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Randomized Controlled Trial
. 2024 Nov 26;22(1):558.
doi: 10.1186/s12916-024-03771-8.

Carrageenan and insulin resistance in humans: a randomised double-blind cross-over trial

Robert Wagner  1   2   3   4   5   6 , Janine Buettner  7 , Martin Heni  8   9   10   11   12 , Louise Fritsche  9   10 , Stephanie Kullmann  9   10   13 , Moritz Wagmüller  8   11 , Andreas Peter  9   10   12 , Hubert Preissl  9   10   13   14 , Jürgen Machann  9   10   15 , Reiner Jumpertz von Schwartzenberg  8   9   10 , Andreas L Birkenfeld  8   9   10 , Ulrich-Frank Pape  7   16 , Gerrit van Hall  17   18 , Peter Plomgaard  18 , Hans-Ulrich Häring  8   9   10 , Andreas Fritsche  8   9   10 , Kelsey N Thompson  19 , Reinhild Klein  20 , Norbert Stefan  8   9   10
Affiliations
Randomized Controlled Trial

Carrageenan and insulin resistance in humans: a randomised double-blind cross-over trial

Robert Wagner et al. BMC Med. .

Abstract

Background: The potential impact of specific food additives, common in Western diets, on the risk of developing type 2 diabetes is not well understood. This study focuses on carrageenan, a widely used food additive known to induce insulin resistance and gut inflammation in animal models, and its effects on human health.

Methods: In a randomised, double-blind, placebo-controlled, cross-over trial conducted at a university hospital metabolic study centre, 20 males (age 27.4 ± 4.3 years, BMI 24.5 ± 2.5 kg/m2) participated. The intervention involved oral intake of carrageenan (250 mg) or placebo in the morning and in the evening and each intervention lasted 2 weeks. The primary outcome measured was insulin sensitivity (using oral glucose tolerance test [OGTT] and hyperinsulinaemic-euglycaemic clamp). Additional end-points included whole body and hepatic insulin sensitivity, MRI-measured brain inflammation and insulin resistance, intestinal permeability (via lactulose-mannitol test and plasma zonulin levels), and gut microbiome composition. Immune-cell activation and pro-inflammatory cytokine release from peripheral blood mononuclear cells were measured.

Results: Overall insulin sensitivity did not show significant differences between the treatments. However, interactions between BMI and treatment were observed (OGTT-based insulin sensitivity index: p=0.04, fasting insulin resistance: p=0.01, hepatic insulin sensitivity index: p=0.04). In overweight participants, carrageenan exposure resulted in lower whole body and hepatic insulin sensitivity, a trend towards increased brain inflammation, and elevated C-reactive protein (CRP) and IL-6 levels compared to placebo. Additionally, carrageenan was associated with increased intestinal permeability. In vitro natural killer (NK-)cell activation and increased pro-inflammatory cytokine release were found after carrageenan exposure in the participant's peripheral blood mononuclear cells.

Conclusions: These findings suggest that carrageenan, a common food additive, may contribute to insulin resistance and subclinical inflammation in overweight individuals through pro-inflammatory mechanisms in the gut. Further investigation into the long-term health impacts of carrageenan and other food additives is warranted.

Trial registration: NCT02629705.

Keywords: Carrageenan; Emulsifiers; Gut microbiome; Insulin sensitivity; Intestinal permeability; Type 2 diabetes.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was approved by the Ethical Committee of the Medical Faculty of the University of Tübingen, Germany (project number 359/2012BO1). All participants provided written informed consent. Consent for publication: All authors have reviewed and approved the manuscript for submission. Competing interests: RW reports lecture fees from NovoNordisk, Eli Lilly, Boehringer-Ingelheim and Sanofi, and travel grants from Eli Lilly, Sanofi and NovoNordisk. He served on the advisory board of Akcea Therapeutics, Daiichi Sankyo, Sanofi and NovoNordisk. Outside of the current work, MH reports research grants from Boehringer Ingelheim and Sanofi to the University Hospital of Tübingen, participation in advisory board for Boehringer Ingelheim and Sanofi and lecture fees from Amryt, Bayer, Sanofi, Eli Lilly, Novo Nordisk and Boehringer Ingelheim.

Figures

Fig. 1
Fig. 1
A–C Differences in whole-body insulin sensitivity (A) and organ-related insulin sensitivity (predominantly skeletal muscle (B), liver (C)) after placebo (PCB) and carrageenan (CGN) administration in the study. Box plots indicate median values with thick horizontal lines. The upper and lower hinges correspond to the first and third quartiles (the 25th and 75th percentiles). The whiskers extend from the hinges to the lowest/highest value that is within 1.5 * interquartile range (IQR) of the hinge. Dashed lines show individual changes between treatment phases. The p-values were determined comparing within-subject differences between the two exposition sequences (placebo–carrageenan vs. carrageenan–placebo) with two-sided non-paired t-tests, and n indicates the numbers (differences) tested
Fig. 2
Fig. 2
A, B Intestinal permeability expressed by lactulose-mannitol ratio (A) and plasma zonulin levels (B) after treatments with placebo (PCB) and carrageenan (CGN). Box plots indicate median values with thick horizontal lines. The upper and lower hinges correspond to the first and third quartiles (the 25th and 75th percentiles). The whiskers extend from the hinges to the lowest/highest value that is within 1.5 * interquartile range (IQR) of the hinge. Dashed lines show individual changes between treatment phases. The p-values were determined comparing within-subject differences between the two exposition sequences (placebo–carrageenan vs. carrageenan–placebo) with two-sided non-paired t-tests, and n indicates the numbers (differences) tested
Fig. 3
Fig. 3
A–F Interaction between BMI and treatment (placebo–PCB, carrageenan–CGN) on predefined study endpoints. Interaction plots show the modelled association between BMI and whole-body insulin sensitivity (OGTT (Matsuda index (A)), HOMA2-IR (B), insulin sensitivity of glucose disposal (clamp, M/I) (C), hepatic insulin sensitivity (D), C-reactive protein (E), and hypothalamic inflammation (F) for the placebo and carrageenan treatments in the study. The p-values are provided for BMI × treatment interaction terms in mixed models. AU, arbitrary units
Fig. 4
Fig. 4
A, B In vitro analysis of peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals before carrageenan exposure. A The proliferation of PBMCs and activation (CD69-expression) of T helper cells (CD4 +), cytotoxic T cells (CD8 +), B cells (CD19 +), and NK cells (CD56 +) via carrageenan. B The carrageenan-induced cytokine production
See this image and copyright information in PMC

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