressing islets were substantially higher than untreated or control-treated T2D human islets. Conclusion: Introduced PAX4 expression in T2D human islets improves ß-cell function, thus could provide therapeutic benefits for T2D treatment.
Type II diabetes (T2D) results from insulin resistance, with ß-cell dysfunction playing a pivotal role in its progression. Deficits in ß-cell mass and function have been attributed primarily to ß-cell death through apoptosis; however, recent studies suggest ß-cell failure can also arise from ß-cell dedifferentiation that is, ß cells undergo a loss of mature identity, adopting either progenitor-like or glucagon-producing α cell states during T2D development. Therefore, a strategy preventing ß-cell dedifferentiation while promoting its survival is beneficial for T2D treatment. In this study, we explored whether PAX4, a critical transcription factor for ß differentiation and survival, could alleviate ß-cell dysfunction in human islets derived from T2D patients. To accomplish that, human PAX4 cDNA was delivered into human islets isolated from T2D donors by an adenoviral vector-based vector, Ad5.Pax4 and its effects on ß-cell function were evaluated. The results showed PAX4 expression significantly improved ß-cell survival and increased ß-cell composition in the T2D islets. Notably, PAX4-treated T2D islets exhibited significantly higher basal insulin secretion and glucose-stimulated insulin secretion than control-treated islets. The data demonstrate that PAX4 gene delivery into T2D human islets enhances ß-cell mass and function, and thus may offer therapeutic benefits in the treatment of T2D.
Assuntos
Diabetes Mellitus Tipo 2 , Proteínas de Homeodomínio , Células Secretoras de Insulina , Insulina , Fatores de Transcrição Box Pareados , Humanos , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Fatores de Transcrição Box Pareados/genética , Células Secretoras de Insulina/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Insulina/metabolismo , Secreção de Insulina , Técnicas de Transferência de Genes , Sobrevivência Celular , Ilhotas Pancreáticas/metabolismo , Terapia Genética/métodosRESUMO
Pancreatic ß cells secrete insulin in response to elevated levels of glucose. Stem cell derived ß (SCß) cells aim to replicate this glucose-stimulated insulin secretion (GSIS) function, but current preparations cannot provide the same level of insulin as natural ß cells. Here, we develop an assay to measure GSIS at the single cell level to investigate the functional heterogeneity of SCß cells and donor-derived islet cells. Our assay involves randomly depositing single cells and insulin capture microbeads in open-top nanowells (40 × 40 × 55 µm3) fabricated on glass-bottom imaging microwell plates. Insulin secreted from single cells is captured on microbeads and then stained using a detection antibody. The nanowell microstructure limits diffusion of secreted insulin. The glass substrate provides an optically flat surface for quantitative microscopy to measure the concentration of secreted insulin. We used this approach to measure GSIS from SCß cells and donor-derived islet cells after 15 minutes exposure to 3.3 mM and 16.7 mM glucose. Both cell types exhibited significant GSIS heterogeneity, where elite cells (<20%) produced the majority of the secreted insulin (55-78%). This assay provides an immediate readout of single cell glucose-stimulated insulin secretion in a flexible well plate-based format.
Assuntos
Glucose , Secreção de Insulina , Células Secretoras de Insulina , Insulina , Análise de Célula Única , Glucose/metabolismo , Secreção de Insulina/efeitos dos fármacos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Análise de Célula Única/instrumentação , Camundongos , HumanosRESUMO
Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes.