Onset Of Insulin-dependent Diabetes Research Articles

Liver transplantation for alcoholic cirrhosis.

Because of the donor shortage, there are concerns for liver transplantation in patients with alcoholic cirrhosis. We therefore analyzed patients transplanted for alcoholic cirrhosis at our center with respect to patient and graft survival, recurrence of disease, and postoperative complications. Out of 1000 liver transplantations performed in 911 patients, 167 patients were transplanted for alcoholic cirrhosis; 91 patients received CsA- and 76 patients FK506-based immunosuppression. Recurrence was diagnosed by patient's or relative's declaration, blood alcohol determination, and delirium. Diagnosis and treatment of acute and chronic rejection was performed as previously described. One- (96.8% versus 91.3%) and 9-year patient survival (83.3% versus 80%) compared well with other indications. Five of 15 patients died due to disease recurrence. Recurrence of disease was significantly related to the duration of alcohol abstinence prior to transplantation. In patients who were abstinent for less than 6 months (17.1%), recurrence rate was 65%, including four of the five patients who died of recurrence. Recurrence rate decreased to 11.8%, when abstinence time was 6-12 months and to 5.5%, when the abstinence times was > 2 years. Next to duration of abstinence, alcohol relapse was significantly related to sex, social environment, and psychological stability. The incidence of acute rejection compared well with other indications (38.1%); CsA: 40.1% versus 33.3% in FK506 patients. In all, 18.2% of CsA patients experienced steroid-resistant rejection compared with 2.6% of FK506 patients. Seven patients (7.6%) in the CsA group and one patient (1.3%) in the FK506 group developed chronic rejection. A total of 57.1% developed infections; 5.7% were life-threatening. CMV infections were observed in 14.3% (versus 25% for other indications). New onset of insulin-dependent diabetes was observed in 8.6% and hypertension in 32.4%. In conclusion, alcoholic cirrhosis is a good indication for liver transplantation with respect to graft and patient survival and development of postoperative complications. FK506 therapy was favourable to CsA treatment. Patient selection is a major issue and established criteria should be strictly adhered to. Patients with alcohol abstinence times shorter than 6 months should be excluded, since recurrence and death due to recurrence was markedly increased in this group of patients.

Type 1 diabetes mellitus and oral health: assessment of periodontal disease.

The periodontal disease status of 320 dentate adults, diagnosed 23.7 years previously with Type 1 insulin dependent diabetes mellitus, was evaluated. These patients had been monitored at 2-year intervals as part of a large University of Pittsburgh longitudinal study assessing the medical complications associated with insulin dependent diabetes. During one of their regularly scheduled medical examinations, a group of 320 adult dentate subjects (mean age of 32.1 years) received a periodontal examination as part of a comprehensive oral health assessment. The oral health assessment collected data regarding demographics, oral health behaviors, tooth loss, coronal and root caries, salivary functions, and soft tissue pathologies. For the periodontal assessments, 3 facial sites (mesial, midcervical, distal) of the teeth in the right maxillary/left mandibular or left maxillary/right mandibular quadrants were evaluated for calculus, bleeding on probing (BOP) and loss of gingival attachment (LOA). Attachment loss was significantly greater for older patients whereas BOP and calculus levels were relatively constant across age categories. Univariate analyses of factors possibly related to extensive periodontal disease (LOA > or =4 mm for at least 10% of sites examined) indicated an association with older age; lower income and education; past and current cigarette smoking; infrequent visits to the dentist; tooth brushing less than once per day; older age of onset; longer duration of diabetes; and the diabetic complication of neuropathy. A multivariate regression model of all possibly significant factors found current cigarette use (odds ratio [OR] = 9.73), insulin dependent diabetes onset after 8.4 years of age (OR = 3.36), and age greater than 32 years (OR = 3.00) explained the majority of the extensive periodontal disease in this group of diabetic patients. Management and prevention of extensive periodontal disease for Type 1 diabetic patients should include strong recommendations to discontinue cigarette smoking.

Small artery elasticity index but not large artery elasticity index is related to the disease duration in early onset insulin dependent diabetes mellitus

Small artery elasticity index but not large artery elasticity index is related to the disease duration in early onset insulin dependent diabetes mellitus

Comparison of a novel micro-assay for insulin autoantibodies with the conventional radiobinding assay

Measurement of insulin autoantibodies (IAA) with a novel micro radiobinding assay which requires only 20 microl of serum was compared with that in a conventional radiobinding assay which uses 600 microl of serum. IAA were measured with both assays in samples from 94 new onset insulin-dependent diabetes mellitus (IDDM) patients, 97 control subjects. and 48 first degree relatives of IDDM patients selected for having IAA in the conventional radiobinding assay. Overall, 227 (95%) of 239 samples tested were concordant. and IAA levels correlated well (r2 = 0.7) between the two assays. Discordant results were obtained in 7 new onset patients, 4 control subjects, and 1 first degree relative, and these had low IAA levels in the respective assays. Sensitivity and specificity in the new onset IDDM patients and control subjects were 69% and 98% for the micro radiobinding assay and 72% and 98% for the conventional radiobinding assay. The use of the micro radiobinding assay should greatly facilitate islet related antibody screening, particularly in children.

Factors predicting cerebral edema in young children with diabetic ketoacidosis and new onset type I diabetes.

We have attempted to identify any characteristics which could be used to predict the development of cerebral edema in four children under 5 years of age with new onset insulin-dependent diabetes mellitus and diabetic ketoacidosis. We retrospectively analysed and compared the concentration of serum sodium (corrected for serum glucose value) and effective serum osmolality of these 4 children with values of 10 age-matched controls with new onset insulin-dependent diabetes mellitus who did not develop cerebral edema during treatment of diabetic ketoacidosis. The initial serum sodium values of the two groups were not statistically different. Patients who developed cerebral edema had lower initial serum glucose values and effective serum osmolality. During treatment, patients who developed cerebral edema had consistently lower mean serum sodium and osmolality than controls at each 4-h interval after the first 4 h of therapy. Serum sodium and osmolality declined progressively after the initiation of therapy in cerebral edema patients, while remaining stable in controls. These data suggest that children who develop cerebral edema during treatment for diabetic ketoacidosis initially may have a relatively normal serum osmolality and subsequently develop progressive hyponatremia and/or a trend of declining serum sodium before developing cerebral edema.

Incidence trends in childhood onset IDDM in four countries around the Baltic sea during 1983-1992.

We present secular trends of childhood onset insulin-dependent diabetes mellitus (IDDM) in Finland, Estonia, Latvia and Lithuania during the period of 1983-1992. Incidence data were obtained from the national IDDM registries. The average age-standardized incidence per 100,000/year was 35.0 in Finland, followed by 10.2 in Estonia, 7.1 in Lithuania and 6.5 in Latvia. A male excess in incidence was recorded in Finland (1.15) and Latvia (1.01). In all countries, the highest age-specific risk of IDDM was observed in the 11-13 year age range. The large difference in incidence between Finland and other Baltic countries was see even in 1-2 year-old children. During the 10-year study period overall changes in incidence of IDDM were relatively small in these four countries. The incidence increased in Finland and Lithuania on average by 1% and 1.4% per year, respectively. A statistically significant increase was recorded only in 0-4 year old children in Finland, at 5.6% per year. In Estonia, an 8.3% increase in this age group, however, was not statistically significant. The different trends in the age-group specific incidence rates were confirmed in Finland. In conclusion, from 1983 to 1992 the incidence of childhood onset IDDM was increasingly in Finland and Lithuania, while in Latvia and Estonia it was stable. There are still great differences in IDDM incidence between the countries around the Baltic Sea.

Non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) occurs predominantly after the age of 50 years but is not easy to distinguish from late onset insulin-dependent diabetes. It is likely that misclassification is rare in a Caucasian population. Whilst NIDDM is widely believed to be genetically determined, recent epidemiological observations have consistently revealed statistical associations between indices of poor fetal and infant growth with susceptibility to loss of glucose tolerance in adult life. A possible explanation of these observations is that environmental constraints on fetal growth lead to permanent changes in organogenesis such that a poor capacity of insulin secretion and insulin resistance result. It is postulated that these adaptive responses serve to preserve the growth of certain organs, such as the brain, at the expense of others, such as the viscera. In addition, alterations in the function of organs, such as the liver, serve to aid survival of the offspring under conditions of poor postnatal nutrition. The results of studies of an animal model in which pregnant rats were fed a reduced protein diet are consistent with these concepts.

Personality traits and metabolic control: a study in insulin-dependent diabetes mellitus patients.

In the present study the authors evaluated the relationship between personality traits (according to DSM-III-R) and poor metabolic control in an adult onset insulin-dependent diabetes mellitus sample (n = 77). Personality traits were assessed with the Personality Diagnostic Questionnaire--Revised. Metabolic control was evaluated through glycosilated hemoglobin (HbA1c): poor metabolic control was defined as HbA1c > or = 9% (normal values < 6.0%). Principal Component Analysis revealed three personality profiles: 'Cluster A/C Mixed', 'Cluster B Dependent' and 'Cluster B Aggressive'. Oneway ANCOVA, using sex as covariate, revealed a significant association (p = 0.01) only between poor metabolic control and Cluster B Dependent profile. No correlation was found between HbA1c and the other profiles. These data suggest that a specific personality profile is associated with poor metabolic control.

Increased Numbers of in vivoActivated T cells in Patients with Recent Onset Insulin-dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus is a T-cell dependent immune mediated disease. Conflicting results regarding the distribution of various T lymphocyte phenotypes in recently diagnosed diabetic patients and in patients with established IDDM compared to controls have been reported. In the present study we evaluated phenotypic characteristics of lymphocytes in IDDM patients. Lymphocytes from 77 newly diagnosed IDDM patients, 58 IDDM patients with disease duration >6 months and 30 non-diabetic controls (including patients with several inflammatory conditions) were analyzed for membrane expression of CD4, CD8, CD45RA, CD45RO and CD27 molecules by FACS analysis. No differences in the percentage of CD8 +T cells were found between any of the groups. However, the percentage of CD4 +T cells, and consequently the CD4/CD8 ratio were significantly increased in PBL of recently diagnosed diabetic patients compared to the non-diabetic control group ( P<0.005). Interestingly, the fraction of lymphocytes coexpressing CD45RO and CD45RA molecules was significantly increased in recent onset IDDM patients, as well as IDDM patients with disease for a longer duration, compared to controls ( P<0.0009 and P<0.007, respectively). IDDM patients had a lower percentage of resting memory T cells (CD45RO +CD27 +) than the non-diabetic controls. The proportion of CD45RO +lymphocytes lacking the CD27 molecule ((re)-activated memory cells) was similar in IDDM patients and non-diabetic controls. Our findings confirm and extend previous observations that a disturbance in lymphocyte subset distribution is present in patients with IDDM showing an increase in the percentages of circulating CD4 lymphocytes.

Intrauterine growth pattern and risk of childhood onset insulin dependent (type I) diabetes: population based case-control study.

To investigate whether prenatal growth affects the risk of development of childhood onset insulin dependent (type I) diabetes mellitus. Population based case-control study. Data from a nationwide childhood diabetes case register were linked with data from the nationwide Swedish Medical Birth Registry. Data from a total of 4584 diabetic children born after 1973 and diagnosed with diabetes from 1978 to 1992 were studied. For each child with insulin dependent diabetes three control children were randomly selected from among all infants born in the same year and at the same hospital as the proband. Birth weight, gestation, maternal age and parity, number of previous spontaneous abortions, and sex specific birth weight by gestational week expressed as multiples of the standard deviation (SD). There was a clear trend in the odds ratio for childhood onset diabetes according to SD of birth weight. The odds ratio (95% confidence interval) for small for gestational age after stratification for maternal age, parity, smoking habits, and maternal diabetes was 0.81 (0.65 to 0.99) and for large for gestational age after similar stratification was 1.20 (1.02 to 1.42). Intrauterine conditions that affect prenatal growth seem also to affect the risk of development of childhood diabetes in the way previously described for postnatal growth: a poor growth decreases and an excess growth increases the risk. The mechanism for this association is unclear.

Seasonality of birth of patients with childhood diabetes in Britain

Indirect evidence suggests that early environment is important in the causation of insulin dependent diabetes mellitus.1 Viral infection is thought to be the most likely trigger. Although biochemical and immunological abnormalities develop several years before the clinical onset of insulin dependent diabetes, the age at which exposure to infection might induce the disease is unclear. The high prevalence of diabetes mellitus in patients with the congenital rubella syndrome shows that the process may be initiated in utero.1 As most viral infections are seasonal, the pattern of dates of birth of people with diabetes should differ from that of the general population if a significant proportion of cases was caused by intrauterine or perinatal viral infection. We therefore examined seasonality of birth in three large independent populations …

Number of autoantibodies (against insulin, GAD or ICA512/IA2) rather than particular autoantibody specificities determines risk of type I diabetes.

We previously evaluated radioassays for insulin autoantibodies (IAA), glutamate decarboxylase autoantibodies (GAA) and ICA512bdc autoantibodies (ICA512bdcAA) in the prediction of type I diabetes. Among first degree relatives, the five year risk of diabetes was 0% if no autoantibody was positive, 15% if only one was positive, 44% if two were positive and 100% if all three were positive. We measured IAA, GAA and ICA512bdcAA in 45 patients with new onset type I diabetes (sampled within 7 days of insulin therapy), 882 first degree relatives of patients with type I diabetes, and 217 control subjects. ICA512bdc is a construct of the ICA512/IA2 molecule (amino acid residues 256-979), including the intracellular domain. Based on receiver-operating characteristic plots, there was no significant difference between the three assays in their ability to discriminate between disease and control subjects. The upper limits of normal for the assays were determined as the 99th percentile of levels in the control subjects or higher. Using these cut-offs, 76% of new onset patients were positive for two or more autoantibodies, and 98% were positive for one or more. In comparison, none of 198 control subjects tested for all three assays were positive for more than one autoantibody. In relatives with a single autoantibody, or exactly two autoantibodies, there was no difference in diabetes-free survival according to which one of the autoantibodies was present (P = 0.70, logrank test), or which particular combination of autoantibodies was present (P = 0.56, logrank test) respectively. Our conclusions were as follows: the number of autoantibodies (counting IAA, GAA and ICA512bdcAA) is important in prediction, rather than the particular autoantibody specificities present. Among patients with new onset insulin-dependent diabetes, the absence of any of these autoantibodies justifies the consideration of non-autoimmune forms of diabetes in the differential diagnosis.

Recent onset insulin dependent diabetes mellitus evaluated with a duplex-doppler study of the splenic artery, preliminary results

Recent onset insulin dependent diabetes mellitus evaluated with a duplex-doppler study of the splenic artery, preliminary results

Islet cell antibodies: variable immunostaining of pancreatic islet cells and carcinoid tissue

Islet cell antibodies (ICA) in sera of patients with autoimmune diabetes mellitus generally stain not only the insulin-producing beta cells but also the non-beta cells of the islets of Langerhans. The antibodies have been reported to react also with the chromaffin cells of carcinoid tissue. In the present study, we examined in detail the reactivity of 10 ICA-positive sera of patients with new onset insulin-dependent diabetes mellitus (IDDM) and two sera of patients with stiff-man syndrome. The sera were analysed by immunofluorescence and by immunoperoxidase staining of human islets as well as by immunoprecipitations using 35S-methionine labelled rat islet lysates. In addition, immunofluorescence analyses of carcinoid tissues were carried out. Eight of the 10 IDDM-positive sera reacted with all islet endocrine cells, whereas two sera showed staining restricted to the beta cells, as did the two sera of the patients with stiff-man syndrome. All beta cell 'selective' sera, but only 6 of 8 'whole' islet positive sera, immunoprecipitated the 64.kDa glutamic acid decarboxylase (GAD) antigen. The staining of carcinoid tissue was variable and did not correlate with the 'whole' or 'selective' staining pattern of islets. The data underline a heterogeneity of ICA and indicate the presence of a separate, non-GAD antigen in islet cells. It is possible that in future studies, a resolution of ICA titres with respect to different types of islet cellular reactivity might provide insights into the pathogenesis of IDDM and improve the prognostic implications of antibody determinations.

Dermatoglyphics, fetal growth, and insulin dependent diabetes in children under 5 years.

Examination of dermatoglyphic patterns in 112 diabetic children under 5 years and matched controls found no difference between the groups. Either those developing diabetes under 5 do not experience the same genetic and environmental conditions that influence its development in later life or the dermatoglyphic abnormalities described in later onset insulin dependent diabetes mellitus reflect the vast number of pattern formations available for study, which has inevitably led to some statistically significant associations.

Anti-ganglioside antibodies in new onset type 1 diabetic patients and high risk subjects.

Insulin dependent (type 1) diabetes mellitus appears to be a genetically determined autoimmune disease. Gangliosides have been implicated in type 1 diabetes as antigenic determinants recognized by islet cell antibodies (ICA) and shown to be able to modulate autoimmune phenomena in experimental diabetes. In order to explore in type 1 diabetes the humoral immune reactivity against gangliosides, taking into account their pancreatic localization and molecular characteristics, antibodies to gangliosides GM3, GM2, GM1, GD3, GD1a, GD1b, and GT1b have been investigated in sera from new onset type 1 diabetics and relatives of type 1 diabetic patients with or without insulin (CIAA) and/or islet cell autoantibodies. Using a purposefully designed sensitive ELISA method we found that presence of antibodies directed against the pacreatic disialo-ganglioside GD3 in a significant percentage of newly diagnosed type 1 diabetics (p < 0.001 vs normal controls) but not in CIAA and/or ICA positive relatives of type 1 diabetics. These findings confirm the involvement of gangliosides in autoimmune phenomena related to type 1 diabetes and suggest disialo-ganglioside GD3 as target of a humoral immune response associated with the onset of insulin-dependent diabetes.

Extrahepatic expression of P450 proteins in insulin-dependent diabetes mellitus.

1. Male Wistar rats were rendered diabetic by the administration of a single intraperitoneal dose of streptozotocin; the levels of the xenobiotic-inducible P450 proteins were determined in the lung and kidney using diagnostic substrates and immunoblotting employing polyclonal antibodies. The glutathione conjugation system in the cytosol of these tissues was also investigated. 2. The onset of insulin-dependent diabetes did not influence the O-dealkylations of methoxyresorufin, ethoxyresorufin and pentoxyresorufin in either kidney or lung. 3. Lauric acid hydroxylase activity, however, was induced in the kidney but no activity was detectable in the lung. Immunoblot analysis of kidney microsomes using antibodies to P4504A1 revealed the presence of two bands, both of which were clearly inducible in diabetes. In pulmonary microsomes a single faint band was detected which also appeared to be higher in the diabetic rats. 4. Aniline p-hydroxylase activity was not detectable in the kidney, but activity was measurable in the lung and was suppressed in diabetes. Immunoblot analysis of pulmonary microsomes using antibodies to P4502E1 immunodetected a single band which was suppressed in diabetes. In the kidney microsomes a single band was also detected which was, however, markedly elevated in diabetes. 5. Glutathione S-transferase activity was modestly higher in the kidney, but not lung, of the diabetic animals. Glutathione reductase and total glutathione levels were not influenced by the presence of diabetes. 6. It is concluded that streptozotocin-induced insulin-dependent diabetes modulates extrahepatic P450 proteins, the effect being both tissue- and isoform-specific.

GAD65 Autoantibodies Increase the Predictability but not the Sensitivity of Islet Cell and Insulin Autoantibodies for Developing Insulin Dependent Diabetes Mellitus

The clinical onset of insulin-dependent diabetes (IDD) can be predicted by determination of autoantibodies to several pancreatic-islet cell antigens. Islet-cell autoantibodies (ICA) and insulin autoantibodies (AA) are most commonly used. We have developed a recombinant human glutamic acid decarboxylase (GAD65) radioimmunoassay and measured autoantibodies to GAD65 (GAD65A) in the sera of 73 documented prediabetic individuals, 76 newly-diagnosed patients, 103 relatives of IDD probands at increased risk for the development of IDD because they were positive for ICA and/or IAA, 72 ICA and IAA negative relatives, and 207 healthy controls. Our data demonstrate that GAD65A are strongly associated with the currently established autoantibody markers of IDD. Their presence in prediabetic subjects with only ICA or IAA enhances their risk for progression to IDD, yet does not much enhance the screening sensitivity already available through conventional ICA and IAA for IDD prediction.

Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile.

Insulin-dependent diabetes mellitus (IDDM), in which only the pancreatic beta cells are destroyed by the autoimmune response, is the paradigm of organ-specific autoimmunity. As a result of a combination of factors, the number of immunohistologic/cellular/molecular studies of pancreas in IDDM is very limited. We report here studies conducted in the pancreata of two IDDM patients: one newly diagnosed (case 1) and one long standing (case 2). In case 1, we demonstrated the presence of morphologically normal viable beta cells without evidence of viral infection. In both cases the expression of the autoantigens defined by islet cell Abs and by glutamic acid decarboxylase was markedly reduced in the islet cells whereas expression of hsp60, another putative autoantigen, was normal. Over-expression of HLA class I was detected in 58% of the islets in pancreatic sections and in cultured beta cells in case 1 and also in 30% of islets in case 2 but it was not restricted to any insular cell type. In case 1, there was "inappropriate" HLA class II expression in islets cells but it was a rare finding and not beta cell specific. The analysis of the correlation between class I overexpression, residual insulin, and insulitis suggests that the first event is the increase of HLA class I expression. Of adhesion molecules, ICAM-1, VLA, VCAM, and LFA-3 were normal and only ICAM-1 was moderately overexpressed in and around the islets of case 1 insulitis, as was detected by immunofluorescence which showed that 18% of the islets of case 1 had CD8+ lymphocytes as the predominant population. Reverse transcription-PCR demonstrated moderate V beta skewing and the profile of cytokines expected in CTLs: IL-2, IL-4, IL-10, and IFN-gamma negative, perforin positive. In addition, IFN-alpha, IFN-beta, and IL-6 transcripts were detected in the case 1 pancreas, consistent with the existence of a silent viral infection. Overall, the results indicated that, differently from spontaneous animal models of diabetes, in the pancreas of IDDM patients there are no elements of the inductive phase of the autoimmune response.

Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives.

Islet cell antibodies (ICA) in the sera of nondiabetic relatives of patients with insulin-dependent diabetes (IDD) are predictive of the disease, a finding that permits the design of intervention strategies to prevent it. However, 85% or more of patients with new onset IDD have no affected relative. We therefore screened 9,696 schoolchildren between the ages of 5 and 18 yr (mean age 10.7 yr) in Pasco County, Florida for ICA in three surveys during 1984/5, 1987/8, and 1990/1 and have followed them prospectively. Approximately 4,000 of these children have been followed for nearly 8 yr. ICA titers > or = 10 Juvenile Diabetes Foundation units on replicate tests were detected in 57 of the children (0.59%). 10 children have developed diabetes so far, and all had ICA detected beforehand. The likelihood of developing IDD among the ICA-positive children was compared with 2,959 age-matched nondiabetic first degree relatives of IDD probands who were screened for ICA by our laboratory during the same time period and also followed prospectively. Of 103 (3.5%) ICA-positive relatives, 31 have developed IDD. Life table analysis reveals no statistically significant differences in the probability of developing IDD between the ICA-positive schoolchildren and ICA-positive first degree relatives (P = 0.3). The estimated risk of developing IDD by 7 yr in the ICA-positive schoolchildren was 45% (95% confidence interval 15-74%) compared with 43% (confidence interval 22-63%) in the relatives. We conclude that ICA appear to be as predictive of IDD in low-risk schoolchildren as they are in high-risk relatives. These data suggest that it is feasible to predict IDD by screening a general population of schoolchildren for ICA and that those found to be positive could be considered, in addition to relatives, for intervention protocols to prevent the disease.