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Glucagon-like peptide 1 and type 1 diabetes: NOD ready for prime time?

Diabetes mellitus is considered the epidemic of the 21st century, affecting close to 170 million people in 2000, and expected to double in incidence by 2030 (1). The two major types of diabetes (types 1 and 2) are characterized by chronic hyperglycemia due to a loss of insulin secretion and/or defective insulin action; however, the etiopathogenesis of each type is distinct. Type 1 diabetes mellitus (T1DM) is an autoimmune disorder, resulting from lymphocyte-mediated destruction of insulin-producing -cells, whereas type 2 diabetes is a complex metabolic disorder, caused by a combination of insulin resistance and a concomitant impairment in insulin secretion. Currently, there is no cure for type 1 or 2 diabetes. The dominant treatment for T1DM continues to be insulin replacement therapy. Although multiple oral hypoglycemic and injectable agents are used for the treatment of type 2 diabetic patients, these agents do not appear to prevent the progressive loss of -cell mass and function that accompanies the natural history of type 2 diabetes, so that eventually many patients require exogenous insulin administration. Given the pathophysiology of T1DM, the most effective way to prevent the development of -cell destruction and insulin deficiency is by interfering with the autoimmune attack. Unfortunately, due in part to difficulties inherent in identifying patients at high risk and lack of effective agents, most immune-based prevention trials have not yielded noteworthy results. Consequently, the majority of clinical trials are now focused on intervention therapies, targeting recentonset diabetic patients to prevent further -cell destruction (2). One of the most promising clinical trials involves shortterm treatment with humanized anti-CD3 monoclonal antibodies. Treatment with anti-CD3 antibodies generated promising results in diabetic animal models (3, 4) and preserved -cell function in two independent human trials (5, 6). The mechanism of action of the anti-CD3 therapy is not fully understood; however, the long-term beneficial effects are believed to be mediated via enhancement of specific populations of regulatory T cells, observed both in murine models (7) and in diabetic human subjects (8). The work of Sherry et al. (9) in this issue of Endocrinology examines whether the addition of exendin-4 [a glucagon-like peptide 1 (GLP-1) receptor agonist] to anti-CD3 immunotherapy enhances diabetes remission. Given the reported decline in -cell function after the first year of a single course of anti-CD3 monotherapy in human studies, the authors reasoned that a major determinant of successful response to treatment is the extent of -cell function at diagnosis. Hence, the authors hypothesized that the addition of exendin-4 (a molecule that stimulates -cell proliferation and inhibits apoptosis in preclinical studies) after induction of immune tolerance may improve -cell mass and function, and thus result in an improved response to the anti-CD3 immune therapy. Indeed, the rate of diabetes reversal was higher in NOD mice (a model of T1DM) receiving a 5-d course of anti-CD3 antibody in combination with a 10-d course of exendin-4 upon onset of hyperglycemia, compared with mice receiving the corresponding monotherapies and control treatments. However, the addition of exendin-4 to the antiCD3 immunotherapy was only beneficial when there was residual functional -cell mass upon initiation of treatment (reflected by ambient glucose levels 350 mg/dl). Contrary to expectations, the authors did not observe an enhancement of -cell area or positive effects on the rate of -cell proliferation and -cell death when exendin-4 was added to the anti-CD3 immunotherapy. Furthermore, the authors showed that exendin-4 treatment had no detectable effects on the autoimmune response because modulation of immune function could have been an alternative explanation for the improved remission rate of diabetes. Rather, what Sherry et al. (9) discovered is that the mechanism accounting for the beneficial effects of combining exendin-4 with immunotherapy involves the recovery of residual -cell function by replenishing and enhancing the insulin stores. The effects of exendin-4 were demonstrated by the authors both in vivo, by performing glucose tolerance tests, as well as by measuring the total pancreatic insulin content, and in vitro, by measuring glucose-stimulated insulin release and insulin content of cultured islets upon treatment with exendin-4. In both settings, exendin-4 resulted in a significantly improved insulin response to glucose stimulation as well as significantly enhanced total islet insulin content. Thus, the authors conclude that the beneficial effects of adding exendin-4 to the anti-CD3 antibody are accounted for via revival of -cell function. What are the implications of this preclinical study for clinical efforts directed at preservation of -cell function in newly diagnosed subjects with T1DM? Although the results from the anti-CD3 clinical trials are encouraging, deterioration in the levels of C peptide in patients 18 months after the single-course treatment indicates that the efficacy of the treatment needs to be improved. Due to safety concerns, an increase in the dose of the drug may not be recommended because anti-CD3 may induce reactivation of latent EpsteinBarr virus infection (5). An alternative approach to overcome the limitations of anti-CD3 monotherapy is the addition of agents with complementary methods of action that promote -cell regeneration. There is considerable attention focused on -cell growth factors, including gastrin, epidermal Abbreviations: GLP-1, Glucagon-like peptide 1; GLP-1R, glucagonlike peptide 1 receptor; T1DM, type 1 diabetes mellitus.