RESUMEN
Non-insulin-dependent (type II) diabetes mellitus (NIDDM) is characterized by hyperglycaemia and insulin resistance, and affects nearly 5% of the general population. Inherited factors are important for its development, but the genes involved are unknown. We have identified a large pedigree in which NIDDM, in combination with a sensorineural hearing loss, is maternally inherited. The maternal inheritance and the observed decrease in mitochondrial enzyme activities of the respiratory chain indicate a genetic defect in the mitochondrial DNA. An A to G transition was identified at nucleotide 3,243, a conserved position in the mitochondrial gene for tRNA(Leu)(UUR). This mutation cosegregates with the disease in this family and is absent in controls, and indicates that a point mutation in mitochondrial DNA is a pathogenetic factor for NIDDM.
Asunto(s)
ADN Mitocondrial/genética , Sordera/genética , Diabetes Mellitus Tipo 2/genética , Mutación Puntual , ARN de Transferencia de Leucina/genética , ARN/genética , Secuencia de Bases , Células Cultivadas , Niño , ADN Mitocondrial/aislamiento & purificación , Sordera/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Tamización de Portadores Genéticos , Células HeLa , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Músculos/metabolismo , Oligodesoxirribonucleótidos , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , ARN Mitocondrial , Mapeo RestrictivoRESUMEN
AIMS: To examine a disputed association between the Lewis(a(-)b(-)) phenotype and Type 1 diabetes (T1D). METHODS: Lewis red blood cell phenotyping was performed for 97 T1D White patients and 100 control subjects using monoclonal antibodies. Two historical cohorts were also included as a control population. RESULTS: T1D patients had a lower frequency (4.1%) of Lewis(a(-)b(-)) blood group compared with simultaneously tested healthy control subjects (10.0%) and the historical control group (11.1%, P = 0.02). Male T1D patients showed a Lewis(a(-)b(-)) frequency of 8.0%, which was similar to both matched healthy male donors (9.8%) and historical (9.5%) male control subjects. Unexpectedly, none of the female T1D patients displayed Lewis(a(-)b(-)) phenotype, vs. 10.3% and 10.8% of female control subjects (P = 0.039 and 0.017). CONCLUSIONS: The Lewis(a(-)b(-)) phenotype occurs less frequently in T1D compared with healthy control subjects with a strong female gender bias.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Infecciones por Helicobacter/sangre , Helicobacter pylori/inmunología , Antígenos del Grupo Sanguíneo de Lewis/genética , Adolescente , Adulto , Anciano , Anticuerpos Antibacterianos/análisis , Diabetes Mellitus Tipo 1/sangre , Femenino , Humanos , Inmunofenotipificación , Antígenos del Grupo Sanguíneo de Lewis/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Factores SexualesRESUMEN
The risk of cardiovascular morbidity and mortality is highly increased in patients with diabetic nephropathy. Postulating that the generalized vasculopathy observed in these patients may enhance transcapillary filtration of lipids and lipoproteins resulting in a more atherogenic interstitial lipid profile, we set out to analyze the composition of their interstitial fluid. We studied healthy control subjects (n = 9), normoalbuminuric insulin-dependent diabetes mellitus (IDDM) patients (n = 16), and IDDM patients with diabetic nephropathy (n = 11) matched for age, body mass index, smoking habits, duration of diabetes, and metabolic control. Interstitial fluid was collected after an overnight fast by applying mild suction (200 mmHg) to the skin. Interstitial apolipoprotein A-I (apoA-I) levels were significantly lower in patients with nephropathy (0.18 +/- 0.10 milligram [mean +/- SD]) compared with normoalbuminuric diabetic patients (0.29 +/- 0.08 milligram) and healthy control subjects (0.30 +/- 0.09 milligram). Interstitial apolipoprotein B:apoA-I ratios tended to be higher in patients with diabetic nephropathy. In these patients, normal interstitial low-density lipoprotein cholesterol concentrations were observed in the presence of lower apoA-I levels. Transcapillary filtration of apoA-I was significantly lower in patients with diabetic nephropathy. Furthermore, an altered multiple regression model explaining interstitial apoA-I levels was observed in diabetic nephropathy. In this model, transcapillary protein (IgG) filtration and serum apoA-I levels no longer explained interstitial apoA-I levels. If we assume that interstitial apoA-I is involved in reverse cholesterol transport, these data suggest a more atherogenic interstitial lipoprotein profile in IDDM patients with nephropathy.
Asunto(s)
Apolipoproteína A-I/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Nefropatías Diabéticas/metabolismo , Adulto , Apolipoproteínas/sangre , Apolipoproteínas/metabolismo , Capilares/metabolismo , Enfermedades Cardiovasculares/etiología , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/complicaciones , Espacio Extracelular/metabolismo , Humanos , Metabolismo de los Lípidos , Lípidos/sangre , Lipoproteínas/sangre , Lipoproteínas/metabolismo , Masculino , Persona de Mediana Edad , Análisis de Regresión , Factores de RiesgoRESUMEN
We have recently reported an A to G transition at nucleotide position 3243 in the mitochondrial DNA (mtDNA) tRNA(Leu(UUR)) gene in a large family with non-insulin-dependent diabetes mellitus (NIDDM). Characteristic was its maternal transmission and an associated sensorineural hearing loss. In a screening of a Dutch and French NIDDM population for the presence of the tRNA(Leu(UUR)) mutation we identified two new pedigrees in which NIDDM is present in combination with deafness. The mode of inheritance agrees with a maternal one. This result shows that patients with a phenotype of NIDDM and deafness can be identified within groups of NIDDM patients based on the tRNA(Leu(UUR)) mutation. The same mutation has also been linked to the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). How the same mutation can give rise to different clinical phenotypes is not clear. We obtained the complete mtDNA sequence from our initial pedigree and identified a number of additional mutations that could confer the phenotype of the tRNA(Leu(UUR)) mutation to diabetes. We examined the presence of these additional, potentially pathogenic mutations in the mtDNA from the two new pedigrees and from a previously described British pedigree. The absence of these mutations in all three pedigrees shows that the tRNA(Leu(UUR)) mutation alone associates with the phenotype of NIDDM and deafness. We conclude that maternally inherited diabetes and deafness is a distinct subtype of diabetes that is associated with a single mitochondrial tRNA(Leu(UUR)) mutation. We propose the abbreviation MIDD for this particular subtype.
Asunto(s)
ADN Mitocondrial/genética , Sordera/genética , Diabetes Mellitus Tipo 2/genética , Pérdida Auditiva Sensorineural/genética , Mutación Puntual , Polimorfismo de Longitud del Fragmento de Restricción , ARN de Transferencia de Leucina/genética , Secuencia de Bases , Femenino , Humanos , Síndrome MELAS/genética , Masculino , Datos de Secuencia Molecular , Madres , Conformación de Ácido Nucleico , Sondas de Oligonucleótidos , Linaje , Reacción en Cadena de la Polimerasa , ARN de Transferencia de Leucina/químicaRESUMEN
Adequate metabolic control is central to the concept of islet transplantation, but has received limited attention. We studied metabolic control in 8 dogs at 6-9 months after intrasplenic autografting of approximately 25% of the normal mass islets--as compared to 30 controls. A similar posttransplant reduction to approximately 25% of the insulin secretory capacity as assessed by intravenous arginine stimulation during 35 mM glucose clamps, mirrored the reduction of the islet mass. Postprandially, in contrast, the insulin response had increased to 140% in the islet recipients--with a concomitant rise of glycemia to approximately 8.5 mM. Posttransplant, the insulin secretory capacity correlated both with the index of insulin action (which averaged 55% of the normal value) as assessed by euglycemic hyperinsulinemic clamps, and--inverse--with the postprandial glucose excursions. Because insulin action did not correlate with postprandial glucose, the insulin secretory capacity appears to be the primary determinant of the impaired glucose tolerance. Marked postprandial hyperglucagonemia, and a virtually absent pancreatic polypeptide response in the grafted animals, may also have contributed to the impaired glucose tolerance. Posttransplant, infusion of a physiological dose of the gut hormone glucagon-like peptide-1 during 8.5 mM glucose clamps--mimicking the postprandial glycemia--potentiated glucose-stimulated insulin 175%. Thus, after transplantation of a suboptimal islet mass, postprandial glucose excursions are restrained by hyperglycemic potentiation of the entero-insular axis, which may account for the difference in the insulin response to the intravenous and oral challenges. Because, the insulin secretory capacity reflects the islet mass and appears to be the major determinant of glucoregulation, transplantation of a larger islet mass may allow near-normal glycemic control.
Asunto(s)
Insulina/metabolismo , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/metabolismo , Fragmentos de Péptidos/farmacología , Animales , Perros , Polipéptido Inhibidor Gástrico/farmacología , Glucagón/farmacología , Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/fisiologíaRESUMEN
OBJECTIVES: To examine the effect of diabetes mellitus on the pharmacokinetics of tolrestat and to investigate its effect on red blood cell sorbitol levels according to a new pharmacodynamic model for this class of drugs. METHODS: Single and multiple doses of tolrestat (200 mg/twice a day) were administered to 12 patients with insulin-dependent (type I) diabetes and 12 healthy volunteers in an open parallel trial. RESULTS: Tolrestat disposition was characterized by first-order absorption and biexponential disposition: In normal subjects the terminal disposition half-life (t1/2) was 13 +/- 3 hours (mean +/- SD) and the apparent oral clearance (CL/F) was 48 +/- 9 ml/hr/kg, similar to the values in patients with type I diabetes mellitus (t1/2 = 14 +/- 4 hours; CL/F = 55 +/- 10 ml/hr/kg). Red blood cell sorbitol concentrations, which declined because of tolrestat's inhibition of aldose reductase, were characterized by an indirect-response model including a 50% inhibition constant (IC50) for production of sorbitol by aldose reductase. The removal of sorbitol (kout) was slower in patients with diabetes. The plasma IC50 averaged 2.0 +/- 1.3 micrograms/ml in normal subjects and 2.5 +/- 1.9 micrograms/ml in patients with diabetes. IC50 values expressed in free (unbound) concentrations (fu = 0.64%), which ranged from 12 to 16 ng/ml, were similar to the in vitro IC50 for inhibition of sorbitol accumulation in human red blood cells. CONCLUSIONS: Tolrestat pharmacokinetics were similar in normal subjects and in patients with diabetes; however, the patients with diabetes had higher baseline sorbitol levels (11 versus 5 nmol/ml for normal subjects) and slower sorbitol efflux rates. The proposed biochemically realistic, dynamic model characterized well the red blood cell sorbitol response patterns after administration of single and multiple doses of tolrestat.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Inhibidores Enzimáticos/farmacología , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Naftalenos/farmacología , Sorbitol/sangre , Adulto , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Masculino , Análisis por Apareamiento , Naftalenos/farmacocinéticaRESUMEN
BACKGROUND: Monitoring of insulin secretion and sensitivity after pancreas transplantation remains a practical problem. METHODS: We introduced the simple structural model, continuous infusion of glucose with model assessment (CIGMA), to obtain insulin secretion and insulin sensitivity estimations after 35 successful simultaneous pancreas-kidney transplantations. Eighteen non-diabetic kidney transplant recipients were used as control group. RESULTS: The baseline characteristics were equal between the two groups except for higher fasting insulin levels in the pancreas transplant group. After the 1-hr CIGMA glucose load, the pancreas transplant group reached a mean +/- SD blood glucose of 8.2+/-1.7 mmol/L compared with 7.3+/-1.0 mmol/L in the control group (P = 0.05). Concurrent stimulated insulin and C-peptide levels were 48+/-28 mU/L and 2.3+/-0.9 nmol/L in the pancreas transplant group compared with 36+/-21 mU/L and 2.9+/-1.1 nmol/L in the control group (P = 0.1 and P = 0.03, respectively). Both the CIGMA estimation for secretion as well as the CIGMA estimation for sensitivity were lower in pancreas transplant group (P = 0.003 and P = 0.01, respectively). Mean +/- SE coefficients of variation for the model estimations were 15+/-4% for secretion and 17+/-6% for sensitivity. CONCLUSIONS: We conclude that CIGMA can be used clinically to evaluate carbohydrate metabolism in pancreas-kidney transplant recipients. These patients have a reduction in insulin secretory capacity and evidence of more insulin resistance than non-diabetic kidney transplant recipients.
Asunto(s)
Glucosa , Resistencia a la Insulina , Insulina/metabolismo , Trasplante de Riñón , Trasplante de Páncreas , Adulto , Femenino , Humanos , Infusiones Intravenosas , Secreción de Insulina , Masculino , Persona de Mediana Edad , Estudios Prospectivos , SolucionesRESUMEN
Pancreatic graft procurement, preservation, and transplantation surgery may result in damage to and loss of the integrity of endocrine cells and consequently in leakage of cell products into the insular vascular capillaries. Thus, the amount of alpha-, beta-, and pancreatic polypeptide (PP) cell products released into the vascular space of the recipient immediately after graft reperfusion may reflect islet cell injury. To test this hypothesis, we assessed glucagon, PP, C-peptide, and insulin levels in a prospective study of 22 consecutive renal-pancreatic transplantations. Transplantation-related parameters were used to account for differences in hormone release. Five grafts were preserved using Euro-Collins preservation fluid and 17 grafts were preserved using University of Wisconsin solution (UW). The first sign of a reinstalled physiological axis was the decrease of the blood glucose concentration after a median duration of 40 min (range 5-90 min) and the association of the recipient's ambient blood glucose levels with insulin release between 25 and 180 min after reperfusion. The delay period before a fall in blood glucose was observed correlated with cold ischemia time (rs = 0.73, P < 0.001, n = 21). An immediate and marked increase in plasma levels of glucagon (from 180 +/- 18 to 585 +/- 99 ng/L, mean +/- SEM), PP (from 57 +/- 8 to 122 +/- 13 pmol/L), C-peptide (from < 0.06 +/- 0.02 to 5.43 +/- 0.63 nmol/L), and insulin (from 0.15 +/- 0.21 to 2.05 +/- 0.26 nmol/L) was observed. C-peptide release correlated with glucagon (r = 0.76, P < 0.001) and PP (r = 0.60, P < 0.01). The hormone release was compared with computed tomography scans that were performed in the immediate postoperative period in 15 UW-preserved allografts. The diameter of the pancreatic head was increased and ranged from 4.5 to 7.7 cm (mean 6.2 cm). Peroperative C-peptide release significantly correlated with morphological graft changes reflected by the pancreatic head diameter (r = 0.58, P = 0.02). In a stepwise multiple regression analysis, cold ischemia time was a significant factor for the release of PP (r2 = 0.18, P = 0.049) and C-peptide (r2 = 0.35, P = 0.004). We suggest that peroperative hormone release reflects endocrine tissue damage. Furthermore, cold ischemia time may jeopardize the pancreatic allograft after relatively short preservation times, even when UW is used.
Asunto(s)
Isquemia/complicaciones , Trasplante de Páncreas/efectos adversos , Páncreas/irrigación sanguínea , Hormonas Pancreáticas/metabolismo , Adulto , Glucemia/análisis , Péptido C/análisis , Frío , Femenino , Humanos , Masculino , Persona de Mediana Edad , Preservación de Órganos , Polipéptido Pancreático/metabolismo , Análisis de Regresión , Factores de Tiempo , Obtención de Tejidos y ÓrganosRESUMEN
Corneal epithelial permeability for fluorescein was determined after provocation by a local anesthetic in 18 non-insulin-dependent diabetes mellitus (NIDDM) patients, 23 insulin-dependent diabetes mellitus (IDDM) patients, and 22 healthy controls to evaluate the corneal epithelial barrier function in diabetes. All volunteers had Oxybuprocaine instilled into one eye and saline into the other eye. The epithelial permeability values were determined by fluorophotometry, and the ratio between both eyes was calculated for each individual. The mean permeability values of the saline-instilled eyes in the diabetic patients did not differ significantly from those in the healthy controls (P greater than 0.2). The individual ratios between Oxybuprocaine- and saline-instilled eyes in the NIDDM and IDDM patients differed significantly from those in the healthy controls (mean ratios: 2.6, 1.9, and 1.0, respectively; P less than 0.002). The permeability ratios and the percentage glycosylated hemoglobin (HbAlc) were linearly correlated in the NIDDM patients but not in the IDDM patients (r = 0.73, P less than 0.001, and r = 0.09, P greater than 0.68, respectively). The results showed that the corneal epithelial barrier function in the diabetic patients was not impaired compared with that in the healthy controls. After provocation by a local anesthetic, the barrier function was impaired in the diabetic patients only.
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Córnea/fisiopatología , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Procaína/análogos & derivados , Adolescente , Adulto , Anciano , Córnea/efectos de los fármacos , Epitelio/efectos de los fármacos , Epitelio/fisiopatología , Fluoresceína , Fluoresceínas/farmacocinética , Fluorofotometría , Hemoglobina Glucada/análisis , Humanos , Persona de Mediana Edad , Permeabilidad , Procaína/farmacologíaRESUMEN
The physiological glucoregulatory mechanisms after islet transplantation have been incompletely investigated. We studied the insulin secretory capacity (ISC) by intravenous arginine stimulation during 35-mM glucose clamps, insulin action during hyperinsulinemic euglycemic clamps, and mixed-meal stimulation at 6-9 mo after intrasplenic islet autotransplantation in 8 dogs, as compared with 30 controls. The enteroinsular axis in the recipients was examined by infusion of porcine glucose-dependent insulinotropic polypeptide (GIP) and human glucagon-like peptide-1 (GLP-1) (7-36 amide) under 8.5-mM glycemic clamp conditions in order to mimic the postprandial glycemia after transplantation. The grafts comprised 25% of the native islet mass, and the ISC likewise averaged 25% of the control value. The postprandial insulin response, in contrast, had increased to 140% after transplantation--albeit with a concomitant glucose excursion to approximately 8.5 mM. Insulin action declined on average by 45% posttransplant. The ISC correlated both with the postprandial glucose excursion and insulin action in the grafted dogs. Insulin action did not correlate with the postprandial glucose excursion. Infusion of GIP had no effect, but GLP-1 nearly doubled glucose-stimulated insulin. Thus, a hyperglycemia-enhanced insulinotropic effect of GLP-1, and perhaps other gut hormones, may account for the difference in the insulin response to the intravenous and oral challenges. Because the ISC reflects the engrafted islet mass and appears to be the primary determinant of glucose tolerance, transplantation of higher islet doses should allow prolonged near-normal glucoregulation--at least in the autotransplant setting.
Asunto(s)
Glucemia/metabolismo , Insulina/metabolismo , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/metabolismo , Animales , Perros , Femenino , Polipéptido Inhibidor Gástrico/farmacología , Péptido 1 Similar al Glucagón , Glucosa/farmacología , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Hiperglucemia/metabolismo , Insulina/sangre , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Péptidos/farmacología , Periodo PosprandialRESUMEN
The relative influence of diabetes mellitus-related and physiological factors on vibration perception thresholds was assessed in 353 patients in a hospital-based setting (173 insulin-dependent and 180 non-insulin dependent patients, aged 51.1 +/- 15.9 years) and 80 healthy controls (aged 43.3 +/- 15.2 years) employing a Biothesiometer. Vibration perception thresholds were bilaterally measured at the thumbs, medial malleoli and halluces. Sixty (17.0%) older patients had off-scale thresholds (> 50 V). As no systematic side differences were found, values of contralateral sites were averaged. Considering the effects of age, height, gender and skin temperature in controls, age accounted for 46.7 and 52.2% threshold variance at the ankles and halluces, respectively, while height explained 5.1 and 5.1%, respectively. At the thumbs, only age was of relevance. Age relationships with vibration thresholds in health did not differ from published reports at any site. In the patient group, influences of age, height, gender, skin temperature, years from diagnosis, HbAlc, serum creatinine, drop in systolic blood pressure on standing, and ankle/arm blood pressure indices were assessed for each type of diabetes. For both types, age and height again had relevant effects at the lower extremities as did age and gender at the thumbs. Skin temperature was only marginally significant at the halluces of NIDDM patients. Of the disease-related factors, HbAlc had the strongest effect: for both IDDM and NIDDM higher levels were associated with lower vibration sensitivity. Increasing disease duration led to significantly higher thresholds in IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Umbral Sensorial , Adulto , Factores de Edad , Análisis de Varianza , Tobillo , Estatura , Dedos/inervación , Hemoglobina Glucada/análisis , Humanos , Persona de Mediana Edad , Valores de Referencia , Análisis de Regresión , Caracteres Sexuales , Temperatura Cutánea , Dedos del Pie/inervación , VibraciónRESUMEN
This review provides a compact overview on the contribution of mutations in mtDNA to the pathogenesis of diabetes mellitus, with emphasis on the A3243G mutation in the tRNA(Leu, UUR) gene. This mutation associates in most individuals with maternally inherited diabetes and deafness (MIDD) whereas in some other carriers the MELAS syndrome or a progressive kidney failure is seen. Possible pathogenic mechanisms are discussed especially the question why particular mutations in mtDNA associate with distinct clinical entities. Mutations in mtDNA can affect the ATP production, thereby leading to particular clinical phenotypes such as muscle weakness. On the other hand mtDNA mutations may also alter the intracellular concentration of mitochondrial metabolites which can act as signalling molecules, such as Ca or glutamate. This situation may contribute to the development of particular phenotypes that are associated with distinct mtDNA mutations.
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ADN Mitocondrial/genética , Diabetes Mellitus/genética , Mutación , Adenosina Trifosfato/metabolismo , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/terapia , Humanos , Fenotipo , ARN de Transferencia de Leucina/genéticaRESUMEN
Diabetes mellitus comprises a number of diseases with hyperglycemia as hallmark. Currently, multiple genetic factors are being recognized which contribute to the development of diabetes or which may modulate its clinical expression. This review presents an overview of our current knowledge on a diabetic subtype which associates with a single mutation in mitochondrial DNA. Based on the triad of Maternal Inheritance, Diabetes and Deafness we propose the name Maternally Inherited Diabetes and Deafness (MIDD) for this syndrome. In Northwestern Europe MIDD affects approximately 1.3% of all diabetic individuals.
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ADN Mitocondrial/genética , Sordera/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Impresión Genómica , Adulto , Niño , Femenino , Humanos , Masculino , Mutación Puntual , Factores Sexuales , SíndromeRESUMEN
Tolrestat is an aldose reductase inhibitor that is undergoing extensive clinical investigation for the treatment of diabetic complications including polyneuropathy. As part of a larger European trial, we report here the results from a single clinical center on the efficacy of tolrestat in patients with confirmed diabetic neuropathy. The trial was conducted in two phases: a 6-month double-blind, placebo-controlled phase, and a 6-month open-label phase in which most patients were treated with tolrestat. Following the double-blind phase, motor and sensory nerve conduction velocity had significantly deteriorated in the placebo group, which did not occur during treatment with tolrestat. Deterioration of vibration threshold also occurred during placebo treatment and did not occur with tolrestat. During the open-label phase, motor nerve condition velocity and vibration threshold improved with tolrestat. Moreover, the deterioration of motor nerve conduction velocity and vibration threshold that had occurred in patients initially treated with placebo, was stopped during open-label treatment with tolrestat.
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Aldehído Reductasa/antagonistas & inhibidores , Neuropatías Diabéticas/tratamiento farmacológico , Naftalenos/uso terapéutico , Neuropatías Diabéticas/fisiopatología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Examen NeurológicoRESUMEN
BACKGROUND: The insertion-deletion (I/D) polymorphism of the angiotensin converting enzyme gene is a diallelic polymorphism that constitutes a genetic influence on the progression of renal diseases such as IgA nephropathy. Patients with the DD genotype have an accelerated progression towards end stage renal failure in these diseases. The role of the I/D polymorphism in the pathogenesis of diabetic nephropathy in IDDM is unresolved. PATIENTS AND METHODS: We therefore set out to study the contribution of the I/D polymorphism in 79 patients (age 39.5 +/- 7.6 years (mean +/- SD) with end stage renal failure due to diabetic nephropathy, who were recipients of a combined kidney-pancreas transplantation (n = 60), or who were on the waiting list for such a procedure (n = 19). The control series consisted of 82 patients (age 39.5 +/- 9.6 years) without microalbuminuria after fifteen years of IDDM. RESULTS: The ACE genotype distribution in patients was not in accordance with the Hardy-Weinberg equilibrium due to a significant overrepresentation of the DD genotype (X2 = 8.9, p = 0.01). This resulted in a significant increase of the D-allele frequency in the cases compared to controls (X2 = 4.9, p = 0.03). The presence of one D-allele did not increase the risk of end stage renal failure (odds ratio ID/II = 1.0, 95% CI 0.4-2.2). The presence of the DD genotype increased the risk of end stage renal failure twofold compared to the other genotypes (odds ratio 2.1, 95% CI 1.1-4.0). The risk estimate seemed slightly higher in patients with good metabolic control (odds ratio 2.6, 95% CI 1.0-7.1), than in patients with poor control (odds ratio 1.6, 95% CI 0.59-4.3). CONCLUSION: It is concluded that the risk of end-stage renal failure in patients with IDDM is twofold increased in patients with the DD genotype as compared to patients with other genotypes.
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Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/genética , Fallo Renal Crónico/genética , Peptidil-Dipeptidasa A/genética , Adulto , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/etiología , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Fallo Renal Crónico/etiología , Masculino , Polimorfismo Genético , Medición de RiesgoRESUMEN
We analyzed the overall results of 24 simultaneous pancreas and kidney transplantations (SPK), performed in our hospital between April 1986 and June 1990. All patients had type I diabetes mellitus and end-stage renal failure. We used bladder drainage of the pancreatic exocrine secretions through a duodenocystostomy. The blood vessels of both grafts were anastomosed to the iliac vessels. The immunosuppressive management was triple-therapy with cyclosporin, azathioprine and prednisone. All organs were transplanted without matching donors and recipients for HLA. At the time of transplantation, mean recipient age was 37 yr; the average duration of diabetes was 22 yr. After disappointing results in the first 4 patients, the pancreas was placed intraperitoneally instead of extraperitoneally and the antibiotic drug regimen was altered. In the second group (n = 20), patient survival was 100%; 1-yr pancreas and kidney graft survival were 65 and 62%, respectively. Duration of hospitalization and pancreas and kidney graft loss were positively correlated with the number of rejection episodes. After 1 yr of follow-up, the mean creatinine clearance was 62 ml/min and the mean HbA1c was 5.5%. Blood glucose levels and oral glucose tolerance tests were also normal. We conclude that patient and graft survival after SPK are satisfactory, although rejection-related morbidity is still a major problem.
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Diabetes Mellitus Tipo 1/cirugía , Nefropatías Diabéticas/cirugía , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Trasplante de Páncreas , Adulto , Diabetes Mellitus Tipo 1/complicaciones , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Reacción Huésped-Injerto , Humanos , Terapia de Inmunosupresión , Fallo Renal Crónico/complicaciones , Trasplante de Riñón/métodos , Masculino , Persona de Mediana Edad , Trasplante de Páncreas/métodos , Complicaciones Posoperatorias/epidemiología , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Asymptomatic myocardial disease has been described in relation to longstanding insulin-dependent diabetes mellitus. To detect myocardiopathy in a selected group of 14 patients (aged 21-38 years, duration of diabetes 10-20 years) with insulin-dependent diabetes, we have performed equilibrium gated nuclear angiography with Fourier filtered analysis. These patients had no clinical or echocardiographic signs of cardiac disease. We examined six patients with severe proliferative retinopathy, and eight patients with no signs of retinopathy at fluorescence angiography. The global ejection fraction was within normal limits in all cases. Fourier analysis of scintigraphic data, however, revealed wall motion abnormalities (abnormal amplitude and phase shift) of the left ventricle in all 14 patients, particularly in the anterior and/or septal region. No correlation was found between the degree of wall motion disturbances and prevailing blood glucose or HbA1 concentrations or the presence of retinopathy or autonomic neuropathy. It is concluded that equilibrium gated nuclear angiography in combination with Fourier filtered analysis is a sensitive method of detecting myocardial abnormalities in patients suffering from insulin-dependent diabetes mellitus without cardiac symptoms.
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Cardiomiopatías/diagnóstico por imagen , Diabetes Mellitus Tipo 1/complicaciones , Corazón/diagnóstico por imagen , Adulto , Cardiomiopatías/fisiopatología , Retinopatía Diabética/complicaciones , Femenino , Análisis de Fourier , Humanos , Masculino , Cintigrafía , Volumen Sistólico , Medronato de Tecnecio Tc 99mRESUMEN
Maturity-onset diabetes of the young (MODY) exhibits an autosomal dominant pattern of inheritance and can be divided in at least five subtypes (MODY 1 to 5), each subtype being caused by mutations in a specific gene. The unambiguous molecular diagnosis of the specific MODY subtype facilitates an early diagnosis of diabetes and can help to reduce the development of diabetic complications. Furthermore, MODY2 patients generally have a milder clinical course and fewer complications than MODY3 patients, who consequently require a more aggressive therapeutic approach.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Insulina/metabolismo , Mutación/genética , Adulto , Glucemia/metabolismo , Análisis Mutacional de ADN , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/clasificación , Diabetes Mellitus Tipo 2/epidemiología , Pruebas Genéticas , Glucoquinasa/deficiencia , Glucoquinasa/genética , Humanos , Incidencia , Insulina/sangre , Islotes Pancreáticos/metabolismo , Países Bajos/epidemiología , Índice de Severidad de la EnfermedadRESUMEN
MIDD is a maternally inherited disorder with diabetes and impaired hearing due to a reduced perception of high tones. The disorder is caused by an A to G mutation at position 3243 in mitochondrial DNA. Approximately 1.3% of insulin-dependent diabetic patients in the Netherlands has this mutation. The main defect in these patients seems to be a reduced secretion of insulin by the pancreas in response to glucose stimulation.
Asunto(s)
ADN Mitocondrial/genética , Sordera/genética , Diabetes Mellitus/genética , Pérdida Auditiva de Alta Frecuencia/genética , Insulina/metabolismo , Mutación/genética , Adenina/metabolismo , Adulto , Sordera/epidemiología , Complicaciones de la Diabetes , Diabetes Mellitus/epidemiología , Femenino , Guanina/metabolismo , Pérdida Auditiva de Alta Frecuencia/epidemiología , Humanos , Secreción de Insulina , Masculino , Países Bajos/epidemiología , Páncreas/metabolismo , Prevalencia , ARN de Transferencia/genéticaRESUMEN
Diabetes mellitus comprises many subtypes, the pathogenesis of each of which involves a combination of inherited and environmental factors. Recently a new subtype of diabetes mellitus was recognized in a Dutch pedigree, designated as 'maternally inherited diabetes and deafness' (MIDD). Impaired hearing is an associated phenomenon of the disease. Approximately 1.3% of all diabetic cases in the Netherlands exhibit the MIDD subtype. MIDD shows a strictly maternal heredity. In MIDD there is a guanine-for-adenine substitution at position 3243 in mitochondrial DNA. Mitochondria carrying this mutation exhibit a decreased functionality. In carriers of the MIDD mutation the insulin secretion by the pancreas in response to stimulation by glucose is impaired.