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capacity for insulin production by residual β‐cells and suppress glucagon secretion, as well as the need for therapeutics to reduce β‐cell stress co‐administered with immunomodulatory therapy to reverse autoimmunity in symptomatic T1D. Hence, therapies once considered only applicable to those with T2D may be of potential benefit for those with T1D. In this regard, ongoing T1D immunotherapy trials are investigating the potential benefits on β‐cell function in C‐peptide positive early diagnosed T1D patients.

In a post hoc analysis of pooled data from five randomized, placebo‐controlled studies, the dipeptidyl peptidase 4 (DPP‐4) inhibitor saxagliptin improved β‐cell function as assessed by HOMA2 of β‐cell function and post‐prandial C‐peptide from baseline in patients with Latent Autoimmune Diabetes in the Adult (LADA) [56]. Another small study found that sitagliptin, as an add‐on treatment to insulin, had a beneficial effect on C‐peptide decline compared with insulin alone. Moreover, a recent trial evaluated the effect of saxagliptin in combination with vitamin D3 in subjects with LADA with promising results [57]. As far as T1D is concerned, the effect of saxagliptin on immune regulation have been investigated in a phase IV trial (NCT02307695). Similarly, a phase III randomized controlled trial is evaluating the action of vildagliptin in the prevention of progressive β‐cell dysfunction in patients with newly diagnose of T1D (NCT01559025). In another ongoing study, researchers are testing the efficacy of 4 weeks rapamycin treatment and 4 weeks rapamycin treatment plus 3 months vildagliptin treatment versus placebo in increasing endogenous insulin production and correcting glycemic lability (NCT02803892). Glucagon‐like peptide (GLP‐1) analogues have been tested in large‐scale clinical trial to prove their various benefits for β‐cell and glucolipid metabolism in T2D and obesity patients. This has led to concerns regarding the potential applications in T1D patients. A small phase II randomized controlled trial (NCT02617654) is currently investigating the effect of 52 weeks of treatment with liraglutide 1.8 mg/day, compared to placebo, on stimulated C‐peptide concentrations in patients with long‐standing type 1 diabetes and residual insulin production (primary outcome: MMTT C‐peptide at 12 months).

      Other studies on preservation of β‐cell function using incretin‐based therapies are currently active but not recruiting participants (NCT02443155; NCT02127047). Results from these studies are warranted to prove that incretin‐based therapy might preserve C‐peptide secretion (Table 2.3).

Conclusions

      Today, one of the therapeutic goals in T1D is the preservation of the residual C‐peptide secretion that is detected in a significant percentage of patients at diagnosis and which potentially may influence the clinical course of the disease.

      Several studies have been demonstrated that residual C‐peptide secretion, after T1D diagnosis, depends on genetic factors, the patient's age at the diabetes diagnosis, the number of anti‐islet antibodies, and the residual C‐peptide secretion. In the same way, intensive insulin therapy and immunomodulators drugs may be useful in this direction.

      The ultimate goal of any therapeutic intervention is to prevent or reverse T1D by abrogation of pathogenic autoreactivity and by preservation or restoration of the β‐cell mass and function to physiologically sufficient levels to maintain stable glucose control. Early diagnosis of T1D is crucial if we want to restore and to save β‐cell mass. Different trials using antigen‐specific or non‐specific interventions have shown some benefit in modulation of the autoimmune process and in preventing the loss of insulin secretion in the short term after early diagnosis of T1D.

      Unfortunately, there are still limitations to current strategies, including a lack of suitable markers to predict and monitor the success of interventions, uncertainty about the long‐term adverse effects or the duration of treatment effect and the feasibility of restoration of β‐cell mass. Moreover, we should remember that T1D is a heterogeneous disease with an age at onset spanning from childhood to adult age.

      Ideally, the interventions would be specific for T1D, free of adverse effects, and effective prior to disease onset, with long‐term and clinically meaningful improvements over standard therapies. The success of these approaches will eventually be evaluated by their impact on glycemic control as this is the definitive determinant of long‐term outcome of the disease.

      In conclusion we can affirm that early diagnosis of T1D is very valuable and is not a Pyrrhic victory. Hopefully a better comparison would be with the encounter of David and Goliath, where early immune intervention dramatically changes the clinical course of T1D.

Acknowledgments

      We would like to thank Juvenile Diabetes Research Foundation (JDRF), National Institute of Health (NIH) Consortia, Centro Internazionale Studi Diabete (CISD), Diabete e Metabolismo (DEM) Foundation and University Campus Bio‐Medico that support clinical research on T1D in our University Hospital.

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