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AIMS: This study aimed to investigate whether the response to adding metformin to insulin in young adults with type 1 diabetes (T1D) differs according to weight phenotype and insulin sensitivity index. METHODS: A prospective pilot study was conducted over 26 weeks in which insulin plus metformin (2 g/day) was administered to 35 individuals, ranging from normal weight (NW) to overweight (OW) to obese (OB) T1D individuals, to correlate insulin sensitivity indices and other clinical variables. RESULTS: At the end of the follow-up period, all groups showed an increase in the eGDR (NW: 7.37 vs 8.16, p = 0.002; OW: 7.28 vs 8.24, p < 0.001; OB: 6.33 vs 7.52 p < 0.001). KITT and SEARCH SCORE improved only in the OB group (2.15 vs 3.14, p < 0.001 and 5.26 vs 5.72, p = 0.007, respectively). Furthermore, HbA1c and BMI were significantly greater in the OB group (- 0.62%, p < 0.001; - 1.12 kg/m2, p = 0.031, respectively). Regression analysis revealed that the serum levels of triglycerides and uric acid were significantly (0.059, p = 0.013; 0.076, p = 0.001) associated with insulin sensitivity indices. CONCLUSIONS: The study showed that eGDR improved independently of basal weight after metformin treatment. However, the KITT and SEARCH indices improved only in the obese group. Triglycerides and uric acid are associated with insulin sensitivity indices. These results highlight the heterogeneity of the mechanisms underlying insulin resistance and its response to metformin in individuals with T1D.
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BACKGROUND: Recurrent DKA (rDKA) remains an acute type 1 diabetes complication even in post-insulin era. This study aimed to analyze the predictors and effects of rDKA on the mortality of patients with type 1 diabetes. METHODS: Patients hospitalized (n = 231) wih diabetic ketoacidosis (between 2007 and 2018) were included. Laboratorial and clinical variables were collected. Mortality curves were compared in four groups: diabetic ketoacidosis as a new-onset type 1 diabetes (group A), single diabetic ketoacidosis episode after diagnosis of type 1 diabetes (group B), 2-5 diabetic ketoacidosis events (group C), and > 5 diabetic ketoacidosis events during follow-up period (group D). RESULTS: During the follow-up period (approximately 1823 days), the mortality rate was 16.02% (37/231). The median age at death was 38.7 years. In the survival curve analysis, at 1926 days (5 years), the probabilities of death were indicated by ratios of 7.78%, 4.58%, 24.40%, and 26.63% in groups A, B, C, and D, respectively. One diabetic ketoacidosis episode compared with ≥ 2 events had a relative risk of 4.49 (p = 0.004) of death and > 5 events had 5.81 (p = 0.04). Neuropathy (RR 10.04; p < 0.001), retinopathy (relative risk 7.94; p < 0.01), nephropathy (RR 7.10; p < 0.001), mood disorders (RR 3.57; p = 0.002), antidepressant use (RR 3.09; p = 0.004), and statin use (RR 2.81; p = 0.0024) increased the risk of death. CONCLUSIONS: Patients with type 1 diabetes with > 2 diabetic ketoacidosis episodes have four times greater risk of death in 5 years. Microangiopathies, mood disorders, and use of antidepressants and statins were important risk factors for short-term mortality.
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BACKGROUND: Pancreas transplant is an effective treatment for insulin-dependent diabetic individuals with end-stage renal disease, yet immunosuppression-associated adverse events may adversely affect patient and graft survival. The aim of the study was to document whether mammalian target of rapamycin inhibitors (mTORi) are safe and effective as a second-line drug after pancreas transplant. METHODOLOGY: An observational single-center study was performed in a cohort of 490 simultaneous pancreas-kidney transplant and 45 pancreas-after-kidney transplant individuals after conversion to mTORi (n = 13) owing to adverse events of either tacrolimus or mycophenolate. RESULTS: mTORi conversion was performed 11.5 ± 10.1 (range, 1-28) months after pancreas transplant, mainly owing to cytomegalovirus infection and gastrointestinal intolerance. We frequently observed clinical complications after mTORi conversion, yet creatinine, eGFR, proteinuria, fasting plasma glucose, HbA1c, and C-peptide remained stable throughout the study (mean follow-up 8.2 ± 5, range 1-17) years, as did the lipid profile (P > .05). However, graft loss occurred in almost 20% of patients owing to chronic alterations. LIMITATIONS: The small number of patients and a single-center cohort were limitations of the study. CONCLUSIONS: Late mTORi conversion is a safe and effective approach when tacrolimus or mycophenolate-mediated adverse events occur after pancreas transplant.
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Everolimus/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Páncreas/métodos , Sirolimus/uso terapéutico , Adulto , Sustitución de Medicamentos/métodos , Femenino , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Terapia de Inmunosupresión/métodos , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
ABSTRACT Objective To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. Subjects and methods We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. Results We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. Conclusion The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).
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Humanos , Adulto , Persona de Mediana Edad , Nefropatías Diabéticas/genética , Enfermedades Renales Quísticas/genética , Factor Nuclear 1-beta del Hepatocito/genética , Hiperglucemia/genética , Mutación , Fenotipo , Polimorfismo Genético/genética , Brasil , Estudios de Cohortes , Eliminación de Gen , Nefropatías Diabéticas/complicaciones , Enfermedades Renales Quísticas/complicaciones , Hiperglucemia/complicacionesRESUMEN
OBJECTIVE: To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. SUBJECTS AND METHODS: We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. RESULTS: We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. CONCLUSION: The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).
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Nefropatías Diabéticas/genética , Factor Nuclear 1-beta del Hepatocito/genética , Hiperglucemia/genética , Enfermedades Renales Quísticas/genética , Mutación , Adulto , Brasil , Estudios de Cohortes , Nefropatías Diabéticas/complicaciones , Eliminación de Gen , Humanos , Hiperglucemia/complicaciones , Enfermedades Renales Quísticas/complicaciones , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético/genéticaRESUMEN
Thirty-two patients with diabetes negative for point mutations in GCK and HNF1A underwent further molecular screening of GCK, HNF1A, HNF4A, and HNF1B by MLPA analysis. We described the first Brazilian case of MODY5 due to a heterozygous whole-gene deletion in HNF1B, who developed rapidly progressive renal failure and death.
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Diabetes Mellitus Tipo 2/genética , Eliminación de Gen , Factor Nuclear 1-beta del Hepatocito/genética , Adulto , Brasil , Estudios de Casos y Controles , Enfermedades del Sistema Nervioso Central , Esmalte Dental/anomalías , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Glucoquinasa/genética , Factor Nuclear 1-alfa del Hepatocito/genética , Heterocigoto , Humanos , Hallazgos Incidentales , Enfermedades Renales Quísticas , Masculino , FenotipoRESUMEN
The aim of this study was to evaluate subclinical atherosclerosis and related factors in young type 1 diabetes (T1D) patients and healthy peers. Carotid intima-media thickness (cIMT) and anthropometric/laboratorial data were obtained for 83 T1D patients (mean age 19.5 ± 4.0 years, disease duration 9.8 ± 4.8 years) and for 36 matched healthy subjects. Considering all the participants as one group, male sex (p = 0.008), weight (p = 0.016) and T1D (p < 0.001) were positively associated with a higher cIMT. High-density lipoprotein (HDL) (p = 0.036) was negatively associated with cIMT in T1D. In the male T1D patients, HDL ≤47.5 mg/dL had a sensitivity of 87.5% and specificity of 57% (p = 0.035) in detecting those belonging to a higher cIMT tercile. In conclusion, weight and T1D were associated with increased cIMT. HDL levels ≤47.5 mg/dL were related to a higher cIMT in male T1D patients.
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Aterosclerosis/metabolismo , Glucemia/análisis , Peso Corporal/fisiología , Grosor Intima-Media Carotídeo , HDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico , Adolescente , Adulto , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico , Diabetes Mellitus Tipo 1/complicaciones , Femenino , Humanos , Masculino , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Immunosuppressive regimen is associated with several metabolic adverse effects. Bone loss and fractures are frequent after transplantation and involve multifactorial mechanisms. METHODS: A retrospective analysis of 130 patients submitted to simultaneous pancreas-kidney transplantation (SPKT) and an identification of risk factors involved in de novo Charcot neuroarthropathy by multivariate analysis were used; P<0.05 was considered significant. RESULTS: Charcot neuroarthropathy was diagnosed in 4.6% of SPKT recipients during the first year. Cumulative glucocorticoid doses (daily dose plus methylprednisolone pulse) during the first 6 months both adjusted to body weight (>78 mg/kg) and not adjusted to body weight were associated with Charcot neuroarthropathy (P=0.001 and P<0.0001, respectively). Age, gender, race, time on dialysis, time of diabetes history, and posttransplantation hyperparathyroidism were not related to Charcot neuroarthropathy after SPKT. CONCLUSIONS: Glucocorticoids are the main risk factors for de novo Charcot neuroarthropathy after SPKT. Protocols including glucocorticoid avoidance or minimization should be considered.
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Artropatía Neurógena/etiología , Diabetes Mellitus Tipo 1/cirugía , Glucocorticoides/efectos adversos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Trasplante de Páncreas/efectos adversos , Artropatía Neurógena/diagnóstico , Relación Dosis-Respuesta a Droga , Femenino , Articulaciones del Pie/diagnóstico por imagen , Articulaciones del Pie/patología , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Imagen por Resonancia Magnética , Masculino , Radiografía , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: We used homeostasis model assessment to investigate insulin sensitivity and secretion after a simultaneous pancreas-kidney transplant or kidney transplant alone. In that model, fasting plasma glucose and C-peptide levels are used to evaluate insulin sensitivity and beta-cell function. MATERIALS AND METHODS: Factors (eg, age, sex, race, delayed kidney allograft function) were correlated with homeostasis model assessment of beta-cell function and homeostasis model assessment of insulin sensitivity values after simultaneous pancreas-kidney transplant (n=89) or kidney transplant alone (n=68), and the results were compared with those in healthy subjects (n=49). RESULTS: Homeostasis model assessment of beta-cell function values were similar in patients who underwent kidney transplant alone or a simultaneous pancreas-kidney transplant, and were higher than homeostasis model assessment of beta cell function values in healthy subjects. The homeostasis model assessment of insulin sensitivity showed intermediate values for patients who underwent a simultaneous pancreas-kidney transplant and correlated with prednisone dosages (in those who underwent kidney transplant alone) and tacrolimus levels (in patients who underwent a simultaneous pancreas-kidney transplant). Homeostasis model assessment of beta-cell function values correlated with prednisone dosages in both groups and with tacrolimus levels in only those who underwent a simultaneous pancreas-kidney transplant. The body mass index of subjects who underwent kidney transplant alone correlated with both homeostasis model assessment of beta-cell function results and homeostasis model assessment of insulin sensitivity results. A family history of diabetes in subjects who underwent a simultaneous pancreas-kidney transplant correlated with homeostasis model assessment of beta-cell function results and homeostasis model assessment of insulin sensitivity results. CONCLUSIONS: Immunosuppressive regimen and body mass index were linked with reduced insulin sensitivity after kidney transplant. A family history of diabetes was linked with higher values of insulin secretion and lower insulin sensitivity in patients who underwent a simultaneous pancreas-kidney transplant.
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Diabetes Mellitus/genética , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Trasplante de Riñón/fisiología , Trasplante de Páncreas/fisiología , Linaje , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Péptido C/sangre , Estudios de Casos y Controles , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatología , Femenino , Homeostasis/fisiología , Humanos , Inmunosupresores/uso terapéutico , Secreción de Insulina , Células Secretoras de Insulina/fisiología , Trasplante de Riñón/inmunología , Masculino , Modelos Biológicos , Prednisona/uso terapéutico , Tacrolimus/uso terapéuticoRESUMEN
Pancreas transplantation is an invasive procedure that can restore and maintain normoglycemic level very successfully and for a prolonged period in DM1 patients. The procedure elevates the morbimortality rates in the first few months following the surgery if compared to kidney transplants with living donors, but it offers a better quality of life to patients.Although controversial, several studies have shown the stabilization or the improvement of some of the chronic complications related to diabetes, as well as the extra number of years of life that patients submitted to a double pancreas-kidney transplantation may gain.Recent studies have demonstrated clashing outcomes regarding isolated pancreas transplantations, a fact which reinforces the need for a more discerning selection of patients for this procedure.
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BACKGROUND: Diabetes is a disease of increasing worldwide prevalence and is the main cause of chronic renal failure. Type 1 diabetic patients with chronic renal failure have the following therapy options: kidney transplant from a living donor, pancreas after kidney transplant, simultaneous pancreas-kidney transplant, or awaiting a deceased donor kidney transplant. For type 2 diabetic patients, only kidney transplant from deceased or living donors are recommended. Patient survival after kidney transplant has been improving for all age ranges in comparison to the dialysis therapy. The main causes of mortality after transplant are cardiovascular and cerebrovascular events, infections and neoplasias. Five-year patient survival for type 2 diabetic patients is lower than the non-diabetics' because they are older and have higher body mass index on the occasion of the transplant and both pre- and posttransplant cardiovascular diseases prevalences. The increased postransplant cardiovascular mortality in these patients is attributed to the presence of well-known risk factors, such as insulin resistance, higher triglycerides values, lower HDL-cholesterol values, abnormalities in fibrinolysis and coagulation and endothelial dysfunction. In type 1 diabetic patients, simultaneous pancreas-kidney transplant is associated with lower prevalence of vascular diseases, including acute myocardial infarction, stroke and amputation in comparison to isolated kidney transplant and dialysis therapy. CONCLUSION: Type 1 and 2 diabetic patients present higher survival rates after transplant in comparison to the dialysis therapy, although the prevalence of cardiovascular events and infectious complications remain higher than in the general population.
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O transplante de pâncreas-rim (TSPR) é um dos tratamentos mais efetivos para o paciente com diabetes melito e insuficiência renal crônica. Métodos: Foram realizadas análises retrospectivas da sobrevida de 150 pacientes submetidos ao TSPR pela regressão de COX e determinação das curvas de Kaplan-Meier, além das análises uni - e multivariadas para identificação dos fatores de risco tradicionais e aqueles relacionados ao transplante. Resultados: As taxas de sobrevidas em um ano dos pacientes, dos enxertos renais e pancreáticos foram de 82,0%, 80,0% e 76,7%, respectivamente. Função retardada do enxerto renal (FRR) (P = 0,001, RR 5,41), rejeição aguda renal (P = 0,016, RR 3,36) e infecção intra-abdominal (IIA) (P < 0,0001, RR 4,15) foram os principais fatores de risco que influenciaram a sobrevida do paciente em um ano. A sobrevida do paciente em um ano esteve relacionada à ocorrência de FRR (P = 0,013, RC 3,39), à rejeição aguda renal (P = 0,001, RC 4,74) e à IIA (P = 0,003, RC 6,29). A sobrevida do enxerto pancreático em um ano esteve relacionada à IIA (P < 0,0001, RC 12,83), à trombose vascular (P = 0,002, RC 40,55), à rejeição aguda renal (P = 0,027, RC 3,06), ao sódio do doador > 155 mEq/L (P = 0,02, RC 3,27) e ao uso de dopamina > 7,6 µcg/kg/min (P = 0,046, RC 2,85). Discussão: A ocorrência de função retardada do enxerto renal e infecção intraabdominal teve impacto na sobrevida em um ano tanto do paciente quanto dos enxertos renal e pancreático
Simultaneous pancreas-kidney transplantation (SPKT) is one of the treatments for insulin-dependent patients with chronic renal failure. Methods: One-year patient and kidney allograft survival rates of 150 patients submitted to SPKT analyzed by COX regression and Kaplan-Meier. Uni- and multivariate analysis identified the risk factors involved with either allograft or patient survival. Results: One-year patient and kidney allograft survival rates were 82% and 80%, respectively. Delayed graft function from kidney (DGF) (P = 0.001, HR 5.41), acute kidney rejection (P = 0.016, HR 3.36) and intra-abdominal infection (IAI) (P < 0.0001, HR 4.15) were related to the 1-yr patient survival. One-year kidney allograft survival was also related to DGF (P = 0.013, OR 3.39), acute rejection (P = 0.001, OR 4.74) and IAI (P = 0.003, OR 6.29). Main risk factors for DGF: time on dialysis > 27 months (P = 0.046, OR 2.59), kidney cold ischemia time > 14 hours (P = 0.027, OR 2.94), donor age > 25 years (P = 0.03, OR 2.82) and donor serum sodium > 155 mEq/l (P < 0.0001, OR 1.09). Conclusions: Delayed kidney allograft function and IAI had an important impact on either patient or kidney allograft survival rates. Improving deceased donor care may reduce DGF occurrence.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Análisis de Supervivencia , Trasplante de Páncreas/estadística & datos numéricos , Trasplante de Páncreas/mortalidad , Trasplante de Páncreas , Trasplante de Riñón/estadística & datos numéricos , Trasplante de Riñón/mortalidad , Trasplante de RiñónRESUMEN
OBJECTIVES: Simultaneous pancreatic-renal transplant is an effective treatment for insulin-dependent patients with chronic renal failure. We sought to identify the main influences on pancreatic and patient survival rates after simultaneous pancreas-kidney transplants. PATIENTS AND METHODS: The 1-year patient and pancreas survival rates of 150 patients who had undergone simultaneous pancreas-kidney transplant were analyzed by the Cox proportional hazards regression model and the Kaplan-Meier method. Uni and multivariate analyses were performed in terms of transplant-, recipient-, and donor-related risk factors. RESULTS: At 1 year, patient and pancreatic allograft survival rates were 82% and 76.7%, respectively. Delayed graft function in the kidney (P = .001, HR 5.41), acute kidney rejection (P = .016, HR 3.36), and intra-abdominal infection (P < .0001, HR 4.15) were the main factors related to 1-year patient survival. Pancreatic allograft survival at 1 year was related to intra-abdominal infection (P < .0001, OR 12.83), vascular thrombosis (P = .002, OR 40.55), acute kidney rejection (P = .027, OR 3.06), donor sodium greater than 155 mEq/L (P = .02, OR 3.27), and dopamine administration exceeding 7.6 microg/kg/min (P = .046, OR 2.85). CONCLUSIONS: Delayed kidney allograft function and intra-abdominal infection had an important effect on both patient and pancreatic allograft survival rates.
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Supervivencia de Injerto , Trasplante de Riñón/mortalidad , Riñón/fisiopatología , Riñón/cirugía , Trasplante de Páncreas/mortalidad , Páncreas/fisiopatología , Páncreas/cirugía , Adolescente , Adulto , Brasil/epidemiología , Enfermedades Transmisibles/mortalidad , Enfermedades Transmisibles/fisiopatología , Funcionamiento Retardado del Injerto/mortalidad , Funcionamiento Retardado del Injerto/fisiopatología , Dopamina/efectos adversos , Femenino , Rechazo de Injerto/mortalidad , Rechazo de Injerto/fisiopatología , Humanos , Estimación de Kaplan-Meier , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Trasplante de Páncreas/efectos adversos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Sodio/sangre , Análisis de Supervivencia , Trombosis/mortalidad , Trombosis/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Thrombotic microangiopathy (TMA) is rare after transplantation and is associated with a high incidence of kidney graft dysfunction. Between December 2000 and March 2006, 136 simultaneous pancreas-kidney transplantations were performed with an incidence of TMA of 5.1% (71.4% localized to kidney allograft). All cases were diagnosed during the first three months and were attributed to tacrolimus; 74% were women. Systemic TMA presented higher values of lactate dehydrogenase (2658 +/- 659 U/L vs. 1331 +/- 473 U/L, p = 0.04) and a greater decrease in hematocrit (45.8 +/- 17.7% vs. 19.2 +/- 6%, p = 0.02) than in localized TMA. Acute kidney rejection complicated almost 90% of the cases with 43% of kidney graft lost. Tacrolimus was switched to sirolimus and fresh-frozen plasma was administered. Creatinine clearance after a mean follow-up of two yr was 100.7 mL/min/1.73 m(2) and 57.9 mL/min/1.73 m(2) in patients with systemic and localized TMA, respectively. In conclusion, sirolimus is an alternative to TMA associated with tacrolimus.