Acute interleukin-1β antagonism decreases systemic inflammation, increases GLP-1 release, and modulates insulin secretion in individuals with prediabetes

Metabolic stress in obesity and diabetes activates innate immunity. Chronic IL-1β antagonism improves insulin secretion in type 2 diabetes. However, it is unclear how rapidly this effect occurs, whether it is also present in individuals with prediabetes, and if IL-1β influences GLP-1 secretion. Therefore, we acutely antagonized IL-1β in patients with prediabetes overnight. Two injections of anakinra significantly reduced total leucocyte count (<i>P</i> < 0.001), neutrophils (<i>P</i> < 0.001), monocytes (<i>P</i> = 0.006), and CRP (<i>P</i> = 0.030) compared with placebo. Lymphocytes were slightly elevated (<i>P</i> = 0.045). A mixed meal tolerance tests showed a trend toward increased early insulin (<i>P</i> = 0.11) and GLP-1 responses (<i>P</i> = 0.055), with GLP-1 (<i>P</i> = 0.020) and glucagon (<i>P</i> = 0.003) levels being significantly higher at 120 min under anakinra. Cytokine analysis showed elevated baseline concentrations of IL-1β, IL-6, and IL-1Ra under anakinra (all <i>P</i> < 0.001), with IL-1β (<i>P</i> < 0.001) and IL-18BP (<i>P</i> = 0.048) decreased, and IL-6 increased (<i>P</i> = 0.059) after 60 min. Therefore, an acute injection of anakinra significantly reduces CRP and leucocyte counts in individuals with prediabetes, indicating effective innate immune modulation even after immediate treatment. Despite seeing no significant improvements in insulin secretion or glucose metabolism, we observed a trend toward earlier insulin secretion, along with increased release of IL-6 and GLP-1. We conclude that acute IL-1 antagonism dampens systemic inflammation in prediabetes, with the potential to improve insulin secretion via IL-6-induced GLP-1.<b>NEW & NOTEWORTHY</b> Acute IL-1 blockade with anakinra markedly reduced CRP and leukocyte counts within 12 h, demonstrating rapid anti-inflammatory efficacy. Anakinra induced a trend toward earlier insulin secretion and significantly increased postprandial IL-6 and GLP-1 levels. The study demonstrates that even short-term IL-1 blockade can modulate both immune and incretin responses in prediabetes. Early IL-1β antagonism may represent a preventive, anti-inflammatory approach to preserve GLP-1 secretion and β-cell function in individuals with prediabetes.