Islet cell and insulin autoantibodies in organ-specific autoimmune patients. Their behaviour and predictive value for the development of Type 1 (insulin-dependent) diabetes mellitus. A 10-year follow-up study

Summary To evaluate the behaviour and predictive value of islet cell and insulin autoantibodies in patients with organspecific autoimmune diseases, we followed 21 non-diabetic subjects for a mean period of 84±27 months. Ten patients were persistently seropositive for complement-fixing islet cell antibodies and high titres of immunoglobulin G islet cell antibodies ( 18). The prevalence of persistent insulin autoantibodies in this group was 67%. Seven patients (70%) developed Type 1 (insulin-dependent) diabetes mellitus after a latency period of 2–60 months. The predictive value of complement-fixing islet cell antibodies was 65%, and in the presence of both complement-fixing islet cell and insulin autoantibodies the predictive value rose to 76%. Eleven patients were seronegative for complement-fixing islet cell antibodies and had low immunoglobulin G islet cell antibodies titres (< 18) that were either persistent or transient, or that fluctuated during follow-up. The prevalence of persistent insulin autoantibodies in this group was 45%; only one subject developed Type 1 diabetes. The predictive value of persistent islet cell antibodies (complement-fixing positive/negative) was 54%, and it rose to 70% when both islet cell and insulin autoantibodies were present. Individuals with only insulin autoantibodies or immunoglobulin G islet cell antibodies did not develop diabetes mellitus. A high frequency of HLA-DR3 and/or DR4 was found in patients who developed diabetes mellitus. Thus, the presence of both islet cell and insulin autoantibodies in patients with organ-specific autoimmune disease appears to confer the highest risk of progression toward Type 1 diabetes.Deceased 29 June 1986     

Predictive value of islet cell and insulin autoantibodies for Type 1 (insulin-dependent) diabetes mellitus in a population-based study of newly-diagnosed diabetic and matched control children

Summary Most studies evaluating immune markers for prediction of Type 1 (insulin-dependent) diabetes mellitus have focused on first degree relatives, although only 10 % of newly-diagnosed patients have an affected first degree relative. The Swedish Childhood Diabetes Register identifies 99 % of all diabetic children at diagnosis. In this population-based study, islet cell antibodies and insulin autoantibodies in 0–14-year-old Swedish consecutively-diagnosed patients and control subjects were analysed to define their sensitivity and specificity. Over 16 months (1986–1987), 515 Swedish children developed diabetes. Plasma samples were obtained from 494 (96 %) patients, and 420 matched control children. Among patients, the frequency of islet cell antibodies was 84 % (415 of 494), insulin autoantibodies 43 % (145 of 334); 40 % (135 of 334) were positive for both and 88 % (294 of 334) were positive for one or both. Among control children, 3 % (14 of 420) had islet cell antibodies, 1 % (4 of 390) insulin autoantibodies, and 4 % (16 of 390) had either autoantibody marker. The predictive value of finding a patient with the disease was only 7% since 4 % of the control children were antibody-positive and the cumulative incidence rate up to 15 years of age is 0.38 %. None of the autoantibody-positive (n = 21) or negative control children developed diabetes during 3 to 5 years of follow-up. Longitudinal investigations of islet cell or insulin-autoantibody-positive healthy children are necessary to accurately determine the conversion rate from marker positivity to disease onset.     

On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth

Summary For the first time the incidence of insulin autoantibodies and islet cell antibodies were evaluated in a prospective study from birth. Consecutive neonates (168) from mothers with Type 1 (insulin-dependent) diabetes mellitus (n=113) and gestational diabetes (n=55) were included at birth. To date, follow-up sera were obtained from 90 of 168 mother-child-pairs 9 months postpartum and from 39 of 168, 2 years postpartum. At birth, there was a strong correlation between the presence of antibodies in the cord blood of neonates and in maternal circulation [Type 1 diabetic mothers: 20% islet cell antibodies 20 JDF-U (detection threshold of our islet cell antibody assay), 74% insulin antibodies >49 nU/ml (upper limit of normal range in sera of healthy control subjects aged 0.5 to 46 years); neonates: 21% islet cell antibodies 20 JDF-U, 76% insulin antibodies >49 nU/ml; gestational diabetic mothers: 11% islet cell antibodies 20 JDF-U, 18% insulin antibodies >49 nU/ml; neonates: 13% islet cell antibodies 20 JDF-U, 55% insulin antibodies >49 nU/ml]. This supports transplacental passage of insulin antibodies and islet cell antibodies from diabetic mothers to their offspring. During follow-up, the majority of children lost antibody-positivity after birth. A few offspring, however, exhibited or developed antibodies consistently, whereby insulin autoantibodies preceded islet cell antibodies in each case (antibody-positivity: 9 months: 0% islet cell antibody positive, 3.3% insulin autoantibody positive; 2 years: 2.6% islet cell antibody positive, 7.7% insulin autoantibody positive). Persisting antibody-positivity in follow-up samples of offspring of diabetic mothers was significantly correlated with older maternal age at delivery (median 38 vs 28 years, p<0.001). It is concluded that antibodies are common in cord blood of neonates of mothers with Type 1 and gestational diabetes, but they normally disappear after birth. In several children, however, islet cell autoimmunity is detected at very young age.     

Islet cell antibodies in the Japanese population and subjects with Type 1 (insulin-dependent) diabetes

Summary Islet cell antibodies were studied in 1,112 non-diabetic adults, 473 normal school children and 162 Type 1 (insulin-dependent) diabetic patients in a Japanese population. The prevalence of islet cell antibodies was 0.5%, 0.4% and 32%, respectively. Most islet cell antibodies positive subjects with Type 1 diabetes had short duration of the disease. No patients who had over 10 years from the onset had islet cell antibodies. Six non-diabetic adults with islet cell antibodies were followed for 4 years. Only one with Hashimoto's thyroiditis showed a diabetic pattern in her oral glucose tolerance test. However, none developed overt insulin-dependent diabetes until 1984. Two out of these six subjects continued to be positive for both islet cell antibodies and antithyroid antibodies or antinuclear antibodies. Islet cell antibodies in the remaining four patients disappeared during the second year. It is difficult to predict the onset of Type 1 diabetes by islet cell antibodies in non-diabetic individuals because they may be transient.     

Anti-glutamate decarboxylase and other antibodies at the onset of childhood IDDM: a population-based study

Summary Sera obtained at diagnosis from 273 children (0–14 years) with insulin-dependent diabetes mellitus (IDDM) were studied to compare different autoantibody levels. The subjects comprise 75% of all incident cases in New South Wales, Australia, for a 2-year period (ascertainment >99% complete). Antibodies against glutamate decarboxylase were measured by radioimmunoprecipitation, insulin autoantibodies (on 176 sera collected within 4 days of initiation of insulin therapy) by radioimmunoassay, thyroid peroxidase and antigliadin IgA antibodies by enzyme-linked immunoassay, and anti-endomysial IgA and islet cell antibodies by indirect immunofluorescence. Reference ranges for anti-glutamate decarboxylase and insulin autoantibodies were determined in a group of non-diabetic children. Of the sera 69% were positive for anti-glutamate decarboxylase, 65% for insulin autoantibodies, 71% for islet cell antibodies (20 Juvenile Diabetes Foundation units), 10% for anti-thyroid peroxidase, 2.6% for antigliadin and 3.0% for anti-endomysial antibodies. Islet cell antibodies and insulin autoantibodies were both negative in 13.7% of the sera, while only 5.8% were negative for all three of islet cell antibodies, insulin autoantibodies and anti-glutamate decarboxylase. There was a higher frequency of anti-glutamate decarboxylase among girls than boys (75% vs 63%, p=0.03) and a negative correlation between the level of insulin autoantibodies and age at diagnosis (r=–0.41, p<0.0001). A higher frequency of antithyroid peroxidase was found with increasing age (p=0.05). Higher titres of islet cell antibodies were associated with a higher frequency of both anti-glutamate decarboxylase (p<0.0001) and insulin autoantibodies (p=0.003). Five children (1.8%) with clear elevations of antigliadin and anti-endomysial antibodies were found to have asymptomatic coeliac disease by small bowel biopsy.Abbreviations IDDM insulin-dependent diabetes mellitus - ICA islet cell antibodies - IAA insulin autoantibodies - anti-GAD antibodies against glutamate decarboxylase - anti-TPO antibodies against thyroid peroxidase - AGA antigliadin IgA antibodies - AEA anti-endomysial antibodies - JDF U Juvenile Diabetes Foundation units - PBS phosphate buffered saline     

Latent Autoimmune Diabetes Mellitus in Adults (LADA): the Role of Antibodies to Glutamic Acid Decarboxylase in Diagnosis and Prediction of Insulin Dependency

Type 1 diabetes mellitus in adults may present in a manner similar to that of Type 2 diabetes but with a late development of insulin dependency. We studied 65 patients who presented with ‘adult-onset’ diabetes after the age of 30 years. Of these patients, 19 required insulin therapy. The insulin-treated patients were significantly younger, their onset of diabetes was at an earlier age, and their postprandial serum C-peptide levels were lower than those of the non-insulin-treated group. Moreover, the insulin-treated subjects had a higher mean concentration of antibodies to glutamic acid decarboxylase (GAD) (66.8 ± 10.2 units) than the patients who did not require insulin (9.9 ± 1.9 units) (p < 0.001) and their frequency of anti-GAD positivity was 73.7% versus 4.3% (p < 0.001). Thus, among patients attending a diabetes clinic, the majority (73.7%) of subjects who presented with diabetes after 30 years of age and who subsequently required therapy with insulin, actually have the islet cell lesion of Type 1 diabetes which progresses at a slower tempo than in children. We conclude that testing for anti-GAD in adult-onset non-obese diabetic patients should be a routine procedure in order to detect latent insulin-dependency at the earliest possible stage, since this assay can assist in the correct classification of diabetes, and more appropriate therapy.     

Risk for developing Type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies

Summary First-degree relatives of Type 1 (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a M_r 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type 1 diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type 1 diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high (n=6) and low (n=30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive while six (20%) were positive for 64K antibodies. In contrast, of the six subjects with progressively declining Beta-cell function who are therefore at high risk, two of whom have already developed Type 1 diabetes, two (33%) were positive for insulin autoantibodies, four (67%) were islet cell antibody positive, while all six (100%) were positive for 64K antibodies. We conclude that antibodies to the M_r 64,000 islet protein correlate with progressive Beta-cell dysfunction more closely than either islet cell antibodies or insulin autoantibodies, but can sometimes be present in individuals whose Beta-cell function remains stable over several years.     

Frequency of severe hypoglycaemia in type 1 and type 2 diabetes during conventional insulin therapy.

To determine the frequency of severe hypoglycaemia during conventional insulin therapy in juvenile-onset and adult-onset type 1 and in type 2 diabetes mellitus (DM), we retrospectively analysed the medical records of 165 Turkish diabetic patients who have been treated with conventional insulin. Patients were divided into 3 subgroups with respect to the type of diabetes: 33 had juvenile-onset Type 1 DM, 18 had adult-onset type 1 DM, and 114 had type 2 DM. The diabetic subgroups were found to be comparable with regard to mean frequency of severe hypoglycaemia (juvenile-onset type 1 DM: 0.20 episode x patient(-1) x year-1, adult-onset type 1 DM: 0.10 episode x patient(-1) x year(-1), type 2 DM: 0.15 episode x patient(-1) x year(-1)). Frequency of severe hypoglycaemia necessitating in-hospital treatment was 0.05 episode x patient(-1) x year(-1) for all diabetic subgroups. The data clearly indicate that the extent of the problem of severe hypoglycaemia during conventional insulin therapy in type 2 DM is comparable with both juvenile and adult-onset forms of type 1 DM in Turkish diabetic population.     

Antibodies to the Mr 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired Beta-cell function

Summary A prospective study of a normal childhood population identified 44 islet cell antibody positive individuals. These subjects were typed for HLA DR and DQ alleles and investigated for the presence of antibodies to the M_r 64,000 (64K) islet cell antigen, complement-fixing islet cell antibodies and radiobinding insulin autoantibodies to determine their potency in detecting subjects with impaired Beta-cell function. At initial testing 64K antibodies were found in six of 44 islet cell antibody positive subjects (13.6%). The same sera were also positive for complement-fixing islet cell antibodies and five of them had insulin autoantibodies. During the follow-up at 18 months, islet cell antibodies remained detectable in 50% of the subjects studied. In all six cases who were originally positive, 64K antibodies were persistently detectable, whereas complement-fixing islet cell antibodies became negative in two of six and insulin autoantibodies in one of five individuals. HLA DR4 (p < 0.005) and absence of asparic acid (Asp) at position 57 of the HLA DQ chain (p < 0.05) were significantly increased in subjects with 64K antibodies compared with control subjects. Of 40 individuals tested in the intravenous glucose tolerance test, three had a first phase insulin response below the first percentile of normal control subjects. Two children developed Type 1 (insulin-dependent) diabetes mellitus after 18 and 26 months, respectively. Each of these subjects was non-Asp homozygous and had persistent islet cell and 64K antibodies. We conclude that 64K antibodies, complement-fixing islet cell antibodies and insulin autoantibodies represent sensitive serological markers in assessing high risk for a progression to Type 1 diabetes in islet cell antibody positive non-diabetic individuals.     

Anti-tubulin antibodies in recent onset Type 1 (insulin-dependent) diabetes mellitus: comparison with islet cell antibodies

Summary Antibodies to tubulin, the fundamental protein of microtubules, were studied by radioimmunoassay in patients with Type 1 (insulin-dependent) diabetes of varying duration and in healthy control subjects. Elevated levels of anti-tubulin antibodies were found in 46% of 28 patients with Type 1 diabetes of recent onset ( 6 months) and in only 6.2% of 64 patients with long-standing Type 1 diabetes (duration 6–43 years). None of 34 DR3-positive normal subjects and none of 20 Type 2 (non-insulin-dependent) diabetic patients were positive for anti-tubulin antibodies. Anti-tubulin antibody levels were elevated in two out of 26 first-degree relatives of Type 1 diabetic patients. The specificity of the detection of anti-tubulin antibodies was demonstrated by (1) dilution of the sera, (2) competitive binding experiments between labelled and unlabelled tubulin, (3) immunoblotting. Antibodies to tubulin were elevated in 60% of patients with islet cell surface antibodies and there was a significant association between anti-tubulin antibodies and islet-cell surface antibodies. These antibodies, however, recognize different specificities, since adsorption of islet cell surface antibody by rat islets did riot alter the anti-tubulin antibody activity. Elevated anti-actin antibody responses were found in two out of 17 and one out of 26 patients with recent onset and long-standing Type 1 diabetes, respectively. In conclusion, anti-tubulin antibodies are detected in a high proportion of patients with diabetes of recent onset, are associated with islet cell surface antibodies and like islet cell surface antibodies decrease or disappear during the course of the disease. Therefore, elevation of antitubulin antibodies could represent another marker of the immunological features of Type 1 diabetes. However, these findings, together with our previous observation of an elevation of anti-tubulin antibodies in autoimmune thyroid disorders, indicate a wider involvement of autoimmunity with tubulin and suggest that similar autoimmune phenomena could develop in Type 1 diabetes and some other diseases.     

Preclinical and manifest diabetes mellitus in young patients with friedreich's ataxia: no evidence of immune process behind the islet cell destruction

Summary Friedreich's ataxia is known to be associated with diabetes mellitus in up to 20% of the patients. However, type, development and course of diabetes mellitus are not well characterised. We report on 3 patients (2 female and 1 male, age 13–20 years) with the combination of Friedreich's ataxia and diabetes mellitus. Diabetes mellitus was characterised as follows: (1) it was strictly insulin-dependent and ketosis-prone, (2) the average insulin requirement was 1 U/kg body weight, (3) the HLA haplotype was not typical of Type 1 (insulin-dependent) diabetes mellitus, (4) there were no positive immune parameters typical of Type 1 diabetes at the clinical onset of diabetes mellitus and (5) there was no remission. To evaluate a preclinical phase as in common autoimmune Type 1 diabetes, i.v. glucose tolerance tests (0.5 g glucose/kg body weight) were performed in 8 patients with Friedreich's ataxia without diabetes mellitus. Seven patients had normal early phase insulin response. In contrast, the glucose disappearance rate was slow in 4 and normal in 3 patients. One of the 8 patients showed a prediabetic metabolic state: the early-phase insulin response was abolished and the glucose disappearance rate was abnormal. The results suggest that diabetes in Friedreich's ataxia is caused by a loss of islet cells similar to common Type 1 diabetes but without HLA-association and without serologic evidence for autoimmune destruction of the islet cells.     

Adult human pancreatic islet cells in tissue culture: function and immunoreactivity

In order to obtain an appropriate tissue model to study human diabetes we isolated islet cells from pancreata obtained from brain-dead, heart-beating kidney donor subjects by collagenase dispersion and tissue culture. The presence of viable islet cells was confirmed by both immunofluorescence staining and hormone release experiments. Insulin and somatostatin release were determined on culture day 3 or 4 when amylase measurements indicated an absence of functional exocrine cells. Glucose, alpha-ketoisocaproic acid, theophylline, glucagon, and tolbutamide each stimulated insulin release 2- to 3-fold and somatostatin release 1.5- to 2-fold. Epinephrine and somatostatin both inhibited glucose-stimulated insulin release. Successful subculture of islet cells was achieved after dispersion of primary cultures with dispase. Subcultured islet cells released insulin into the medium during a subsequent 8-day period and when challenged with glucose responded with a 1.6-fold increase in insulin output. Cells cultured on glass coverslips were used to detect, by indirect immunofluorescence, islet cell surface antibodies (ICSA) in the sera of patients with insulin-dependent diabetes mellitus. Of 15 sera from patients with newly diagnosed insulin-dependent diabetes mellitus 9 were ICSA positive, whereas all of 10 control sera were negative; in contrast, using rat insulinoma cells only 4 diabetic sera were positive, as well as 2 control sera. These findings demonstrate the functional viability of adult human islet cells in primary and secondary culture. Cultured human islet cells are a novel, sensitive, and specific system for detecting ICSA and for studying autoimmune effects, and provide a potential source of islet cells for transplantation.     

Islet cell autoimmunity and mitochondrial DNA mutation in Korean subjects with typical and atypical Type I diabetes

Aims/hypothesis: The 1997 American Diabetes Association classification of diabetes mellitus included a subset of Type I diabetic patients who do not need insulin for several years but eventually progress to complete insulin deficiency i. e. atypical Type I diabetes mellitus. In Caucasian populations, most Type I diabetic patients have auto-antibodies against islet cells. We examined the frequency of the auto-antibodies against islet cells and mitochondrial DNA 3243 mutation in Koreans with typical and atypical Type I diabetes mellitus. Methods: We measured plasma C-peptide level in 1870 consecutive Korean diabetic patients. Of these, 56 patients had insulin deficiency (fasting and glucagon-stimulated plasma C-peptide concentrations ≤ 0.2 nmol/l and ≤ 0.32 nmol/l, respectively), and they were subdivided into typical (n = 26) and atypical Type I (insulin-dependent) diabetes mellitus (n = 30) according to clinical manifestation. Islet cell antibody was measured by indirect immunofluorescence. Anti-GAD antibody and anti-ICA512 antibody were measured by radioimmunoassay. Mitochondrial DNA 3243 mutation was detected using restriction enzyme Apa-I digestion of the amplified genomic DNA. Results: The overall prevalence of auto-antibodies in the typical and atypical groups was 77 % and 57 %, respectively. Mitochondrial DNA 3243 mutation was found in 3 out of 30 (10 %) of atypical Type I (insulin-dependent) diabetic patients but not in typical Type I (insulin-dependent) diabetic patients. Conclusion/interpretation: Autoimmunity might not be the only cause of progressive insulin deficiency in Koreans. Mitochondrial DNA mutation is another identifiable cause but the cause(s) of insulin deficiency in the remainder of Type I diabetic patients without autoimmunity is not clear. [Diabetologia (2001) 44: 2187–2191] Received: 5 June 2001 and in revised form: 27 July 2001     

Diagnostic criteria for acute‐onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute‐onset Type 1 Diabetes Mellitus

Type 1 diabetes is a disease characterized by destruction of pancreatic β‐cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute‐onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute‐onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti‐islet autoantibodies are diagnosed with ‘acute‐onset type 1 diabetes mellitus (autoimmune)’. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C‐peptide immunoreactivity <0.6 ng/mL) without verifiable anti‐islet autoantibodies are diagnosed simply with ‘acute‐onset type 1 diabetes mellitus’. Patients should be reevaluated after certain periods in case their statuses of anti‐islet autoantibodies and/or endogenous insulin secretory capacity are unknown.     

Low acute insulin response to intravenous glucose. A sensitive but non-specific marker of early stages of Type 1 (insulin-dependent) diabetes

Summary Preventive treatment of Type 1 (insulin-dependent) diabetes presupposes early and accurate diagnosis of prediabetic states. The low acute insulin response to intravenous glucose has been proposed as a marker of both pre-Type 1 and pre-Type 2 (non-insulin-dependent) diabetes. In order to test the reliability of this marker for clinical detection of Type 1 diabetes we looked for this anomaly in 150 first degree relatives of Type 1 diabetic patients, 31 relatives of Type 2 diabetic patients and 39 young non-obese diabetic patients with mild or transient hyperglycaemia. The low acute insulin response was defined by a peak insulin value (sum of plasma insulin at 2 and 5 min after glucose load, 0.3 g/kg body weight) below 50 U/ml. It was observed in 12% of the relatives of Type 1 diabetic patients (2 of them became diabetic) and in 13% of the relatives of Type 2 diabetic patients. Reproducibility of the peak insulin value in 2 subsequent tests (r=0.749) was inadequate to interpret small variations in one individual. In the population of 39 diabetic patients, 10 subsequently developed typical Type 1 diabetes, 9 were low insulin responders. In the 29 patients who are still non-insulin-dependent 3 years later, the anomaly was found in the 3 islet cell antibody-positive subjects and 11 out of 26 patients with no detectable antibodies. In conclusion, low acute insulin response to glucose is a sensitive but non-specific marker of early stages of Type 1 diabetes as this anomaly is shared by both Type 2 and Type 1 diabetes.     

Diabetic microangiopathy in patients with pancreatitic diabetes mellitus

Summary Clinically evident diabetic microangiopathy (retinopathy and nephropathy) occurred in 18% of diabetic patients with acute pancreatitis and 14% of diabetic patients with chronic pancreatitis. The presence of diabetic retinopathy and nephropathy in patients with pancreatitic diabetes without a family history of diabetes mellitus suggests that these patients have primary diabetes mellitus unmasked by the pancreatitis. The occurrence of diabetic microangiopathy is significantly correlated with the duration of diabetes. The frequency of these diabetic complications seems to increase when there is a family history of diabetes in patients whose pancreatitis is simultaneous with or precedes the onset of diabetes. The majority of patients with diabetic microangiopathy were on insulin therapy, but the need for insulin treatment is an indication of the severity of the diabetes, rather than the insulin being a causative factor of the microangiopathy. The degree of steatorrhea in diabetic patients with chronic pancreatitis did not protect against the development of microangiopathy.     

Prevention or delay of Type 1 (insulin-dependent) diabetes mellitus in children using nicotinamide

Summary A controlled trial of oral nicotinamide to prevent the onset of diabetes mellitus in high risk children was conducted in two centres. The selection criteria were age less than 16 years, islet cell antibody 80 IUs, and first phase insulin release < 5th percentile. All of eight untreated control subjects have developed diabetes, whereas only 1 of 14 treated children has diabetes to date. This data suggests that nicotinamide has an effect in preventing Type 1 (insulin-dependent) diabetes and that randomized controlled studies are now indicated.     

Five-year follow-up of islet cell antibodies in Type 2 (non-insulin-dependent) diabetes mellitus

Summary The aim was to study the frequency and appearance of cytoplasmic islet cell antibodies in relation to impairment of insulin secretory capacity and some clinical characteristics in a representative group of middle-aged (45–64 years) patients with Type 2 (non-insulin-dependent) diabetes mellitus (70 male, 63 female) at the time of diagnosis and at five-year follow-up. Non-diabetic control subjects (62 male, 82 female) were similarly examined at five-year intervals. At the baseline five out of 133 (3.8%) diabetic patients were positive for conventional and four (3.0%) for complement-fixing islet cell antibodies. Ten patients had become positive by the second screening for conventional antibodies and six for complement-fixing antibodies, but none showed negative conversion. Two non-diabetic subjects (1.5%) became antibody positive during the follow-up. Insulin treatment was started during the follow-up for four out of 15 (27%) conventional antibody positive and for one out of 121 (0.8%) antibody negative diabetic patients (p=0.001). The sensitivity of the positive conventional and complement-fixing antibody for identifying patients who developed an impairment of insulin secretory capacity (post-glucagon C-peptide 0.60nmol/l at 5-year) was 75%. The respective specificity was 90% and the positive predictive values were highest in the case of high positivity (50%). The negative predictive value of antibody positivity was close to 100%. In conclusion, islet cell antibody positivity in patients classified as Type 2 was persistent during the follow-up and predicted the future development of insulin deficiency especially in those patients with high or increasing antibody titres.     

Sexual dimorphism in transmission of expression of islet autoantibodies to offspring

Summary To help elucidate the mode of inheritance of insulin-dependent diabetes mellitus (IDDM), we measured GAD (glutamic acid decarboxylase) autoantibodies (GAD65Ab), insulin autoantibodies (IAA), and cytoplasmic islet cell autoantibodies (ICA) in 292 sequentially screened non-diabetic offspring of patients with IDDM. The prevalence of these islet autoantibodies was higher in offspring of diabetic fathers than in offspring of diabetic mothers. The prevalences of GAD65Ab, IAA, and ICA in the offspring of diabetic fathers were 11.5%, 10.8%, and 8.1% vs 2.1%, 1.4%, and 2.8%, respectively in the offspring of diabetic mothers (p<0.002, p<0.001, and p=0.06 NS). Amongst autoantibody-positive relatives the IAA and ICA levels were significantly higher in offspring of diabetic fathers than of diabetic mothers (p<0.002 and p<0.01, respectively). The frequencies of these autoantibodies were equal in male and female offspring. We conclude that IDDM mothers transmitted islet autoimmunity less frequently to their offspring than IDDM fathers. Given the markedly lower frequency of autoantibodies in offspring of mothers, larger sample sizes will be required to determine whether islet autoantibodies are influenced by age of IDDM onset of mothers, maternal age of pregnancy, and presence of diabetes in these mothers prior to conception.Abbreviations IDDM Insulin-dependent diabetes mellitus - GAD glutamic acid decarboxylase - GAD65Ab glutamic acid decarboxylase autoantibodies - IAA insulin autoantibodies - ICA cytoplasmic islet cell autoantibodies - JDF Juvenile Diabetes Foundation     

Antibodies to a Mr-64000 islet cell protein in Swedish children with newly diagnosed Type 1 (insulin-dependent) diabetes

Summary Sera from 40 Swedish children diagnosed as having Type 1 (insulin-dependent) diabetes mellitus during a one year period along with 40 age and geographically matched control subjects were tested for antibodies to a M_r-64000 islet protein by immunoprecipitation of ³⁵S-methionine-labelled rat islet amphiphilic proteins. Of the 40 diabetic patients, 29 (73%) were found to be positive whereas all 40 control subjects were negative. Samples were also tested for titres of islet cell cytoplasmic antibodies by indirect immunofluorescence on frozen sections of human pancreas. In the diabetic group, 30 of the 40 patients (75%) were positive for islet cell cytoplasmic antibodies compared with 2 of the 40 control subjects (5%). A comparison of levels of antibodies to the M_r-64000 protein with islet cell cytoplasmic antibodies revealed a weak (r _s=0.46), but significant (p<0.01) correlation between the two tests. There was no effect of age or sex on levels of antibodies to the M_r-64000 protein. These results in population-based diabetic children and control subjects demonstrate a high frequency of antibodies to the M_r-64000 protein at the time of clinical onset.