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1.
Nat Genet ; 28(4): 365-70, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11479539

RESUMEN

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.


Asunto(s)
Cromosomas Humanos Par 11/genética , Subunidades gamma de la Proteína de Unión al GTP , Lipodistrofia/congénito , Lipodistrofia/genética , Proteínas/genética , Acantosis Nigricans/complicaciones , Cromosomas Humanos Par 9/genética , Análisis por Conglomerados , Análisis Mutacional de ADN , Complicaciones de la Diabetes , Femenino , Genes Recesivos , Ligamiento Genético , Marcadores Genéticos , Pruebas Genéticas , Haplotipos , Hepatomegalia/complicaciones , Proteínas de Unión al GTP Heterotriméricas/genética , Humanos , Hiperandrogenismo/complicaciones , Hipertrigliceridemia/complicaciones , Resistencia a la Insulina/genética , Líbano/epidemiología , Lipodistrofia/complicaciones , Lipodistrofia/epidemiología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Noruega/epidemiología , Especificidad de Órganos , Linaje , Estructura Terciaria de Proteína , Proteínas/metabolismo , Homología de Secuencia de Aminoácido
2.
J Clin Invest ; 80(6): 1607-12, 1987 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-3316278

RESUMEN

Anti-islet cell and anti-insulin antibody production was studies over a 12-mo period in 82 recently diagnosed diabetics randomly receiving either cyclosporin or placebo. Cyclosporin had only minimal effects on the production of anti-islet cell antibodies whether directed to islet cytoplasmic (immunofluorescence) or membrane (cytotoxicity assay) antigens even in patients undergoing remission. These data suggest that these antibodies do not play a major role in the pathogenesis of the disease particularly since their (irregular) presence is not predictive of the clinical response to cyclosporin. Conversely, cyclosporin completely suppressed the synthesis of antibodies elicited by exogenous insulin irrespective of the insulin doses received, and decreased the autoantibody production against thyroid antigens, indicating that cyclosporin has variable effects on antibody production against various antigens.


Asunto(s)
Formación de Anticuerpos/efectos de los fármacos , Ciclosporinas/farmacología , Diabetes Mellitus Tipo 1/inmunología , Autoanticuerpos/análisis , Ensayos Clínicos como Asunto , Citotoxicidad Inmunológica , Humanos , Insulina/inmunología , Islotes Pancreáticos/inmunología , Placebos , Distribución Aleatoria , Glándula Tiroides/inmunología
3.
J Clin Invest ; 52(12): 3190-200, 1973 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-4750449

RESUMEN

The metabolic response to the first fast experienced by all mammals has been studied in the newborn rat. Levels of fuels and hormones have been compared in the fetal and maternal circulations at term. Then, after cesarean section just before the normal time of birth, sequential changes in the same parameters were quantified during the first 16 h of the neonatal period. No caloric intake was permitted, and the newborns were maintained at 37 degrees C. Activities of three key hepatic enzymes involved in glucose production were estimated. Marked differences in maternal and fetal hormones and fuels were observed. Lower levels of glucose, free fatty acids, and glycerol but higher levels of lactate, alpha-amino nitrogen, alanine, and glutamine were present in the fetus. Pyruvate, glutamate, and ketone bodies were not significantly different. The combination of a strikingly higher fetal immunoreactive insulin and a slightly lower immunoreactive glucagon (pancreatic) resulted in a profound elevation in the insulin-to-glucagon ratio, a finding consistent with an organism in an anabolic state. The rat at birth presents a body composition with respect to fuels available for mobilization and conversion which is dominated by carbohydrate and protein, since little fat is present. However, at birth a transient period of hypoglycemia occurred, associated with a rapid fall in insulin and rise in glucagon, causing reversal of the insulin-to-glucagon relationship toward ratios such as were observed in the mother. After a lag period, hepatic activities of phosphorylase, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased. Concurrent with these enzyme changes, the blood glucose returned to levels at or above those of the fetus. Interestingly, the fall observed in levels of the gluconeogenic precursors, lactate and amino acids, preceded the rise in enzyme activities and restoration of blood glucose. After 4 h, however, hypoglycemia recurred, during a period of decreasing hepatic glycogen content and blood lactate, pyruvate, and glycerol levels but of stable or increasing amino acid concentrations. Hepatic gluconeogenesis in this phase of depleted glycogen stores was insufficient to maintain euglycemia. Substrates derived from fat showed early changes of smaller magnitude. The rise in free fatty acids which occurred was less than twofold the value at birth, though this rise persisted up to 6 h. Whereas glycerol rose transiently, acetoacetate did not change and beta-hydroxybutyrate concentration fell. Both ketone bodies showed a marked rise at 16 h. at a time of diminished free fatty acid levels. Plasma growth hormone, though higher in the fetal than the maternal circulation, showed no consistent change during the period of observation. The changes in levels of the endocrine pancreatic hormones at birth were appropriate in time, magnitude, and direction to be implicated as prime regulators of the metabolic response during the neonatal period in the rat.


Asunto(s)
Aminoácidos/metabolismo , Animales Recién Nacidos , Metabolismo de los Hidratos de Carbono , Glucagón/metabolismo , Insulina/metabolismo , Hígado/metabolismo , Acetoacetatos/sangre , Aminoácidos/sangre , Animales , Glucemia/análisis , Ácidos Grasos/sangre , Glucagón/sangre , Glucosafosfato Deshidrogenasa/análisis , Glucosiltransferasas/análisis , Glicerol/sangre , Hidroxibutiratos/sangre , Hipoglucemia/fisiopatología , Insulina/sangre , Lactatos/sangre , Hígado/enzimología , Glucógeno Hepático/metabolismo , Piruvatos/sangre , Ratas
4.
J Clin Invest ; 90(6): 2242-50, 1992 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-1469084

RESUMEN

The association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-on-set IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB1*03, DRB1*04, DQB1*0201, DQB1*0302, DQA1*0301, and DQA1*0501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB1*03-DQB1*0201 and the DRB1*0402 or DRB1*0405-DQB1*0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3/non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage of DR3/4 genotypes. These non-DR3/non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Genes MHC Clase II , Antígenos HLA-DR/genética , Adolescente , Adulto , Factores de Edad , Alelos , Antígenos HLA-DQ/genética , Haplotipos , Humanos , Factores de Riesgo
5.
Diabetes ; 26(4): 300-7, 1977 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-849811

RESUMEN

The glucagon-secreting potency of 22 amino acids was investigated in the rat isolated perfused pancreas. Arginine and the structurally related amino acids were the most potent A2-cell stimulators that induced a biphasic and sustained glucagon release. Dose-response curver were different for L(+) and D(+)arginine, and the suppressor effect of glucose on the response to L(+) arginine was not detected in the presence of D(+) arginine or homoarginine. Citrulline was the only exception among the arginine-related amino acids; it displayed neither stimulatory nor inhibitory potency on glucagon release. The A2-cell response to D(+) amino acids and artificial analogues of arginine is a strong case for the theory of amino acid receptors' triggering the release of the hormone before (or in the absence of) further metabolism. The prominent rank of arginine and ornithine amont stimulatory amino acids and some other physiologic evidence suggest that A2-cell may play a regulatory role in the metabolsm of ammonia by the liver.


Asunto(s)
Aminoácidos/farmacología , Glucagón/metabolismo , Páncreas/metabolismo , Animales , Arginina/análogos & derivados , Arginina/farmacología , Citrulina/farmacología , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Masculino , Ornitina/farmacología , Páncreas/efectos de los fármacos , Ratas , Estimulación Química
6.
Diabetes ; 35(2): 198-203, 1986 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-3510925

RESUMEN

The diabetic db/db mice of the C57 BL/KsJ strain display anti-islet immunity, thymic dysfunction, and lymphopenia. In the present work, lymphocytes, T-cells, and T-cell subsets were enumerated in thymus and spleen from diabetic db/db mice and their db/ + heterozygote littermates from the 10th day to the 10th month of life. A significant lymphopenia was detected in thymus and spleen from the second month on, involving specifically the T-cell compartment, as assessed by use of a monoclonal anti-Thy1 antibody in indirect fluorescence. The study of T-cell subsets by monoclonal anti-Lyt1 and anti-Lyt2 antibodies revealed a significant increase in Lyt1+ cells and a decrease in Lyt2+ cells, with a corresponding increase of the Lyt1+/Lyt2+ ratio. These anomalies appeared early in life, and were apparently linked neither with the degree of hyperglycemia nor with weight loss or infection. The T-cell depletion in thymus was more pronounced in young male (less than 3 mo) than in young female db/db mice. These alterations may correspond to an increase in the helper/suppressor-cytotoxic ratio and could be linked with the thymic anomalies present in these mice, contributing to the development of anti-islet autoimmunity.


Asunto(s)
Linfopenia/inmunología , Ratones Obesos/inmunología , Linfocitos T , Animales , Autoanticuerpos/inmunología , Linfocitos B , Glucemia/análisis , Peso Corporal , Perros , Insulina/sangre , Islotes Pancreáticos/inmunología , Recuento de Leucocitos , Macrófagos , Ratones , Ratones Endogámicos C57BL/inmunología , Ratas , Factores Sexuales , Bazo/citología , Timo/citología
7.
Diabetes ; 33(2): 135-40, 1984 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-6363167

RESUMEN

Anti-islet immunity was studied in six spontaneously insulin-dependent diabetic (IDD) dogs, using mouse islets of Langerhans cells as targets, in vitro. Insulinopenia was demonstrated in all dogs by an i.v. glucose tolerance test. A significant lymphocytopenia was detected in the peripheral blood of this diabetic group. Pancreatic tissue from one of these animals was obtained shortly after death and the islets displayed a marked loss in beta cells without significant changes in the other types of islet cells. No insulitis was observed. Circulating mononuclear cells from the diabetic dogs induced an increased basal insulin (IRI) release from islet cells and a suppressed stimulated IRI release. Damage to or depth of beta cells may account for these findings. The stimulated IRI release was also suppressed when islets were incubated with the diabetic sera + complement, while the D-cell response to arginine was not altered, and the A-cell response was reduced but not abolished. A lysis of islet cells in the presence of IDD sera + complement was demonstrated by an increased release of 51Cr from labeled cells. These anomalies were observed neither when complement was heat-inactivated nor in the presence of control sera + complement. Canine IDD may be a new animal model for the study of anti-islet cellular and humoral immunities.


Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Islotes Pancreáticos/inmunología , Animales , Cromo/metabolismo , Perros , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Recuento de Leucocitos , Linfocitos/inmunología , Ratones , Ratas
8.
Diabetes ; 24(9): 791-800, 1975 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-808437

RESUMEN

Eighteen diabetic patients with lactic acidosis (L.A.) were analyzed for possible causal factors, metabolic changes, and efficacy of treatment. An antecedent phenformin therapy was performed in fifteen cases and was associated with renal insufficiency in ten cases and liver disease in eight cases. Tissular anoxia of primary hemodynamic or respiratory origin was absent in all cases. The severe metabolic acidosis (pH m.93 +/- 0,03; HCO3-= 6 +/- 1 MM; PaCO2 = 18 +/- 2 MM. Hg) and hyperlactatemia (14.2 +/- 0.3 mM) were associated with high lactate/pyruvate ration (70 +/- 22). High alanine levels (up to 4.6 mM) were measured in some of these patients. High beta-hydroxybutrate levels were sometimes measured (up to 7.6 mM), and substantial amounts of acetoacetate were also detected in twelve cases. Glucagon level was always increased (1,050 +/- 240 pg./ml.), and insulin/glucagon ratio was low. Cortisol (49 +/- 10 mug./100 ml.) and HGH (10.8 +/- 0.6 ng./ml.) were also elevated. Increased plasma levels of phenformin were measured in five L.A. diabetic subjects (50 +/- 5 mug./ml.) by comparison with other phenformin-treated diabetic subjects. The specificity of the assay was investigated, and phenformin metabolites were characterized by thin-layer chromatography. Por the treatment of L.A., adjunction of dialysis and furosemide improved the efficacy of early and massive sodium bicarbonate infusion. It is suggested that accumulation of phenformin via renal insufficiency plays a determinant role in causing L.A. through an impairment of lactate metabolism in the liver. An accelerated epuration of the drug may be helpful in therapy of L.A. Phenformin treatment should be avoided in case of renal and/or liver insufficiency.


Asunto(s)
Cetoacidosis Diabética/inducido químicamente , Lactatos/metabolismo , Fenformina , Adulto , Anciano , Bicarbonatos/sangre , Glucemia/metabolismo , Dióxido de Carbono/sangre , Diabetes Mellitus/tratamiento farmacológico , Cetoacidosis Diabética/metabolismo , Cetoacidosis Diabética/terapia , Femenino , Furosemida/uso terapéutico , Humanos , Cuerpos Cetónicos/sangre , Fallo Renal Crónico/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Diálisis Peritoneal , Fenformina/efectos adversos , Fenformina/uso terapéutico , Piruvatos/sangre
9.
Diabetes ; 31(1): 40-5, 1982 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-6759211

RESUMEN

Four patients, treated with pentamidine because of Pneumocystis carinii pneumonitis, displayed severe fasting hypoglycemia during this treatment. Diabetes mellitus appeared later, requiring insulin therapy in the three of them who survived more than a few weeks. The metabolic study, performed in two cases during the hypoglycemic period, demonstrated inappropriately high insulin levels in the postabsorptive state. 28 +/- 1 microunits/ml (blood glucose 41 +/- 4 mg/dl) and 86 +/- 5 microunits/ml (blood glucose 15 +/- 5 mg/dl) vs. 15 +/- 3 microunits/ml in 10 control subjects and 55 +/- 3 microunits/ml in 6 patients with a verified B-cell tumor, respectively. Poor B-cell secretory responses followed the stimulations by oral glucose (maximal increment over basal: +5 microunits/ml vs. + 40 microunits/ml in control group and +77 microunits/ml in the insulinoma group), by i.v. arginine (maximal increment + 10 and +28 microunits/ml, respectively, vs. +55 in the controls and +90 microunits/ml in the insulinoma group) and by i.v. glucagon (+10 and +23 microunits/ml, respectively) vs. +40 microunits/ml in both the control and the insulinoma groups). Plasma cortisol and glucagon, and the A-cell response to arginine were higher than normal. These high, nonsuppressible, nonstimulable insulin levels and the sequence of hypoglycemia followed by insulin-dependent diabetes mellitus is consistent with the hypothesis of a selective toxicity turned towards the B-cells. In vitro incubation of islets with pentamidine 10(-10) M produced a passive release of insulin, followed by a significant decrease in B-cell response to glucose + theophylline. It is suggested that pentamidine can induce hypoglycemia because of an early cytolytic release of insulin, and then diabetes mellitus because of B-cell destruction and insulin deficiency.


Asunto(s)
Amidinas/efectos adversos , Diabetes Mellitus/etiología , Hipoglucemia/inducido químicamente , Pentamidina/efectos adversos , Adulto , Anciano , Glucemia/análisis , Humanos , Hipoglucemia/complicaciones , Insulina/sangre , Masculino , Persona de Mediana Edad , Neumonía por Pneumocystis/tratamiento farmacológico
10.
Diabetes ; 32(8): 768-73, 1983 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-6347773

RESUMEN

In order to assess the interrelationships between stomach and pancreas regarding the secretions of somatostatin-like immunoreactivity (SLI), glucagon (IRG), and insulin (IRI), concentrations of the three hormones were assayed in portal plasma and portal blood flow was measured in enterectomized rats before and after the selective removal of stomach or pancreas. Portal plasma SLI, IRG, and IRI concentrations were significantly increased by i.v. arginine in control rats (pancreas + stomach present). After gastrectomy, SLI, IRG, and IRI concentrations were, respectively, 52 +/- 13% (N = 15; P less than 0.005), 234 +/- 40% (P less than 0.001), and 119 +/- 15% (NS) of the pregastrectomy values. A decreased SLI secretion, an increased IRG release, and an unmodified basal IRI release were estimated by portal flow measurement. The A- and B-cell responses to arginine in the gastrectomized rats were significantly higher than in the control rats, while the D-cell response was no longer detectable. After pancreatectomy, by contrast, SLI concentrations were 360 +/- 75% of the prepancreatectomy values (N = 12; P less than 0.001). This reflected an actual increment of SLI release, taking into account the concomitant measurement of portal blood flow. The concentrations of IRG declined by 51 +/- 5% (P less than 0.001) and IRI was no longer measurable. A- and B-cell responses to arginine also were no longer detectable. These results suggest that in these experimental conditions (1) the stomach restrained pancreatic A- and B-cell responses to arginine, perhaps through the SLI released from the stomach and (2) the pancreas restrained gastric SLI secretion, perhaps through insulin.


Asunto(s)
Glucagón/sangre , Insulina/sangre , Páncreas/fisiología , Péptidos/sangre , Estómago/fisiología , Animales , Arginina/farmacología , Gastrectomía , Masculino , Pancreatectomía , Vena Porta , Ratas , Ratas Endogámicas
11.
Diabetes ; 25(11): 1026-30, 1976 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-992223

RESUMEN

Blood glucose and plasma insulin and glucagon concentrations were determined in full-term rats delivered by cesarean section and exposed to 37 degrees C. or 24 degrees C. environmental temperature during the first hours of extrauterine life. When newborn rats were maintained at thermal neutrality (37 degrees C.), a transient period of hypoglycemia of two hours occurred, associated with a rapid fall in plasma insulin and a rise in plasma glucagon concentrations. During cold exposure (24 degrees C.), the blood glucose level remained stable over the four hours studied; the decrease of plasma insulin was sluggish while the rise of plasma glucagon was unchanged. In newborn rats maintained at 37 degrees C., an intraperitoneal glucose load one hour after delivery produced a marked rise in blood glucose and plasma insulin concentrations one hour later. The distribution of experimental points suggested a sigmoidal dose-response curve. By contrast in newborn rats kept at room temperature (24 degrees C.) the same glucose load did not induce any increase in plasma insulin in spite of hyperglycemia. However, phentolamine resulted in pronounced plasma insulin rise in hypothermic newborns in response to glucose administration. From these observations it is concluded that the in-vivo unresponsiveness of the beta cells to glucose at birth, reported by others, is mainly due to the experimental conditions.


Asunto(s)
Animales Recién Nacidos/fisiología , Glucosa , Hipotermia/metabolismo , Insulina/sangre , Factores de Edad , Animales , Glucemia/metabolismo , Temperatura Corporal , Cesárea , Femenino , Glucagón/sangre , Fentolamina/farmacología , Embarazo , Ratas
12.
Diabetes ; 30(12): 1051-7, 1981 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7030831

RESUMEN

To explore humoral immunity in insulin-dependent diabetic (IDDM) patients, we studied insulin release from isolated mouse islets stimulated by glucose + theophylline after incubation with the sera of these patients and complement. Eleven of 21 IDDM sera suppressed the stimulated insulin release while the arginine-stimulated glucagon release remained unchanged. Morphologic evidence and the trypan-blue exclusion test suggested that the suppression of insulin release was due to a cytotoxic effect of the sera. No beta-cell inhibition of morphologic damage was detectable in the presence of sera from 30 healthy subjects, 8 non-insulin-dependent diabetic patients, and 5 nondiabetic patients with autoimmune diseases. Beta-cell inhibition by IDDM sera was not observed when complement was omitted. After serum fractionation, the cytotoxic potency of IDDM sera was located in the immunoglobulin G fraction. Using human islets, insulin release was suppressed by 3 of 6 IDDM sera. Complement-dependent cytotoxicity was found in 1 of 5 recent-onset IDDM patients and 11 of 16 IDDM patients with autoimmune phenomena. It was associated in all cases with the presence of islet cell antibodies as detected by immunofluorescence, and with the presence of circulating lymphocytes which suppressed insulin release in vitro. Complement-fixing antibodies may contribute to the selective beta-cell damage in IDDM.


Asunto(s)
Formación de Anticuerpos , Bioensayo , Pruebas de Fijación del Complemento , Diabetes Mellitus Tipo 1/inmunología , Insulina/metabolismo , Islotes Pancreáticos/inmunología , Adolescente , Adulto , Anciano , Animales , Arginina , Niño , Femenino , Técnica del Anticuerpo Fluorescente , Glucagón/metabolismo , Humanos , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Persona de Mediana Edad
13.
Diabetes ; 34(4): 373-9, 1985 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-3882501

RESUMEN

UNLABELLED: Peripheral lymphocyte subsets were enumerated, using OKT monoclonal sera, in 56 diabetic (43 adults and 13 children) and 20 control subjects. Concomitantly, anti-islet humoral and cellular immunity was tested in vitro and serum thymulin level was measured. In the newly diagnosed patients (less than 30 days; 18 cases), the percent of OKT4+ and OKT8+ cells was reduced, the OKT8+ depletion being particularly pronounced in children. Tests for cellular immunity were positive in 83% of the newly diagnosed diabetic subjects and anti-islet cytotoxic antibodies were detected in 50%. The serum thymulin level was decreased in 2 children. Later on in the course of the disease, a marked reduction in OKT3+, OKT4+, and OKT8+ cell percentage was observed, the mean OKT4/OKT8 ratio being normal or lower than normal. The percent of antibody-positive sera rose to 64%, while anti-islet cellular immunity was detectable in 54%. When extrapancreatic manifestations of probable autoimmune nature were present, anti-islet cellular immunity was detected in 100% of cases, accompanied by cytotoxic antibodies in 54%. CONCLUSIONS: (1) the magnitude of T-cell depletion and/or imbalance in diabetic subjects depended mainly on the duration of the disease, (2) anti-islet cellular immunity was the anomaly most frequently detectable, and (3) a decrease in serum thymulin level was infrequently detected.


Asunto(s)
Autoanticuerpos/análisis , Diabetes Mellitus Tipo 1/inmunología , Islotes Pancreáticos/inmunología , Linfocitos T/clasificación , Factor Tímico Circulante/biosíntesis , Hormonas del Timo/biosíntesis , Adolescente , Adulto , Anciano , Formación de Anticuerpos , Bioensayo , Niño , Preescolar , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/clasificación , Femenino , Humanos , Inmunidad Celular , Lactante , Insulina/metabolismo , Secreción de Insulina , Recuento de Leucocitos , Masculino , Persona de Mediana Edad
14.
Diabetes ; 39(7): 768-74, 1990 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-2191883

RESUMEN

Remission from insulin dependency in insulin-treated recent-onset type I (insulin-dependent) diabetic patients can result from a partial recovery of insulin secretion, an improvement in tissue sensitivity to insulin, or both. The same hypothesis must be analyzed when remission occurs in cyclosporin A (CsA)-treated patients. In this study, plasma C-peptide levels were serially measured in the basal state and after stimulation in 219 recent-onset type I diabetic patients; 129 received CsA, and all patients were similarly monitored and insulin treated. The results were analyzed in view of the occurrence of remission. Remission was defined as good metabolic control in the absence of hypoglycemic treatment for greater than or equal to 1 mo. Remission occurred in 44% of the CsA-treated group and lasted for mean +/- SE 10.0 +/- 0.9 mo vs. 21.6% in the non-CsA-treated group with a duration of 4.4 +/- 0.8 mo. Plasma C-peptide levels were initially dramatically lower than normal in both groups in the basal and stimulated states. C-peptide levels increased significantly later, at 3 and 6 mo, in both groups. C-peptide values were proportional to the rates of remission in both groups. In the non-CsA-treated group, C-peptide levels later decreased, and these patients inexorably relapsed to insulin dependency. In contrast, in the CsA-treated group, the initial recovery in insulin secretory capacity was maintained over the 18-24 mo of the study. Furthermore, higher remission rates and longer-lasting remission were obtained in patients who reached higher C-peptide levels at the 3rd mo of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Biomarcadores/sangre , Péptido C/sangre , Ciclosporinas/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Insulina/uso terapéutico , Adulto , Glucemia/metabolismo , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 1/sangre , Quimioterapia Combinada , Ingestión de Alimentos , Femenino , Glucagón , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Valores de Referencia
15.
Diabetes ; 34(9): 904-10, 1985 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-3896899

RESUMEN

The BB rat develops a spontaneous type I diabetic syndrome with anti-islet autoimmunity. Sera from diabetic and nondiabetic BB rats (from diabetes-prone litters), nondiabetic BB rats (from low-risk lines), and nondiabetes-prone Sprague-Dawley rats were collected twice a week from age 40 days to 160 days. Sera were tested for: (1) complement-dependent toxicity to 51Cr-labeled islet cells in vitro; (2) immunoglobulin binding to RIN-5 F insulinoma cells; and (3) ability to selectively suppress insulin secretion from normal islets in vitro. All sera from rats that subsequently became diabetic or glucose-intolerant were toxic to islet cells from various rat strains in the presence of complement. They were toxic neither to hepatocytes nor to fibroblasts. The toxic potency was associated with the globulin fraction. It was, in most cases, maximal either before or immediately after the onset of the disease. Sera from the nondiabetes-susceptible BB rats and the rats which, in diabetes-prone litters, died too early to be classified tended toward greater toxicity to islets. Immunoglobulins from diabetic sera bound to RIN-5 F cells more than did the serum globulins from other groups, their maximal binding capacity occurring after the onset of diabetes. Furthermore, BB diabetic sera were capable of selectively inhibiting the insulin secretion from normal rat islets in vitro either in the presence or, in some cases, in the absence of complement. The A- and D-cell functions were not suppressed. The combination of such results suggests the presence of one or more antibodies capable of binding to beta cells, inhibiting their function, and inducing their lysis.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Anticuerpos/inmunología , Diabetes Mellitus Experimental/inmunología , Islotes Pancreáticos/inmunología , Ratas Brattleboro/inmunología , Ratas Mutantes/inmunología , Animales , Glucemia/análisis , Proteínas del Sistema Complemento/inmunología , Citotoxicidad Inmunológica , Diabetes Mellitus Experimental/sangre , Ensayo de Inmunoadsorción Enzimática , Fibroblastos/inmunología , Fibroblastos/metabolismo , Inmunoglobulina G/inmunología , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/patología , Hígado/citología , Hígado/inmunología , Ratones , Ratones Endogámicos DBA , Ratas , Ratas Endogámicas , Factores de Tiempo
16.
Diabetes ; 32(11): 1048-54, 1983 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-6357903

RESUMEN

Anti-islet immune reactions were studied in vitro in genetically diabetic homozygote C57BL/KsJ db/db mice, using murine islet cells as a target. Spleen lymphocytes inhibited insulin secretion by the islet cells. This inhibition was abolished when T-cells were eliminated by treatment with anti-Thy 1.2 monoclonal antibody in the presence of complement. Anti-islet complement-dependent antibody (CDA) and antibody-dependent cell cytotoxicity (ADCC) were also found in the sera of these mice. This anti-islet immunity was detectable as early as the tenth day of life and lasted throughout the entire life span of the animals. A significant lymphopenia was detected in thymus and spleen cell populations. None of these anomalies was found in control heterozygote mice. Thymic function was explored in the same mice by evaluating their serum thymic factor (FTS) levels using a rosette assay. The age-dependent decline of FTS levels was significantly accelerated in diabetic mice as compared with heterozygous littermates. Furthermore, FTS inhibitory immunoglobulins were detected in db/db mouse sera, which inactivated in vitro the biologic potency of synthetic FTS. Histologically, the thymus displayed an accelerated involution. It was shown by indirect immunofluorescence using anti-FTS monoclonal antibodies that the number of FTS+ cells was reduced in db/db mouse thymuses. Histologic study of the islets of Langerhans showed early signs of beta-cell hyperactivity and hypertrophy, followed by beta-cell rarefaction and profound dislocation of islet architecture. Insulitis was not detected.


Asunto(s)
Autoanticuerpos/análisis , Diabetes Mellitus/veterinaria , Islotes Pancreáticos/inmunología , Ratones Endogámicos C57BL/inmunología , Ratones Mutantes/inmunología , Timo/fisiopatología , Animales , Anticuerpos Monoclonales , Citotoxicidad Celular Dependiente de Anticuerpos , Proteínas del Sistema Complemento/fisiología , Diabetes Mellitus/inmunología , Diabetes Mellitus/patología , Insulina/metabolismo , Secreción de Insulina , Recuento de Leucocitos , Linfocitos , Ratones , Enfermedades de los Roedores/inmunología , Enfermedades de los Roedores/patología , Bazo/patología , Factor Tímico Circulante/metabolismo , Timo/patología
17.
Diabetes Care ; 5 Suppl 2: 63-6, 1982.
Artículo en Inglés | MEDLINE | ID: mdl-6765544

RESUMEN

The hypoglycemic potencies of human insulin (recombinant DNA) and bovine NPH insulin were compared in insulin-dependent diabetic subjects. The same dosages of the two preparations were alternately injected, for two successive 5-day periods, on a twice-a-day schedule. Blood glucose profiles were monitored by finger pricking 6 times/day. Slight but significant differences in glucose time appeared, suggesting that human NPH insulin acts faster than bovine NPH, and for a shorter time.


Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Insulina Isófana/uso terapéutico , Insulina/uso terapéutico , Adulto , Anciano , Animales , Bovinos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico
18.
Diabetes Care ; 18(1): 47-55, 1995 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-7698047

RESUMEN

OBJECTIVE: To assess the prevalence, presentation, and risk factors of pentamidine-induced dysglycemia. RESEARCH DESIGN AND METHODS: Blood glucose values were screened in 244 consecutive immunocompromised patients with Pneumocystis carinii pneumonia: 116 being treated with cotrimoxazole and 128 others with pentamidine. RESULTS: Two cotrimoxazole patients developed diabetes as a result of necrotizing pancreatitis (1.7%); the others remained euglycemic. Forty-eight pentamidine-treated patients (38.5%) developed severe glucose homeostasis disorders: hypoglycemia in 7, hypoglycemia and then diabetes in 18, and diabetes alone in 23 (P < 0.001 vs. the cotrimoxazole group). Hypoglycemia was early, sudden, often recurrent, and life-threatening, associated with inappropriately high insulin levels in plasma; the B-cell response to stimuli was poor. Of the 41 diabetic patients, 26 required insulin therapy; their plasma C-peptide levels were lower than normal, and the B-cell secretory responses to stimuli were poor. Islet cell antibodies, insulin antibodies, and insulitis were not detected. The pentamidine-treated dysglycemic patients differed from their euglycemic counterparts by higher pentamidine doses (P < 0.001), higher plasma creatinine levels (P < 0.001), and more severe anoxia (P < 0.05) and shock (P < 0.001). Most of them had received pentamidine mesylate parenterally (n = 36; 75%); six others received the isethionate salt and six exclusively pentamidine aerosols. CONCLUSIONS: Pentamidine-induced dysglycemic accidents are primarily due to inappropriate insulin release and toxicity to the islet B-cells. Drug accumulation due to excessive doses, iterative courses, and/or renal impairment is the determining risk factor.


Asunto(s)
Diabetes Mellitus/inducido químicamente , Hiperglucemia/inducido químicamente , Hipoglucemia/inducido químicamente , Pentamidina/efectos adversos , Combinación Trimetoprim y Sulfametoxazol/efectos adversos , Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Adulto , Femenino , Humanos , Infusiones Intravenosas , Masculino , Neumonía por Pneumocystis/complicaciones , Neumonía por Pneumocystis/tratamiento farmacológico , Radioinmunoensayo , Estudios Retrospectivos , Factores de Riesgo
19.
Diabetes Care ; 18(11): 1487-90, 1995 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-8722075

RESUMEN

OBJECTIVE: To measure the effects of cyclosporin A (CyA) with no insulin therapy on glucose tolerance and beta-cell function in the preclinical phase of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: beta-cell responses to the intravenous glucose tolerance test (IVGTT), hyperglycemic clamp, intravenous arginine, and intravenous glucagon were evaluated before and after a 6-month course of CyA in seven patients (mean age 19.6 years) with asymptomatic IDDM. RESULTS: Initial insulin secretory responses were severely decreased when the patients were compared with eight healthy control subjects: IVGTT (1 + 3 min): 106 +/- 16 vs. 884 +/- 190 pmol/l (P < 0.001); hyperglycemic clamp: 102 +/- 16 vs. 310 +/- 42 pmol/l (P < 0.001); intravenous arginine: 346 +/- 72 vs. 1104 +/- 168 pmol/l (P < 0.01); and intravenous glucagon: 170 +/- 37 vs. 247 +/- 35 pmol/l (NS). The beta-cell responses remained markedly abnormal after 6 months of CyA, although the response to intravenous glucose and oral glucose tolerance tests improved in three subjects. All the patients became insulin-dependent after 5-36 months. CONCLUSIONS: CyA alone is not a suitable treatment for asymptomatic IDDM. Earlier identification of subjects with substantial beta-cell secretory capacity and newer nontoxic intervention strategies are required for the prevention of IDDM.


Asunto(s)
Ciclosporina/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Inmunosupresores/uso terapéutico , Insulina/metabolismo , Insulina/uso terapéutico , Adolescente , Adulto , Arginina/farmacología , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Péptido C/sangre , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Estudios de Seguimiento , Glucagón/farmacología , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/fisiopatología , Masculino , Valores de Referencia
20.
Endocrinology ; 115(5): 1722-8, 1984 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-6436006

RESUMEN

To clarify the impact of hypothermia on the hormonal control of glucose metabolism, rats were rendered hypothermic (25 C) after catheterization of the portal vein. Glucose, insulin, glucagon, and catecholamine concentrations were serially monitored, and the regional blood flows were measured, allowing the estimation of hormone outputs. Hypothermia reduced the portal blood flow by 50% without changing arterial blood pressure, blood gases, or pH. Portal plasma insulin secretion dropped (0.05 +/- 0.01 vs. 0.23 +/- 0.04 mU/min), and glucagon secretion increased (0.81 +/- 0.18 vs. 0.38 +/- 0.10 ng/min). The B cell responses to glucose, arginine, and glucagon were abolished, while the A cell response to arginine was not significantly affected. Glucose intolerance was apparent after iv glucose or arginine loads. Haloperidol and to a lesser extent phentolamine suppressed the cold-induced glucagon rise. Phentolamine and to a lesser extent haloperidol alleviated the cold-induced suppression of insulin release. Propranolol, naloxone, and atropine were relatively inactive. The cold-induced glucose intolerance was not corrected by phentolamine treatment. A marked resistance to iv insulin was apparent in these rats, which is in contrast to a normal sensitivity to iv glucagon.


Asunto(s)
Glucagón/metabolismo , Hipotermia Inducida , Insulina/metabolismo , Animales , Arginina/farmacología , Atropina/farmacología , Glucemia/análisis , Presión Sanguínea/efectos de los fármacos , Temperatura Corporal , Dióxido de Carbono/sangre , Gasto Cardíaco , Catecolaminas/sangre , Haloperidol/farmacología , Concentración de Iones de Hidrógeno , Secreción de Insulina , Circulación Hepática , Masculino , Naloxona/farmacología , Oxígeno/sangre , Presión Parcial , Fentolamina/farmacología , Propranolol/farmacología , Ratas , Ratas Endogámicas
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