Cyclosporine in recent onset type I diabetes mellitus: Effects on islet β cell function

doi:10.1016/1056-8727(92)90016-E

Journal of Diabetes and its Complications

Volume 6, Issue 2, April–June 1992, Pages 77-88

https://doi.org/10.1016/1056-8727(92)90016-E Get rights and content

Abstract

To confirm the immunological basis of type I diabetes and to determine if immune intervention alters the course of the disease, we studied the use of cyclosporine in a 1-year randomized, double-masked, placebo-controlled trial in 23 subjects enrolled within 6 weeks of diagnosis. Subjects included 12 males and 11 females, ages 9–38 years (mean, 19.7 ± 1.8 years). Initial dosage of cyclosporine was 10 mg/kg/day, given as a single daily dose, adjusted on the basis of side effects and trough cyclosporine levels. Glycemic control and insulin dosage were similar in both cyclosporine and placebo groups. The frequency of freedom from insulin usage also was similar in both groups; however, it is not possible to draw conclusions about response rates, because of the very small sample size. Glucose tolerance, as measured by rate of intravenous glucose disposal did not differ between groups. Islet β cell function was measured by determining C-peptide response to three secretogogues: intravenous glucagon, intravenous glucose, and a mixed formula meal (Sustacal). There were no differences between groups in the C-peptide responses either to intravenous glucagon or intravenous glucose. Moreover, acute insulin response to intravenous glucose was not restored in any subject. On the other hand, in comparison to the placebo group, the cyclosporine group did show an increased meal-stimulated C-peptide response after 3, 6, 9, and 12 months. When measured by regression analysis, the slope defining the rate of decline of β cell function was significantly slower for the cyclosporine group than the placebo group (p < 0.05). Thus, as measured in response to a physiological stimulus (meal challenge), cyclosporine preserves islet β cell function when used in recent onset type I diabetes. Side effects were minimal and reversible upon cessation of immune intervention. The preservation of islet β cell function by immune intervention is consistent with the hypothesis that type I diabetes has an immune mechanism involved in its pathogenesis.

References (45)

G Feutren et al.
Cyclosporin increases the rate and length of remissions in insulin dependent diabetes of recent onset: Results of a multicentre double-blind trial
Lancet
(1986)
LA Grajwer et al.
Control of Juvenile Diabetes Mellitus and Its Relationship to Endogenous Insulin Secretion as Measured by C-Peptide Immunoreactivity
J Pediatr
(1977)
GS Eisenbarth
Type I diabetes mellitus: A chronic autoimmune disease
N Engl J Med
(1986)
JS Skyler et al.
Etiology and pathogenesis of insulin-dependent diabetes mellitus
Pediatr Ann
(1987)
LC Harrison et al.
Type I Diabetes: Immunology and immunotherapy
Adv Endocrinol Metab
(1990)
Cyclosporin-induced remission of IDDM after early intervention: Association of 1 year of cyclosporin treatment with enhanced insulin secretion
Diabetes
(1988)
LC Harrison et al.
Increase in remission rate in newly diagnosed type I diabetic subjects treated with azathioprine
Diabetes
(1985)
J Silverstein et al.
Immunosuppression with azathio-prine and prednisone in recent onset insulin-dependent diabetes mellitus
N Engl J Med
(1988)
Implementation of a multicomponent process to obtain informed consent in the Diabetes Control and Complications Trial
Controlled Clin Trials
(1989)
DS Schade et al.

JS Skyler et al.

Algorithms for Adjustment of Insulin Dosage by Patients Who Monitor Blood Glucose

Diabetes Care

(1981)

AJL Clark et al.

Capillary tubes for blood glucose sampling

Diabetologia

(1982)

LG Heding

Radioimmunological determination of human C-peptide in serum

Diabetologia

(1975)

LG Heding

Determination of total serum insulin (IRI) in insulin-treated diabetic patients

Diabetologia

(1972)

H Kuzuya et al.

Determination of free and total insulin and C-peptide in insulin treated diabetes

Diabetes

(1977)

Staff Research Resources Branch, NIAID, NIH

Lymphocyte microcytotoxicity techniques

D Rodbard

Lessons from the computerization of radioimmunoassays: An introduction to the basic principles of modeling

PF Bougneres et al.

Factors associated with early remission of type I diabetes in children treated with cyclosporine

N Engl J Med

(1988)

S Martin et al.

Follow-up of cyclosporin A treatment in type I (insulin dependent) diabetes mellitus: Lack of long-term effects

Diabetologia

(1991)

PF Bougneres et al.

Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with lowdose cyclosporine

Diabetes

(1990)

R Burcelin et al.

Time course of insulin resistance in type I diabetic patients from onset to treatment induced remission and during relapse to insulin dependency

Diabetes

(1991)

BD Myers et al.

Cyclosporin associated chronic nephropathy

N Engl J Med

(1984)

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Citation Excerpt :
Significant nephrotoxicity was observed, probably related to the higher dose used (10 mg/kg/day). Other trials using cyclosporin were subsequently carried out in children which, however, did not always include a placebo group, that as we discussed is a problem for definitive interpretation of results [41–43]. Nevertheless, results obtained in children showed a similar trend to those reported in adult patients indicating that, in terms of response to immunotherapy, the disease did not appear to show distinctive features depending on the age.
Type 1 diabetes is an autoimmune disease. It was thus logical to attempt preventing or stopping the progression of the disease by immunotherapy. Following the strategies used in organ transplantation, the first trials in the 80 s used cyclosporin in patients presenting recently diagnosed Type 1 diabetes. The effect was spectacular but waned when the treatment was stopped as the effect was non antigen-specific. Going back from bed to bench-side major efforts were then devoted to device strategies allowing induction or restoration of self-tolerance. Two major approaches provided encouraging results when used in spontaneous models of autoimmune diabetes that are the use of β-cell autoantigens and of monoclonal antibodies to CD3. Based on these results academic phase II trials and subsequently pharmaceutically driven phase III trials were launched. Results are now available and when critically analyzed in the frame of these last three decades they provide support to the possibility of making step by step immunotherapy available to all new onset diabetic patients with a hope of inducing long-term remission of the disease if the treatment is started sufficiently early, immediately after diagnosis.
Prevention of Autoimmune Disease: Type 1 Diabetes as a Paradigm
2006, The Autoimmune Diseases, Fourth Edition
It is noted that in the case of type 1 diabetes (T1D) the disease process begins months to years before major loss of beta-cell function heralds symptoms of hyperglycemia. Increasing knowledge of the mechanisms of beta-cell destruction and the ability to identify individuals at risk for T1D, together with proof-of-principle for therapeutic intervention in the non-obese diabetic (NOD) mouse model, are platforms for T1D prevention in humans. Indeed, T1D can be seen as a paradigm for the preclinical diagnosis and prevention of autoimmune disease in general. Preventing T1D applies not only to people at risk but also to those with clinical diabetes, in order to preserve residual beta-cell function, allow possible beta-cell regeneration and prevent recurrent autoimmune disease after therapeutic betacell replacement or regeneration. Furthermore, T1D can be eradicated by primary prevention aimed at avoiding or averting the environmental factors that are thought to precipitate disease in genetically at-risk individuals. Prevention is, however, mostly applicable to subclinical disease, rather than to clinical disease when beta-cell destruction is end-stage.
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Original articleCyclosporine in recent onset type I diabetes mellitus: Effects on islet β cell function

Abstract

Lancet

J Pediatr

Type I diabetes mellitus: A chronic autoimmune disease

N Engl J Med

Etiology and pathogenesis of insulin-dependent diabetes mellitus

Pediatr Ann

Type I Diabetes: Immunology and immunotherapy

Adv Endocrinol Metab

Cyclosporin-induced remission of IDDM after early intervention: Association of 1 year of cyclosporin treatment with enhanced insulin secretion

Diabetes

Increase in remission rate in newly diagnosed type I diabetic subjects treated with azathioprine

Diabetes

Immunosuppression with azathio-prine and prednisone in recent onset insulin-dependent diabetes mellitus

N Engl J Med

Implementation of a multicomponent process to obtain informed consent in the Diabetes Control and Complications Trial

Controlled Clin Trials

Algorithms for Adjustment of Insulin Dosage by Patients Who Monitor Blood Glucose

Diabetes Care

Capillary tubes for blood glucose sampling

Diabetologia

Radioimmunological determination of human C-peptide in serum

Diabetologia

Determination of total serum insulin (IRI) in insulin-treated diabetic patients

Diabetologia

Determination of free and total insulin and C-peptide in insulin treated diabetes

Diabetes

Lymphocyte microcytotoxicity techniques

Lessons from the computerization of radioimmunoassays: An introduction to the basic principles of modeling

Factors associated with early remission of type I diabetes in children treated with cyclosporine

N Engl J Med

Follow-up of cyclosporin A treatment in type I (insulin dependent) diabetes mellitus: Lack of long-term effects

Diabetologia

Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with lowdose cyclosporine

Diabetes

Time course of insulin resistance in type I diabetic patients from onset to treatment induced remission and during relapse to insulin dependency

Diabetes

Cyclosporin associated chronic nephropathy

N Engl J Med

Original article
Cyclosporine in recent onset type I diabetes mellitus: Effects on islet β cell function