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AIM: To explore the effect of Mankai, a cultivated aquatic duckweed green plant, on postprandial glucose (PG) excursions in type 2 diabetes (T2D). METHODS: In a 4-week, randomized crossover-controlled trial, we enrolled 45 adults with T2D (HbA1c range: 6.5%-8.5%) from two sites in Israel. Participants were randomized to drink Mankai (200 mL of raw-fresh-aquatic plant + 100 mL of water, 40 kcal, ~10 g of dry matter equivalent) or water (300 mL) following dinner, for 2 weeks each, with a 4-day washout interval, without dietary, physical activity or pharmacotherapy alterations. We used continuous glucose monitoring (CGM) devices. RESULTS: Forty patients (adherence rate = 88.5%; 743 person-intervention-days, 68.9% men, age = 64 years, HbA1c = 6.8%) completed the study with a consistent diet and complete CGM reads. Only two-thirds of the individuals responded beneficially to Mankai. Overall, Mankai significantly lowered the PG peak by 19.3% (∆peak = 24.3 ± 16.8 vs. 30.1 ± 18.5 mg/dL; P < .001) and delayed the time-to-peak by 20.0% (112.5 [interquartile range: 75-135] vs. 90 [60-105] min; P < .001) compared with water. The PG incline and decline slopes were shallower following postdinner Mankai (incline slope: 16.8 vs. water: 29.9 mg/[dL h]; P < .001; decline slope: -6.1 vs. water: -7.9 mg/[dL h]; P < .01). Mean postprandial net incremental area-under-the-glucose-curve was lowered by 20.1% with Mankai compared with water (P = .03). Results were consistent across several sensitivity and subgroup analyses, including across antidiabetic pharmacotherapy treatment groups. Within 2 weeks, the triglycerides/high-density lipoprotein cholesterol ratio in the Mankai group (-0.5 ± 1.3) decreased versus water (+0.3 ± 1.5, P = .05). CONCLUSIONS: Mankai consumption may mitigate the PG response in people with T2D with an ~20% improvement in glycaemic values. These findings provide case-study evidence for plant-based treatments in T2D to complement a healthy lifestyle and pharmacotherapy.
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AIM: To assess the association between urinary albumin-to-creatinine ratio (UACR) categories within the normal range with mortality and adverse cardiovascular outcomes. MATERIALS AND METHODS: PubMed and Embase were systematically searched for real-world evidence studies. Studies were manually evaluated according to predefined eligibility criteria. We included prospective and retrospective cohort studies of the association between UACR categories <30 mg/g and cardiovascular outcomes or mortality. Published information regarding study design, participants, UACR categorization, statistical methods, and results was manually collected. Two UACR categorization approaches were defined: a two-category (UACR <10 mg/g vs. 10-30 mg/g) and a three-category division (UACR <5 mg/g vs. 5-10 and 10-30 mg/g). A random effects meta-analysis was performed on studies eligible for the meta-analysis. RESULTS: In total, 22 manuscripts were identified for the systematic review, 15 of which were eligible for the meta-analysis. The results suggest an association between elevated UACR within the normal to mildly increased range and higher risks of all-cause mortality, cardiovascular death, and coronary heart disease, particularly in the range of 10-30 mg/g. Compared with UACR <10 mg/g, the hazard ratio [HR (95% confidence interval, CI)] for UACR between 10 and 30 mg/g was 1.41 (1.15, 1.74) for all-cause mortality and 1.56 (1.23, 1.98) for coronary heart disease. Compared with UACR <5 mg/g, the risk of cardiovascular mortality for UACR between 10 and 30 mg/g was more than twofold [HR (95% CI): 2.12 (1.61, 2.80)]. Intermediate UACR (5-10 mg/g) was also associated with a higher risk of all-cause mortality [HR (95% CI): 1.14 (1.05, 1.24)] and cardiovascular mortality [HR (95% CI): 1.50 (1.14, 1.99)]. CONCLUSIONS: We propose considering higher UACR within the normoalbuminuric range as a prognostic factor for cardiovascular morbidity and mortality. Our findings underscore the clinical significance of even mild increases in albuminuria.
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AIMS: With advances in cloud-based technologies, there has been a rise in remote T1D care. We hypothesized that transitioning T1DM care to a virtual, multidisciplinary clinic could improve measures beyond HbA1c. METHODS: To assess the impact of transitioning from standard to virtual T1DM care, we evaluated glycemic measures and patient reported outcomes. RESULTS: Sixty-one adults with T1DM were included, with mean age 40.2 ± 13.5 years and diabetes duration 16.9 ± 9.0 years. Most patients were treated with insulin pumps and CGM. The number of annual diabetes care encounters rose from 2.1 ± 4.2 to 12.8 ± 5.5. Baseline HbA1c was 7.9 ± 1.6 %(63 ± 16.9 mmol/mol), declining to 7.3 ± 1.1 %(56 ± 8.5 mmol/mol) and 7.1 ± 1.0 %(54 ± 7.7 mmol/mol) at 6 and 12 months respectively (p < 0.001 for both). In parallel, TIR improved from 63.1 ± 19.3 % to 69.2 ± 13.8 % (p < 0.001) and 67.5 ± 19.4 % (p = 0.03) at 6 and 12 months respectively, while TBR declined. Scores from validated diabetes treatment and self-management questionnaires rose significantly and these rises were associated with a reduction in HbA1c, the latter score was also associated with increased TIR. There was a trend toward a correlation between encounter frequency and improvement in HbA1c and TIR. CONCLUSIONS: Transitioning from standard to virtual, coordinated, multidisciplinary T1DM care is associated with increased visit frequency, improving glycemic control, treatment satisfaction and self-care behaviors.
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Diabetes Mellitus Tipo 1 , Autogestão , Adulto , Humanos , Pessoa de Meia-Idade , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 1/terapia , Satisfação do Paciente , Insulina , Hemoglobinas Glicadas , Glicemia , Automonitorização da GlicemiaRESUMO
INTRODUCTION: Neonates of individuals with type 1 diabetes (T1D) are at increased risk of neonatal hypoglycaemia. It is hypothesised that this is a result of birthing-individual hyperglycaemia and subsequent foetal hyperinsulinemia. AIMS: To test for association between clinically significant neonatal hypoglycaemia (requiring intravenous glucose treatment) and cord-blood c-peptide (CBCP) concentrations in birthing-individuals with T1D. MATERIALS AND METHODS: This is a prospective cohort study of individuals with T1D followed at a single tertiary centre. Clinical variables and glucose control during pregnancy were recorded. Cord-blood was collected and CBCP concentrations determined. The correlation between clinically significant neonatal hypoglycaemia and CBCP concentrations was determined. RESULTS: Fifty-four pregnant individuals and their newborns were included in the study. Individuals to neonates who experienced hypoglycaemia had longer diabetes duration (19 vs. 13 years, respectively, p = 0.023), higher HbA1c at conception (7.3 [6.3-8.8] vs. 6.5 [6.0-7.0], respectively, p = 0.042) and higher rates of caesarian section (73.3% vs. 28.2%, respectively, p = 0.005) than individuals to those who did not. CBCP levels were significantly higher in neonates with clinically significant neonatal hypoglycaemia as compared to those who did not experience hypoglycaemia (3.3 mcg/L vs. 1.9 mcg/L, respectively, p = 0.002). After adjustment for possible confounders, every 1 unit higher in CBCP level was associated with a 1.46 (1.02-2.09, p = 0.035)-fold greater risk for neonatal hypoglycaemia. No significant differences were observed in either birthing individual complications or glucose control indices during pregnancy between the two groups. CONCLUSIONS: In neonates of individuals with T1D, higher CBCP levels are an independent risk factor for clinically significant neonatal hypoglycaemia.
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Diabetes Mellitus Tipo 1 , Hipoglicemia , Gravidez , Feminino , Recém-Nascido , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glicemia , Peptídeo C , Sangue Fetal , Estudos Prospectivos , Hipoglicemia/etiologiaRESUMO
BACKGROUND: Trabecular bone score (TBS) reflects vertebrae microarchitecture and assists in fracture risk assessment. The International Society of Clinical Densitometry postulates that the role of TBS in monitoring antiresorptive therapy is unclear. Whether changes in TBS correlate with bone resorption measured by bone turnover markers is not known. OBJECTIVES: To determine whether longitudinal changes in TBS correlate with C-terminal telopeptide (CTX) of type I collagen. METHODS: Examinees with two bone mineral density (BMD) measurements were detected via the institutional database. Over 5.8% change in TBS was considered least significant and patients were grouped accordingly (increment, decrement, or unchanged). CTX, BMD, co-morbidities, incident fractures, and medication exposure were compared between the groups by Kruskal-Wallis. The correlation between TBS and BMD change and CTX in a continuous model was analyzed by Pearson's correlation coefficient. RESULTS: In total, 110 patients had detailed medical records. In 74.5%, TBS change was below least significant change. Two other TBS categories, fracture incidence or medication exposure, did not differ by CTX. In the continuous model, BMD and TBS change was positively correlated (r = 0.225, P = 0.018). A negative correlation was observed between BMD change and CTX. The decrease in BMD level was associated with higher CTX (r = -0.335, P = 0.004). No correlation was observed between CTX and TBS. CONCLUSIONS: No correlation between TBS dynamics and bone resorption marker was found. Clinical interpretation and implication of longitudinal TBS changes should be further explored.
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Reabsorção Óssea , Fraturas Ósseas , Humanos , Osso Esponjoso/diagnóstico por imagem , Seguimentos , Remodelação ÓsseaRESUMO
Pancreatic ß-cells couple glucose-stimulated insulin secretion (GSIS) with oxidative phosphorylation via cytochrome c oxidase (COX), a mitochondrial respiratory-chain enzyme. The Cohen diabetic-sensitive (CDs) rats exhibit hyperglycemia when fed a diabetogenic diet but maintain normoglycemia on a regular diet. We have previously reported a decreased COX activity in CDs rats and explored its relevance for type 2 diabetes (T2D). In this study, we investigated the relation between COX activity in islets, peripheral-blood mononuclear cells (PBMCs), and GSIS during diabetes development in CDs rats fed a diabetogenic diet for 4, 11, 20, and 30 days and during reversion to normoglycemia in hyperglycemic CDs rats fed a reversion diet for 7, 11, and 20 days. An oral glucose-tolerance test was performed at different periods of the diets measuring blood glucose and insulin concentrations. COX activity was determined in islets and PBMCs isolated from rats at the different periods of the diets. We demonstrated a progressive reduction in COX activity in CDs-islets that correlated positively with the decreasing GSIS (R2 = 0.9691, p < 0.001) and inversely with the elevation in blood glucose levels (R2 = 0.8396, p < 0.001). Hyperglycemia was initiated when islet COX activity decreased below 46%. The reversion diet restored >46% of the islet COX activity and GSIS while re-establishing normoglycemia. Interestingly, COX activity in PBMCs correlated significantly with islet COX activity (R2 = 0.8944, p < 0.001). Our data support islet COX activity as a major metabolic regulator of ß-cells function. The correlation between COX activity in PBMCs and islets may serve as a noninvasive biomarker to monitor ß-cell dysfunction in diabetes.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Glucose/metabolismo , Hiperglicemia/metabolismo , RatosRESUMO
This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype-phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55-17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.
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Complexo de Carney/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Neoplasias Cardíacas/genética , Mixoma/genética , Adulto , Feminino , Genótipo , Células Germinativas , Neoplasias Cardíacas/patologia , Humanos , Fígado/patologia , Masculino , Mixoma/patologia , Fenótipo , Estudos RetrospectivosRESUMO
OBJECTIVE: Patients with pancreatic neuroendocrine tumors (PNET) have variable prognosis, even with comparable tumor grade and stage. In the current study we aimed to evaluate the prognostic utility of the intrapancreatic PNET anatomical site. DESIGN: Cohort study based on the Surveillance Epidemiology and End Results database. METHODS: Patients diagnosed with non-functioning PNET between 2004 and 2015 were compared by anatomic site for disease-specific mortality and all-cause mortality, using log-rank test and by multivariable cox regression analysis. RESULTS: Overall, 4171 patients (1839 women (44.1%), median age strata 60-64 years, range 10-14 to ≥85 years) were included in our analysis. Patients with PNETs located at the head vs body/tail of the pancreas had comparable tumor diameter, as well as ethnicity, gender and age distributions, but had higher rates of grade III and IV NET (13.2 vs 6.6% and 4.4 vs 1.9%, respectively, P < 0.001). NETs located at the head vs body/tail of pancreas were more likely to be locally advanced (32.2 vs 19.9%) with no difference in distant metastases (36.4 vs 33.5%, respectively, P < 0.001). Patients with NETs of the head vs. body/tail of the pancreas had higher disease-specific mortality risk in univariate (log-rank test, P < 0.001) and multivariable analysis (hazard ratio (HR): 1.34, 95% confidence interval: 1.10-1.65, P = 0.004). Multivariable analysis for all-cause mortality also showed increased risk for patients with pancreatic head vs. body/tail PNET (HR: 1.23, P = 0.013). CONCLUSIONS: PNET anatomical location is associated with the mortality risk and should be considered as a prognostic factor, and as an additional consideration in directing patients management.
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Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/mortalidade , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida/tendênciasRESUMO
OBJECTIVE: To evaluate the impact of temozolomide (TMZ) introduction on the survival of patients with pituitary carcinoma (PC) compared to aggressive pituitary adenoma (APA). METHODS: Retrospective analysis of the Surveillance Epidemiology and End-Results database (SEER), including patients diagnosed with PC or APA between 1973 and 2015. Age-adjusted Kaplan-Meier analyses were performed, comparing all-cause mortality (ACM) rates before the year 2006, the time of TMZ introduction ("period 1"), and afterwards ("period 2"), in patients harboring PC and APA. RESULTS: Among 107 patients, 18 (16.8%) harbored PC. The prevalence of PC and APA was comparable between genders, ethnicities and age strata. Patients harboring any pituitary tumor (PC or APA) had comparable risk for ACM and disease-specific mortality between the two time periods. However, among patients harboring PC, the risk for ACM was significantly lower in period 2 vs. period 1 (p = 0.021), becoming comparable to the risk of ACM in patients diagnosed with APA (p = 0.48). CONCLUSIONS: In this large cancer-database-based analysis we observed improved overall survival in patients harboring PC in the years following the introduction of TMZ.
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Adenoma/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Temozolomida/uso terapêutico , Adenoma/mortalidade , Idoso , Carcinoma/mortalidade , Feminino , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/mortalidade , Prevalência , Estudos RetrospectivosRESUMO
OBJECTIVE: To assess treatment satisfaction and the effectiveness of a flash glucose monitoring (FGM) system in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODS: A total of 101 patients with type 2 diabetes on multiple daily insulin injections (MDI) for at least 1 year were assigned randomly to the FGM intervention (n = 53) or the standard care (control) group (n = 48) and followed for 10 weeks. Both groups were instructed to adjust their insulin doses in face-to-face and telephone visits. Satisfaction with treatment, quality of life, comfort using FGM, HbA1c, and frequency of hypoglycemic events were evaluated. RESULTS: The intervention group found treatment significantly more flexible (P = 0.019) and would recommend it to their counterparts (P = 0.023). Satisfaction using the FGM system was high. The changes in HbA1c were -0.82% (9 mmol/mol) vs. -0.33% (3.6 mmol/mol) in the intervention and control group, respectively (P = 0.005); in nonprespecified post hoc analysis, 68.6% of the patients in the intervention group had their HbA1c reduced by ≥0.5% (5.5 mmol/mol) compared with 30.2% in the control group (P < 0.001), and 39.2% had their HbA1c reduced by ≥1.0% (10.9 mmol/mol) vs. 18.6% in the control group (P = 0.0023) without an increased frequency of hypoglycemia. CONCLUSIONS: FGM tends to improve treatment satisfaction and may lead to amelioration of glycemic control in patients with type 2 diabetes on MDI without increasing the frequency of hypoglycemia.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Equipamentos e Provisões , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Satisfação do Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas Biossensoriais/instrumentação , Glicemia/efeitos dos fármacos , Automonitorização da Glicemia/instrumentação , Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Esquema de Medicação , Líquido Extracelular/química , Líquido Extracelular/metabolismo , Feminino , Glucose/análise , Glucose/metabolismo , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Injeções Subcutâneas , Sistemas de Infusão de Insulina/psicologia , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente/estatística & dados numéricos , Qualidade de Vida , Padrão de CuidadoRESUMO
INTRODUCTION: Accumulating data from recent studies has altered the gold standard of care for diabetes treatment. In patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or those at high risk for CVD, subsequently to lifestyle changes and metformin therapy, the administration of an SGLT-2 inhibitor with established benefits for cardiovascular outcome (CVOT) should be considered. Areas covered: Tofogliflozin is the most selective SGLT-2 inhibitor and has been approved for the treatment of T2D in Japan. This review summarizes the available data on Tofogliflozin as compared to other SGLT-2 inhibitors, and primarily the three SGLT-2 inhibitors with published CVOT: Empagliflozin, Canagliflozin and Dapagliflozin. Expert opinion: Tofogliflozin's higher selectivity profile increases the positive effects on cardiovascular (CV) outcomes and death and reduces side effects. However, the clinical data on Tofogliflozin from both clinical and real-world studies remain sparse and much less abundant than the other main 3 SGLT-2 inhibitors, thus calling for caution and underscoring the need for further research.
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Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/farmacocinética , Doenças Cardiovasculares/etiologia , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/patologia , Glucosídeos/efeitos adversos , Glucosídeos/farmacocinética , Hemoglobinas Glicadas/análise , Meia-Vida , Humanos , Hipoglicemia/etiologia , Cetose/etiologia , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: Mitochondria hold crucial importance in organs with high energy demand especially the heart. We investigated whether chronic kidney disease (CKD), which eventually culminates in cardiorenal syndrome, could affect cardiac mitochondria and assessed the potential involvement of angiotensin II (AngII) in the process. METHODS: Male Lewis rats underwent 5/6 nephrectomy allowing CKD development for eight months or for eleven weeks. Short-term CKD rats were administered with AngII receptor blocker (ARB). Cardiac function was assessed by echocardiography and cardiac sections were evaluated for interstitial fibrosis and cardiomyocytes' hypertrophy. Electron microscopy was used to explore the spatial organization of the cardiomyocytes. Expression levels of mitochondrial content and activity markers were tested in order to delineate the underlying mechanisms for mitochondrial pathology in the CKD setting with or without ARB administration. RESULTS: CKD per-se resulted in induced cardiac interstitial fibrosis and cardiomyocytes' hypertrophy combined with a marked disruption of the mitochondrial structure. Moreover, CKD led to enhanced cytochrome C leakage to the cytosol and to enhanced PARP-1 cleavage which are associated with cellular apoptosis. ARB treatment did not improve kidney function but markedly reduced left ventricular mass, cardiomyocytes' hypertrophy and interstitial fibrosis. Interestingly, ARB administration improved the spatial organization of cardiac mitochondria and reduced their increased volume compared to untreated CKD animals. Nevertheless, ARB did not improve mitochondrial content, mitochondrial biogenesis or the respiratory enzyme activity. ARB mildly upregulated protein levels of mitochondrial fusion-related proteins. CONCLUSIONS: CKD results in cardiac pathological changes combined with mitochondrial damage and elevated apoptotic markers. We anticipate that the increased mitochondrial volume mainly represents mitochondrial swelling that occurs during the pathological process of cardiac hypertrophy. Chronic administration of ARB may improve the pathological appearance of the heart. Further recognition of the molecular pathways leading to mitochondrial insult and appropriate intervention is of crucial importance.
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Apoptose , Regulação da Expressão Gênica , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/patologia , Ratos , Ratos Endogâmicos Lew , Insuficiência Renal Crônica/patologiaRESUMO
Interleukin (IL)-1ß, the sole proinflammatory cytokine released from pancreas-infiltrating macrophages, inhibits glucose-stimulated insulin secretion (GSIS), causing hyperglycemia in Cohen diabetes-sensitive (CDs) rats fed a diabetogenic-diet (CDs-HSD). Because IL-1ß blockade is a potential therapeutic target in diabetes, we examined whether treating CDs rats with IL-1ß antibody (IL-1ßAb; 0.5 mg/kg body weight) could counteract the inhibition of GSIS and hyperglycemia. We found that daily IL-1ßAb injections had a beneficial effect on glucose tolerance and insulin secretion in CDs-HSD rats. In the oral glucose tolerance test, IL-1ßAb-treated CDs-HSD rats showed lower blood glucose concentrations (P < 0.001) and higher GSIS (P < 0.05) compared with nontreated CDs-HSD rats. IL-1ßAb treatment also protected the exocrine pancreas; the number of infiltrating macrophages decreased by 70% (P < 0.01) and IL-1ß expression decreased by 85% (P < 0.01). In parallel, a 50% reduction (P < 0.01) in the rate of apoptosis and in fat infiltration (P < 0.05) was noted in the exocrine parenchyma of IL-1ßAb-treated CDs-HSD rats compared with nontreated CDs-HSD rats. Altogether, these data demonstrate that blocking IL-1ß action by IL-1ßAb counteracted ß-cell dysfunction and glucose intolerance, supporting the notion that prevention of pancreas infiltration by macrophages producing IL-1ß is of crucial importance for the preservation of ß-cell function and prevention of diabetes.
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Anticorpos Monoclonais/uso terapêutico , Diabetes Mellitus/prevenção & controle , Células Secretoras de Insulina/fisiologia , Interleucina-1beta/imunologia , Animais , Anticorpos Monoclonais/imunologia , Carboidratos da Dieta/toxicidade , Teste de Tolerância a Glucose , Tamanho do Órgão , Pâncreas/patologia , Ratos , Ratos Endogâmicos , Sacarose/administração & dosagem , Sacarose/toxicidadeRESUMO
A high-sucrose, low-copper-diet (HSD) induces inhibition of glucose-sensitive rats (CDs) but not Cohen diabetes-resistant rats (CDr). Copper-supplemented HSD increased activity of the copper-dependent mitochondrial respiratory chain enzyme cytochrome c oxidase (COX) and reversed hyperglycemia. This study examined the mechanism by which interleukin-1ß modulates GSIS and the role of COX in this process. We measured COX activity, ATP content, GSIS, iNOS expression, and nitrite production with and without IL-1ß, N(ω)-nitro-l-arginine, copper, or potassium cyanide in isolated islets of CDs and CDr fed different diets. We found reduced COX activity, ATP content, and GSIS in isolated islets of CDs rats fed a regular diet. These were severely reduced following HSD and were restored to regular diet levels on copper-supplemented HSD (P < 0.01 vs. CDr islets). Potassium cyanide chemically reduced COX activity, decreasing GSIS and thus reinforcing the link between islet COX activity and GSIS. Interleukin-1ß (2.5 U/ml) reduced GSIS and COX activity in CDs islets. Exposure to 10 U/ml interleukin-1ß decreased GSIS and COX activity in both CDs and CDr islets, inducing a similar nitrite production. Nevertheless, the effect on GSIS was more marked in CDs islets. A significant iNOS expression was detected in CDs on the HSD diet, which was reduced by copper supplementation. N(ω)-nitro-l-arginine and copper prevented the deleterious effect of interleukin-1ß on COX activity and GSIS. We conclude that reduced islet COX activity renders vulnerability to GSIS inhibition on low-copper HSD through two interrelated pathways: 1) by further reducing the activity of COX that is essential for ß-cell ATP-production and insulin secretion and 2) by inducing the expression of iNOS and nitric oxide-mediated COX inhibition. We suggest that islet COX activity must be maintained above a critical threshold to sustain adequate GSIS with exposure to low-copper HSD.
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Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Insulina/metabolismo , Interleucina-1beta/metabolismo , Ilhotas Pancreáticas/metabolismo , Óxido Nítrico/metabolismo , Animais , Cobre/deficiência , Cobre/metabolismo , Cobre/uso terapêutico , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Sacarose Alimentar/efeitos adversos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Resistência à Insulina , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Concentração Osmolar , Ratos , Ratos Endogâmicos , Técnicas de Cultura de TecidosRESUMO
ß-Cell mitochondrial dysfunction as well as proinflammatory cytokines have been suggested to contribute to reduced glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. We recently demonstrated that Cohen diabetic sensitive (CDs) rats fed a high-sucrose, low-copper diet (HSD) developed hyperglycemia and reduced GSIS in association with peri-islet infiltration of fat and interleukin (IL)-1ß-expressing macrophages, whereas CD resistant (CDr) rats remained normoglycemic on HSD. We examined: 1) the correlation between copper concentration in the HSD and progression, prevention, and reversion of hyperglycemia in CDs rats, 2) the relationship between activity of the copper-dependent, respiratory-chain enzyme cytochrome c oxidase (COX), infiltration of fat, IL-1ß-expressing macrophages, and defective GSIS in hyperglycemic CDs rats. CDs and CDr rats were fed HSD or copper-supplemented HSD before and during hyperglycemia development. Blood glucose and insulin concentrations were measured during glucose tolerance tests. Macrophage infiltration and IL-1ß expression were evaluated in pancreatic sections by electron-microscopy and immunostaining. COX activity was measured in pancreatic sections and isolated islets. In CDs rats fed HSD, GSIS and islet COX activity decreased, while blood glucose and infiltration of fat and IL-1ß-expressing macrophages increased with time on HSD (P < 0.01 vs. CDr-HSD rats, all parameters, respectively). CDs rats maintained on copper-supplemented HSD did not develop hyperglycemia, and in hyperglycemic CDs rats, copper supplementation restored GSIS and COX activity, reversed hyperglycemia and infiltration of fat and IL-1ß-expressing macrophages (P < 0.01 vs. hyperglycemic CDs-HSD rats, all parameters, respectively). We provide novel evidence for a critical role of low dietary copper in diminished GSIS of susceptible CDs rats involving the combined consequence of reduced islet COX activity and pancreatic low-grade inflammation.