Interleukin-1β (IL-1β) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1β activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1β. The vaccine hIL1bQb consisting of full-length, recombinant IL-1β coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1β-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1β-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1β and represents a new treatment option for IL-1β-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).

Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.

OBJECTIVE Metabolic activation of the innate immune system governed by interleukin (IL)-1β contributes to β-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti–IL-1β antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity. RESULTS The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG2, with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. CONCLUSIONS This novel IL-1β–neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.

A 62-year-old male patient with type 2 diabetes for 16 years developed a severe anaphylactic shock upon administration of intravenous, short-acting regular insulin. The patient’s medical history comprised allergic reactions to an unknown agent as a child as well as injection site reactions, urticaria, and dyspnea to subcutaneous NPH-insulin injections. The diagnostic work-up revealed a type 1 IgE-mediated insulin allergy by positive skin prick tests and elevated specific IgE levels against insulins of human, porcine, and bovine origin by ImmunoCAP-Assay. The insulins used were free of proinsulin. Skin prick tests with all solvents and additives of the insulin solutions were negative. Genetic sequencing of the patient’s insulin molecule revealed a normal insulin gene. Because of unsatisfactory glycemic control, specific desensitization (1) and maintenance therapy with insulin detemir was performed, but improvement of urticaria and …

Several diseases including microbial infection, rheumatoid arthritis, multiple sclerosis, and cancer have been linked to fatigue. They all have in common an upregulation of cytokines, including interleukin (IL)-1β and tumor necrosis factor-α (TNF-α), which may interfere with clock gene functions (1). Increasing evidence associates type 2 diabetes with inflammatory processes characterized by elevated production of proinflammatory cytokines and infiltration of immune cells. Reducing IL-1 activity in prediabetes and diabetes improves insulin secretion, glycemic control, and markers of systemic inflammation (2–4). Given this background, we hypothesized that fatigue levels may be increased in type 2 diabetes and may be improved by IL-1β antagonism. Within a placebo-controlled, double-blind study of IL-1β antagonism with a monoclonal anti–IL-1β …