I Insulin-dependent Diabetes Mellitus Research Articles

Infection in diabetic foot

Objectives The present study was carried out to determine the prevalence of aerobic and anaerobic pathogens in diabetic foot infections (DFIs), detect their susceptibility to different antimicrobial agents, investigate the microbiological profiles of DFIs in relation to different grades of Wagner classification, and assess the risk factors for DFIs. Background DFI is the most frequent reason for diabetes-related hospitalization. It develops because of several diabetes-related factors including arterial insufficiency, neuropathy, foot deformities, previous ulcers, previous amputation, and local trauma. Materials and methods The study was carried out on clinical specimens taken from 100 diabetic patients (50 patients had type I insulin-dependent diabetes mellitus (IDDM) and 50 patients had type II noninsulin-dependent diabetes mellitus (NIDDM) and 50 nondiabetic patients with foot infection during the period from May 2011 to July 2012. The specimens were cultured using aerobic and anaerobic microbiological techniques, and antibiotic susceptibility testing was performed according to the methods recommended by the Clinical and Laboratory Standards Institute (CLSI). Multidrug-resistant organisms were detected including oxacillin-resistant and vancomycin-resistant staphylococci and gram-negative bacilli extended-spectrum beta-lactamase producers. Results DFIs were polymicrobial in 76% of cases. Staphylococcus aureus was the most common aerobic isolate (17.6%) (including 74.4% methicillin resistant and 23.1% vancomycin resistant). Peptostreptococcus spp. were the most common anaerobic isolate (39.4%). Extended-spectrum β-lactamase production was detected in 53.4% of Gram-negative bacilli. About 62% of diabetic patients were infected with multidrug-resistant organisms. The risk factors for DFIs were duration of diabetes more than 1 year, random blood sugar of at least 200 mg/dl, trauma, previous ulcer and amputation, and comorbidities related to diabetes. Conclusion Imipenem was the most effective drug against all isolates. Effective glycemic control and educating patients on the prophylactic foot care are of key importance for decreasing DFIs.

Insulin-dependent diabetes: strategy for immune intervention.

Increasingly, experimental results are underlining the role played by autoimmune mechanisms in the pathogenesis of type I insulin-dependent diabetes mellitus (IDDM). It has appeared logical to attempt to preclude the onset of IDDM by suppressing immune responses, but trials using steroids or azathioprine were unequivocal. Subsequently, a Canadian and a French group performed pilot studies to assay a new immunosuppressive drug, cyclosporine A (CyA) in human diabetes (Stiller et al., 1984; Assan et al., 1985). However, further testing is required to evaluate and confirm its potential benefits and possible risks.

Discrimination between granulocytes from type I and type II diabetics patients by calorimetry

We report the application of calorimetric method for evaluating the metabolic response of human granulocytes either from type I-insulin-dependent diabetes mellitus (IDDM) or from type II-noninsulin-dependent diabetes mellitus (NIDDM) in comparison to cells of healthy donors. Granulocytes either from patients (type I or type II diabetics patients) or from healthy subjects were exposed in a calorimeter to 4-β-phorbol-12,13-dibutyrate (PDB) or Zymosan opsonized particle (ZC3b). The total heat released by both PDB-activated or phagocyting granulocytes from type I-IDDM patients was significantly higher than that produced by granulocytes either from type II-NIDDM patients or from healthy subjects ( p<0.05). The heat production by granulocyte from healthy subjects and from type II-NIDDM patients were similar ( p>0.05). These results demonstrate, for the first time, the discrimination between human granulocytes from type I-IDDM and type II-NIDDM patients by calorimetry. Thus, we suggest that due to its high sensitivity, calorimetry may be used as an auxiliary method for discriminating type I-IDDM from type II-NIDDM patients based on granulocyte reactivity.

Molecular mimicry: Basis for autoimmunity

Structural similarity between a viral protein and a self-component can trigger an autoimmune response, which is the basis of molecular mimicry. Alternatively an invading virus can induce an inflammatory response which in turn can initiate an attack by hitherto dormant T cells on a specific self-antigen, a phenomenon which is referred to as Bystander Activation. Several viruses share amino acid sequences with target self-proteins. A widely studied viral interaction is the structural mimicry of a small portion of coxsackie virus to a specific region of the enzyme glutamic acid decarboxylase (GAD) which is expressed by the β cells of the islet of Langerhans in the pancreas leading to the destruction of insulin producing cells and the onset of Type I insulin dependent diabetes mellitus (IDDM). Knowledge of specific epitopes in GAD susceptible to autoimmune attack can permit devising therapeutic strategies for the prevention and suppression of IDDM.

Decreased opioid-induced antinociception but unaltered G-protein activation in the genetic-diabetic NOD mouse

Previous evaluation of antinociceptive action in experimental diabetes has been conducted almost exclusively in chemically induced diabetes mellitus. The purpose of the present study was to evaluate antinociceptive response and G-protein activation by μ-opioid receptor and δ-opioid receptor agonists in the genetic non-obese diabetic (NOD) mouse, a model of type I insulin-dependent diabetes mellitus (IDDM). Tail-flick latency before and after hyperglycemia was unaltered. Hyperglycemic NOD mice were hyporesponsive to intracerebroventricular (i.c.v.) injections of [ d-Ala 2]deltorphin II but not to [ d-Ala 2, N-MePhe 4, Gly-ol 5]enkephalin (DAMGO); however, G-protein activation in pons/medulla assessed by [ 35S]GTPγS binding was not diminished. This suggests that a G-protein defect in signaling cannot account for the hyporesponsiveness of antinociception in this genetic model of IDDM.

Risk factors for cardiovascular disease in children with Type I diabetes.

The major cause of morbidity and mortality in individuals with Type I insulin-dependent diabetes mellitus (IDDM) is premature and extensive atherosclerotic cardiovascular disease (CVD). To determine the prevalence and predictors of hypercholesterolemia and to examine the distribution and interrelationship of risk factors for CVD. This observational (mixed-longitudinal) study, guided by an epidemiologic framework, assessed a sample of 140 children with IDDM. Total cholesterol (TC) and diabetes control were measured in the total sample. Standard CVD risk factors were measured in a subsample of 67 children. Observed frequency of TC greater than the 75th percentile and greater than the 95th percentile was significantly more than expected (p < 0.01 and p < 0.0001, respectively). In the total sample, TC-CVD risk factor associations were not observed. However, diabetes control and physical activity were correlated with TC in the risk sample of children at highest risk, as demonstrated by hypercholesterolemia. Results demonstrate the importance of assessing the lipid profile in children with IDDM and monitoring CVD risk factors in hyperlipidemic children with IDDM. Future research should focus on prospective longitudinal studies in population-based multiethnic samples of children with IDDM.

Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling.

Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mice, and suppress type I insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. To determine whether repeated TNF injections suppress T cell function in adult mice, we studied the responses of influenza hemagglutinin-specific T cells derived from T cell receptor (HNT-TCR) transgenic mice. Treatment of adult mice with murine TNF for 3 wk suppressed a broad range of T cell responses, including proliferation and cytokine production. Furthermore, T cell responses of HNT-TCR transgenic mice also expressing the human TNF-globin transgene were markedly reduced compared to HNT-TCR single transgenic littermates, indicating that sustained p55 TNF-R signaling is sufficient to suppress T cell function in vivo. Using a model of chronic TNF exposure in vitro, we demonstrate that (a) chronic TNF effects are dose and time dependent, (b) TNF suppresses the responses of both Th1 and Th2 T helper subsets, (c) the suppressive effects of endogenous TNF produced in T cell cultures could be reversed with neutralizing monoclonal antibodies to TNF, and (d) prolonged TNF exposure attenuates T cell receptor signaling. The finding that anti-TNF treatment in vivo enhances T cell proliferative responses and cytokine production provides evidence for a novel regulatory effect of TNF on T cells in healthy laboratory mice. These effects are more pronounced in chronic inflammatory disease. In addition, our data provide a mechanism through which prolonged TNF exposure suppresses disease in animal models of autoimmunity.

Molecular genetic studies in monogenic and polygenic human diseases

The main goal of this study was to determine and characterise the types of mutations in two monogenic human disorders: cystic fibrosis (CF) and Duchenne/Becker muscular dystrophy (DMD, BMD) and the susceptibility allele frequency in a polygenic disease: type I insulin-dependent diabetes mellitus (IDDM). After analysing 220 chromosomes for mutations in the CF (Cystic Fibrosis Transmembrane Conductance Regulator = CFTR) gene, delta F508 mutation was most abundant (41%) and out of the non-delta F508 CF mutations 5% was identified as G542X, G551D, R553X, N1303K and W1282X. The CF haplotype analysis by using linked markers to the CFTR gene revealed that the CF "B" haplotype occurred in 66.7% of patients, and this haplotype was 57.2% in patients carrying the delta F508 mutation. Prenatal genetic diagnosis for CF was performed in 10 fetuses: 3 were affected, 6 were carriers, and 1 without any CF mutation. Fifty % of 66 patients with DMB/BMD muscular dystrophy had one or more exon deletions in the dystrophin gene. Eighty-five % of the deletions occurred at the 3' and 15% at the 5' end of the gene. Out of the three prenatal diagnosis in one case DMD was substantiated. Thirty-six % of 50 patients with IDDM possessed four, 44% three and 20% two susceptibility markers in the HLA-DQA1, -DQB1 region. The onset of the disease correlated with the number of susceptibility alleles.

Integrated analysis of erythrocyte NA +/H + antiport activity and left ventricular myocardial function in type I insulin-dependent diabetes mellitus

Membrane NA +/H + exchanger regulates cell pH, volume, and growth. Abnormal activities have been reported in essential hypertension and type I insulin-dependent diabetes mellitus (IDDM). The aim of this study was to analyze the relationship between erythrocyte NA +/H + antiport activity and myocardial anatomical and functional parameters in normotensive type I insulin-dependent diabetic patients. We evaluated 26 insulin-dependent diabetic patients (20 normo- and 6 microalbuminuric) and 17 age- and sex-matched healthy controls. Plasma and urine analytes as well as erythrocyte NA +/H + antiport rate were measured. M-Mode- and 2D echocardiograms with Doppler analysis were performed in all subjects. Diabetic people, both normo- and microalbuminuric, had a Na +/H + antiport activity significantly higher than control subjects ( p < 0.01). All echocardiographic parameters relative to left ventricular volume, cardiac mass and systolic function overlapped in the study groups. Of Doppler indexes, evaluating the left ventricular diastolic filling, the late peak flow velocity (peak A) was significantly higher in diabetic patients ( p < 0.01). E/A ratio was heightened in the control group compared to diabetics, as a whole as well separately considered ( p < 0.01). Antiport significantly correlated with PWTh, STh, E/A, UAER, serum sodium, and gender ( p < 0.0001). The linear and significant correlation found between Na +/H + exchange and some cardiac indexes suggest the increased Na +/H + antiport activity as possible predictive risk factor for the development of diabetic cardiomyopathy.

Atopic allergy and delayed hypersensitivity in children with diabetes

The prevalence of atopy was studied in 61 children with type I insulin-dependent diabetes mellitus (IDDM) and 72 age- and sex-matched control subjects. The two groups had a similar prevalence of atopic disease and did not differ significantly with respect to history, clinical findings, skin prick test results, total serum IgE levels, or presence of circulating IgE antibodies to allergen. We also studied delayed-type hypersensitivity reactions in 37 of the children with IDDM and 46 of the control subjects. Children with IDDM, as compared with those without IDDM, more often had other autoimmune diseases in their family histories ( p < 0.01). They also had significantly stronger delayed hypersensitivity reactions than the control subjects, as determined with tetanus toxoid ( p < 0.05) and mumps antigen ( p < 0.01). The reactivity to purified protein derivate of tuberculin and Candida antigen was similar in the two groups. The study does not confirm previous suggestions of an inverse relationship between IDDM and atopic disease but does confirm that IDDM is associated with other immunologic disturbances. The different genetic and immunologic traits do not prevent allergic manifestations in children with diabetes. (J A LLERGY C LIN I MMUNOL 1995;96:188-92.)

Effects of Various Environmental Stress Paradigms and Adrenalectomy on the Expression of Autoimmune Type 1 Diabetes in the Non-obese Diabetic (NOD) Mouse

The effects of long-term chronic stress (induced by repeated restraint, overcrowding or both), short-term chronic stress (induced by a triad of stressors over a short period of time early in life) and adrenalectomy were investigated on the prevalence, on the degree of insulitis and various physiological and immunological parameters in the NOD mouse, a spontaneous model of type I-insulin-dependent diabetes mellitus (IDDM). Long-term chronic stress, obtained by restraint once a week or overcrowding, significantly protected NOD females, while both applied concomitantly had only a tendency to protect against diabetes. In contrast, short-term chronic stress had no significant effect on diabetes expression, whereas adrenalectomy resulted in a trend toward accelerated diabetes onset. The various long-term chronic stress paradigms exerted different effects on the progression of insulitis: repeated restraint tended to protect against insulitis, overcrowding had no effect but, when associated with restraint, significantly counteracted the beneficial effect of restraint alone. Adrenalectomy and short-term chronic stress had no significant effect on the development of insulitis. Various parameters, such as body, thymus and spleen weights, thymus and spleen cellularities, mitogen-induced spleen cell proliferation and serum corticosterone levels were also studied under the various experimental conditions. Taken together, the observations suggest that stressors modulate the expression of spontaneous autoimmune diabetes by exerting pleiotropic effects on immune and/or inflammatory components at the pancreas level and on peripheral glucose metabolism.

The platelet angiotensin II receptor in type I diabetes: studies in patients with and without nephropathy.

Experimental studies demonstrate impaired regulation of the mesangial angiotensin II (AII) receptor in diabetes. This could contribute to the disturbance of glomerular blood flow and the development of diabetic nephropathy. The aim of this study was to determine whether a similar receptor abnormality occurs in patients with type I insulin-dependent diabetes mellitus (IDDM) and if so whether this is more prevalent in patients with micro- or macro-albuminuria. The platelet AII receptor was chosen because of its availability from the circulation and its comparable regulatory properties to tissue-based receptors. The interaction between plasma AII and its platelet receptor was examined in 45 patients with IDDM and 36 age- and sex-matched control subjects. Seven patients had clinical nephropathy and two had persistent micro-albuminuria. The duration of diabetes varied from 1 month to 42 years. There was a significant inverse correlation between plasma AII and the logarithm of receptor number in the control group (r = -0.555, P < 0.001). This relationship was not observed in the diabetic patients irrespective of the duration of disease or the presence of nephropathy. Receptor expression in patients without nephropathy showed no correlation with either duration of disease or the degree of glycaemic control. However, a significant relationship between AII receptor number and duration of diabetes was noted in the group with nephropathy (r = 0.723, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced metabolism of arachidonic acid by macrophages from nonobese diabetic (NOD) mice

The inbred nonobese diabetic (NOD) mouse spontaneously develops an autoimmune diabetes, which is now recognized as an experimental model for human type I insulin-dependent diabetes mellitus (IDDM). The autoimmune reaction, specifically directed against pancreatic β cells (insulitis), involves both macrophages and T lymphocytes. The study of the production of cyclooxygenase and lipoxygenase derivatives of arachidonic acid metabolism shows that in some conditions, and in particular in the presence of zymosan A, macrophages from NOD mice produced significantly more 6-keto-prostaglandin F1α (6-keto-PGF1α) and leukotriene C4 (LTC4) than macrophages from age- and sex-matched C57BL 6 mice. Moreover, zymosan A-stimulated macrophages from NOD females produced significantly more LTC4 than did macrophages from NOD males. These results may be of interest, given the bidirectional relationship between the various cytokines involved in the destruction of β cells of the islets of Langerhans and different eicosanoids.

Detection of cell-mediated immunity in Type I diabetes mellitus

Type I insulin dependent diabetes mellitus (IDDM) is thought to result from chronic, cell-mediated, ‘autoimmune’ islet damage. Antibody testing is extensively used to define and follow the pre-diabetic population. However, the assay for cell mediated immunity (CMI) should be more predictive of impending disease. This report shows that it is possible to detect human islet reactive CMI in the IDDM patient. Groups of athymic CD-1 nu/nu mice were injected intraperitoneally with either mononuclear blood cells (MBCs) or plasma from 10 newly diagnosed Type I diabetic patients and 10 normal control subjects. Both glycemic control and histopathology were used to assay islet specific CMI in diabetic individuals. None of the injected mice showed any impairment of glycemic control. However, MBCs from six of 10 diabetic patients, but from none of the 10 normal subjects, induced significant mononuclear cell infiltrate in the pancreas of the recipient mice ( P=0.005). The infiltrate was focused on the islet tissue and no damage was seen in control tissues. No histological abnormalities were observed when plasma was transferred. We conclude that cellular reactivity seen in this model is tissue specific and disease associated. Our findings provide evidence that CMI to human islet tissue can be detected in IDDM patients.

Irreversible progression of severe retinopathy in young type I insulin-dependent diabetes mellitus patients after improved metabolic control

The impact of metabolic control on the development of rapidly progressive severe retinopathy was studied in 14 young type I insulin-dependent diabetes mellitus (IDDM) patients. Glycosylated hemoglobin (HbA lc) levels 45 months prior to and 12 months after the diagnosis of retinopathy were compared with HbA lc levels in 17 type I IDDM patients with no or minimal background retinopathy, matched for age and duration of diabetes. HbA lc levels were generally higher in patients with severe retinopathy ( p < 0.05) from 39 months until 6 months before the diagnosis of retinopathy. Thereafter, there was a gradual decrease in HbA lc levels reaching the same level as in control patients 6 months after diagnosis of retinopathy. Patients with severe retinopathy required higher doses of insulin prior to the diagnosis of retinopathy ( p < 0.05), but the insulin requirement decreased, and 12 months afterward, the insulin dosage was similar to patients with background retinopathy. Systolic blood pressure levels were slightly increased and higher in patients with severe retinopathy compared with control patients from 18 months before to diagnosis of retinopathy ( p < 0.05). Diastolic blood pressure levels likewise differed at 18 and 12 months before and at the time of diagnosis of retinopathy as well as 12 months afterward ( p < 0.05); however, no differences were seen in urinary albumin or serum creatinine levels between the groups. Thus, years of poor metabolic control, drastically improved, preceded the development of irreversible severe retinopathy in these young type I IDDM patients.

Phagocyte oxidative metabolism in cyclosporine-or placebo-treated patients with insulin-dependent (Type I) diabetes mellitus of recent onset

Several lines of evidence suggest that phagocyte-mediated oxidative processes are involved in damage to pancreatic islet cells of Type I insulin-dependent diabetes mellitus (IDDM). This hypothesis, however, has not yet been explored at the clinical onset of IDDM. Similarly, the possibility that cyclosporine A (Cy-A) might exert a selective influence on these phagocyte-mediated oxidative reactions has also not yet been investigated as compared to a placebo. The present study tested both hypotheses in 32 patients with recently diagnosed IDDM who were part of the recent French multicenter randomized therapeutic trial of Cy-A. The production of reactive oxygen intermediates (ROI) by circulating polymorphonuclear (PMN) and mononuclear (MN) phagocytes was determined by luminol-dependent chemiluminescence (CL), both directly within microamounts of whole blood and in purified PMN or MN phagocyte suspensions. Lastly, CL production was measured in the absence (resting CL) and the presence of a panel of particular and soluble phagocyte membrane-stimulating agents. We found that on entry into the trial, i.e. within less than 2 months of the clinical onset of IDDM, patients had normal whole blood CL production in the absence of a stimulating agent and upon phagocytic challenge with latex or opsonised zymosan particles. By contrast, whole blood CL responses to soluble stimuli such as phorbol myristate acetate (PMA), concanavalin A (Con-A) and F Met-Leu-Phe (FMLP) were significantly higher than in the control group of 52 normal subjects ( P<0.01). In purified PMN and MN phagocyte suspensions, both resting and stimulated CL productions were normal, regardless of the type of stimulating agent. After 3 months of treatment, whole blood CL responses to Con-A and FMLP returned to almost normal levels in patients treated with Cy-A (15 cases) but not in those receiving the placebo (17 cases); PMA-induced CL responses were also decreased, but this was found in both groups of patients. In purified phagocyte suspensions we detected no effect of Cy-A on PMN, whereas MN phagocytes from Cy-A-treated patients showed reduced CL responses to FMLP but not to other stimuli. Altogether, these results demonstrate for the first time that the capacity of circulating PMN and MN phagocytes to generate ROI is normal at the clinical onset of IDDM and suggest that circulating substances increase oxidative responses to soluble, but not particulate, stimuli. With regard to the in vivo effect of Cy-A, it appears that Cy-A does not influence PMN oxidative response-potential, whereas it selectively alters MN oxidative responses to chemotactic agents such as FMLP. This latter finding suggests that, as already described for T lymphocytes, Cy-A may interfere with calcium-dependent activation pathways of monocytes.

THE GROWTH HORMONE RELEASING HORMONE (GHRH) RESPONSE TO A MIXED MEAL IS BLUNTED IN YOUNG ADULTS WITH INSULIN-DEPENDENT DIABETES MELLITUS WHEREAS THE SOMATOSTATIN RESPONSE IS NORMAL

Following a standard mixed meal, plasma concentrations of growth hormone releasing hormone (GHRH), somatostatin (SMS) and growth hormone (GH) were measured every 30 min for 300 min in six young adults with type I insulin-dependent diabetes mellitus (IDDM) and five normal controls. Mean blood glucose concentrations were higher and mean free insulin levels lower in the diabetics compared with controls both in fasting specimens and at all times following the mixed meal. Basal concentrations (mean +/- SEM) of GHRH were similar in diabetic (12.7 +/- 1.8 pg/ml) and control subjects (11.8 +/- 1.1 pg/ml). Following ingestion of the mixed meal, a rise in GHRH was observed in the control subjects maximal between 30 and 240 min (P less than 0.025) but the response was blunted in the diabetics. Mean GHRH concentrations were greater in the controls than in the diabetic subjects at all stages during the test, the maximum difference being noted at 120 mins (P less than 0.04). Basal SMS concentrations and those observed after the mixed meal were similar in diabetic and control subjects. These results indicate that glucose and insulin may play a role in the regulation of GHRH release following a mixed meal but circulating levels of GHRH and SMS are unlikely to be relevant to the abnormal regulation of GH in IDDM.

HLA DQβ3.2 identifies subtypes of DR4 + haplotypes permissive for IDDM

The HLA class II-related susceptibility to type I insulin-dependent diabetes mellitus (IDDM) is examined in 94 multiplex families sorted by the presence or absence of a DR4+ haplotype in at least one diabetic family member. The families with DR4+ haplotypes are then sorted by the presence or absence of a DR4-linked DQ beta 3.2 allele. Further analysis assumes each multiplex family to represent a single diabetic genetic event and identifies the HLA class II haplotype(s) present in all affected members. The DQ beta 3.2 allele is present in over 95% of the multiplex families where DR4+ haplotypes segregate with IDDM, implying a major permissive role in determining susceptibility to IDDM.

Regulatory T cell control of autoimmune destruction of beta cells in the BB rat.

Type I insulin-dependent diabetes mellitus (IDDM) in humans appears to be an autoimmune-mediated disease process that selectively destroys the pancreatic beta cells (1). Numerous lines of evidence support the concept of an autoiimnune pathogenesis of IDDM. A mononuclear cell infiltration of the islets of Langerhans (insulitis) is observed in diabetics, consisting predominately of Ia+ activated T cells and monocytes. Islet cell autoantibodies are readily detectable in the serum of people with IDDM, and lymphocytes from acutely diabetics children can kill human insulinoma cells in vitro. Futhermore, IDDM appears to have a genetic component that is strongly associated with the major histocompatibility complex, and patients with IDDM have a high incidence of other autoimmune disorders (1).

Presence and persistence of islet cell antibodies in children with type I diabetes mellitus

It is wellknown that immune responses play a major role in the development of type I insulin dependent diabetes mellitus (IDDM). This mixed crosssectional and longitudinal study was undertaken to evaluate the presence of islet cell antibodies (ICA) in diabetic children in relation to age and to duration of diabetes. Cytoplasmic ICA were determined by immunofluorescence in 72 patients (40 boys and 32 girls) aged 9 months to 17 years, with IDDM. ICA were measured only once in 54 patients and at regular intervals in 18, amounting to a total of 95 samples collected. ICA were present in 10 out of 11 patients at the time of diagnosis of IDDM. They were still found in 10 out of 61 patients in whom IDDM lasted for at least 2 years (persistent ICA). In the other patients ICA were not detected or disappeared within a 2 years duration of diabetes (non persistent ICA). HLA-DR3 type was found in all patients with persistent ICA for at least 2 years and in 65% of the others; HLA-DR4 was found in both groups of patients at an incidence of 70% and 62% respectively. None of the 21 children who became diabetic before the age of 5 years, had persistent ICA whereas 25% of the patients becoming diabetic after that age had persistent ICA. These data clearly show the importance of genetic factors and of age at onset of diabetes in the development and persistence of ICA in infancy and childhood.