Altered islet Beta-cell function before the onset of Type 1 (insulin-dependent) diabetes mellitus

Summary To define the glucose to insulin dose-response relationship before the onset of diabetes, we studied 22 nondiabetic co-twins of patients with Type 1 (insulin-dependent) diabetes mellitus and nine control subjects. All had intravenous glucose tests at 0.02, 0.1 and 0.5 g/kg and were followedup prospectively for at least 6 years. Seven twins developed diabetes a mean of 7 months later; the remaining 15 are now unlikely to develop diabetes. The seven pre-diabetic twins had higher fasting insulin levels than control subjects (4.2±2.0 vs 1.8±1.8 nmol/l; p<0.05); but lower glucose clearance (1.0±0.5 vs 1.9±0.7 %/min; p<0.05), first phase insulin response at 0.5 g/kg (21.1±23.2 vs 143±50 nmol/l; p<0.0001), and total insulin responses at 0.1 g/kg (p<0.05) and 0.5 g/kg (p<0.00005). Using a curve-fitting programme, the normal glucose to insulin relationship was lost in prediabetic twins who had lower coefficient of determination (R²) than control subjects (p<0.01). In contrast, 15 low-risk twins and their nine control subjects had similar fasting glucose and insulin levels, glucose clearance, R² and insulin secretory responses to different glucose loads. The positive predictive values of subnormal R² and subnormal first phase insulin response were 67 % and 58 % respectively. These observations demonstrate an altered glucose to insulin dose-response relationship and loss of maximum insulin secretory response to glucose before the onset of Type 1 diabetes.     

Long-term follow-up after transplantation of insulin-producing pancreatic islets into patients with Type 1 (insulin-dependent) diabetes mellitus

Summary Purified human islets and a kidney from the same donor were transplanted into four patients with Type 1 (insulin-dependent) diabetes mellitus. Two of the patients received additional islets that were isolated from multiple donors, cryopreserved, and stored in a tissue bank. The islets were embolized into the liver via the portal vein. Immunosuppression was induced with antilymphocyte globulin and maintained with azathioprine, prednisone and cyclosporine. In the first two patients, fasting serum C-peptide rose to levels of 0.5–2.0 ng/ml during the first 4–8 weeks and mixed meal feeding elicited increases to 2–3 ng/ml. C-peptide secretion persisted for 8 months, but at progressively lower levels and insulin therapy could not be withdrawn. In the next two patients who received cryopreserved islets in addition to fresh islets, serum C-peptide levels (fasting/post-meal) rose to 4–7 ng/ml and serum glucose was more stable, allowing withdrawal of insulin therapy after 69 days in one patient, and reduced insulin doses in the other. The insulin-independent patient has maintained normal fasting glucose, glycosylated haemoglobin, and oral glucose tolerance at 1 year following cessation of daily insulin therapy. Episodes of renal graft rejection occurred in three patients, including the insulin-independent patient. High-dose steroid therapy reversed the rejection in all instances, with apparent preservation of C-peptide secretion. These data show that transplantation of purified freshly-prepared and cryopreserved islets into Type 1 diabetic patients results in prolonged insulin secretion, and that sufficient function could be provided in one patient to sustain euglycaemia in the absence of insulin therapy at 1 year of follow-up.     

Follow-up of cyclosporin A treatment in Type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects

Summary In the Canadian/European randomized controlled study on cyclosporin A (CsA) in recent onset Type 1 (insulin-dependent) diabetes, treatment with the immunosuppressive drug had increased and maintained Beta-cell function and clinical remission during the first 12 months. Following discontinuation of the study drug and double-blinding after a mean of 13.8 months former CsA patients doubled the daily insulin dose within 6 months reaching the level of former placebo patients. The difference in Beta-cell function between the two groups was also lost. Metabolic control (HbA_1c) was transiently worse in the former CsA group. Adverse effects of cyclosporin A on systolic blood pressure, haemoglobin levels, serum potassium and creatinine levels also remitted during that time. We conclude that treatment with cyclosporin A for a mean of 13.8 months had no long-lasting effect on the course of Type 1 diabetes persisting beyond drug discontinuation.Prepared by the authors on behalf of The Canadian/European Randomized Control Trial Group (Please see acknowledgements for complete listing).     

Normoglycaemia after transplantation of freshly isolated and cryopreserved pancreatic islets in Type 1 (insulin-dependent) diabetes mellitus

Summary Purified islets of Langerhans and a kidney were transplanted into a 36-year-old patient who suffeded from renal failure secondary to a 25 year history of Type 1 (insulin-dependent) diabetes mellitus. The islet graft contained 243 000 fresh islets (mean islet diameter 150 m) that were syngeneic with the kidney fraft and 368 000 cryopreserved islets that had been collected from four other donors. The total of 10 000 islets/kg body weight was infused into the liver via the umbilical vein. Immunosupperession was induced with antilymphocyte globulin and maintained with prednisone, cyclosporine and azathioprine. Serum C-peptide levels (ng/ml) during fasting and after standard mixed metal feeding (Sustacal) were <0.12 preoperatively. Postoperatively, insulin secretion was restored: fasting C-peptide rose during the first 4 weeks to levels of 4 to 5 and Sustacal elicited a further rise to 6 to 7. Transplant renal function was stable. Dialy fasting glucose (mmol/l, mean±SD) was 5.6±1 and 5.3±0.6 during the first and second months respectively and post-Sustacal glucose was 5.7+-0.8. Exogenous insulin therapy was progressively withdrawn and stopped duting the ninth week. Thereafter, fasting glucose was 4.7+-0.5, 24 h mean glucose was 6.6+-0.5, and normoglycaemia was maintained after Sustacal. These data show that this mass of freshly isolated and cryopreserved islets from multiple donors provided sustained function (3 months) that reversed insulin-dependence in an immunosuppressed Type 1 diabetic patient treated with simultaneous islet-kedney transplantation.     

Pancreatic cytokeratin: an antigen of pancreatic exocrine cell autoantibodies in Type 1 (insulin-dependent) diabetes mellitus

Summary Autoantibodies reacting with human pancreatic exocrine cells were investigated by immunofluorescent techniques in 107 patients with Type 1 (insulin-dependent) diabetes mellitus, 20 first-degree relatives of the Type 1 diabetic patients, 347 patients with Type 2 (non-insulin-dependent) diabetes, 34 with alcoholic pancreatitis, 26 with rheumatoid arthritis and 107 normal control subjects. Both immunoblotting analysis and double-immunostaining methods were used to characterize the antigens targeted by the pancreatic exocrine cell autoantibodies. Sera positive for human pancreatic exocrine cell cytoplasm, producing a fine fibrillar pattern, were found in 21% (23/107) of the Type 1 diabetic patients. The autoantibodies were present in 39% (15/38) of Type 1 diabetic patients diagnosed within 3 months, and the prevalence decreased with duration of diabetes. The antibodies were of the IgM class in 87% (13/15) of recent-onset Type 1 diabetes cases, but IgG-autoantibodies became more prevalent with increasing duration of diabetes. Three out of 347 (0.9%) Type 2 diabetic patients and 4 of 20 (20%) first-degree relatives of Type 1 diabetic patients had autoantibodies targeted against pancreatic exocrine cells. None of the patients with alcoholic pancreatitis or rheumatoid arthritis and none of the control subjects had these antibodies. Immunoblotting analysis and double-immunostaining demonstrated that the autoantibodies reacted with 40 kilodalton cytokeratin in pancreatic exocrine cell cytoplasm. The antibody was absorbed by the Triton X-100-insoluble fraction of pancreatic extract. These results indicate the presence of distinct autoantibodies to pancreatic exocrine cells in Type 1 diabetes. This suggests the provocative concept that the cytoskeletal system of pancreatic exocrine cells is involved in the pathogenetic process of Type 1 diabetes.     

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.     

Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus

Summary An increased proinsulin to C-peptide molar ratio at the onset of Type 1 (insulin-dependent) diabetes mellitus has been suggested. We studied fasting proinsulin levels and proinsulin/C-peptide ratios in the newly diagnosed diabetic subjects participating in the Canadian/European placebo controlled cyclosporin study at entry, during the one year treatment period and six months of follow-up. Available entry data from 176 out of the 188 allocated patients were compared to 60 age and weight matched control subjects. Fasting proinsulin was significantly elevated in male patients compared to male control subjects (p<0.01), whereas the levels only tended to be elevated in female patients. The proinsulin/C-peptide ratio was three to fourfold elevated in the diabetic groups of both sexes, (p<0.001). Further, proinsulin and C-peptide were studied in 83 cyclosporin and 86 placebo-treated subjects during the trial and follow-up. An additional increase of proinsulin/C-peptide ratio was observed during the first three months of placebo treatment. It remained constantly high for nine months and then declined to entry level. This pattern was not seen in the cyclosporintreated group, where the ratio was unchanged during the 12 months trial and follow-up. The effect of cyclosporin on the induction of non-insulin requiring remission was unrelated to fasting and glucagon stimulated C-peptide levels at entry, whereas 64% of the cyclosporin-treated against 28% of the placebo-treated subjects (p<0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024. If the ratio was below 0.024 at entry, 42% and 33% went into non-insulin requiring remission, respectively (NS). We conclude that fasting proinsulin to C-peptide molar ratio is elevated at the onset of Type 1 diabetes mellitus. A further plateaushape elevation lasting nine months was seen during the remission period. Cyclosporin seems to inhibit or delay this development. The proinsulin/C-peptide ratio at diagnosis may show to be of value in the prediction of remission during cyclosporin treatment.Prepared by the authors for The Canadian/European Diabetes Study Group.     

Urinary kallikrein excretion in Type 1 (insulin-dependent) diabetes mellitus

Summary Kidney haemodynamics appear to change after the early phases of diabetic nephropathy: increases in glomerular filtration rate and in renal plasma flow have been widely reported, while kidney size is increased. As the renal kallikrein-kinin system has been demonstrated to regulate kidney blood circulation, we have evaluated the excretion of urinary kallikrein in 87 Type 1 (insulin-dependent) diabetic patients with and without hyperfiltration. Urinary kallikrein excretion was measured in 24-h urine collections. The esterolytic activity was determined by fluorimetric assay. The excretion of urinary kallikreins was significantly higher in hyperfiltering patients (472±125 esterase units/24 h) than in normofiltering (168±77 esterase units/24 h) and control subjects (151±39 esterase units/24 h), p<0.001. Furthermore, we observed a positive correlation between urinary kallikrein excretion and glomerular filtration rate (r=0.785). These data suggest that variations of kallikrein and kinin concentrations may play a role in the alteration of renal haemodynamics in Type 1 diabetes. It is possible that the kinin-kallikrein system, the renin-angiotensin system and the prostaglandins may interact to determine the haemodynamic alterations which are present in the diabetic disease.     

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.     

Glutamic acid decarboxylase (GAD) autoantibodies are additional predictive markers of Type 1 (insulin-dependent) diabetes mellitus in high risk individuals

Summary The prevalence of glutamic acid decarboxylase autoantibodies was determined with an immunotrapping enzyme activity assay in newly-diagnosed Type 1 (insulin-dependent) diabetic patients as well as in first-degree relatives using rat brain homogenate as a source of glutamate decarboxylase. Twenty-six out of 86 islet-cell cytoplasmic autoantibody positive and one out of 24 islet cell autoantibody negative patients of recent onset, had autoantibodies to glutamate decarboxylase above the upper 99% confidence limit obtained from 89 control sera. Among 27 islet cell autoantibody positive relatives including 19 siblings and 8 parents, antibodies to glutamate decarboxylase were found in 8 of 9 (89%) relatives and 7 of 8 (87.5%) siblings with islet cell autoantibody titres above 20 JDF units, in 1 of 19 (5.2%) relatives with islet cell autoantibody titres between 2 and 5 JDF units, in 2 of 263 (0.7%) siblings and 1 of 139 parents without islet cell autoantibodies. In first-degree relatives, high titre islet cell autoantibodies and autoantibodies to glutamate decarboxylase were tightly associated (X²=182, p=0.0001). None of the relatives with low genetic risk (n=64), i.e. HLA-different to the diabetic proband, was found to be antibody positive. Antibodies to glutamate decarboxylase were present only in those relatives sharing at least one haplotype with the diabetic proband, including two islet cell autoantibody negative but HLA-identical siblings. Autoantibodies to glutamate decarboxylase were present in 7 of 9 (77%) relatives who developed the disease, including one islet cell autoantibody negative sibling. Altogether, the simultaneous presence of autoantibodies to glutamate decarboxylase and high titre islet cell autoantibody increases the positive predictive value for the disease from 66% to 75%. This study indicates therefore that autoantibodies to glutamate decarboxylase detected by an immunotrapping enzyme activity assay are additional predictive markers for future development of Type 1 diabetes and should be now prospectively studied in high risk individuals as well as other autoantibodies to Beta-cell autoantigens.     

Incidence of Type 1 (insulin-dependent) diabetes mellitus in Catalonia, Spain

Summary The incidence of Type 1 (insulin-dependent) diabetes mellitus was prospectively evaluated in Catalonia, Spain in patients up to 30 years of age during the period 1987–1990. The population at risk (0–29 years) consisted of 2,690,394 inhabitants (total population of Catalonia 5,978,638). All the cases were independently identified from four sources: endocrinologists, sales of blood glucose monitors and insulin pen injectors, diabetes societies and diabetic summer camps. The degree of ascertainment was 90.1 %. The overall observed incidence rate was 10.7 per 100,000 per year, being 11.5 per 100,000 per year in the 0–14 age group. The incidence in males (12.0 per 100,000 per year) was higher than in females (9.3 per 100,000 per year), with a male/female ratio of 1.36/l. The sex differences were only present in cases over 14 years of age. Age specific incidence rates per 100,000 per year were 4.4 (confidence interval 95%: 3.2–5.7) in the age group 0–4, 9.9 (8.5–11.4) in 5–9, 17.5 (15.7–19.4) in 10–14, 11.4 (9.9–13.0) in 15–19, 11.3 (9.7–13.0) in 20–24 and 8.5 (7.2–9.9) in 25–29. There was a seasonal onset pattern, with the highest incidence in winter (December–February). We conclude that the incidence of Type 1 diabetes observed in Catalonia during the period 1987–1990 is higher than that recently reported in other Mediterranean countries. This study offers the first standardized data on Type 1 diabetes incidence in Catalonia, including cases up to 30 years, and contributes to the knowledge of the epidemiology of diabetes in South Europe.     

Type 1 (insulin-dependent) diabetes mellitus diagnosed during pregnancy: a clinical and prognostic study

Summary The study concerns the clinical outcome and later prognosis (regarding permanent insulin treatment) of patients who develop insulin-dependent diabetes mellitus during pregnancy (which is different from gestational diabetes). Sixty-three such patients (27±1 (SEM) years old) were delivered at the Copenhagen Centre for Diabetes and Pregnancy during the years 1966–1980. Obstetric complications such as toxaemia were seen in 9.5% of these study patients and the perinatal mortality was 6.3%, both percentages being higher than in the general population (1.1%,p<10^–7 and 1.0%,p<10^–3, respectively), but similar to those observed in patients with Type 1 diabetes diagnosed before pregnancy. In contrast, the frequency of malformations was 1.6%, the same as in the general population (1.4%), but lowerthan that seen in patients with long-standing diabetes (8.3%,p<0.05). At follow-up examination 8±1 years after diagnosis all patients were diabetic; 77% were insulin treated, having no or virtually no residual B-cell function, and were clearly Type 1 diabetic patients. After delivery 80% of the patients had a remission period (median 256 days) without insulin treatment. This remission period was absent or shortest in patients with the following characteristics (p0.03): low age, first parity, not overweight, and high blood glucose level at diagnosis. These prognostic parameters should be considered in obligatory, clinical follow-up plans for such patients.     

Transfer of Type 1 (insulin-dependent) diabetes mellitus associated autoimmunity to mice with severe combined immunodeficiency (SCID)

Summary Pancreatic beta-cell destruction and development of Type 1 (insulin-dependent) diabetes mellitus are associated with circulating islet cell antibodies. Mice with severe combined immunodeficiency (SCID mice) were reconstituted with peripheral blood mononuclear cells from Type 1 diabetic patients, one who was antibody positive and one antibody negative, and from healthy individuals. Reconstituted mice were subsequently immunized with rat islets in incomplete Freunds adjuvant or adjuvant alone. Seventeen mice received peripheral blood mononuclear cells obtained at three different time points from the islet cell antibody positive patient. Before immunization with rat islets two mice developed antibodies to glutamic acid decarboxylase, a major target for antibodies in Type 1 diabetes, whereas none were positive for cytoplasmic islet cell antibodies. Following immunization with rat islets, glutamic acid decarboxylase antibodies were detected by immunoprecipitation in three additional mice, two of which also became positive for cytoplasmic islet cell antibodies. Of 22 mice which received peripheral blood mononuclear cells from either the islet cell antibody negative patient (n = 5) or from two healthy individuals (n = 17), none were positive for islet cell autoantibodies before or after immunization. None of the islet cell antibody positive mice became hyperglycaemic, showed impaired glucose tolerance or islet cell damage when studied 40 days after immunization (i.e. 100 days after reconstitution). In conclusion these results show that human B lymphocytes producing diabetes-associated autoantibodies can be transferred to SCID mice and remain antigen sensitive, but also that autoantibodies alone are not sufficient to induce beta-cell destruction.     

Prospective analysis of islet cell antibodies in children with Type 1 (insulin-dependent) diabetes

Summary The prevalence of islet cell antibodies in children with Type 1 (insulin-dependent) diabetes was determined in a cohort of 678 children. The natural course of islet cell antibodies was followed in 375 children at 1 year, 252 and 135 children after 2 and 3 years respectively. Islet cell antibodies were determined by indirect immunofluorescence on cryostat sections of human pancreas. At diagnosis of diabetes 85% of the children had detectable islet cell antibodies (mean titre 10.4). After 3 years 62% of the children were still islet cell antibody positive (mean titre 2.9) indicating a greater persistence of islet cell antibodies than described in earlier studies. In this large cohort a significant correlation between islet cell antibody prevalence or persistence and sex, age or HLA-DR type was not observed except for a faster loss of islet cell antibodies in very young boys and in patients lacking HLA-DR types 3 and 4. Complement fixing islet cell antibodies correlated with high titre islet cell antibodies. Greater persistence of islet cell antibodies was seen for cases with high antibody titre and in children with diagnosis of diabetes during the first half of the year.     

Loss of Ia-positive epidermal Langerhans cells at the onset of Type 1 (insulin-dependent) diabetes mellitus

Summary Immunocompetent antigen-presenting Langerhans cells were investigated in skin biopsies of 20 short-term Type 1 (insulin-dependent) diabetic patients and compared with 17 matched normal control subjects. Langerhans cells in epidermal sheet preparations were visualized with a monoclonal anti-HLA DR antibody using indirect immunofluorescence. A significant decrease of Langerhans cells/mm² body surface area was found in 10 patients immediately at the onset of diabetes compared to 10 patients with 6 months duration of diabetes and to normal control subjects (401±30 vs 559±43 vs 611±33, p<0.01 and p<0.002). There was no significant difference in the number of Langerhans cells between patients with 6 months duration of diabetes and control subjects. Examination of the most likely precursor of Langerhans cells, the blood monocytes, indicated an increase of monocyte counts in Type 1 diabetic patients after 6 months duration (344±37 cells/l vs 191±31 in control subjects, p<0.05) and an inverse correlation between the number of Langerhans cells in skin with the number of monocytes in peripheral blood (at onset: r=–0.73, p<0.01, after 6 months of diabetes: r=–0.61, p<0.05). In addition, a positive correlation between Langerhans cells and daily insulin dose was noted in patients after 6 months of diabetes (r=0.76, p<0.01). The data suggest a loss of Langerhans cells in skin at the onset of Type 1 diabetes and that functional alterations of these and perhaps also other antigenpresenting cells may be involved in the pathogenesis of Type 1 diabetes.     

Distinct cytoplasmic islet cell antibodies with different risks for Type 1 (insulin-dependent) diabetes mellitus

Summary The cytoplasmic islet cell antibody patterns of sera from islet cell antibody positive non-diabetic and diabetic endocrine autoimmune patients, and newly-diagnosed Type 1 (insulin-dependent) diabetic patients were characterised using four layer immunofluorescence with monoclonal antiproinsulin or anti-glucagon antibodies. Two distinct islet cell antibody types were identified. One gave a diffuse cytoplasmic staining in both Beta and Alpha cells (whole islet pattern), and was not affected by pre-incubation with rat brain homogenate. The other had a granular appearance with staining restricted predominantly to Beta cells (selective islet pattern) and was completely inhibited by pre-incubation with rat brain homogenate. Some sera appeared to have a mixed islet pattern, in which glucagon-positive cells gave a weaker cytoplasmic staining than proinsulin-positive cells. The granular selective pattern was found in sera from 19 (79%) of 24 non-diabetic endocrine autoimmune patients, in two (22%) endocrine autoimmune patients who developed Type 1 diabetes (p<0.0001 vs non-diabetic endocrine autoimmune patients), and in none of 19 newly-diagnosed diabetic patients. The whole islet pattern was found only in sera from patients who had, or who subsequently progressed to, Type 1 diabetes. This study has identified a novel islet cell antibody specificity and demonstrates that in islet cell antibody positive endocrine autoimmune patients, only islet cell antibodies which stain both Beta and Alpha cells are associated with progression to Type 1 diabetes.     

Clinical pattern of childhood Type 1 (insulin-dependent) diabetes mellitus in the Sudan

Summary During a 10-year period, 101 children with Type 1 (insulin-dependent) diabetes mellitus were admitted to the Department of Paediatrics of the University Hospital in Khartoum, Sudan. The age distribution of the patients showed a steady increase from age one to ten years followed by a sharper increase around puberty. A higher number of cases were diagnosed during the cooler compared to the warmer months of the year (p<0.05). Family history of Type 1 diabetes was reported in 14.9% of patients. Diabetic ketoacidosis was a presenting symptom in 82 patients (81.2%) and 93 patients (92.1%) have had at least two documented episodes of ketoacidosis during the follow-up period. Almost all patients were treated with bovine insulin given as a single dose per day. An initial remission period was not observed in any of the patients. Four years after diagnosis, the average daily dose of insulin used by the patients was greater than 2.0 U/kg body weight and the mean HbA_1C was 13.4% (reference value 5.3–6.7%). Seventeen patients (16.8%) were known to have died during 399 person-years of observation resulting in a mortality rate of 42.6 per 1000 person-years of follow-up. Another 29 patients (28.7%) for no apparent reason did not attend a follow-up examination after discharge from hospital. Some of these patients might have died in other hospitals or at home. The study emphasizes the need for urgent measures to increase public awareness of diabetes and to improve methods of case-finding and management of diabetic patients.     

Increased aortic stiffness in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary The biomechanical properties of aortic samples from patients with Type 1 (insulin-dependent) diabetes mellitus and age- and sex-matched control subjects were analysed using a materials testing machine. The specimens were prepared from tissue outside areas of visible atherosclerosis in order to discriminate between primary Type 1 diabetic alterations in the aortae and secondary changes due to increased atherosclerosis. We paid special attention to the correction of biomechanical parameters for differences in wall thickness and registration of specimen length values. In the Type 1 diabetic aortae a marked reduction was found in the extensibility and an increase in their stiffness. The reduced extensibility was correlated significantly to the duration of Type 1 diabetes. The pronounced alterations in the mechanical properties could not be explained by the increase in the wall thickness which was observed among the Type 1 diabetic patients and the alterations could not be correlated to the grade of atherosclerosis in the thoracic aorta. The results of the present study, therefore, strongly suggest that Type 1 diabetic patients develop alterations in the arterial connective tissue independent of the presence of atherosclerosis. Such primary alterations in the vessel wall may play a role in the pathogenesis of large vessel disease among these patients.     

Lessons from the NOD mouse for the pathogenesis and immunotherapy of human Type 1 (insulin-dependent) diabetes mellitus

Summary Suitable animal models of human Type 1 (insulin-dependent) diabetes mellitus have long been sought, in particular a model that would permit detailed histological and immunological investigation of changes in the islet preceding the metabolic disorder. This would allow hypotheses as to pathogenesis of the condition to be examined and interventions such as immunotherapy to be tested. The most widely studied models include the low-dose streptozotocin induced diabetic mouse and the BB rat, but both differ in important respects from the human disease. In this review we describe one highly successful model, the non obese diabetic mouse. Selected aspects of pathogenesis and immunotherapy are presented and analogies with human Type 1 diabetes discussed.