Multigenerational inheritance and clinical characteristics of three large pedigrees with early-onset type 2 diabetes in Jamaica / Herencia multigeneracional y características clínicas de la diabetes tipo 2 de inicio temprano en tres árboles genealógicos grandes de Jamaica

OBJECTIVE: To document the existence and clinical characteristics of three large families with multigenerational inheritance of early-onset type 2 diabetes in Jamaica. METHODS: Three probands from large families with multigenerational inheritance of early-onset type 2 diabetes in at least three generations were detected at the University Hospital of the West Indies in Jamaica. Each proband at the time of diagnosis was < 25 years of age, was lean, and did not require insulin therapy. Clinical, metabolic, and genetic assessments were undertaken to profile the diabetes in the three families. RESULTS: Three pedigrees-BK, SU, and CA-consisting of 38, 48, and 113 members, respectively, with multigenerational inheritance of early-onset type 2 diabetes in at least three generations, were investigated. The mean age at diagnosis of the three pedigrees was 31.5 ± 2.9 years, with 10 persons detected below 25 years of age. Findings suggestive of overweight, insulin resistance, low insulin secretion, dyslipidemia, and mild intra-abdominal obesity were present. Islet cell antibodies and sequence variants in MODY1 to -6 genes were absent. CONCLUSIONS: Large families demonstrating multigenerational inheritance of diabetes and other characteristics consistent with early-onset type 2 diabetes are present in the Jamaican population.

OBJETIVO: Documentar la presencia de herencia multigeneracional de la diabetes de tipo II de inicio temprano en tres familias jamaiquinas grandes y describir sus características clínicas. MÉTODOS: En el Hospital Universitario de West Indies en Jamaica, se detectaron tres probandos de familias grandes en las que se observó herencia multigeneracional de la diabetes tipo 2 de inicio temprano en al menos tres generaciones. Al momento del diagnóstico, cada probando tenía # 25 años de edad, era delgado y no necesitó insulinoterapia. Se emprendieron estudios clínicos, metabólicos y genéticos con el fin de determinar las características particulares de la diabetes que presentan estas tres familias. RESULTADOS: Se investigaron tres árboles genealógicos -BK, SU y CA- conformados por 38, 48 y 113 miembros, respectivamente. Cada árbol presentaba herencia multigeneracional de diabetes tipo 2 de inicio temprano en al menos tres generaciones. En los tres árboles genealógicos, la media de la edad al momento del diagnóstico fue de 31,5 ± 2,9 años y 10 personas tenían menos de 25 años. Se observaron signos indicativos de sobrepeso, resistencia insulínica, baja secreción de insulina, dislipidemia y obesidad intrabdominal leve. No se hallaron anticuerpos contra las células de los islotes ni variantes en la secuencia de los genes MODY1 a MODY6. CONCLUSIONES: Algunas familias grandes de la población jamaiquina presentan herencia multigeneracional de la diabetes y otras características indicativas de diabetes tipo 2 de inicio temprano.

Ketosis-onset diabetes in Tunisian adults: immunological markers and beta-cell function

The aim of this study in Tunisia was to classify ketosis-onset diabetes in adult patients. All patients aged >/= 30 years without known diabetes, presenting with ketosis and admitted to our department were studied. Patients with secondary or gestational diabetes and those on corticoid therapy or with coinciding infection were excluded. The data included clinical characteristics, immunological markers and beta-cell function. Of the 63 patients, islet-cell antibodies were present in 27.0%, glutamic acid decarboxylase antibodies in 25.4% and thyrosin phosphatase antibodies in 19.0%. beta-cell functional reserve was preserved in 54.0%. Our results confirm that patients with ketosis-onset diabetes mellitus in adulthood are a heterogeneous group

IIhotas pancreáticas humanas viáveis para o transplante através do aumento da massa de células e do imunoisolamento com microcápsulas biocompatíveis / Obtention of human pancreatic islets for transplantation through an increase in cell mass and an immunoisolation with biocompatible microcapsules

O transplante de ilhotas pancreáticas humanas representa uma estratégia promissora para a cura do diabetes mellitus tipo 1 (DM1) mas a aplicação a todos os pacientes diabéticos ainda é impraticável devido à limitada disponibilidade de ilhotas ou células β e à necessidade de utilização de drogas imunossupressoras pelo paciente transplantado. O tratamento com imunossupressores após o transplante de ilhotas pode ser abolido quando se realiza o microencapsulamento das ilhotas pancreáticas. Neste trabalho investigou-se um novo biomaterial, Biodritina (alginato/sulfato de condroitina) adequado ao microencapsulamento que gelifica na presença de íons de cálcio ou bário. A biocompatibilidade das microcápsulas tem sido avaliada segundo o grau de pureza do alginato utilizado na sua confecção. Amostras de alginato comercial purificado foram analisadas, comprovando-se a presença de impurezas (polifenóis, endotoxinas, proteínas) em níveis elevados, que impedem sua aplicação clínica. Optou-se, portanto pela utilização do alginato comercial ultrapurificado nos experimentos descritos neste trabalho. Das formulações de biomateriais avaliadas, as microcápsulas de bário-Biodritina apresentaram o melhor desempenho em testes de estabilidade físico-química...

Study of islet cell autoantibodies in serum of siblings of type 1 diabetics

Type 1 diabetes is an autoimmune disease that accounts for approximately 15% of the diabetic population. The pathogenesis of Type 1 diabetes could be divided into six stages. Stage I is genetic susceptibility which requires the presence of a triggering event [stage Il] that initiate the development of autoimmunity [stage Ill] which is characterized by lymphocytic infiltration of the islet cells and production of anti-islet autoantibodies e.g. islet cell cytoplasmic autoantibodies [ICCA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA], and autoantibodies against irisulinoma-associated-2 autoantigen [IA-2A]. In stage IV, there is progressive loss of insulin secretion despite normal blood glucose level. Stage V develops when overt diabetes is first recognized. In stage VI, there is complete beta cell destruction. Since the clinical onset of Type 1 diabetes does not occur until 80-90% of the insulin-producing pancreatic beta cells have been destroyed, this prediabetic stage may last for a long time during which the immunologic disease markers are present and measurable. The present study aimed to determine the prevalence of the islet cell autoantibodies in siblings of type I diabetics for the presence of islet autoantibodies in an attempt to allow the opportunity for prediction and/or the prevention the clinical onset of the disease. 108 healthy siblings of Type 1 diabetic children [group I] and 100 healthy control subjects [group II] of matched age and sex were enrolled in the present study. IAA, GADA, and IA-2A autoantibodies were assayed in serum of all subjects by radioimmunoassay. Eight of the control subjects had autoantibodies in their sera which were of the IAA type only. In siblings of Type 1 diabetic children, the prevalence of GADA seropositivity showed the highest percentage [25%], followed by IAA [14.81%], then IA-2A [2.78%]. There was significant association between the brotherhood to Type 1 diabetic children and the presence of GADA alone [i.e. no concomitance with any other autoantibody], total GADA [GADA alone and in combination with other autoantibodies], and GADA+IAA [P=0.000, 0.000, and 0.018 respectively]. IAA+GADA+IA-2A or for IAA+lA-2A combinations were not detected in sera of siblings of Type 1 diabetic children. None of the siblings of Type 1 diabetics had lA-2A autoantibodies alone in the serum. From the present results it could be concluded that some degree of islet cell autoimmunity might develop in siblings of type 1 diabetic children as evidenced by the significant association between the presence of GADA or GADA+IAA and the brotherhood to type 1 diabetics. The present results also revealed that GADA is the most frequent autoantibody in serum of siblings of type 1 diabetics. They also showed that the presence of GADA per se conferred the highest significant association with the brotherhood to Type I diabetic children. However, a larger prospective study is recommended to ascertain the importance of the assay of these immunologic markers for the prediction and possible prevention of type 1 diabetes in individuals at risk e.g. sibling, parents, and offspring of Type 1 diabetics

Secondary prevention of type 1 diabetes mellitus: stopping immune destruction and promoting ß-cell regeneration

Type 1 diabetes mellitus results from a cell-mediated autoimmune attack against pancreatic ß-cells. Traditional treatments involve numerous daily insulin dosages/injections and rigorous glucose control. Many efforts toward the identification of ß-cell precursors have been made not only with the aim of understanding the physiology of islet regeneration, but also as an alternative way to produce ß-cells to be used in protocols of islet transplantation. In this review, we summarize the most recent studies related to precursor cells implicated in the regeneration process. These include embryonic stem cells, pancreas-derived multipotent precursors, pancreatic ductal cells, hematopoietic stem cells, mesenchymal stem cells, hepatic oval cells, and mature ß-cells. There is controversial evidence of the potential of these cell sources to regenerate ß-cell mass in diabetic patients. However, clinical trials using embryonic stem cells, umbilical cord blood or adult bone marrow stem cells are under way. The results of various immunosuppressive regimens aiming at blocking autoimmunity against pancreatic ß-cells and promoting ß-cell preservation are also analyzed. Most of these regimens provide transient and partial effect on insulin requirements, but new regimens are beginning to be tested. Our own clinical trial combines a high dose immunosuppression with mobilized peripheral blood hematopoietic stem cell transplantation in early-onset type 1 diabetes mellitus.

Traditional islet cell autoantibodies in diabetic patients with and without long-term complications

The aim of the present work was to demonstrate the presence of the traditional islet cell related autoantibodies in the diabetic patients with and without long term complications and to identify relevant predisposing markers of pre-clinical diabetic complications. There was a significant difference [P 0.001] between the percentage of islet cell autoantibodies [ICA], glutamic acid decarboxylase autoantibodies [GAD-Ab], and insulin autoantibodies [IAA] positive subjects in the diabetic groups and their matched control and potential groups. Type-1 diabetic groups had a higher percentage [P.0.05] of subjects positive for ICA, GAD-Ab, and IAA than Type-2 diabetic groups. The concentration of ICA in the studied population strongly correlated with the duration of the disease [r=0.705, p 0.05]. There was no significant difference [P>0.05] between the percentage of islet cell antigen-2 autoantibodies [IA2-Ab] positive subjects in the different groups of diabetic population and their control. In conclusion the traditional islet cell antibodies have a role in the detection and development of diabetes especially Type-1 rather than the long-term complications. Other more specific autoantibodies and immune responses, which were not studied, may have a role in the etiology and pre-clinical appearance of these chronic complications. KeyWords: Diabetes,Autoantibodies, Complications

Variantes de la diabetes mellitus: enfoque actual desde la genética y la biología molecular / Variant of the diabetes mellitus: current approach from the genetics and the molecular biology

La Diabetes Mellitus (DM), de acuerdo a la definición clásica, es una enfermedad metabólica caracterizada por la hiperglucemia. Esta a su vez resulta de un defecto en la secreción de insulina, en su acción, o en ambos factores a la vez. Por ello tempranamente se consideró a la DM como heterogénea y de origen multifactorial. Las dos formas típicas son la DM insulinodependiente, infantojuvenil, (DM tipo 1) y la DM no-insulinodependiente, diagnosticada en los adultos (DM tipo 2).Sin embargo, hoy se percibe un panorama mucho más complejo, donde los refinamientos en la subagrupación fenotípica de otras variantes de DM y la nomenclatura propuesta, (DM latente, o LADA, DM tipo 1 del adulto, DM tipo 2 insulinorrequiriente, DM tipo 1 y 1/2 etc.) condujo más a la confusión que a la precisión diagnóstica. Los avances contemporáneos de la genética y de la biología molecular comienzan a brindar las bases etiopatogénicas de la DM en sus distintas variantes. A partir de ello, por ejemplo, se puede comprender mejor la naturaleza de los condicionamientos multigénicos que se traducen en la susceptibilidad para padecer la DM tipo 1, dentro de un grupo mayor de enfermedades autoinmunes. En esta área el reciente desarrollo de los autoantígenos recombinantes a nivel internacional, e incluso local, ha contribuído sustancialmente a la creación de una nueva plataforma analítica de apoyo para la medicina dibetológica. El actual screening precoz y preciso de las formas de DM asociadas a autoinmunidad sirve para la predicción de la enfermedad con hasta una década de antelación y también para disipar algunos de los dilemas que suelen presentarse en los pacientes diabéticos sobre la intervención terapéutica con hipoglucemiantes orales o con insulina, orientando su elección correcta y oportuna.

Tiempo de exposición al gluten y marcadores de riesgo de diabetes mellitus insulino dependiente en pacientes celíacos / Risk markers for insulin-dependent diabetes mellitus and duration of exposure to gluten in celiac patients

Background: Celiac patients are at high risk of developing insulin-dependent diabetes mellitus, a condition that has a long pre-diabetic period. During this lapse, anti-islet cell antibodies serve as markers for future disease. This may be related with the duration of the exposure to gluten. Aim: To test the hypothesis that long term adherence to a gluten free diet decreases the frequency of risk markers for insulin dependent diabetes mellitus during adolescence and early adulthood. Patients and methods: 158 celiac patients were classified as: G1, (n=30 patients) studied at the time of diagnosis; G2 (n=97 patients) exposed to gluten as a result of non compliance with the gluten free diet and, G3 (n=31 patients) who had maintained a long term, strict gluten free diet. Isotype IgG anti-islet cell antibodies were detected by indirect immunofluorescence using monkey pancreas; results were reported in Juvenile Diabetes Foundation (JDF) units. Results: Celiac patients exposed to a gluten containing diet had a significantly higher prevalence of anti-islet cell antibodies than those who had been exposed only briefly (p <0.017). In addition, a significantly higher prevalence of anti-islet cell antibodies was observed in those patients whose exposure to gluten was longer than 5 years than in those whose exposure was shorter (p <0.02). Conclusions: Celiac patients long exposed to gluten have a significantly higher prevalence of anti-islet cell antibodies than those exposed for a short period. This fact supports the hypothesis that the development of these antibodies is associated with the length of the exposure to gluten (Rev Méd Chile 2004; 132: 979-84).

Prevalence des auto anticorps anti - GAD chez des enfants Tunisiens diabetiques de type 1.

The prevalence of GAD antibodies and its correlation with some autoimmune markers: ICA [islet cells antibodies]. Antinuclear antibodies, thyroid antithymune and antimicrosomes antibodies., were studied in 84 Tunisian type 1 diabetic children. The prevalence of GAD antibodies was 51.2% and decreased as a function of increasing duration of the disease. Their frequency was 84.6% in children with newly diagnosed diabetes [within 6 months of diagnosis] and only 29.41% in those with a longer duration of the diabetes [more than 5 years]. ICA were present less frequently [21.4% of the children]. 10.7% of the studied samples were positive with the two antibodies [GAD ab ICA], and 40% were positive only with GAD antibodies. We conclude that the GAD antibodies seems to be more associated to the development of type 1 diabetes than ICA. They are detected more frequently in patients with long standing disease, that's make their determination very interesting as diagnostic and predictive marker

Perfil de auto anticuerpos y lactancia materna en pacientes diabéticos tipo 1 / Auto-antibody levels and history of breast-feeding in type 1 diabetic patients

Background: Islet cell-specific autoantibodies such as islet cell antibody (ICA), antiinsulin (IAA), anti-glutamic acid decarboxylase (GAD) and anti-tyrosine phosphatase (IA2) can be present in patients with type I diabetes. Breast feeding duration and the early exposure to milk substitutes are environmental factors associated to etiology of type 1 diabetes. Aim To study the frequency of the anti-GAD, anti-IA-2 e ICA antibodies in Chilean type 1 diabetic patients and determine the possible modulator effect of the breast feeding. Patients and methods: One hundred thirty four type I diabetic patients, aged one to 15 years old, were studied at the moment of their diagnosis. Patients were classified according to the duration of exclusive breast feeding. IA-2 and GAD were determined by radio immuno assay and ICA by means of indirect immunofluorescence. Results: Subjects with three months or less and those with more than three months of breast feeding were positive for ICA in 78.8 and 90.6 per cent of cases respectively, for GAD in 75 and 54.6 per cent of cases respectively (p=0.024) and for IA-2 in 73 and 43.8 per cent of cases respectively (p=0.001). All three antibodies were positive in 53.9 and 21.8 per cent of children with less or more than three months of breast feeding (p=0.001). Conclusion: Both IA-2 and GAD antibodies are less frequently positive in type 1 diabetic patients who have been breast fed for more than three months. These findings suggest a possible attenuating role of exclusive breast feeding on pancreatic aggression events in patients with type 1 diabetes

Microencapsulation and tissue engineering as an alternative treatment of diabetes

In the 70's, pancreatic islet transplantation arose as an attractive alternative to restore normoglycemia; however, the scarcity of donors and difficulties with allotransplants, even under immunosuppressive treatment, greatly hampered the use of this alternative. Several materials and devices have been developed to circumvent the problem of islet rejection by the recipient, but, so far, none has proved to be totally effective. A major barrier to transpose is the highly organized islet architecture and its physical and chemical setting in the pancreatic parenchyma. In order to tackle this problem, we assembled a multidisciplinary team that has been working towards setting up the Human Pancreatic Islets Unit at the Chemistry Institute of the University of São Paulo, to collect and process pancreas from human donors, upon consent, in order to produce purified, viable and functional islets to be used in transplants. Collaboration with the private enterprise has allowed access to the latest developed biomaterials for islet encapsulation and immunoisolation. Reasoning that the natural islet microenvironment should be mimicked for optimum viability and function, we set out to isolate extracellular matrix components from human pancreas, not only for analytical purposes, but also to be used as supplementary components of encapsulating materials. A protocol was designed to routinely culture different pancreatic tissues (islets, parenchyma and ducts) in the presence of several pancreatic extracellular matrix components and peptide growth factors to enrich the beta cell population in vitro before transplantation into patients. In addition to representing a therapeutic promise, this initiative is an example of productive partnership between the medical and scientific sectors of the university and private enterprises.

Is pancreas development abnormal in the non-obese diabetic mouse, a spontaneous model of type I diabetes?

Despite extensive genetic and immunological research, the complex etiology and pathogenesis of type I diabetes remains unresolved. During the last few years, our attention has been focused on factors such as abnormalities of islet function and/or microenvironment, that could interact with immune partners in the spontaneous model of the disease, the non-obese diabetic (NOD) mouse. Intriguingly, the first anomalies that we noted in NOD mice, compared to control strains, are already present at birth and consist of 1) higher numbers of paradoxically hyperactive ß cells, assessed by in situ preproinsulin II expression; 2) high percentages of immature islets, representing islet neogenesis related to neonatal BETA-cell hyperactivity and suggestive of in utero BETA-cell stimulation; 3) elevated levels of some types of antigen-presenting cells and FasL+ cells, and 4) abnormalities of extracellular matrix (ECM) protein expression. However, the colocalization in all control mouse strains studied of fibroblast-like cells (anti-TR-7 labeling), some ECM proteins (particularly, fibronectin and collagen I), antigen-presenting cells and a few FasL+ cells at the periphery of islets undergoing neogenesis suggests that remodeling phenomena that normally take place during postnatal pancreas development could be disturbed in NOD mice. These data show that from birth onwards there is an intricate relationship between endocrine and immune events in the NOD mouse. They also suggest that tissue-specific autoimmune reactions could arise from developmental phenomena taking place during fetal life in which ECM-immune cell interaction(s) may play a key role

Immunologic and genetic markers in insulin-dependent diabetes mellitus (Type 1) in a argentine population

The objective was to evaluate the prevalence and association of several markers (islet cell antibodies: ICA, ainsulin autoantibodies: IAA, glutamic acid decarboxylase antibodies: GADA and ICA512 antibodies: ICA512A) along with HLA DQB1 genotype in type 1 diabetes mellitus of recent onset, including siblings and individuals without any history of this disease, in an Argentine population. A total of 79 children with type 1 diabetes mellitus of recent onset were studied, as well as 79 control children, and 68 healthy siblings of type 1 diabetic cases. IAA, ICA, GADA, ICA512A and HLA DQB1 alleles were determined. Sensitivity was 67.1 por ciento for ICA, 36.7 percent for IAA, 74.6 por ciento for GADA and 63.4 por ciento ICA512A. None of the control subjects was positive for the immunological markers. Combined sensitivity of ICA-IAA-GADA was 89.8 por ciento, similar to the ICA512A- GADA (87.3 percent) or ICA512A-GADA-IAA combination (91.1 por ciento ). GADA correlated positively with ICA, but no such correlation was found between IAA, ICA512A and ICA. IAA correlated negatively and GADA positively with age. IAA was associated to DQB1*0201, whereas ICA and ICA512A associated to DQB1*0302. Among siblings, 3/68 (4.4 percent) were positive for IAA and a single case (1.5 percent) was positive for GADA and one for ICA512A. Our findings show that the combination of multiple tests increases the sensitivity for prediction, with the ICA512A-GADA combination proving highly sensitive and equivalent to other proposed combinations, such as ICA-IAA-GADA.

Frequency of islet cell autoantibodies (IA-2 and GAD) in young Brazilian type 1 diabetes patients

Type 1 diabetes, as an autoimmune disease, presents several islet cell-specific autoantibodies such as islet cell antibody (ICA), anti-insulin, anti-glutamic acid decarboxylase (GAD) and the antibody (Ab) against tyrosine phosphatase (PTP)-like protein known as ICA-512 (IA-2). In order to determine the frequency of the anti-GAD and anti-IA-2 autoantibodies in Brazilian type 1 diabetes patients we studied 35 diabetes mellitus (DM) type 1 patients with recent-onset disease 12 months and 37 type 1 diabetes patients with long-duration diabetes 12 months who were compared to 12 children with normal fasting glucose. Anti-GAD65 and anti-IA-2 autoantibodies were detected with commercial immunoprecipitation assays. The frequency of positive results in recent-onset DM type 1 patients was 80.0 percent for GADAb, 62.9 percent for IA-2Ab and 82.9 percent for GADAb and/or IA-2Ab. The long-duration type 1 diabetes subjects presented frequencies of 54.1 percent for GADAb and IA-2Ab, and 67.5 percent for GAD and/or IA-2 antibodies. The control group showed no positive cases. Anti-GAD and IA-2 assays showed a high frequency of positivity in these Brazilian type 1 diabetes patients, who presented the same prevalence as a Caucasian population

Características de los anticuerpos antiislotes del adulto, diabético tipo I de reciente diagnóstico, familiares de primer grado de diabéticos tipo 1 y diabetes gestacional / ICA characteristics in latent autoimmune diabetes of adults, new onset type diabetics, first degree relatives of type l diabetics and gestational diabetes

Se estudiaron las características de los sueros con anticuerpos antiislotes pancreáticos (ICA+) títulos, ICA sobre páncreas de ratón (ICA-NR), reactividad a extractos glucolipídicos pancreáticos (REGP) y asociación a anticuerpos anti-GAD65) en diferentes grupos de sujetos: diabetes autoinmune del adulto (LADA, n = 20), diabéticos tipo 1 de reciente diagnóstico (DMIDrd, n = 43), familiares de primer grado de diabéticos tipo 1 (FPG, n = 31) y mujeres con diabetes gestacional (DG, n = 10). Se detectaron ICA e ICA-NR por la técnica de inmunofluorescencia indirecta y los anticuerpos anti-GAD65, por un método RIA de inmunoprecipitación. Se utilizó la fase superior de extractos pancreáticos humanos que contienen glucolípidos para medir REGP de los ICA. Se determinaron las características de los ICA en los diferentes grupos: LADA: alta frecuencia en sus títulos (ü 80 unidades JDF) (80 porciento), anticuerpos anti-GAD65 (100 porciento) y baja frecuencia de ICA-NR (15 porciento) y REGP (15 porciento); DMIDrd: alta frecuencia de anticuerpos anti-GAD65 (72 porciento), ICA-NR (81 porciento) y REGP (86 porciento); FPG: alta frecuencia de ICA-NR (93 porciento) y REGP (87 porciento); DG: Bajos títulos de ICA (< 20 unidades JDF) (60 porciento) y alta frecuencia de REGP (80 porciento), aunque la REGP fue generalmente parcial. Se comprobó que en los grupos estudiados, el proceo de pérdida de la tolerancia inmunológica es disímil porque los ICA reconocen a determinantes antigénicos diferentes. Estos resultados son también importantes para seleccionar el marcador inmunológico correcto para la predicción del proceso autoinmune en cada entidad(AU)

Permanent neonatal diabetes mellitus: epidemiology, mode of presentation, pathogenesis and growth.

Permanent neonatal diabetes mellitus (PNIDDM) is a rare form of IDDM with unclear etiology and pathogenesis. We determined the incidence and prevalence rates and studied the clinical and biochemical features of PNIDDM in the Sultanate of Oman. The mean incidence rate during the study period from January 1989 to December 1994 was 1.788 +/- 0.82 per 100,000 live births per year. At the end of December 1994 the prevalence rate was 2.4 per 100,000 children below the age of 5 years. They constituted 41.6% of all cases of IDDM in this age group. Diarrhoea, fever, lethargy, poor feeding and failure to thrive were the most common presenting symptoms. Dehydration and tachypnoea were the most common signs. All patients who developed IDDM during the neonatal period had intrauterine growth retardation and 4.5 presented with diabetic ketoacidosis (plasma glucose 37 +/- 9 mmol/L, pH 7.12 +/- 0.1). Hypertriglyceridemia was a constant feature (19.4 +/- 4.8 mmol/L). They were products of consanguineous marriage with significantly high prevalence of IDDM and NIDDM in their family members. None of the infants had clinical or immunological evidence of congenital viral infection. Three of the five children had HLA-DR2, the diabetes resistance alleles. C-peptide secretion was absent during and after metabolic control of hyperglycemia in all the studied infants and none had circulating islet cell antibody at presentation or during the first year after diagnosis. Despite marked growth retardation at birth, there was a significant improvement of growth after initiating insulin therapy. Four of the 5 patients had normal developmental milestones, one had mild developmental delay following a severe and prolonged attack of hypoglycemia. None of the patients had exocrine pancreatic deficiency. In summary, the very high rate of parental consanguinity, occurrence in both sexes and in two siblings in the same family, absence of islet cell antibodies and the presence of HLA-DR2 loci in 3/5 of patients suggest that PNIDDM is a different disease process to standard IDDM in childhood and an autosomal recessive mode of transmission.

Prevalencia de anticuerpos anti islotes pancreáticos en 1.021 parientes de diabéticos tipo 1 / Prevalence of anti pancreatic islet antibodies among 1.021 relatives of type 1 diabetic patients

Background: An immunological damage of beta cells in the islets of Langerhans, plays a role in the pathogenesis of type 1 diabetes. Recently, the identification of individuals in pre clinical phase and with high risk of developing type 1 diabetes, has become possible by means of the detection of immune markers such as islet cell antibodies (ICA) and the measurement of first phase response of insulin (FPRI). Subjects and methods: We studied 1,021 first degree relatives of type 1 diabetics, aged 4 to 35 years. ICA were measured using poly-IgG peroxidase in sections of human pancreas. In those subjects with positive ICA and normal oral glucose tolerance test, the FPRI was measured. FPRI was defined as the sum of insulinemias at minutes 1 and 3 after a three minutes 0.5 g/kg glucose load. Results: Thirty subjects were ICA (+), defined as having more than 20 juvenile diabetes foundation units (prevalence of 2.9 percent). No differences in age, sex and closeness of familial relationship was found between ICA (+) and ICA (-) individuals. FPRI was measured in 24 subjects with normal oral glucose tolerance test and was normal in five. Seventeen subjects had a decreased response (between percentiles 1 and 5) and two had a response below percentile 1. No relationship between ICA levels and FPRI was found. Conclusions: The early detection of populations at risk of developing type 1 diabetes should be regarded as an important tool to better understand the natural history of the disease and to develop preventive programs in the future

Latent autoimmune diabetes of adults

This study aimed to determine the prevalence of auto-antibodies against glutamic acid decarboxylase [GAD-antibodies] and pancreatic islet cells [IC-antibodies] in relation to beta-cell function in adults newly diagnosed with diabetes mellitus [n = 40] and control subjects [n = 20] using the standard oral glucose test procedure. Beta-cell function was evaluated by the true insulin response to oral glucose test. Patients were classified into insulin-deficients and non-insulin-deficients on the basis of the normal insulin curve and the sum of the 30 and 60 min incremental response [normal: 340-2440 pmol/L]. The prevalence of GAD antibodies and ICA was determined using kits of radioimmunoassay procedure. In adults presenting with diabetes mellitus as a new diagnosis, the early assessment of beta- cell function can discover a subgroup of subjects with adult-onset insulin-dependent diabetes mellitus. Nearly 15% of adults presenting with diabetes mellitus as a new diagnosis were insulin-deficient using this criterion. On the other hand, loss of beta-cell function in more than 85% of individuals who were insulin-deficient can be identified by anti-GAD and ICA and the early detection of these immune markers of beta-cell damage creates the potential for immune modulation to limit such damage

Diabetes mellitus insulino dependiente (tipo I): actualización sobre su etiopatogenia / Type I insulin dependent diabetes mellitus: etiopathogenic update

La diabetes mellitus es una enfermedad poco frecuente en pediatría, cuyo diagnóstico debe sospecharse frente a un paciente con compromiso del estado general, poliuria y polidipsia y frente a todo paciente que ingresa en coma de causa no precisada. En los últimos años los avances en los estudios inmunológicos, genéticos y epidemiológicos han determinado que la destrucción de las células de los islotes de Langerhans, responsable de la diabetes infantil, es un proceso inmunológico regulado por una susceptibilidad genética. En este artículo se describe una actualización en los conocimientos de la etiopatogenia de la diabetes insulinodependiente o tipo I