Skip to main content
NCBI home page
UKPMC Funders Author Manuscripts logoLink to UKPMC Funders Author Manuscripts
. Author manuscript; available in PMC: 2026 Mar 25.
Published before final editing as: Am J Physiol Endocrinol Metab. 2026 Mar 4:10.1152/ajpendo.00527.2025. doi: 10.1152/ajpendo.00527.2025

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

Justus S Fischer 1, Matthias Hepprich 1,2, Marco Cattaneo 3, Lucia Seeger 1, Stefanie Dobler 4, Marc Y Donath 1,5,6
PMCID: PMC7618929  EMSID: EMS212816  PMID: 41778408

Abstract

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 (p < 0.001), neutrophils (p < 0.001), monocytes (p = 0.006), and CRP (p = 0.030) compared to placebo. Lymphocytes were slightly elevated (p = 0.045). A mixed meal tolerance tests showed a trend toward increased early insulin (p = 0.11) and GLP-1 responses (p = 0.055), with GLP-1 (p = 0.020) and glucagon (p = 0.003) levels being significantly higher at 120 minutes under anakinra. Cytokine analysis showed elevated baseline concentrations of IL-1β, IL-6, and IL-1Ra under anakinra (all p < 0.001), with IL-1β (p < 0.001) and IL-18BP (p = 0.048) decreased, and IL-6 increased (p = 0.059) after 60 minutes. 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 towards 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.

Introduction

The growing obesity “epidemic” has given rise to a plethora of obesity-associated comorbidities (1). Prediabetes deserves special attention among them, due to its role as a precursor to type 2 diabetes. While prediabetes itself is not considered a disease and may be reversed by proper lifestyle and diet adaptations as well as glucose- and weight-reducing therapy, it already impacts overall health. Individuals with prediabetes exhibit increased prevalence of hypertension, dyslipidemia, metabolic-associated steatotic liver disease, heart failure and cardiovascular disease, along with a higher risk of all-cause mortality (2–4).

The deleterious effects of chronic inflammation in type 2 diabetes development and progression are well documented (5–9). The surplus of glucose and non-esterified fatty acids in type 2 diabetes and obesity cause a chronic activation of inflammatory pathways, including the NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-inflammasome. Activation of the NLRP3-inflammasome leads to secretion of the proinflammatory cytokines Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18). Beyond the well-described pathological role of IL-1β in impaired insulin secretion of patients with type 2 diabetes (10), more recently its physiological role in stimulating insulin secretion in response to a meal has been described (11). After food intake, glucose spikes, along with pathogen-associated molecular patterns from microbes in the food and gastrointestinal tract activate the NLRP3-inflammasome, causing an increased IL-1β release and a stimulation of insulin secretion (12). This beneficial effect is lost in type 2 diabetes. The chronic overactivation of IL-1β instead has damaging effects on insulin secretion, due to the prolonged secretory demand leading to β-cell exhaustion and ultimately β-cell failure (13–15). A similar mechanism might be apparent in prediabetes, where a pathological activation of the innate immune system has also been shown (6–8, 16). IL-1β mediated overactivation and dysfunction of β-cells might be responsible for a delayed and exaggerated insulin secretion, resulting in inadequate hyperinsulinemia. While the β-cells in this condition are still able to secrete insulin, they do so in a delayed and exaggerated manner (17). Alongside other factors, such as sustained glucolipotoxicity, this may lead to an increased insulin resistance, resulting in a vicious cycle that progresses towards overt type 2 diabetes. Targeting this process early by alleviating the excessive workload off β-cells – a concept known as inducing “β-cell rest” – may be effective in preventing further β-cell decline (18–20).

One way of doing this is by pharmacologically impeding IL-1 signaling. Blockade with the IL-1R1 antagonist anakinra has shown improvements in β-cell function, insulin secretion and glycemia, while reducing systemic inflammation in patients with obesity people and type 2 diabetes (10, 21, 22). However, it remains unclear how rapidly these effects occur, whether they are also observed in individuals with prediabetes, and what mechanisms are involved. To test this, our study aimed to determine whether short-term IL-1 receptor antagonism with anakinra can restore insulin secretion in individuals with prediabetes, thereby providing mechanistic insight into early disease stages.

Methods

Study design

We conducted a monocentric, placebo-controlled, double-blinded, randomized, cross-over proof-of-concept study. Recruitment took place at the Department of Endocrinology, Diabetology and Metabolism of the University Hospital Basel, Switzerland. The study was conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as well as all national legal and regulatory requirements. All relevant material was reviewed and approved by the responsible Cantonal Ethics Committee “Ethikkommission Nordwest- und Zentralschweiz” (EKNZ 2023-00497). The trial was registered at clinicaltrials.gov (NCT05854251) and the Swiss National Clinical Trials Portal (SNCTP) on www.kofam.ch (SNCTP 000005447).

Participants

We recruited adult patients with prediabetes (defined as HbA1c 5.7-6.4 %, or fasting plasma glucose level of 6.1-6.9 mmol/l), a BMI ≥ 28 kg/m2 and a high sensitivity C-reactive protein (hsCRP) ≥ 2 mg/l. Patients had to be otherwise healthy, and those subjects with a history of upper gastrointestinal surgery or diabetes type 2 diagnosis were excluded. For the full inclusion and exclusion criteria see eligibility criteria in Electronic Supplementary Material (ESM).

Study procedures

Subjects were informed about the study and screened for eligibility after providing informed consent. An overview of the study procedure is provided in Figure 1. Medical history was assessed, followed by a physical exam, vital signs measurement and blood sample collection. Eligible subjects were randomized to receive either two subcutaneous injections of anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB), a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra) in a 100 mg/0.67ml solution or placebo (0.9% saline) in a cross-over design manner. Study participants were instructed to refrain from excessive exercise, smoking, and caffeine consumption for 24 hours before study visits and to avoid high-calorie meals on the prior evening. The pre-medication visit, held the evening before each study visit, involved a short evaluation for adverse events and readiness for the study, followed by the first subcutaneous administration of the allocated study medication by two unblinded staff members not involved in the study. On the subsequent study day, participants arrived fasted, underwent a brief interview, and had a venous catheter placed, followed by a second administration of the study drug. One hour later, a liquid mixed meal was ingested (Ensure plus® 375 ml, 75 g carbohydrates, 562 kcal, drinking time 5 minutes), with regular vital sign monitoring and blood sampling occurring over a 3-hour period. Hypoglycemia was assessed if symptoms appeared, with additional blood samples taken as needed. Patients were allowed to leave upon conclusion of the MMTT. To prevent any carryover effects of the medication, a minimum interval of seven days was maintained between the two main visits, after which patients returned for the second premedication visit followed by main visit 2.

Figure 1.

Figure 1

Open in a new tab

a) Study flow chart. Washout period between visits 3 and 5 had to be at least seven days. b) Study procedure on each study day. Glc: Glucose, Ins: Insulin, C-Pep: C-peptide, GLP-1: Glucagon-like peptide 1, Gluc: Glucagon

Outcomes

Primary outcome was a difference in insulin secretion following a standardized mixed-meal test. Defining parameters of insulin secretion included changes in insulin, glucose & c-peptide concentration and area under curve (AUC), as well as changes in insulinogenic index ((I30 - I0)/(G30 - G0)) under anakinra compared to placebo.

Secondary outcomes were the effects of anakinra compared to placebo during an MMTT on peak and nadir values and slopes of glucose, insulin, GLP-1, glucagon, as well as effects on insulin resistance.

Exploratory outcomes included changes in inflammatory cytokines (IL-1β, IL-1Ra, IL-6, IL-18, IFN-γ) in serum taken at baseline and 60 min after ingestion of the mixed meal.

For the detailed statistic, see ESM table 1 to 10 and ESM figure 1.

Table 1.

Summary of baseline characteristics. All participants completed the first main visit, one person dropped out after and was replaced. No values were missing. 1: n (%); Mean (SD); Median (Q1, Q3)

Characteristic N = 211
Sex
male 9 (43%)
female 12 (57%)
Birth year 1974 (14)
Race
white/caucasian 20 (95%)
black/african 1 (4.8%)
asian 0 (0%)
hispanic 0 (0%)
other 0 (0%)
Weight (kg) 111 (19)
BMI (kg/m2) 37 (34, 42)
Blood parameters
Leucocytes (G/l) 7.92 (1.43)
Erythrocytes (T/l) 4.87 (0.42)
Hemoglobin (g/l) 142 (8)
Hematocrit (l/l) 0.418 (0.024)
MCV (fl) 86 (5)
MCH (pg) 29.80 (28.00, 30.60)
Thrombocytes (G/l) 255 (56)
Neutrophils, absolute (G/l) 4.79 (1.13)
Lymphocytes, absolute (G/l) 2.24 (0.60)
Monocytes, absolute (G/l) 0.55 (0.17)
Eosinophils, absolute (G/l) 0.15 (0.09, 0.28)
Basophils, absolute (G/l) 0.020 (0.020, 0.030)
Sodium (mmol/l) 139 (138, 140)
Potassium (mmol/l) 4.07 (0.19)
Creatinine (umol/l) 78 (11)
Estimated GFR (CDK-EPI, ml/min/1.73m2) 89(18)
Urea (mmol/l) 6.32 (1.89)
Uric acid (umol/l) 380 (57)
ASAT (U/l) 25 (6)
ALAT (U/l) 32 (11)
gGT (U/l) 30 (22, 56)
Triglycerides (mmol/l) 1.71 (0.63)
Total cholesterol (mmol/l) 4.52 (1.13)
HDL (mmol/l) 1.24 (0.29)
LDL (mmol/l) 2.60 (0.95)
Albumin (g/l) 39 (3)
CRP (mg/l) 3.6 (2.4, 6.0)
AP (U/l) 81 (20)
Glucose (mmol/l) 5.40 (5.00, 5.90)
HbA1c (%) 5.87 (0.23)
Open in a new tab

Laboratory Analysis

Bed-side measurements of venous blood glucose were performed using the Biosen C-line Clinic glucose analyzer device (EKF Diagnostics, Penarth, UK). Routine analysis at screening and baseline included blood count and blood chemistry and was conducted in the central laboratory of the University Hospital Basel. Baseline measurements on each visit day were conducted 90 minutes before the start of the MMTT and prior to administration of the second dose of anakinra or placebo, respectively.

Plasma levels of insulin, c-peptide, glucagon, and GLP-1 were measured with Enzyme-linked immunosorbent assays by Mercodia AB, Uppsala, Sweden (assay # 10-1113-01, 10-1136-01, 10-1271-01 and 10-1278-01, respectively) according to the manufacturer’s instructions. Blood samples for inflammatory cytokine measurements were taken right before start of the MMTT and 60 minutes after meal intake. Cytokine concentrations of IL-1β, IL-1Ra, IL-6, IL-18, IL-18BP and IFN-γ were determined in serum using U-PLEX custom biomarker group 1 assay for IL-1β, IL-1Ra, IL-6, IL-18 and IFN-γ and R-PLEX human IL-18BP for IL-18BP (assay # K15067M-1 and K151J5R-2, respectively; Meso Scale Diagnostics LLC, Rockville, USA) according to the manufacturer’s instructions.

Hypoglycemia assessment

Episodes and severity of postprandial hypoglycemia were assessed at each timepoint of the MMTT, starting 30 minutes after food intake. The 11 most common hypoglycemia symptoms were evaluated using the Edinburgh Hypoglycemia Scale, graded by intensity from 0 (no symptoms) to 3 (severe symptoms) (23, 24).

Statistical analysis

All statistical analyses were performed on an intention-to-treat basis on the full analysis set, consisting of all randomized patients. All analyses were conducted with the statistical software package R version 4.4.2 (25), using "two-sided" statistical tests and confidence intervals (with 95% confidence level). The random allocation sequence was generated using a computer-generated random number table by an independent researcher who was not involved in the study. Allocation was implemented using sequentially numbered, opaque, sealed envelopes prepared by unblinded non-study staff at the research center, and neither the study staff enrolling participants nor the study statistician had access to the allocation sequence. Missing data were handled by available-case analyses. All statistical analyses were exploratory, without correction for multiple testing.

Baseline characteristics were summarized: categorical data as absolute and relative frequencies, numerical variables as mean and standard deviation, or as median and interquartile range, as appropriate. AUCs were calculated using linear interpolation from 0 to 180 min after ingestion of the mixed meal. The time to first insulin peak was defined as the time of the last measurement before the first decrease in insulin between 0 and 180 min after ingestion of the mixed meal.

The effects of anakinra vs placebo on all outcomes of interest were analyzed by linear mixed models with medication as fixed effect and patient as random effect. To evaluate the effects of anakinra vs placebo depending on time or a covariate (sex, age, BMI, HbA1c, or CRP), fixed effects for time or covariate and its interaction with medication were included in the linear mixed models. Potential carryover effects of anakinra were analyzed by including also anakinra carryover as fixed effect in the linear mixed models.

Results

Participant characteristics

Between June 2023 and May 2024, 21 patients were included in the study. One subject developed a moderate cold after visit 3 and decided to withdraw from the study. The subject was subsequently replaced. Participants baseline characteristics are displayed in Table 1. Both sexes were equally represented with most participants being white. Median BMI (37 kg/m2; IQR 34, 42) and median CRP (3.6 mg/l; IQR 2.4, 6.0) were elevated, as well as mean HbA1c (5.87 %; SD 0.23) due to inclusion based on these parameters. All other parameters were within normal ranges.

Effect of anakinra on blood parameters at baseline

A single dose of anakinra on the prior evening significantly reduced mean total leucocyte count (5.7 G/l, 95% CI [4.9;6.4]) compared to placebo (7.1 G/l, CI [6.4; 7.8]; p <0.001), mainly via a large reduction in neutrophils (AN: 2.4 G/l, CI [2.0;2.9] vs PL: 4.1 G/l, CI [3.6;4.5]; p <0.001). Mean monocyte count was also significantly reduced (AN: 0.42 G/l, CI [0.36;0.49] vs PL: 0.49 G/l, CI [0.42;0.56]; p =0.006) while there was a slight rise in lymphocytes (AN: 2.4 G/l, CI [2.1;2.8] vs PL: 2.2 G/l, CI [1.9;2.6]; p =0.045). Mean CRP was reduced by 1.1 mg/l (AN: 4.3 mg/l, CI [2.7;5.9] vs PL: 5.4 mg/l, CI [3.8;7.0]; p =0.030)., while mean ASAT was slightly elevated compared to placebo (AN: 24 U/l, CI [21;26] vs PL: 22 U/l, CI [19;24]; p =0.019). Blood parameters are shown in Figure 2. All other parameters were not significantly changed under anakinra. Grouping by order of treatment revealed a small carry-over effect for mean erythrocyte count, when anakinra was given before placebo (ESM figure 2; ESM table 11). No other carry-over effects were found.

Figure 2.

Figure 2

Open in a new tab

Evolution of insulin, c-peptide, glucose, glucagon, and GLP-1 over time during MMTT: mean values for anakinra and placebo according to the linear mixed models, with 95% confidence intervals represented by the shaded colored area.

Measurements of plasma glucose and metabolic hormones over time during the MMTT

Insulin showed a trend towards an increased early secretion (TP 30; AN: 656 pmol/L, CI [513;798] vs PL: 538 pmol/L, CI [394;682]; p =0.11) under anakinra, followed by a reduction later in the MMTT compared to placebo (TP 150; AN: 469 pmol/L, CI [327;611] vs PL: 605 pmol/L, CI [459;751]; p =0.068). Mean plasma glucose was also slightly but not significantly elevated at 30 minutes with anakinra (AN: 8.2 mmol/L, CI [7.7;8.8] vs PL: 7.7 mol/L, CI [7.1;8.3]; p =0.054). GLP-1 showed a similar pattern to insulin, with a trend towards higher concentration after 30 minutes (AN: 12 pmol/L, CI [10;13] vs PL: 9.9 pmol/L, CI [8.4;11]; p =0.055), and a significantly higher secretion two hours after the start of the MMTT under anakinra (AN: 7.8 pmol/L, CI [6.3;9.4] vs PL: 5.8 pmol/L, CI [4.2;7.3]; p =0.020). Blood parameters over time are displayed in Figure 3. No differences between anakinra and placebo were seen for c-peptide and glucagon at any point during the MMTT. Analysis of interactions of medication with covariates sex, age, BMI, HbA1c and CRP also revealed no differences.

Figure 3.

Figure 3

Open in a new tab

Laboratory measurements: anakinra and placebo values for each patient (one placebo value is missing). CRP: C-reactive protein, ASAT: Aspartate aminotransferase

Assessment of insulin secretion indices and AUCs of insulin, glucose and metabolic hormones

In our analysis we observed no significant differences in overall plasma concentration measured by AUC for total insulin, plasma glucose, c-peptide, glucagon, and GLP-1 under treatment with anakinra compared to placebo (ESM figure 1). There were also no differences in insulinogenic index, as well as insulin sensitivity (measured by Matsuda index and insulin sensitivity index)(ESM table 6). Time to first insulin peak, defined as the time of the last measurement before the first decrease in insulin between 0 and 180 minutes after ingestion of the meal, was not significantly shortened under anakinra (ESM table 2). Covariate interaction analysis revealed a statistically significant increase in glucagon AUC in male patients with anakinra compared to placebo (AN: 1321 pmol/L·min, CI [1065;1578] vs PL: 1104 pmol/L·min, CI [845;1363]; p =0.003)(ESM table 5). No other interactions were found.

Plasma cytokine concentrations at baseline and during the MMTT

We measured elevated levels of IL-1β (AN: 0.77 pg/mL, CI [0.67;0.87] vs PL: 0.14 pg/mL, CI [0.03;0.24]; p <0.001), IL-6 (AN: 3.2 pg/mL, CI [2.4;3.9] vs PL: 1.9 pg/mL, CI [1.1;2.6]; p <0.001) and IL-1Ra (AN: 16’432 pg/mL, CI [16’213;16’651] vs PL: 711 pg/mL, CI [488;934]; p <0.001) at timepoint 0’, as well as a trend towards elevated IFN-γ (AN: 54 pg/mL, CI [35;74]) with anakinra compared to placebo (PL: 31 pg/mL, CI [11;51]; p =0.073). Concentration of IL-1β, IL-6 and IL-1Ra remained elevated after 60 minutes, with IL-1β concentration decreasing slightly with anakinra (ΔIL-1βAnakinra -0.19 pg/ml, CI [-0.29;-0.09], p <0.001), while IL-6 showed an increasing trend under anakinra (ΔIL-6Anakinra 0.67 pg/ml, CI [-0.03;1.4], p =0.059), as opposed to placebo (ΔIL-6Placebo -0.56 pg/ml, CI [-1.3;0.15], p =0.12). IL-1Ra concentration remained constant under either medication. IL-18BP concentration decreased after food intake under anakinra (p =0.048), with a similar tendency under placebo (p =0.094). Data shown in Figure 4. Further post-hoc analysis revealed that change in IL-6 from timepoints 0–60 min predicted change in GLP-1 under placebo (p = 0.034) but not under anakinra (p = 0.5) and did not predict change in insulin or any other measured parameters under either placebo or anakinra.

Figure 4.

Figure 4

Open in a new tab

Evolution of IL-1b, IL-6, IL-18, IL-18 binding protein, IL-1Ra, and IFN-gamma over time during MMTT: mean values for anakinra and placebo according to the linear mixed models, with 95% confidence intervals represented by the shaded colored area.

Safety

We observed 20 adverse events, 15 (75%) of which were classified as mild and 5 (25%) as moderate. Of the 5 moderate adverse events, 4 were classified as possibly related to study medication and one as probably related. Most of these were due to flu-like illness which, in the case of the one probable relation, led to discontinuation of the study. Neither severe adverse events nor any episodes of postprandial hypoglycemia were observed.

Discussions

Acute administration of anakinra before the MMTT was enough to elicit changes in early and late postprandial secretion of insulin and GLP-1. Loss of first phase insulin secretion is one of the earliest detectable defects characterizing diabetes type 2 (26), and is already present in prediabetes (27–29). Normalization of the early phase is a sign of improved insulin secretion and associated with remission of type 2 diabetes (30). Our results are reminiscent of a previous study by van Poppel et al. (2014), which observed a stronger improvement in the first-phase insulin secretion than in the present trial. This may be explained by the longer duration of IL-1β antagonism in their study (21). Furthermore, our study was not designed to assess changes in insulin secretion at timepoints earlier than 30 minutes after food intake, which means that the effect of anakinra on first-phase insulin was possibly underestimated.

Another interesting observation was that anakinra increased GLP-1 levels. This together with an improved incretin response mediated by anakinra, may have led to the early increase in insulin levels. Individuals leaving with diabetes type 2 display a reduced incretin effect (31, 32). By blocking chronic IL-1β-mediated proinflammatory signaling, anakinra restores β-cell function(10). We also observed an elevated glucagon secretion in male individuals with anakinra compared to placebo. One could speculate that anakinra affects pancreatic alpha-cells in a similar way as β-cells by improving overall secretory function.

Remarkably, treatment with anakinra had a profound impact on total leukocyte count and CRP levels, significantly reducing both parameters within only 12 hours after the first injection. The effect of IL-1β on myelopoiesis is well documented (33–36). This is mirrored by elevated neutrophil levels (37–39), and the numerous deleterious effects of macrophage tissue infiltration in individuals with obesity or metabolic syndrome (40, 41), especially in pancreatic islets (7, 12, 42–44). IL-1β thus not only promotes insulin resistance (8, 45, 46) and β-cell dysfunction by creating a proinflammatory milieu in peripheral tissue and islet cells respectively, but it also propagates said inflammation by sustaining a steady flow of leukocytes. By antagonizing the IL-1 pathway, this vicious cycle is broken, resulting in the normalization of neutrophil, monocyte and lymphocyte numbers already after short-term treatment.

Treatment with anakinra resulted in significantly elevated circulating IL-1β levels and a marked increase in IL-1Ra, confirming that IL-1 antagonism was effective. IL-6 was also elevated after acute IL-1 antagonism, which was not in line with observations in earlier trials (10, 47, 48). This is somewhat contradictory, as IL-6 secretion is part of a downstream inflammatory cascade initiated by IL-1β (49). We speculate that acute inhibition of chronic IL-1 signaling allows IL-6 to resume its metabolically beneficial role by reducing food intake (50, 51), slowing gastric emptying (52) and improving insulin secretion via increased GLP-1 secretion (53). This would also explain the observed increase in GLP-1 secretion, which was predicted by changes in IL-6 in the early phase up to one hour after food intake and may result from enhanced IL-6 release following anakinra treatment (53).

Our study has several limitations. First, the small sample size of 21 participants limits the generalizability of our findings. To improve statistical efficiency and control for inter-individual variability, we employed a crossover design. Nevertheless, given the exploratory nature of this study and the fact that we did not apply corrections for multiple testing, results should be interpreted with appropriate caution. To mitigate potential carry-over effects of anakinra, we implemented a washout period of at least 7 days based on an earlier study (54). However, we are not able to entirely rule out further residual effects. Additionally, the absence of blood samples prior to 30 minutes after food intake likely resulted in us missing early metabolic responses of insulin and we also did not assess anakinras effect on insulin clearance and hepatic glucose production. We used circulating cytokine and CRP levels as inflammatory markers and as a proxy for tissue inflammation. While these parameters are more easily accessible, they do not fully capture local inflammatory dynamics, particularly within pancreatic islets. Furthermore, the standardized mixed meal was not adjusted for body weight, which could introduce variability in the metabolic challenge among participants. Lastly, the slight imbalance in the male-to-female ratio may have influenced our outcomes, as women tend to be more insulin sensitive than men and exhibit a greater insulin secretory capacity (55). Despite these limitations, the study remains a well-conducted randomized, controlled, double-blind crossover trial.

Our findings provide mechanistic insight into the early metabolic effects of IL-1β antagonism in individuals with prediabetes characterized by low-grade inflammation. The rapid increase in IL-6 and GLP-1 suggests that one of the earliest detectable metabolic effects of IL-1β blockade may involve activation of an IL-6 induced GLP-1 axis (53), potentially preceding measurable improvements in overall insulin secretion or glucose tolerance. Thereby, NLRP3 inhibition or IL-1β antagonism may contribute to the improved insulin secretion through increased GLP-1 secretion.

New and Noteworthy.

Acute IL-1 blockade with anakinra markedly reduced CRP and leukocyte counts within 12 hours, 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.

graphic file with name EMS212816-f005.jpg

Open in a new tab

Acknowledgements

Our thanks also go out to Silke Scarascia, Monica Eichenberger and the team at the outpatient study center of the University Hospital, for their role in the unblinded administration of the study drug.

Funding

J.F. was supported by a grant from the AlumniVerein Basel. M.Y.D. is supported, in part, by Swiss National Science Foundation grants (214900, 212319 and 226049) and the European Union – Horizon/Swiss State Secretariat for Education, Research and Innovation (101095433).

Footnotes

Author contribution statement

J.S.F., M.H. and M.Y.D., designed and advanced the project. J.S.F. and S.D. were responsible for patient recruitment and data collection. M.C. contributed to study design and performed statistical data analysis. J.S.F. wrote the first draft of the manuscript. L.S. performed the laboratory measurements and isolation of PBMCs. M.H. and M.Y.D. supervised the project, coordinated research activities and secured the funding. All authors read, edited, and approved the final version of the manuscript.

Declaration of Interest

Marc Y Donath is member of the clinical advisory board of Olatec Therapeutics LCC. All other authors declare no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

Data availability

All data generated during the trial will be made available in a de-identified fashion for research purposes upon reasonable request.

References

  • 1.Kivimäki M, Strandberg T, Pentti J, Nyberg ST, Frank P, Jokela M, et al. Body-mass index and risk of obesity-related complex multimorbidity: an observational multicohort study. The Lancet Diabetes & Endocrinology. 2022;10(4):253–63. doi: 10.1016/S2213-8587(22)00033-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012;379(9833):2279–90. doi: 10.1016/S0140-6736(12)60283-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Cai X, Liu X, Sun L, He Y, Zheng S, Zhang Y, et al. Prediabetes and the risk of heart failure: A meta-analysis. Diabetes Obes Metab. 2021;23(8):1746–53. doi: 10.1111/dom.14388. [DOI] [PubMed] [Google Scholar]
  • 4.Schlesinger S, Neuenschwander M, Barbaresko J, Lang A, Maalmi H, Rathmann W, et al. Prediabetes and risk of mortality, diabetes-related complications and comorbidities: umbrella review of meta-analyses of prospective studies. Diabetologia. 2022;65(2):275–85. doi: 10.1007/s00125-021-05592-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Boni-Schnetzler M, Meier DT. Islet inflammation in type 2 diabetes. Semin Immunopathol. 2019;41(4):501–13. doi: 10.1007/s00281-019-00745-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Luc K, Schramm-Luc A, Guzik TJ, Mikolajczyk TP. Oxidative stress and inflammatory markers in prediabetes and diabetes. J Physiol Pharmacol. 2019;70(6) doi: 10.26402/jpp.2019.6.01. [DOI] [PubMed] [Google Scholar]
  • 7.Weaver JR, Odanga JJ, Breathwaite EK, Treadwell ML, Murchinson AC, Walters G, et al. An increase in inflammation and islet dysfunction is a feature of prediabetes. Diabetes Metab Res Rev. 2021;37(6):e3405. doi: 10.1002/dmrr.3405. [DOI] [PubMed] [Google Scholar]
  • 8.Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity. 2022;55(1):31–55. doi: 10.1016/j.immuni.2021.12.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Shaikh SR, Beck MA, Alwarawrah Y, MacIver NJ. Emerging mechanisms of obesity-associated immune dysfunction. Nature Reviews Endocrinology. 2024;20(3):136–48. doi: 10.1038/s41574-023-00932-2. [DOI] [PubMed] [Google Scholar]
  • 10.Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517–26. doi: 10.1056/NEJMoa065213. [DOI] [PubMed] [Google Scholar]
  • 11.Dror E, Dalmas E, Meier DT, Wueest S, Thevenet J, Thienel C, et al. Postprandial macrophage-derived IL-1[beta] stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol. 2017;18(3):283–92. doi: 10.1038/ni.3659. [DOI] [PubMed] [Google Scholar]
  • 12.Meier DT, de Paula Souza J, Donath MY. Targeting the NLRP3 inflammasome-IL-1β pathway in type 2 diabetes and obesity. Diabetologia. 2024 doi: 10.1007/s00125-024-06306-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Boni-Schnetzler M, Hauselmann SP, Dalmas E, Meier DT, Thienel C, Traub S, et al. beta Cell-Specific Deletion of the IL-1 Receptor Antagonist Impairs beta Cell Proliferation and Insulin Secretion. Cell Rep. 2018;22(7):1774–86. doi: 10.1016/j.celrep.2018.01.063. [DOI] [PubMed] [Google Scholar]
  • 14.Donath MY, Dinarello CA, Mandrup-Poulsen T. Targeting innate immune mediators in type 1 and type 2 diabetes. Nat Rev Immunol. 2019;19(12):734–46. doi: 10.1038/s41577-019-0213-9. [DOI] [PubMed] [Google Scholar]
  • 15.Böni-Schnetzler M, Méreau H, Rachid L, Wiedemann SJ, Schulze F, Trimigliozzi K, et al. IL-1beta promotes the age-associated decline of beta cell function. iScience. 2021;24(11):103250. doi: 10.1016/j.isci.2021.103250. [Internet] 2021/11// [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Grossmann V, Schmitt VH, Zeller T, Panova-Noeva M, Schulz A, Laubert-Reh D, et al. Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes. Diabetes Care. 2015;38(7):1356–64. doi: 10.2337/dc14-3008. [DOI] [PubMed] [Google Scholar]
  • 17.Magkos F, Lee MH, Lim M, Cook AR, Chhay V, Loh TP, et al. Dynamic assessment of insulin secretion and insulin resistance in Asians with prediabetes. Metabolism. 2022;128:154957. doi: 10.1016/j.metabol.2021.154957. [DOI] [PubMed] [Google Scholar]
  • 18.Lean MEJ, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. 5-year follow-up of the randomised Diabetes Remission Clinical Trial (DiRECT) of continued support for weight loss maintenance in the UK: an extension study. The Lancet Diabetes & Endocrinology. 2024;12(4):233–46. doi: 10.1016/S2213-8587(23)00385-6. [DOI] [PubMed] [Google Scholar]
  • 19.Wajchenberg BL. β-Cell Failure in Diabetes and Preservation by Clinical Treatment. Endocrine Reviews. 2007;28(2):187–218. doi: 10.1210/10.1210/er.2006-0038. [DOI] [PubMed] [Google Scholar]
  • 20.Retnakaran R, Kramer CK, Choi H, Swaminathan B, Zinman B. Liraglutide and the preservation of pancreatic β-cell function in early type 2 diabetes: the LIBRA trial. Diabetes Care. 2014;37(12):3270–8. doi: 10.2337/dc14-0893. [DOI] [PubMed] [Google Scholar]
  • 21.van Poppel PCM, van Asseldonk EJP, Holst JJ, Vilsbøll T, Netea MG, Tack CJ. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance. Diabetes, Obesity and Metabolism. 2014;16(12):1269–73. doi: 10.1111/dom.12357. [DOI] [PubMed] [Google Scholar]
  • 22.van Asseldonk EJ, Stienstra R, Koenen TB, Joosten LA, Netea MG, Tack CJ. Treatment with Anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2011;96(7):2119–26. doi: 10.1210/jc.2010-2992. [DOI] [PubMed] [Google Scholar]
  • 23.McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabetic Medicine. 2001;18(9):690–705. doi: 10.1046/j.1464-5491.2001.00620.x. [DOI] [PubMed] [Google Scholar]
  • 24.Brackenridge A, Wallbank H, Lawrenson RA, Russell-Jones D. Emergency management of diabetes and hypoglycaemia. Emerg Med J. 2006;23(3):183–5. doi: 10.1136/emj.2005.026252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; Vienna, Austria: 2024. URL https://www.R-project.org/ [Google Scholar]
  • 26.Del Prato S, Tiengo A. The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes/Metabolism Research and Reviews. 2001;17(3):164–74. doi: 10.1002/dmrr.198. [DOI] [PubMed] [Google Scholar]
  • 27.van Haeften TW, Pimenta W, Mitrakou A, Korytkowski M, Jenssen T, Yki-Jarvinen H, et al. Disturbances in beta-cell function in impaired fasting glycemia. Diabetes. 2002;51(Suppl 1):S265–70. doi: 10.2337/diabetes.51.2007.s265. [DOI] [PubMed] [Google Scholar]
  • 28.Cohrs CM, Panzer JK, Drotar DM, Enos SJ, Kipke N, Chen C, et al. Dysfunction of Persisting β Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis. Cell Rep. 2020;31(1):107469. doi: 10.1016/j.celrep.2020.03.033. [DOI] [PubMed] [Google Scholar]
  • 29.Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29(5):1130–9. doi: 10.2337/diacare.2951130. [DOI] [PubMed] [Google Scholar]
  • 30.Zhyzhneuskaya SV, Al-Mrabeh A, Peters C, Barnes A, Aribisala B, Hollingsworth KG, et al. Time Course of Normalization of Functional β-Cell Capacity in the Diabetes Remission Clinical Trial After Weight Loss in Type 2 Diabetes. Diabetes Care. 2020;43(4):813–20. doi: 10.2337/dc19-0371. [DOI] [PubMed] [Google Scholar]
  • 31.Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. The Lancet Diabetes & Endocrinology. 2016;4(6):525–36. doi: 10.1016/S2213-8587(15)00482-9. [DOI] [PubMed] [Google Scholar]
  • 32.Nauck MA, Müller TD. Incretin hormones and type 2 diabetes. Diabetologia. 2023 doi: 10.1007/s00125-023-05956-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Hettwer J, Hinterdobler J, Miritsch B, Deutsch M-A, Li X, Mauersberger C, et al. Interleukin-1β suppression dampens inflammatory leucocyte production and uptake in atherosclerosis Cardiovascular Research. 2021;118(13):2778–91. doi: 10.1093/cvr/cvab337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Pietras EM, Mirantes-Barbeito C, Fong S, Loeffler D, Kovtonyuk LV, Zhang S, et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol. 2016;18(6):607–18. doi: 10.1038/ncb3346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Mitroulis I, Ruppova K, Wang B, Chen L-S, Grzybek M, Grinenko T, et al. Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell. 2018;172(1):147–61.:e12. doi: 10.1016/j.cell.2017.11.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Chiba Y, Mizoguchi I, Hasegawa H, Ohashi M, Orii N, Nagai T, et al. Regulation of myelopoiesis by proinflammatory cytokines in infectious diseases. Cell Mol Life Sci. 2018;75(8):1363–76. doi: 10.1007/s00018-017-2724-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Buyukkaya E, Karakaş MF, Karakaş E, Akçay AB, Tanboga IH, Kurt M, et al. Correlation of Neutrophil to Lymphocyte Ratio With the Presence and Severity of Metabolic Syndrome. Clinical and Applied Thrombosis/Hemostasis. 2014;20(2):159–63. doi: 10.1177/1076029612459675. [DOI] [PubMed] [Google Scholar]
  • 38.Shiny A, Bibin YS, Shanthirani CS, Regin BS, Anjana RM, Balasubramanyam M, et al. Association of Neutrophil-Lymphocyte Ratio with Glucose Intolerance: An Indicator of Systemic Inflammation in Patients with Type 2 Diabetes. Diabetes Technology & Therapeutics. 2014;16(8):524–30. doi: 10.1089/dia.2013.0264. [DOI] [PubMed] [Google Scholar]
  • 39.Sanchez-Pino MD, Richardson WS, Zabaleta J, Puttalingaiah RT, Chapple AG, Liu J, et al. Increased inflammatory low-density neutrophils in severe obesity and effect of bariatric surgery: Results from case-control and prospective cohort studies. eBioMedicine. 2022;77 doi: 10.1016/j.ebiom.2022.103910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Moreno-Loaiza O, Soares VC, de Assumpção Souza M, Vera-Nuñez N, Rodriguez de Yurre Guirao A, da Silva TP, et al. IL-1β enhances susceptibility to atrial fibrillation in mice by acting through resident macrophages and promoting caspase-1 expression. Nature Cardiovascular Research. 2025 doi: 10.1038/s44161-025-00610-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Chavakis T, Alexaki VI, Ferrante AW. Macrophage function in adipose tissue homeostasis and metabolic inflammation. Nature Immunology. 2023;24(5):757–66. doi: 10.1038/s41590-023-01479-0. [DOI] [PubMed] [Google Scholar]
  • 42.Westwell-Roper CY, Ehses JA, Verchere CB. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta cell dysfunction. Diabetes. 2013 doi: 10.2337/db13-0863. [DOI] [PubMed] [Google Scholar]
  • 43.Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes. 2007;56(9):2356–70. doi: 10.2337/db06-1650. [DOI] [PubMed] [Google Scholar]
  • 44.Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab. 2013;17(6):860–72. doi: 10.1016/j.cmet.2013.05.001. [DOI] [PubMed] [Google Scholar]
  • 45.Urakawa H, Katsuki A, Sumida Y, Gabazza EC, Murashima S, Morioka K, et al. Oxidative stress is associated with adiposity and insulin resistance in men. J Clin Endocrinol Metab. 2003;88(10):4673–6. doi: 10.1210/jc.2003-030202. [DOI] [PubMed] [Google Scholar]
  • 46.Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440(7086):944–8. doi: 10.1038/nature04634. [DOI] [PubMed] [Google Scholar]
  • 47.Wohlford GF, Buckley LF, Vecchié A, Kadariya D, Markley R, Trankle CR, et al. Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis. J Cardiovasc Pharmacol. 2020;76(1):50–2. doi: 10.1097/FJC.0000000000000847. [DOI] [PubMed] [Google Scholar]
  • 48.Ebrahimi F, Urwyler SA, Straumann S, Doerpfeld S, Bernasconi L, Neyer P, et al. IL-1 Antagonism in Men With Metabolic Syndrome and Low Testosterone: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2018;103(9):3466–76. doi: 10.1210/jc.2018-00739. [DOI] [PubMed] [Google Scholar]
  • 49.Dinarello CA. A clinical perspective of IL-1β as the gatekeeper of inflammation. European Journal of Immunology. 2011;41(5):1203–17. doi: 10.1002/eji.201141550. [DOI] [PubMed] [Google Scholar]
  • 50.Timper K, Denson JL, Steculorum SM, Heilinger C, Engström-Ruud L, Wunderlich CM, et al. IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling. Cell Reports. 2017;19(2):267–80. doi: 10.1016/j.celrep.2017.03.043. [DOI] [PubMed] [Google Scholar]
  • 51.Mishra D, Richard JE, Maric I, Porteiro B, Häring M, Kooijman S, et al. Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism. Cell Rep. 2019;26(11):3011–26.:e5. doi: 10.1016/j.celrep.2019.02.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Lehrskov Lang, Lyngbaek MP, Soederlund L, Legaard GE, Ehses JA, Heywood SE, et al. Interleukin-6 Delays Gastric Emptying in Humans with Direct Effects on Glycemic Control. Cell Metab. 2018;27(6):1201–11.:e3. doi: 10.1016/j.cmet.2018.04.008. [DOI] [PubMed] [Google Scholar]
  • 53.Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nature medicine. 2011;17(11):1481–9. doi: 10.1038/nm.2513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Hepprich M, Wiedemann SJ, Schelker BL, Trinh B, Stärkle A, Geigges M, et al. Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1β. Cell Metab. 2020 doi: 10.1016/j.cmet.2020.02.013. [DOI] [PubMed] [Google Scholar]
  • 55.Tramunt B, Smati S, Grandgeorge N, Lenfant F, Arnal JF, Montagner A, et al. Sex differences in metabolic regulation and diabetes susceptibility. Diabetologia. 2020;63(3):453–61. doi: 10.1007/s00125-019-05040-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data generated during the trial will be made available in a de-identified fashion for research purposes upon reasonable request.

RESOURCES