Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

[Evaluation of diabetic retinopathy screening using fundus photography: Evaluation and epidemiologic factors at Nantes university medical center]. / Dépistage de la rétinopathie diabétique par télétransmission de photographies du fond d'œil : évaluation et aspects épidémiologiques au CHU de Nantes.

INTRODUCTION: The goal of our study was to evaluate the results of screening for diabetic retinopathy using the non-mydriatic fundus camera combined with telemedicine in the university hospital of Nantes. PATIENTS AND METHODS: This is a retrospective study of all diabetic patients hospitalized in the endocrinology department between June and September 2016 inclusive. The photos were taken by a nurse if the patient had an indication for screening as determined by the attending physician. The ophthalmologist then provided a written interpretation of the photos on a consultant's sheet. Quality control with re-reading of a sample of the photos was performed. RESULTS: A total of 442 patients (48% females, 52% males) were studied. 227 patients (51.3%) had undergone an eye examination within the previous year. 160 patients (36.2%) were screened with fundus photography. Fundus photography of at least one eye could not be graded in 10 patients (6.3%). Diabetic retinopathy was detected in 27 patients (16.9%) and diabetic maculopathy in 5 patients. Longer duration of diabetes and the presence of microalbuminuria were significantly associated with incidence of retinopathy. The double reading of 26% of the photos found a 93% of concordance between the 2 readers. Referral to an ophthalmologist was required in 32 patients (20%), of whom 27 were rescheduled at the university hospital, for unreadable photographs, diabetic retinopathy or concomitant eye disease. 38.5% of rescheduled patients did not come to the appointment. CONCLUSION: Non-mydriatic fundus photography combined with telemedicine is attractive for diabetic retinopathy screening and identifies patients requiring further eye examination. In our study, it obviated the need for an ophthalmologic examination in 8 out of 10 cases. It is important to continue to educate patients about the necessity of regular eye examinations and post-screening follow-up.

Clinical and metabolic characteristics of patients with latent autoimmune diabetes in adults (LADA): absence of rapid beta-cell loss in patients with tight metabolic control.

AIM AND METHODS: The present study compared the clinical and metabolic characteristics of latent autoimmune diabetes in adults (LADA) with type 2 diabetes, as well as the residual beta-cell function and progression to insulin treatment, over a 2-year follow-up period, of antibody (Ab)-positive and Ab-negative patients who achieved tight glycaemic control (HbA(1c) 7.0+/-0.8% and 6.5+/-0.9%, respectively, at the time of entry into the study). RESULTS: Glutamic acid decarboxylase antibodies (GADA) and/or islet cell antibodies (ICA) were detected in 10% of patients presenting with non-insulin-dependent diabetes. Around half of Ab-positive patients required insulin treatment during the follow-up. Ab-positive patients displayed lower stimulated C-peptide levels both at entry and during the follow-up compared with Ab-negative patients, although no significant decline in C-peptide levels was observed in either subgroup over two years. Nevertheless, Ab-positive patients progressed more frequently to insulin treatment, and stimulated C-peptide tended to decrease in LADA patients who subsequently required insulin, whereas it remained stable in those who were non-insulin-dependent. In those who progressed, the trend towards C-peptide decline persisted even after starting insulin treatment. CONCLUSION: LADA patients demonstrate lower residual beta-cell function than do type 2 diabetes patients. However, those who achieve tight metabolic control do not present with a rapid decline in beta-cell function. Further studies are needed to determine the optimal treatment strategy in such patients.

Fulminant type 1 diabetes in Caucasians: A report of three cases.

CONTEXT: Fulminant type 1 diabetes is a new clinical entity in which the process of beta-cell destruction, and the subsequent progression of hyperglycaemia and ketoacidosis, are extremely rapid. Until now, this subtype of type 1 diabetes has only been reported in the Asian population, especially Japanese and Koreans. CASES: We report here on three cases of fulminant type 1 diabetes in Caucasian French women. Both the clinical and biological characteristics of these patients are similar to those reported in Japanese studies. Notably, all patients experienced severe ketoacidosis (pH<7.1) that occurred abruptly after the onset of hyperglycaemic symptoms (<6 days), with near-normal HbA(1c) values at diagnosis (5.6, 6.4 and 6.8%). Patients were treated in the intensive care unit with basal-bolus insulin therapy with no remission of their diabetes; pancreatic islet-related autoantibodies were all negative. Fasting C-peptide levels were undetectable, suggesting complete destruction of pancreatic beta-cells. HLA phenotyping of these Caucasian patients did not find the specific HLA haplotype (DRB1*0405-DQB1*0401) previously found to be linked to fulminant type 1 diabetes in Japanese patients. CONCLUSION: These are the first cases of fulminant type 1 diabetes reported in Caucasians. These cases reveal new perspectives as regards the worldwide distribution of this intriguing clinical entity.

Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabète Insuline Orale group.

BACKGROUND: Oral administration of autoantigens can slow the progression of beta-cell destruction in non-obese diabetic mice. We investigated whether oral administration of recombinant human insulin could protect residual beta-cell function in recent-onset type 1 diabetes. METHODS: We enrolled 131 autoantibody-positive diabetic patients aged 7-40 years within 2 weeks of diagnosis (no ketoacidosis at diagnosis, weight loss <10%, polyuria for <6 weeks). They were randomly assigned 2.5 mg or 7.5 mg oral insulin daily or placebo for 1 year, in addition to subcutaneous insulin therapy. Serum C-peptide concentrations were measured in the fasting state and after stimulation, to assess beta-cell function. Autoantibodies to beta-cell antigens were assayed. Analyses were by intention to treat. FINDINGS: Baseline C-peptide and haemoglobin A1c concentrations were similar in the three groups. During follow-up, there were no differences between the groups assigned 2.5 mg or 7.5 mg oral insulin or placebo in subcutaneous insulin requirements, haemoglobin A1c concentrations, or measurements of fasting (mean at 12 months 0.18 [SD 0.17], 0.17 [0.17], and 0.17 [0.12] nmol/L) or stimulated C-peptide concentrations (glucagon-stimulated 0.39 [0.38], 0.37 [0.39], and 0.33 [0.24] nmol/L; meal-stimulated 0.72 [0.60], 0.49 [0.49], and 0.57 [0.51 nmol/L]. Neither age nor C-peptide concentration at entry influenced treatment effects. No differences were seen in the time-course or titres of antibodies to insulin, glutamic acid decarboxylase, or islet antigen 2. INTERPRETATION: At the doses used in this trial, oral administration of insulin initiated at clinical onset of type 1 diabetes did not prevent the deterioration of beta-cell function.

[Acceptability of xenograft in type 1 diabetic patients and by the general French population]. / Acceptabilit¿e de la x¿enogreffe chez des patients diab¿etiques de type 1 et dans la population g¿en¿erale fran"caise.

OBJECTIVE: The possibility of using pig xenografts raises the questions of their acceptability and the reasons for reluctance by patients and society, which have not been clearly investigated in Europe. RESEARCH DESIGN AND METHODS: A survey using a multiple-choice questionnaire was conducted to quantify the acceptability of pig xenografts in type 1 diabetic patients potentially concerned by xenografts (n = 377) as compared to a sample of the French population (n = 697). RESULTS: Willingness to accept a xenograft was significantly greater among diabetic patients than the general population (64% vs 54%, P < 0.001). The notion of using pig xenografts appears to be rather well accepted by the general population, and more information might improve acceptability. The acceptance of xenografts in general and pig tissues in particular was higher in diabetic patients. CONCLUSIONS: Because the general population and type 1 diabetic patients are not aware of the sanitary risks specifically related to a xenograft, the decision to use xenografts cannot be based simply on the expectations of possible recipients. The sanitary risks need to be assessed before further xenografts are performed, particularly in diabetic patients whose risk/benefit ratio is not particularly favourable.

Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD4+ and CD8+ lymphocytes from type I diabetic or healthy subjects.

The intensity and mechanisms of cell-mediated rejection of pig islet cells were studied in 49 Type I diabetic and 34 healthy subjects. Human peripheral mononuclear cells proliferated strongly in response to pig islet cells (p<0.001), though with notable interindividual variations (stimulation index 2 to 215). The variance of stimulation index was higher in diabetic than healthy subjects (p<0.0001). The response to islet cells was stronger (p<0.01) than that to pig splenocytes. Proliferation in response to islet cells was strongly decreased (p<0.01) when CD4+ T cells were blocked with monoclonal antibodies, whereas the blocking of CD8+ cells or NK cells gave less pronounced effects. The response to islet cells was decreased (p<0.01), but not abolished, after antigen-presenting cells were removed. Purified CD4+ cells alone did not proliferate in response to islet cells but recovered their proliferative ability when mixed with antigen-presenting cells, whereas CD8+ cells alone proliferated in the presence of interleukin-2 in response to islet cells. Proliferation was blocked (p<0.01) by anti-DR monoclonal antibodies. During proliferation in response to islet cells, interleukin-10 increased 43-fold (p<0.01) but interferon-gamma increased only slightly. No statistical differences were detected between diabetic and control subjects with respect to lymphocyte subsets and the recognition mechanisms or to interferon-gamma/interleukin-10 production in response to islet cells. These results provide the first detailed information on human cell-mediated xenoreaction to pig islet cells. This situation involves a dominant CD4 class II-restricted Th2 response, with an indirect recognition pathway, as well as a CD8 T-cell response resulting from direct recognition. This strong reaction constitutes a serious obstacle which may vary in degree among subjects.

Multiple antibody status in type 1 diabetic patients and subjects at various risk with islet-cell antibodies.

The frequency of 37/40 kD antibodies and their association with other pancreatic humoral markers were studied in 109 recently diagnosed Type 1 diabetic patients and 116 subjects with islet-cell antibodies (ICA) at various risk for this disease (64 relatives of Type 1 diabetic patients, 23 schoolchildren with no family history of diabetes, and 29 patients with Graves' disease). At the time of diagnosis, 37/40 kD antibodies were detected in 45% of Type 1a and 77% of Type 1b diabetic patients (p = 0.03). Antibodies to glutamic acid decarboxylase (GAD) and/or 37/40 kD were present with the same frequency as ICA (86%). The frequency of 37/40 kD antibodies was not significantly different between the 3 groups at risk, in contrast with GAD antibodies which were found at a lower frequency in schoolchildren (p < 0.02). Frequencies of other pancreatic markers (ICA cross-reactive with mouse pancreas and insulin autoantibodies) and the combination of ICA with at least two other markers were significantly higher in relatives than in the other groups at risk (p < 0.02). Out of 116 ICA-positive non-diabetic subjects, 10 developed diabetes. All 10 displayed 37/40kD and/or GAD antibodies during the prediabetic phase. In 8 of these 10 patients, ICA was combined with at least two other markers, whereas this association was detected in only 17 of the remaining 106 subjects who did not progress to diabetes (p < 10(-4). Thus, 37/40 kD antibodies were found in about half of Type 1 diabetic patients, and with a higher-frequency in Type 1b than 1a. In ICA-positive non-diabetic subjects, our date confirm that a combination of multiple antibodies, including GAD antibodies and 37/40 kD antibodies, can enhance the predictive value for diabetes. Comparison of ICA-positive relatives of diabetic patients, schoolchildren and patients with Graves' disease revealed distinct frequencies and combinations of markers of diabetes. This might reflect different patterns of progression among these 3 groups.

[Postpartum thyroiditis and Basedow disease]. / Thyroïdite du post-partum et maladie de Basedow.

BACKGROUND: The postpartum period is characterized by a rebound in autoimmunity secondary to immune tolerance induced by pregnancy, creating favorable conditions for flare up of Graves' disease or autoimmune thyroiditis. Postpartum thyroiditis is a recognized clinical entity. CASE REPORT: Six years after onset of Graves' disease treated with antithyroid drugs, a 25-year-old woman had a high serum level of antithyroperoxidase antibodies a few months before she became pregnant. Six weeks after delivery, she developed signs of hyperthyroidism and goiter. The diagnosis of postpartum thyroiditis was retained. Her condition regressed spontaneously to euthyroidism then hypothyroidism. DISCUSSION: The therapeutic options involved underline the importance of distinguishing between Graves' disease and postpartum thyroiditis. The diagnosis of postpartum thyroiditis is based on history taking, clinical findings, and laboratory tests, especially isotope uptake.

Reversal of diabetes in non-obese diabetic mice by xenografts of porcine islets entrapped in hollow fibres composed of polyacrylonitrile-sodium methallylsulphonate copolymer.

Intraperitoneal xenografting of islets immunoprotected by semipermeable membranes is a potential method of avoiding rejection by reversal of diabetes without immunosuppression. In this preliminary study, a xenograft of porcine islets, immunoprotected in semipermeable hollow fibres composed of a hydrogel of a polyacrylonitrile-sodium methallylsulphonate copolymer (AN 69), was used to reverse autoimmune insulin-dependent diabetes mellitus (IDDM) in the NOD mouse. A diabetic state was maintained in all 46 NOD mice which received transplants of empty fibres. Transplantation of encapsulated islets reversed the diabetic state in 37% (18/54) of the recipients. In these mice, nonfasting blood glucose concentration decreased within 24 h. Glycaemia was kept below the diabetic control range and the initial pretransplant value for 6 weeks. Recipient NOD mice suffered from the severe insulitis characteristic of clinical diabetes, confirming that reversal of the hyperglycaemic state was due solely to the xenografts. Pretransplant glycaemia was slightly (p < 0.05) higher in mice which remained diabetic after grafts of fibre-containing islets than in animals which experienced reversal of hyperglycaemia after transplantation) for the peritoneal cavity of recipients which had returned to normoglycaemia after grafting with islet-containing fibres. In all 4 cases, the islets responded to glucose during a perifusion assay. In 2 out of 4 grafts removed from mice which remained hyperglycaemic after grafting with islet-containing fibres (11, 13, 15 and 27 days after transplantation), no basal or stimulated insulin secretion was detectable. Histological sections of a total of 75 fibres retrieved from the peritoneal cavities of recipient NOD mice showed surrounding inflammation, with adherent cells, neovascularisation and fibrotic reaction. These preliminary results are promising for the continued development of this bioartificial pancreas for xenogeneic islet transplantation since they demonstrate that xenogeneic islets can survive in the autoimmune environment of the NOD mouse with spontaneous diabetes mimicking human IDDM).

Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group.

Diabetic nephropathy is a glomerular disease due to uncontrolled diabetes and genetic factors. It can be caused by glomerular hypertension produced by capillary vasodilation, due to diabetes, against constitutional glomerular resistance. As angiotensin II increases glomerular pressure, we studied the relationship between genetic polymorphisms in the renin-angiotensin system-angiotensin I converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II, subtype 1, receptor-and the renal involvement of insulin-dependent diabetic subjects with proliferative retinopathy: those exposed to the risk of nephropathy due to diabetes. Of 494 subjects recruited in 17 centers in France and Belgium (GENEDIAB Study), 157 (32%) had no nephropathy, 104 (21%) incipient (microalbuminuria), 126 (25 %) established (proteinuria), and 107 (22%) advanced (plasma creatinine > or = 150 micromol/liter or renal replacement therapy) nephropathy. The severity of renal involvement was associated with ACE insertion/deletion (I/D) polymorphism: chi2 for trend 5.135, P = 0.023; adjusted odds ratio attributable to the D allele 1.889 (95% CI 1.209-2.952, P = 0.0052). Renal involvement was not directly linked to other polymorphisms. However, ACE I-D and AGT M235T polymorphisms interacted significantly (P = 0.0166): in subjects with ACE ID and DD genotypes, renal involvement increased from the AGT MM to TT genotypes. Thus, genetic determinants that affect renal angiotensin II and kinin productions are risk factors for the progression of glomerular disease in uncontrolled insulin-dependent diabetic patients.

Xenografts of porcine islets immunoprotected in hollow fibres reduce the incidence of diabetes in non-obese diabetic mice.

Non-obese diabetic (NOD) mice develop an autoimmune disease with a long prodromal period and constitute a model for investigating the prevention of human insulin-dependent diabetes mellitus. Since insulin injected prophylactically has been shown to reduce incidence of diabetes in NOD mice, we tested a new strategy consisting of prophylactic xenografts of porcine pancreatic islets immunoprotected in semipermeable hollow fibres. Female NOD mice were transplanted twice (at 60 and 180 days of age) with islet-containing or empty fibres. Within the group grafted with protected islets, the incidence of diabetes was reduced (37 vs 75%; p < 0.01), the onset of disease was delayed (p < 0.02), and the severity of lymphocytic inflammation of endogenous islets was reduced (p < 0.02). When already diabetic mice were not taken into account for analysis, blood glucose level was slightly lower in those grafted with islet-containing fibres (p < 0.04). Graft function was also evidenced by HPLC separation of porcine insulin in NOD sera. Histological and perifusion studies of fibres retrieved from recipients confirmed immunoprotection. During co-transfer, T splenocytes from mice grafted with islet-containing fibres were able to reduce the capacity of T cells from diabetic donors to adoptively transfer the disease (p < 0.01). Antigens for islet-cell autoantibodies (ICA) in pancreata from both groups were compared by immunofluorescence with the same ICA-positive human sera to ensure that differences were due to antigen quantitative changes. These antigens, which could serve as an index of a possibly more extensive antigen beta-cell rest, were decreased (p < 0.01) in mice grafted with protected islets. Reduction of diabetes and insulitis following early islet transplantation may thus be due to generation of cellular mechanisms that actively suppress disease, and possibly in part to a decrease in antigens which make beta cells less vulnerable to autoimmune aggression. These effects can be obtained with xenogeneic islets protected in hollow fibres, thereby eliminating the need for immunosuppression. Based on the concept of prophylactic insulin therapy, this form of insulin administration offers a controlled means of delivering insulin to meet the physiological needs of recipients.

Differential beta-cell response to glucose, glucagon, and arginine during progression to type I (insulin-dependent) diabetes mellitus.

Acute insulin responses to glucose (AIRG), glucagon (AIRGln), and arginine (AIRArg) were evaluated prospectively in nine subjects positive for islet-cell antibodies (ICAs) who later progressed to type I diabetes or impaired glucose tolerance (IGT) (progressors), 64 ICA-positive subjects at risk who did not develop type I diabetes, 365 ICA-negative relatives of diabetic patients who also remained free of the disease, and 89 control subjects. Seven progressors already had a low AIRG at entry into the study, and the other two became low responders 3 to 9 months before diabetes or IGT, with a progressive decline of AIRG over serial intravenous (IV) glucose tolerance tests. At entry into the study, the group of progressors displayed lower AIRG, AIRGln, and AIRArg than the other three groups (P<.001). However, AIRArg was less altered than AIRG. During the course of the prediabetic phase, there was a progressive decline in AIRG and AIRGln analyzed as a function either of time (P<.006) or of basal glycemia (P<.05), ie, two different ways of estimating worsening of the disease process. Conversely, there was no significant decrease in AIRArg with time or with increasing basal glycemia, so that AIRArg was not totally blunted in these prediabetic subjects even a few months before the onset of diabetes. The persistence of a substantial response to arginine, ie, higher than the fifth control percentile, even at a late stage, was confirmed in five of nine diabetic patients tested either at onset of the disease or during non-insulin-receiving remission. Whereas AIRG deteriorates during prediabetes, AIRArg appears to be less altered with time and increased basal glycemia, remaining substantial even at the onset of the disease. This reinforces the supposition that the prediabetic state may be associated with a glucose-specific beta-cell functional abnormality in addition to a decreasing beta-cell mass.

Combined analysis of islet cell antibodies that cross-react with mouse pancreas, antibodies to the M(r) 64,000 islet protein, and antibodies to glutamate decarboxylase in type I diabetic patients.

OBJECTIVE: A combined analysis of whether islet cell autoantibodies (ICAs) are cross-reactive with mouse pancreas, with glutamate decarboxylase (GAD) antibodies, and with 64K antibodies was performed in a large sample of recently diagnosed type I diabetic patients. The disappearance rates of these different autoantibodies were compared in some patients after onset of the disease. The aims were to determine patterns in GAD/64K antibodies with regard to cross-species reaction of ICA and to assess whether GAD could contribute to ICA positivity in mouse and human pancreases and whether the simultaneous search for all the antibody specificities enhances the detection of autoimmune stigma. RESEARCH DESIGN AND METHODS: ICA detected by immunofluorescence in human and mouse pancreases, antibodies immunoprecipitating the 64K rat islet antigen, and antibodies immunotrapping brain GAD activity were quantified at diagnosis of diabetes in 95 patients and in sequential samples during 1 year after diagnosis in 13 patients. The contribution of GAD to ICA positivity in mouse and human pancreases was evaluated by the analysis of correlations between tests and by the ability of brain homogenate to block ICA reactivity in pancreases from both species. RESULTS: ICAs were detected in human pancreases in sera from 63 (66%) patients, among which 61% bound also to a mouse pancreas. GAD and 64K antibodies were strongly correlated (P < 0.0001) and were detected in 69 and 73% of the patients, respectively. All but two patients with ICA in human pancreas also displayed either ICA in mouse pancreas or GAD/64K antibodies. Among 32 patients without ICA in human pancreas, 54% displayed either GAD/64K antibodies or ICA in mouse pancreas. Only 16% of the patients displayed neither ICA nor GAD/64K antibodies. A correlation (P < 0.005) was found between ICA in human and mouse pancreases. GAD or 64K antibodies were strongly correlated with ICA in human pancreas (P < 0.0001), but not with ICA in mouse pancreas. After preincubation of six sera with GAD-containing brain homogenate, ICA titers were unaffected in mouse pancreas but reduced in human pancreas. ICA titers in mouse pancreas were decreased after 3 months (P < 0.01) in diabetic patients, contrasting with the stability of ICA in human pancreas and GAD antibodies by 1 year after diagnosis. CONCLUSIONS: According to cross-species reaction, we confirm the heterogeneity of ICA in a large series of type I diabetic patients, ICAs that cross-reacted with mouse pancreas being more frequent than ICAs without cross-species reactivity. GAD and 64K antibodies were also present in a majority of patients. The simultaneous search for all the antibody specificities enhances the detection of autoimmune stigma so that only a few patients did not display any autoantibody at diagnosis. GAD is not the target of ICAs in mouse pancreas, whereas GAD accounts for ICA positivity in human pancreas. The conclusion that ICAs in mouse pancreas are not GAD-reactive is reinforced by the fact that they are more transient after onset of diabetes than are GAD antibodies or the complex mixture of ICAs in human pancreas.

Combined analysis of islet cell antibodies which cross-react with mouse pancreas, antibodies to the M(r) 64,000 islet protein, and antibodies to glutamate decarboxylase in subjects at risk for IDDM.

With regard to progression to diabetes, ICA cross-reactive with mouse pancreas, antibodies to the M(r) 64,000 islet antigen (64K), antibodies immunotrapping brain GAD activity, and IAA were analysed in 53 ICA-positive first-degree relatives of IDDM patients and 18 ICA-positive schoolchildren without a family history of diabetes. Sera from 29 (55%) relatives did not bind to mouse pancreas, whereas 24 (45%) displayed cross-species reaction. ICA titres on human and mouse pancreas were weakly correlated in the overall population (p < 0.05) but more strongly (p < 0.01) in only those subjects who displayed antibodies on tissues from both species. GAD and 64K antibodies were detected in 31% and 35% of relatives. In schoolchildren, the frequencies of cross-species reactive ICA (22%), GAD antibodies (6%), 64K antibodies (22%), and IAA (6%), were lower (p < 0.05) than in relatives. A strong correlation (p < 0.0001) was observed between GAD and 64K antibodies. GAD or 64K antibodies were strongly correlated with ICA on human pancreas (p < 0.0001) but poorly with ICA on mouse pancreas (p = 0.05). After pre-incubation of sera with brain homogenate, ICA titres were unaffected on mouse pancreas but reduced on human pancreas. ICA-positive subjects who displayed neither cross-species reactive ICA nor GAD or 64K antibodies were more frequent (p < 0.05) among schoolchildren than relatives, whereas subjects who displayed all antibody specificities were more numerous (p < 0.04) in relatives. All relatives with ICA binding only to human pancreas, as well as all schoolchildren, permanently displayed an AIRG higher than the first control percentile and remained non-diabetic.(ABSTRACT TRUNCATED AT 250 WORDS)

Predictive value of age-related acute insulin response to glucose in subjects at risk for type 1 diabetes: results of a 6-year follow-up study from west-France.

The acute insulin response to i.v. glucose (AIRG) was evaluated in 344 first-degree relatives of patients with Type 1 diabetes. In 318 relatives aged 3 to 48 years without islet cell antibody and insulin autoantibody, correlations (p < 0.0006) were found between age and fasting insulinaemia, fasting glycaemia, or AIRG, with a peak during puberty. Assuming that these relatives without islet cells and insulin auto-antibodies have a low risk of developing Type 1 diabetes, we provided a "standard age-related chart" for AIRG with a "low" AIRG defined as a value below the 1st percentile for each pubertal stage. Using these cut-off points, predictive characteristics of a low AIRG for progression towards diabetes within 6 years were analysed. Four relatives developed diabetes and one displayed impaired oral glucose tolerance. Four out of these 5 subjects had islet cell and insulin auto-antibodies, but the other one was negative for these markers. Three of these 5 subjects had low AIRG at entry (30, 24 and 1 months before diabetes, respectively). The two others displayed a steady progressive decline (p < 0.02) of age-related during the follow-up before impaired oral glucose tolerance and diabetes appeared (rate of decline: 15 microU/ml/year). Thus, independently of the presence of islet cell antibodies, the predictive value of a low age-related AIRG during the follow-up is greater than the single low AIRG at entry.(ABSTRACT TRUNCATED AT 250 WORDS)