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UNLABELLED: ABSTRACT AIMS/HYPOTHESIS: This study aimed to define the immunological parameters which could be used to identify patients with the distinct metabolic features of adult latent autoimmune diabetes. METHODS: Sera of 312 patients with short-term diabetes (duration < 5 years) over 35 years of age at diagnosis were screened for ICA, GAD- and IA2-Ab by antibody assays validated in workshops. The antibody status was correlated with age, BMI, residual beta-cell function, measured by fasting C-peptide, onset of diabetes-related complications and markers of the metabolic syndrome (hypertension and hyperlipidaemia). RESULTS: A total of 51 antibody positive patients were identified. These patients had lower fasting C-peptide and less neuropathy and hypertension compared with matched antibody-negative patients. However, only patients with two or more antibodies had reduced residual beta-cell function compared with antibody-negative or single antibody-positive (ICA or GAD-Ab only) patients. Patients with two or more antibodies were also leaner and had diabetes-related complications or hypertension less frequently than single antibody-positive or antibody negative-patients. IA2 antibody status did not substantially contribute to the diagnosis or differentiation of LADA patients. CONCLUSION/INTERPRETATION: We concluded that the combination of ICA and GAD antibodies and high titre of GAD antibodies are characteristic of patients with insulin deficiency with the clinical features of Type I (insulin-dependent) diabetes mellitus (LADA-type 1). Single antibody positivity and low titre antibodies are markers for LADA-type 2 associated with the clinical and metabolic phenotype of Type II (non-insulin-dependent) diabetes patients.

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OBJECTIVE: Young age at onset is a relevant parameter associated with a rapid progression of IDDM. Our major aim was to define differences between IDDM patients with age at diagnosis > 40 years and adult IDDM with onset at a younger age. RESEARCH DESIGN AND METHODS: The correlation between islet-related antibodies (islet cell antibodies [ICAs] and antibodies [Abs] to GAD and the tyrosine phosphatase IA2), T-cell responses to GAD peptides and HLA class II isotypes was investigated in 23 IDDM patients 12-38 years of age at onset (group 1), 24 patients with IDDM > 40 years of age at onset (group 2), and 12 healthy control subjects. ICAs were measured by indirect immunofluorescence, and GAD-Ab and IA2-Ab were measured by immunoprecipitation tests. T-cell responses against GAD peptides, which had been identified as typical for IDDM, were tested by 5-day proliferation assays. HLA class II alleles were typed by polymerase chain reaction. RESULTS: ICAs and GAD-Abs were more prevalent in IDDM patients than in control subjects (P < 0.001), but only IDDM group 1 had IA2-Abs (P < 0.001 compared with IDDM group 2 and control subjects). Moreover, antibody combinations differed between IDDM patients of groups 1 and 2. T-cell responses to GAD peptides were seen in 67% of IDDM group 1 and in 71% of IDDM group 2 (P < 0.02 compared with control subjects). IDDM patients of group 1 were more frequently DR4+/DQ8+ and less frequently DR2+/DQ0602+ compared with IDDM patients of group 2 (P < 0.05). CONCLUSIONS: Our data provide strong evidence for humoral and cellular autoimmunity in adult IDDM patients with onset both before and after 40 years of age. However, late-onset differs from young-onset IDDM with respect to Ab profiles, especially a lack of IA2-Ab, and HLA class II types. These findings have consequences for the diagnostic strategy for identifying slow-onset IDDM in individuals after 40 years of age.

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After the societal change in the "New Federal States" of Germany Saxon diabetologists developed an integrated concept for care of diabetic patients: the Saxon Care Model (SCM). It aims at quality assurance in diabetes care and is based on services by cooperating general practitioners and specialists. This model was evaluated. First results were obtained describing the quality of care for 510 patients at baseline. This sample was collected at two specialized diabetologists (level 2), two specialized out-patient units at universities (level 2) and two general practitioners (level 1). The design of the study is a descriptive evaluation. Process and outcome quality at specialized and primary care units working according to the SCM is relatively high. HbA1c measurements were taken in order to quantify outcome quality. The results for primary as well as specialized care units ranged from acceptable to very good. They unfortunately cannot be generalized. The patients expressed that their quality of life was limited only scarcely. The presented preliminary results indicate a high effectiveness of the SCM with regard to relevant process-related outcome-variables. The large variance between single practices of both levels demonstrates that deficits in early diagnosis of diabetes-related complications still exist. On the other hand this points towards resources of quality improvement. The influence of quality assuring measures, e.g. quality circles, will be assessed in a three-year follow up.

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Peripheral blood mononuclear cells (PBMC) from newly diagnosed type I diabetic patients induced a significantly higher cytotoxic insulin leakage from isolated rat islets during a 20-h incubation. compared with PBMC from healthy controls (13.9 +/- 7.7 versus 2.6 +/- 3.2 ng insulin/islet/20 h). The addition of PBMC from healthy subjects in a ratio of 1:4 suppressed the cytotoxic effect (13.9 +/- 7.7 to 6.7 +/- 4.4 ng insulin/islet/20 h). Depletion of CD8+ T lymphocytes from the PBMC of healthy subjects abolished their suppressive capacity, while depletion of CD4+ T lymphocytes and pre-incubation with CD3 monoclonal antibodies had no effect.

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In 19 patients with newly diagnosed Type I diabetes mellitus a single transfusion of 1.9 x 10(9) to 1.5 x 10(10) lymphocytes was performed. Fifteen Type I diabetic patients who did not receive a transfusion were used as controls. Anti-beta-cell cell-mediated cytotoxicity was measured using an insulin release assay. Stimulated C-peptide secretion (100 g glucose orally, 1 mg glucagon i.v.) was used to estimate residual beta-cell function. Both parameters were measured prior to transfusion and after 12 months. The transfusions were followed by a fall of cytotoxicity below the 95% confidence limit of the controls in 11 of the 19 patients ('responders') (15.7 +/- 1.7 ng insulin/islet/20 h vs 6.7 +/- 1.3 P less than 0.001), while the other eight transfused patients ('non-responders') (13.5 +/- 1.9 vs 17.1 +/- 2.9, ns) and the non-transfused control patients (11.6 +/- 1.1 vs 14.2 +/- 2.4, ns) displayed persistently high cytotoxicity levels. In the responder group a slight improvement in stimulated C-peptide secretion was observed (136 +/- 43 pmol/dl vs 148 +/- 38, ns) whereas in the non-responder (127 +/- 28 vs 106 +/- 25, ns) and in the control group (130 +/- 17 vs 97 +/- 19, P less than 0.05) the stimulated C-peptide responses declined during the 12-month follow-up. Thus, lymphocyte transfusion may have beneficial effects by suppressing anti-beta-cell cytotoxicity and preserving C-peptide secretion.

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The effect of lymphocytes from patients with newly diagnosed insulin dependent diabetes on isolated rat or human islets during a 20 h in vitro incubation was investigated by morphological and biochemical methods. All stages of target cell reaction of lymphocytes against beta-cells were observed. Cytoplasmic projections towards and contacts with beta-cells, circumscribed lysis of the outer cell membrane at the contact side and complete lysis of beta-cells were seen. Such findings could not be registered with alpha- or other non beta-cells and in control experiments using lymphocytes from healthy persons. In some cases the lymphocytes were phenotyped using monoclonal antibodies by the indirect immuno-gold technique. It could be demonstrated that lymphocytes in contact with necrotic beta-cells were of the CD8+ve subset. In addition the morphological investigations were supplemented by quantitative biochemical studies measuring the non-secretory insulin release ("cytotoxic" release) from islets into the culture medium and their ability to respond to a consecutive stimulation by arginin with insulin and glucagon secretion. The mean cytotoxic insulin release was 11.3 +/- 1.5 ng/islet/20 h (n = 25) in the diabetic group versus 0.56 +/- 0.15 ng/islet/20 h (n = 15) in the control subjects (alpha less than 0.001). Functional testing of the islets following incubation with lymphocytes from diabetic patients showed diminished insulin (58.6 +/- 5.1%, n = 18, alpha less than 0.001) and unchanged glucagon response (103.0 +/- 3.4%, n = 10, n.s.) when compared with untreated islets (= 100%).(ABSTRACT TRUNCATED AT 250 WORDS)

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In 29 out of 30 type I diabetic patients the peripheral blood lymphocytes induced an insulin release from isolated rat islets which was regarded as a cytotoxic effect, i.e. a model of beta cell destruction in diabetes mellitus. In 11 out of 12 cases, this effect was inhibited by the in-vitro addition of lymphocytes from healthy probands. Thus the activation of cytotoxic T-cells demonstrated by this observation might be the consequence of a defect in suppressor cell function. Consequently, the transfusion in vivo of lymphocytes from healthy probands strongly reduced the cytotoxic reaction of the lymphocytes from newly diagnosed diabetic recipients in vitro.

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In 20 patients with a newly diagnosed type I diabetes mellitus a cytotoxic effect of blood lymphocytes against beta cells of the pancreas of neonatal rats could be demonstrated. This effect remained nearly unchanged during the first 12 months of control. During the course up to 18 months, the cytotoxicity decreased significantly. After stimulation with glucose and glucagon, a C-peptide secretion was demonstrated in all patients during the first 12 months but it decreased thereafter. The follow-up study showed cell-mediated immune reactions against beta cells in type I diabetics as long as the existence of beta cells can be assumed on the basis of functional tests. Thus the immune process seems to depend on the presence of the specific antigen.

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In 69 patients with a gestational diabetes-diagnosed by reproducible pathological results of two oral glucose loads (50 g) or by fasting blood glucose values of greater than or equal to 6.7 mmol/l in pregnancy the carbohydrate metabolism was checked postgestationally again with a glucose tolerance test (75 g) in a period of 6 weeks up to 2 years post partum. The postgestational classification showed the following results: manifested diabetes n = 15 (21.7%), impaired glucose tolerance n = 15 (21.7%), non-classificable disturbed carbohydrate tolerance n = 10 (14.5%), normal test results n = 29 (42%). The high rate of diabetic manifestations underlines the necessity of a postgestational classification of the so-called gestational diabetes controlled by the delivering center. The high risk of manifestation is calculable in the whole group, but not predictable for the single case. The risk is the higher the earlier a glucosuria in pregnancy can be found (before the 24th week), the earlier an insulinisation is necessary to guarantee a normoglycemia and the higher individual deviations of the individual blood glucose values during the daily course are observed (measurable with the glycemic index acc. Michaelis et al.). Additional risk factors are: obesity, an age over 30 years at the beginning of pregnancy, and heredity of first degree. From the retrospective point of view of a postgestational classification new therapeutic aspects could not be verified to avoid diabetes manifestation. Nevertheless an exact normoglycemic control and a very early start of treatment, a correct screening of risk factors and an immediate diagnosis of a gestational diabetes are a supposition to avert hyperglycemic dangers from the child.

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UNLABELLED: In 83 diabetics insulin secretion was examined after a mean diabetes duration of 7.5 years, when an insufficient metabolic situation could be found. Insulin secretion was stimulated with 100 g glucose (orally) and 1.0 mg glucagon i.v. (60 min after glucose intake). We investigated additionally in a retrospective manner blood-glucose and urine glucose behaviour as well as the development of the body weight. In dependence of the actual body weight at the time of investigation of insulin secretion, two groups were formed: b. w. less than 120% acc. Broca index, group A, n = 38; b. w. greater than 120% acc. Broca index. group B, n = 45). Immediately after manifestation of the disease 71 diabetes were treated with pure dietetic measures. At the examination of insulin secretion all patients were treated with glibenclamide. After this examination in 20 patients of the group A and in 17 patients of the group B an insulinisation was started. In the others glibenclamide treatment was continued. The general characteristics of the whole group was a significant reduction of the maximum stimulability of insulin secretion, compared with the insulin secretion of n = 19 healthy probands (11 probands with normal body weight and 8 obese probands). A hyperinsulinism (maximum values higher than mean + 1 s of the health persons) could not be found in any case. The mean of the maximum insulin values was below mean - 1 s of the healthy persons. Insulinisation provoked an improvement of the metabolic situation. This was correlated with an additional improvement of the subjective behaviour. CONCLUSION: Evaluation of insulin secretion in obese diabetics with bad metabolic situation is necessary to find out those who are to be treated with insulin. We have no clinical or other possibilities to recognize patients with a hyperinsulinism or reduced insulin secretion than by evaluation of insulin secretion alone. But higher degrees of decompensated metabolism are nearly always explained by a significant reduction of insulin secretion.

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In 7 patients with newly diagnosed insulin-dependent diabetes mellitus a cytotoxic effect of blood lymphocytes against B-cells could be demonstrated by incubation of isolated rat islets with the lymphocytes. The addition of lymphocytes from healthy persons significantly reduced this effect in vitro. The transfusion of 1.9 X 10(9) - 1.5 X 10(10) lymphocytes from the parents to the patients produced a significant decrease of the cytotoxic effect of the lymphocytes from the patients. This effect could be demonstrated during the preliminary control period up to 12 weeks.

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A cytotoxic effect of peripheral blood mononuclear cells from 22 out of 23 newly diagnosed Type 1 (insulin-dependent) diabetic patients against B cells of isolated rat islets was demonstrated. The addition of peripheral blood mononuclear cells from healthy subjects reduced the cytotoxic effect in 9 out of 10 patients. The addition of peripheral blood mononuclear cells from other diabetic patients was without significant effect in 14 out of 16 cases. The results indicate functional abnormalities of peripheral blood mononuclear cells in newly diagnosed Type 1 diabetes. Beside cytotoxic effects against B cells, a defect in the suppressor function seems to exist. The activation of T-lymphocytes might be a consequence of such a defect.

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A highly significantly decreased prevalence of insulin-dependent childhood-onset diabetes (less than 1/3 of the initial prevalence rate) could be achieved in Berlin/GDR since 1973 by improving systematically diagnostic and therapeutic measures for pregnant diabetics, particularly for non-insulin-dependent gestational diabetics. In addition, a highly significantly increased incidence rate of diagnosed, diet-treated and delivered non-insulin-dependent pregnant diabetics was found between 1979 and 1983 in Berlin/GDR, Halle and Leipzig as compared to the other districts of the GDR. Simultaneously, a highly significantly decreased prevalence rate of diabetic children (less than 1/3), who were born during this period, was found in 1983 for Berlin, Halle and Leipzig as compared to the other districts of the GDR. Finally, a highly significant inverse correlation could be demonstrated for the 15 districts of the GDR between the incidence rates of diagnosed, diet-treated and delivered non-insulin-dependent pregnant diabetics and the prevalence rates of diabetic children who were born during this period (1979-1983). In view of these findings, an interruption and even a reversal of the continued dramatic increase of idiopathic insulin-dependent diabetes mellitus appears to be possible in the developed countries by preventing maternal hyperglycaemia during pregnancy and hence hyperinsulinism in the foetuses and newborns.

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The influence of Sodium-salicylate on insulin secretion and blood glucose behaviour was examined in 6 metabolic healthy persons and 9 type II-diabetics. Insulin secretion and blood glucose were twice examined under a combined stimulation with 100 g glucose (orally), 0.33 g glucose (Bolus injection) and 1.0 mg glucagon (i. v.) with and without a simultaneous infusion of Sodium salicylate during the whole period of examination (40 mg over 120 min). Sodium salicylate effected in type II-diabetics and metabolic healthy persons higher insulin levels. Qualitative differences of the insulin secretion pattern were not to be seen. In spite of higher insulin levels blood glucose was not influenced by Sodium salicylate. It is discussed if the results could be explained by a direct effect of Sodium salicylate on the cells ore on the metabolism of insulin and the gluconeogenesis.

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This is a report on results and problems in taking care of pregnant diabetics in the delivering center Leipzig with special regard of women with a gestational diabetes. In the period between 1971 and 1983 a total of 314 patients were treated with manifest diabetes or a gestational diabetes. We investigated in with manifest diabetes or a gestational diabetes. We investigated in non-selected cases the morbidity of children and the perinatal mortality. The evaluation took into consideration among others the quality of metabolic guidance, the possible causes of perinatal mortality and the therapeutical indications in gestational diabetes. Depended on the changed concept of the care system we considered separately the results of two periods (first period: 1971 until 1978, 136 deliveries; second period: 1979 until 1983, 178 deliveries). We could demonstrate that a complex interdisciplinary care system can reduce the perinatal mortality and morbidity. But it is necessary to diagnose patients with a gestational diabetes earlier than actually usual.

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Many cases of type II diabetes present an anomaly of insulin secretion which is characterized by a missing, reduced, or delayed glucose-stimulated insulin output from the beta cell. We aimed at finding out whether this characteristic disorder is a consequence of reduced beta cell mass or of a more functional disturbance. In the latter case it was to be clarified whether the disturbed beta cell "glucoreceptor" function represents a qualitative or rather a quantitative difference. By the evaluation of insulin secretion and of carbohydrate tolerance during oral and/or intravenous intake of glucose, and after intravenous application of tolbutamide or glucagon the defective insulin secretion in type II diabetics was found to represent a more functional disturbance which could not be explained by reduction of beta cell mass. Thus it was concluded that the anomaly of insulin secretion mentioned above might be a consequence of a qualitative defect of the glucoreceptor. To prove this, isolated human islets (insulin secretion under incubation with glucose, measurements of 3H-leucine incorporation and of the insulin content) were also studied. In contrast to the in vivo results, insulin release of the isolated islets of type II diabetics was normal. From this it must be concluded that the glucoreceptor of the beta cell, which in vivo reacts in a qualitatively different manner from that of subjects with intact metabolism, is not irreversibly disturbed.(ABSTRACT TRUNCATED AT 250 WORDS)

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It is reported on investigations carried through between age at manifestation of a type II diabetes and stimulated insulin secretion. In a group of 130 recently manifested diabetics and non selected diabetics no differences between insulin secretion, stimulated by glucose (orally given) and glucagon could be found when we compared the resulted in dependence on the age. Patients were grouped in four classes of age: less than 50, 51 less than or equal to 60, 61 less than or equal to 70, greater than 70. Similar results of insulin secretion were to be seen as well in a group of diabetics, selected at random, when glucose-, tolbutamide- and glucagon stimulation of insulin secretion were evaluated as in patients first examined after longer diabetes duration (about 6,5 years, n = 51). The entire insulin secretion after all three stimuli was nearly identical with those of probands, who were examined immediately after the manifestation and 5 years later (n = 34). In diabetics both in investigations at the manifestation of the disease and after prolonged diabetes and in follow-up studies wee found no hints, that with progressing age and disease a reduction of insulin secretion in the type II develops. These findings contradict the assumption that a permanent hyperglycemic stimulus provokes a gradual loss of the B-cell function. With the manifestation of the disease already a change of the B-cell function seems to exist which remains constant in nearly the same degree. A possibly concomitant physiological process of aging evidently does not significantly influence the remaining function of the B-cells. The disturbed insulin secretion and the insulin resistance in type II diabetes seem to processes developing in parallel, which are being on the same pathogenetic principle.

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A description is given of the electron microscopic-morphometric findings obtained for the islets of Langerhans of the pancreas and for the glucagon-producing A cells of one patient suffering from longstanding insulin-dependent diabetes mellitus (IDDM, type I diabetes), two patients with longstanding insulin-independent diabetes mellitus (NIDDM, type II diabetes), and one non-diabetic. A morphometric determination of the volume densities of the vascular connective tissue and the various endocrine cells per islet tissue and organelles/ultrastructures per A cell was made, and the diameters of the A-granules were measured. So far, no such studies have been made for human diabetes mellitus, and only a few are available for humans with sound metabolism. In general, the qualitative and, particularly, the quantitative electron microscopic results found for the IDDM patient show greater and clearer deviation from the control with normal metabolism than the findings obtained for the NIDDM patients. As regards the cellular composition of the pancreatic islets and changes caused by diabetes mellitus, the morphometric values obtained from electron micrographs are in essential agreement with comparable findings reported in the literature for light microscopic-histochemical and -immunohistochemical morphometry. The patient with insulin-dependent diabetes has a higher proportion of vascular connective tissue in the pancreatic islets than the non-diabetic. This increase is both relative and absolute and is primarily connected with the loss of B cells in this type of diabetes. In the IDDM patient, A cells were found in the islets but also scattered as single cells in the exocrine tissue and in the walls of pancreatic ductules. The ultrastructural composition of the A cells varies within wide limits even in persons with sound metabolism. Diabetes mellitus does not cause major qualitative alterations in the A cells. The A cells of the IDDM patient contained a remarkable number of nuclei and rarely showed A-granule crinophagia. The casuistic electron microscopic findings, most of which have been obtained for the first time, are discussed. Nothing can be said at this stage about the general applicability of the findings. The morphometric results obtained for the A cells can be interpreted as indicating increased metabolism with heightened glucagon synthesis and secretion in the case of the insulin-dependent diabetic and, to a lesser extent, in the NIDDM patients. This interpretation would support the assumption of a normally existing mutual local paracrine regulation of the A and B cells which stems from close topographical relations (contact, gap junctions).

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