Effects of Cyclosporine Immunosuppression in Insulin-Dependent Diabetes Mellitus of Recent Onset

Stiller, C. R.; Dupré, J.; Gent, Michael; Jenner, M.; Keown, P. A.; Laupacis, Andreas; Martell, R.; Rodger, N. W.; Graffenried, B. von; Wolfe, B. M.

doi:10.1126/science.6367043

Cited by 560 publications

(205 citation statements)

References 21 publications

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“…The present data suggest it may ultimately be possible to DIET CAN PREVENT DIABETES IN THE BB RAT correct immune system defects and prevent or delay onset of IDDM in a manner that presents far less risk to the individual than treatment only after diagnosis of the disease with powerful immunosuppressant agents such as cyclosporin, 23 which has detrimental side effects. 24 …”

Section: Discussionmentioning

confidence: 83%

Diet Can Prevent Diabetes in the BB Rat

et al. 1985

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SUMMARYWhen compared with laboratory chow, a defined, semipurified diet prevented diabetes, reduced the frequency of insulitis, increased thymus weight and total white blood cell count, and doubled thymus T-helper/T-suppressor cell ratios in diabetes-prone BB rats. These data show that the diabetic syndrome in BB rats may be prevented or delayed by changes in diet, which may occur through alteration of pathogenic defects in the immune system. DIABETES 1985; 34:1059-62.T he fact that only up to 50% of unaffected twins of individuals with type I, insulin-dependent diabetes mellitus (IDDM) become diabetic underscores the major role of environmental factors in the expression of this genetically transmitted disease. With the exception of tropical malnutrition diabetes, a unique ketosis-resistant form of IDDM in which there is an acknowledged involvement of diet, 1 there are no data directly linking diet to incidence of type I IDDM in humans. 2 The two main obstacles have been the inability to identify prospective diabetic humans and the inherent difficulties in obtaining accurate and representative dietary information.The recent availability of the spontaneously diabetic BB rat has provided a unique model that has many of the features of human type I diabetes, permitting long-term prospective studies to be carried out. 34 BB rat diabetes appears to be an autoimmune disease resulting from the destruction of the insulin-producing beta cells of the pancreas by the animal's own immune system. Development of overt diabetes may require inheritance of at least three characteristics: mononuclear cell infiltration of the pancreas (insulitis), the pres- ence of the major histocompatibility complex haplotype (RT1 U ), and lymphopenia. 56 The protective effect of neonatal thymectomy, 78 decreased thymus (T)-derived lymphocytes in blood and lymphoid organs, 9 reduced T-helper (T h )/T-suppressor (T s ) cell ratios, 6 and decreased thymus weight in diabetes-prone BB rats all point to a key role for the thymus in the pathogenesis of this syndrome.Diet can have dramatic effects on the immune system, particularly the thymus, which seems uniquely sensitive to manipulation of nutritional variables. 10 Furthermore, it has recently been hypothesized that environment (diet) could be an important factor influencing development of diabetes in BB rats. 811 In previous studies we observed differences in incidence and age at onset, which suggested that, compared with a chow diet, a defined, semipurified AIN-76 diet 12 might modify development of the syndrome. 8 Any approach to this question must consider at least three points: (1) effect of diet on insulitis, diabetes incidence, age at onset; (2) net diet/ immune system interactions (i.e., varying susceptibility of specific T-cell subsets); and (3) presence or absence of diabetogens in the diet. MATERIALS AND METHODSExperiment 1. This experiment was designed to examine directly the effects of ad libitum feeding of a ground laboratory rat chow diet (N = 40) or a defined, semipurified AIN-76 ...

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Section: Discussionmentioning

confidence: 83%

Diet Can Prevent Diabetes in the BB Rat

et al. 1985

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“…Previously tested agents did not have lasting effects on the disease once the drug was discontinued and therefore required continuous treatment to prevent progression of β-cell loss (1–5). For example, treatment with cyclosporin A enhanced the rates of non–insulin- and partial insulin-requiring remissions, but the clinical remission was lost once the agent was discontinued (6).…”

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confidence: 99%

A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes

et al. 2005

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Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3γ1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 ± 9.6% of response at study entry in drug-treated patients vs. 53 ± 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA1c and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8+ T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.

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“…The test has now become widely used in patients with Type 1 diabetes [4][5][6][7][8][9] but also in patients with Type 2 diabetes mellitus [8][9][10][11]. The test has also been used in attempts to discriminate between Type 2 diabetic patients with and without insulin requirement in order to control hyperglycaemia [8,9].…”

mentioning

confidence: 99%

Fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and urinary C-peptide in relation to clinical type of diabetes

Gjessing¹,

Matzen²,

Faber³

et al. 1989

Diabetologia

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Summary. Many patients with Type 2 (non-insulin-dependent) diabetes mellitus are treated with insulin in order to control hyperglycaemia. We studied fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and 24 h urinary Cpeptide in relation to clinical type of diabetes in 132 insulin treated diabetic subjects. Patients were classified clinically as Type 1 (insulin-dependent) diabetic subjects in the presence of at least two of the following criteria: 1) significant ketonuria, 2)insulin treatment started within one year after diagnosis, 3) age of diagnosis < 40 years, and 4) weight below 110% of ideal weight of the same age and sex. Eighty patients were classified as Type 1 and 52 as Type 2 diabetic subjects. A second classification of patients into 6 C-peptide classes was then performed. Class I consisted of patients without islet Bcell function. Class II-VI had preserved islet B-cell function and were separated according to the 20%, 40%, 60% and 80% C-peptide percentiles. The two classifications of patients were compared by calculating the prevalence of clinical Type I and Type 2 diabetes in each of the C-peptide classes. This analysis showed that patients with a fasting plasma C-peptide value < 0.20 nmol/1, a glucagon stimulated plasma C-peptide value < 0.32 nmol/1, and a urinary C-peptide value < 3.1 nmol/1, or < 0.54 nmol/mmol creatinine/24 h, or < 5.4 nmol/24 h mainly were Type I diabetic patients; while patients with Cpeptide levels above these values mainly were Type 2. At these limits the percentage, predictive value of positive tests as indicators of Type 2 diabetes were as follows: fasting C-peptide 83%, stimulated C-peptide 86%, and urinary C-peptide expressed as nmol/1 76%, as nmol/mmol creatinine/24 h 79%, and as nmol/24 h 78%. Similarly, the percentage predictive value of negative tests as indicators of Type 1 diabetes were as follows: fasting C-peptide 86%, stimulated C-peptide 88%, and urinary C-peptide expressed as nmol/1 79%, as nmol. mmol creatinine-24 h 81%, and as nmol/24 h 80%. If patients without detectable C-peptide were excluded, the predictive value of negative tests were as follows: fasting C-peptide 81%, stimulated C-peptide 88%, urinary C-peptide expressed as nmol/161%, as nmol/mmol creatinine/24h 69%, and as nmol/24 h 64%. In conclusion, post glucagon C-peptide gives a good distinction between Type 1 and Type 2 diabetes mellitus in insulin treated diabetes while 24 h urinary C-peptide gives a less sensitive distinction between the clinical types of diabetes.

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Effects of Cyclosporine Immunosuppression in Insulin-Dependent Diabetes Mellitus of Recent Onset

Cited by 560 publications

References 21 publications

Diet Can Prevent Diabetes in the BB Rat

Diet Can Prevent Diabetes in the BB Rat

A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes

Fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and urinary C-peptide in relation to clinical type of diabetes

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