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BACKGROUND: Establishing an optimal insulin regimen is crucial for maintaining glycemic control in patients with type 1 diabetes (T1D). The aim of the present study was to determine the insulin dose required to achieve an HbA1c concentration ≤7.5% in Japanese patients with T1D. METHODS: The present multicenter cross-sectional study was performed at three institutes in Japan. Information was collected regarding patient age, sex, body weight, body mass index (BMI), HbA1c, total daily insulin dose (TDD), and total basal insulin dose (TBD), and the effects of these factors on achieving HbA1c ≤7.5% were investigated. RESULTS: Of 107 patients with T1D, 92 had no detectable endogenous insulin secretion: 39 had HbA1c ≤7.5% (well-controlled group) and 53 had HbA1c >7.5% (poorly controlled group). No significant differences in age, sex, height, body weight, BMI, diabetes duration, stage of diabetic kidney disease, treatment, or TDD were noted between the poorly and well-controlled groups. The TBD as a percentage of TDD (%TBD) was lower in patients with well-controlled diabetes ( P < 0.05) after adjustment for age, gender, and diabetes duration. In the well-controlled group, TDD was correlated with body weight ( R = 0.51), BMI ( R = 0.44), body surface area ( R = 0.41), and TBD ( R = 0.73; P < 0.01 for all), but TBD was not correlated with BMI or body surface area. In our population, a %TBD of approximately 30% was appropriate, without considering BMI. CONCLUSIONS: To achieve HbA1c ≤7.5 in patients with T1D, TDD should be calculated based on body weight, and the %TBD should be set at 30% in the Japanese population.
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Biomarcadores/análise , Peso Corporal , Diabetes Mellitus Tipo 1/sangue , Hemoglobinas Glicadas/análise , Índice Glicêmico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos Transversais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Seguimentos , Humanos , Lactente , Japão , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
We studied effect of high glucose levels on coronary artery endothelial cell proliferation and human colon cancer cell proliferation. To examine the long-term effect of glucose exposure on cell growth, cells were cultured for 14 days in the absence or presence of 183 mg/dL D-glucose addition in the culture medium. Short effect of elevated glucose levels was examined by addition of 183 mg/dL D-glucose addition in the culture medium for just one hour per day followed by changing the culture to standard medium (5.5 mM D-glucose) during the next 23-hours period. Cell proliferation was estimated by 2,3-Bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carbox-anilide (XTT) assay and phosphor-Erk western blot analysis. We found that coronary artery endothelial cell proliferation was significantly increased in the culture medium with the acute one-hour addition of 183 mg/dL D-glucose compared to the absence or chronic presence of 183 mg/dL D-glucose addition in the culture medium. In contrast, colon cancer cell proliferation was significantly increased in the continuous presence of 183 mg/dL D-glucose addition in the culture medium compared to the acute one-hour addition of glucose. The extent of Erk2 phosphorylation paralleled with the relative changes in cellular proliferation in both cell types. Taken together, these results suggested that continuous or transient high level of glucose exposure differentially effects coronary artery endothelial and human colon cancer cell proliferation.
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OBJECTIVE: Optimum therapy for patients with diabetes depends on both acute and long-term changes in plasma glucose, generally assessed by glycated hemoglobin (HbA1c) levels. However, the correlation between HbA1c and circulating glucose has not been fully determined. Therefore, we carefully examined this correlation when glucose levels were assessed by continuous glucose monitoring (CGM). METHODS: Fifty-one patients (70% female, 30% male) were examined; among them were 28 with type 1 diabetes and 23 with type 2 diabetes. Clinically determined HbA1c levels were compared with blood glucose determined by CGM during a short time period. RESULTS: Changes in HbA1c levels up to 8.0% showed a clear and statistically strong correlation (R = 0.6713; P<.0001) with mean blood glucose levels measured by CGM, similar to that observed in the A1c-derived Average Glucose study in which patients were monitored for a longer period. However, we found no statistical correlation (R = 0.0498; P = .83) between HbA1c and CGM-assessed glucose levels in our patient population when HbA1c was >8.0%. CONCLUSION: Short-term CGM appears to be a good clinical indicator of long-term glucose control (HbA1c levels); however, cautions should be taken while interpreting CGM data from patients with HbA1c levels >8.0%. Over- or underestimation of the actual mean glucose from CGM data could potentially increase the risks of inappropriate treatment. As such, our results indicate that a more accurate analysis of CGM data might be useful to adequately tailor clinical treatments. ABBREVIATIONS: ADAG = A1c-Derived Average Glucose CGM = continuous glucose monitoring %CV = percent coefficient of variation HbA1c = glycated hemoglobin.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hemoglobinas Glicadas/metabolismo , Monitorização Fisiológica/métodos , Adulto , Idoso , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Sistemas de Infusão de Insulina , Masculino , Pessoa de Meia-IdadeRESUMO
The present study examined the long-term efficacy of insulin pump therapy for type 1 diabetes patients when carried out using carbohydrate counting with bolus calculators for 1 year. A total of 22 type 1 diabetes patients who had just started continuous subcutaneous insulin infusion were examined and divided into two groups: one that was educated about carbohydrate counting using bolus calculators (n = 14); and another that did not use bolus calculators (n = 8). After 1 year, the hemoglobin A1c levels of the patient group that used bolus calculators decreased persistently and significantly (P = 0.0297), whereas those of the other group did not. The bodyweight, total daily dose of insulin and bolus percentage of both groups did not change. Carbohydrate counting using bolus calculators is necessary to achieve optimal and persistent glycemic control in patients undergoing continuous subcutaneous insulin infusion.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Carboidratos da Dieta/análise , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
CONTEXT: Nesfatin-1 is a neuroendocrine peptide with potent anorexigenic activity in rodents. The potential role of nesfatin-1 on the regulation of energy balance, metabolic functions and inflammation is currently debated in obese humans. In the present study, nesfatin-1 fluctuations and their associations with metabolic factors were investigated in severely obese patients who underwent biliopancreatic diversion with duodenal switch (BPD/DS) and severely obese controls (SOC). BASIC PROCEDURES: Sixty severely obese patients who underwent BPD/DS and 15 SOC (matched for BMI and age) were included in the study. Associations between nesfatin-1 levels and body composition, glucose metabolism, lipid profile as well as inflammatory markers were evaluated at baseline and over a post-surgery12-month (12M) period. MAIN FINDINGS: Body weight was reduced at 6M and at 12M in BPD/DS patients (P<0.001). Nesfatin-1 levels were reduced at 6M (women: P<0.05) and at 12M (men and women; P<0.001) in BPD/DS patients. At baseline, nesfatin-1 levels negatively correlated with weight, fat (FM) and fat-free mass (FFM) in the whole population (combined BPD/DS and SOC patients). At 12M, nesfatin-1 concentrations positively correlated with weight, FM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, triglyceride and apoB values. At 12M, % changes in nesfatin-1 were positively associated with% changes in weight, FM, FFM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, apoB and C-reactive protein. CONCLUSION: Nesfatin-1 levels decrease following BPD/DS-induced weight loss and are significantly associated with parameters of metabolic health.
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Proteínas de Ligação ao Cálcio/sangue , Proteínas de Ligação a DNA/sangue , Proteínas do Tecido Nervoso/sangue , Obesidade Mórbida/sangue , Adulto , Cirurgia Bariátrica , Desvio Biliopancreático , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nucleobindinas , Obesidade Mórbida/patologia , Obesidade Mórbida/cirurgia , Resultado do Tratamento , Redução de PesoRESUMO
Expression of adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1 (APPL1) promoted glucose transporter 4 (GLUT4) translocation and glucose uptake in adipose and muscle tissues in response to stimulation with insulin, adiponectin, or exercise. In response to mechanical stretch, knockdown of APPL1 in C2C12 myotubes suppressed glucose uptake. APPL1-induced increased glucose uptake was mediated by protein kinase C (PKC) ζ but not AKT, AMPK, or calmodulin-dependent protein kinase. In myotubes overexpressing APPL1, PKCζ was phosphorylated and translocated to the plasma membrane (PM) in response to mechanical stretch. Phosphorylated PKCζ co-immunoprecipitated with protein phosphatase 2A (PP2A) under basal conditions, but dissociated upon myotube stretching. Moreover, stretch-induced phosphorylated PKCζ co-immunoprecipitated with non-muscle myosin IIa. Blebbistatin, an inhibitor of myosin II ATPase activity, suppressed APPL1-mediated stretch-induced glucose uptake and PKCζ translocation. Taken together these data demonstrate that in response to mechanical stretch, APPL1 enhances glucose uptake by modulating the activation and localization of PKCζ, as well as its functional interaction with both PP2A and myosin IIa. These findings support a new function for non-muscle myosin IIa in differentiated myotubes.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Glucose/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Proteína Quinase C/metabolismo , Estresse Mecânico , Adenilato Quinase/metabolismo , Animais , Linhagem Celular , Membrana Celular/metabolismo , Desoxiglucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Fosforilação , Proteína Fosfatase 2/metabolismo , Transporte ProteicoAssuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnóstico , Idoso de 80 Anos ou mais , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Feminino , Humanos , Masculino , PrognósticoRESUMO
Dapagliflozin is a SGLT2 (Sodium/Glucose cotransporter 2) inhibitor that reduces circulating glucose levels in type 2 diabetic patients by blocking the SGLT2-dependent reabsorption of glucose in the kidney. Dapagliflozin is metabolized by UGT1A9 (UDP Glucuronosyltransferase 1 family, Polypeptidase A9), suppressing its SGLT2 inhibitor activity. However little information is available on whether dapagliflozin acts in the absence of dapagliflozin metabolism. Treatment with 0.5µM dapagliflozin significantly reduced the number of HCT116 cells, which express SGLT2 but not UGT1A9. This was independent of SGLT2 inhibition, as the SGLT2 inhibitor phlorizin had no effect. Dapagliflozin also enhanced Erk phosphorylation but without changing levels of uncleaved and cleaved PPAR and uncleaved caspase-3, suggesting that the cause of the decrease in HCT116 cell number was apoptosis independent cell death. Taken together, these data indicate a new potential role for dapagliflozin as an anticancer reagent in tumor cell populations that do not express UGT1A9.
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Antineoplásicos , Compostos Benzidrílicos/farmacologia , Neoplasias do Colo/patologia , Glucosídeos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/metabolismo , Contagem de Células , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/metabolismo , Glucuronosiltransferase/metabolismo , Células HCT116 , Humanos , Hipoglicemiantes , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose , UDP-Glucuronosiltransferase 1ARESUMO
INTRODUCTION: Animal studies have reported that treatment with angiotensin II receptor blockers reduced kidney sodium-dependent glucose cotransporter expression. We therefore hypothesized that patients with hypertension treated with an angiotensin II receptor blocker (candesartan) would probably have an increased response to sodium-dependent glucose cotransporter inhibitor therapy (ipragliflozin) compared with patients treated with alternative hypertensive medications such as calcium channel blockers (nifedipine). Although sodium-dependent glucose cotransporter inhibitor (ipragliflozin) is a new anti-diabetic medicine, the clinical efficacy in the Japanese population has not been fully evaluated. We compared the combined effect of angiotensin II receptor blocker candesartan plus ipragliflozin with nifedipine plus ipragliflozin therapy and found that the combination of candesartan plus ipragliflozin was more effective in increasing glycosuria and lowering plasma glucose. CASE PRESENTATION: A 57-year-old Japanese man with essential hypertension was treated with candesartan. Candesartan was switched to nifedipine for the initial 10 days of an observation period and 5 days later he was started on ipragliflozin (day 6 of nifedipine treatment) with nifedipine for the next 5 days. Thereafter (from day 11 to day 20), candesartan was started instead of nifedipine and ipragliflozin was continued. In the last 5 days ipragliflozin was stopped and he was treated with candesartan alone. Neither nifedipine alone (0.038+/-0.004) nor candesartan alone (0.048+/-0.006) produce any trace amount of glycosuria. However, the extent of glycosuria under ipragliflozin with candesartan treatment (37.5+/-8.45) was significantly greater than that of ipragliflozin with nifedipine (23.75+/-0.35; P<0.05). CONCLUSION: Candesartan demonstrated additive actions with ipragliflozin to increase glycosuria compared to ipragliflozin with nifedipine treatment.
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Benzimidazóis/uso terapêutico , Glucosídeos/uso terapêutico , Glicosúria/tratamento farmacológico , Nifedipino/uso terapêutico , Tetrazóis/uso terapêutico , Tiofenos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Compostos de Bifenilo , Bloqueadores dos Canais de Cálcio/uso terapêutico , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
The physiology of insulin signaling under normal and disease conditions is well studied in classical insulin target tissues, but not in podocytes. To examine insulin stimulation of podocyte GLUT4 translocation, we established a protocol involving treatment with the PPARα agonist fenofibrate to induce E11 podocyte differentiation within 48 hours rather than 7-10 days, which is required for differentiation under the reported protocol. This allowed us to transiently introduce GLUT4 reporter cDNA and RNAi and thereby to examine the regulatory pathway involved. Here we demonstrate that treatment with 200 µM fenofibrate for 36 hours following transfection had a dramatic effect on podocyte morphology, induced several podocyte specific protein expression markers (G protein-coupled receptor 137B, chloride intracellular channel 5, and nephrin) and resulted in insulin-stimulated GLUT4 translocation. In addition, Nucleobindin-2 was found to constitutively associate with Septin 7 (the repressor of GLUT4 translocation), and knockdown of Nucleobindin-2 was found to completely abrogate insulin-stimulated GLUT4 translocation. Together, these data suggest that Nucleobindin-2 may repress Septin7-induced inhibition of insulin-stimulated GLUT4 translocation in podocytes.
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Proteínas de Ligação ao Cálcio/fisiologia , Proteínas de Ligação a DNA/fisiologia , Fenofibrato/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Podócitos/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Insulina/fisiologia , Camundongos , Nucleobindinas , Podócitos/metabolismo , Septinas/metabolismoRESUMO
The insulin responsive Glut4 transport vesicles contain the v-SNARE protein Vamp2 that associate with the plasma membrane t-SNARE protein Syntaxin 4 to drive insulin-stimulated Glut4 translocation in skeletal muscle and adipocytes. The syntaxin 4 interacting protein (Synip) binds to syntaxin 4 in the basal state and dissociates in the insulin-stimulated state allowing for the subsequent binding of Vamp2 containing Glut4 vesicles and fusion with the plasma membrane. In this study, we have found that Synip binds phosphatidylinositol 3,4,5-triphosphate (PIP3), but not phosphatidylinositol 3 phosphate (PIP) or phosphatidylinositol 3,4-biphosphate (PIP2) through the Synip WW domain as deletion of this domain (Synip ΔWW) failed to bind PIP3. Over-expressed Synip ΔWW in 3T3L1 adipocytes reduced the basal levels of Glut4 at the plasma membrane with no effect on the binding to syntaxin 4 in vitro. Subcellular fractionation demonstrated that the amount of Synip ΔWW at the PM was decreased in response to insulin in 3T3L1 adipocytes whereas the amount of Synip WT increased. These data suggest that in the presence of insulin, the dissociated Synip remains anchored to the plasma membrane by binding to PIP3.
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Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Qa-SNARE/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Células 3T3-L1 , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insulina/farmacologia , Camundongos , Proteínas Mutantes/metabolismo , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Transporte Proteico/efeitos dos fármacos , Proteínas de Transporte Vesicular/químicaRESUMO
Nucleobindin-2 is a 420 amino acid EF-hand Ca²âº binding protein that can be further processed to generate an 82 amino terminal peptide termed Nesfatin-1. To examine the function of secreted Nucleobindin-2 in adipocyte differentiation, cultured 3T3-L1 cells were incubated with either 0 or 100 nM of GST, GST-Nucleobindin-2, prior to and during the initiation of adipocyte differentiation. Nucleobindin-2 treatment decreased neutral lipid accumulation (Oil-Red O staining) and expression of several marker genes for adipocyte differentiation (PPARγ, aP2, and adipsin). When Nucleobindin- 2 was constitutively secreted into cultured medium, cAMP content and insulin stimulated CREB phosphorylation were significantly reduced. On the other hand, intracellularly overexpressed Nucleobindin-2 failed to affect cAMP content and CREB phosphorylation. Taken together, these data indicate that secreted Nucleobindin-2 is a suppressor of adipocyte differentiation through inhibition of cAMP production and insulin signal.
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Adipócitos/citologia , Adipogenia , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Proteínas de Ligação ao Cálcio/sangue , Proteínas de Ligação ao Cálcio/química , AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/química , Humanos , Insulina/metabolismo , Camundongos , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/química , Nucleobindinas , RatosRESUMO
Nucleobindin-2 is a 420-amino-acid EF-hand calcium-binding protein that undergoes proteolytic processing to generate an 82-amino-acid amino-terminal peptide termed nesfatin-1. To determine whether nucleobindin-2 has any biological function, nucleobindin-2 was either overexpressed or knocked down by short hairpin RNA in cultured CHO cells expressing the human insulin and epidermal growth factor (EGF) receptors (CHO/IE) and in 3T3-L1 cells. Reduction in nucleobindin-2 expression inhibited EGF-stimulated MAPK kinase (S217/S221) and Erk phosphorylation (T202/Y204). In contrast, there was no significant effect on EGF-stimulated EGF receptor phosphorylation, EGF receptor internalization, or 52-kDa Shc and c-Raf phosphorylation. Although kinase suppressor of Ras-1 and protein phosphatase 2A expression was not changed, intracellular calcium concentrations and PP2A activity was significantly increased in nucleobindin-2 knocked-down cells. Concomitant with these alterations in EGF-stimulated signaling, cell proliferation was significantly reduced in nucleobindin-2 knocked-down cells. Moreover, reduced nucleobindin-2 expression in 3T3-L1 preadipocytes resulted in a greater extent of 3T3-L1 cell adipocyte differentiation. Taken together, these data indicate that nucleobindin-2 regulates EGF-stimulated MAPK kinase/Erk signaling, cell proliferation, and adipocyte differentiation.