Clinical Considerations of Insulin Dependent Diabetes Mellitus

CLINICAL CONSIDERATIONS

Diagnosis

IMMUNOASSAYS

Several assays have been proposed to detect and quantitate islet-specific auto-immunity. Because IDDM is T-cell medi-ated, one would certainly prefer to use T-cell-based rather than humoral assays. Unfortunately, this has proven difficult. No fully reliable T-cell assay has so far been described that is sufficiently sensi-tive (positive in a significant proportion of patients) and disease-specific (negative in most controls). Some hope relies in more recent studies using peptides eluted from IDDM-predisposing HLA molecules, but the results obtained must be confirmed and rendered applicable to their routine usage. One may also hope that other new T-cell targets will become available, such as IGRP, which stimulates CD8 T cells. The emergence of the tetramer technol-ogy could prove useful, particularly for CD8+ T cells.

At variance with T-cell-based assays, autoantibody detection has been extremely informative. Islet cell-specific autoanti-bodies (ICA) were first detected by indi-rect immunofluorescence using sections of human pancreas (ICA). These tests proved extremely useful for several decades. It is not fully quantitative and has now been replaced by assays using chemi-cally defined β-cell antigens. There is not of insulin therapy, protecting patients from exposure to the risk of degenerative complications associated with unsatisfac-tory metabolic control (usually observed when insulin dependency is progressively recognized).

PREDIABETES

A large (and yet ill-defined) propor-tion of β cells are destroyed at the clinical onset of IDDM, even though there is still a significant number of livingβ cells that are rescuable by anti-CD3 antibodies. In any event, reserving immunotherapy for subjects with high β-cell mass would be highly desirable. This can be achieved by identifying subjects progressing toward IDDM but still capable of maintaining normal glycemia despite some reduction of theβ-cell mass. These subjects can be recognized by the early presence of islet-specific autoantibodies using the reliable assays described earlier. These predia-betic subjects can be identified with a high degree of precision. Subjects with the three autoantibodies (insulin, GAD, and IA-2) will become diabetic within five years in more than 90 percent of cases. However, the situation is less clear for subjects with only one or two antibodies. Furthermore, diabetes prediction in the general popula-tion (in the absence of an IDDM heredity) is much less efficacious than in relatives of diabetic patients in whom it is essen-tially performed today both because of the higher risk (7 percent versus 0.2 percent) and the higher prediction value of the autoantibody assays.

One may complement autoantibody detection by genetic testing, which is today essentially limited to HLA, DR3, and DR4 (or their DQ equivalents). This approach has been used for systematic DR3/DR4 screening of young children born of

a single IDDM target autoantigen, but rather autoantibodies are found against a variety of islet autoantigens using highly reliable assays. Anti-insulin autoantibodies are measured using a radioimmunoassay rather than ELISA, whose interpretation is hampered by low-avidity autoantibodies. Anti-GAD and anti-IA-2 autoantibodies are measured by radioligand assays in which the autoantigen is synthesized de novo in vitro as a radiolabeled (35S) recombinant protein in cell-free transla-tion systems.

HELP FOR DIAGNOSIS

The diagnosis of IDDM is essentially made on a metabolic basis (hyperglycemia and glycosuria). There are certain settings, however, where confirmation of the pres-ence of islet-specific autoimmunity may be useful.

At the onset of clinical diabetes, there may be some hesitation about the auto-immune origin of the disease even in relatively young subjects (young adults) particularly in non-HLA DR3 non-DR4 subjects. It may be important to confirm the presence of islet-specific autoimmu-nity, which will become critical when more patients are enrolled in immuno-therapy trials in which nonautoimmune patients are excluded.

Another important setting in this context is that of LADA. These patients appear to be conventional type II diabetes patients (with the exception of an unusual absence of excess weight). Orientation toward LADA (slowly progressing IDDM) is done in the presence of β-cell-specific autoantibodies. Recognition of LADA is important clinically because the knowl-edge of a likely short- or medium-term evolution toward insulin dependency will prompt clinicians to accelerate the onset diabetic parents, starting antibody moni-toring at birth.

IMMUNOTHERAPY

Insulin is not a fully satisfactory treat-ment for IDDM. It is associated with major constraints (monitoring) and hazards (hypoglycemia) and above all does not com-pletely prevent the onset of degenerative complications; hence, the interest given over the past two decades to the immuno-therapeutic approach.

On the basis of results obtained in ani-mal models, treatment was first attempted with recently diagnosed IDDM patients with nonspecific immunosuppressants, namely, cyclosporin A and azathioprin. A significant retardation of disease pro-gression was obtained with observation of complete disease remission in a sta-tistically significant percentage of cases. Drug-specific side effects were observed and the disease relapsed when treatment was stopped. Inasmuch as chronic immu-nosuppression is hardly possible in young subjects like IDDM patients, it was con-sidered that the immunotherapy research should be oriented toward induction of long-term restoration of islet-specific tol-erance after a short course of induction treatment, considering the side effects of long-term immunosuppression. Two approaches were undertaken. The first one was inspired by the remarkable abil-ity of some β-cell autoantigens to induce long-term tolerance and diabetes preven-tion in NOD mice when administered at an early age either parenterally or orally. It was rapidly realized that oral insulin did not slow IDDM progression in recently diagnosed subjects. Similar negative results were observed when administering parenteral insulin in prediabetic subjects, even though the trial was performed in a large number of patients. More recently, a new approach was developed based on the demonstration that administration of nonmitogenic anti-CD3 antibodies could induce long-term remission of recently diagnosed diabetes, an effect associated with the parallel elimination of effector cells and resetting of immunoregulatory TGF β-dependent regulatory T cells. An open phase I/II trial provided promising results that have now been confirmed in a phase II randomized placebo-controlled study. Importantly, in the latter trial, there was not only maintenance of β-cell func-tion but also real rescue in a large propor-tion of patients, confirming that at the time of diabetes onset, there is a significant role for reversible islet inflammation in addi-tion to β-cell destruction.

Other trials are now in progress using β-cell-antigen peptides or altered peptides. It will be important to determine whether the antigen-specific approach is operational in advanced disease. Perhaps the solution will be the combined usage of tolerance-inducing regimens of the CD3 antibody type complemented in a second phase by antigen-specific therapy.

One should also follow with interest the prolific research of new immunothera-peutic methods tested in the NOD mouse, with the caveat of not overinterpreting data obtained in early treatments that may act in a nonspecific fashion or at least in conditions that do not correspond to the clinical setting.