Intermittent fasting and changes in Galectin-3: A secondary analysis of a randomized controlled trial of disease-free subjects
Introduction
Galectin-3, a 250 amino acid 31 kDa protein, is found throughout the body in intracellular and extracellular spaces, including the heart, blood, and lungs. Its functions are varied and are involved in cell growth, differentiation, angiogenesis, inflammation, host defense, and apoptosis [1]. It is expressed in neutrophils, macrophages, and other immune cells and responds directly and indirectly to respiratory and non-respiratory infections: e.g., binding to pathogens, and activating the innate immune system [1]. Galectin-3 modulates inflammation for human benefit [[1], [2], [3]], and may be impacted by intermittent fasting given the reported influence of fasting in controlling the infection-related T cell response and inflammatory cytokine cascade [4,5].
Galectin-3 may also be impacted by intermittent fasting through fasting's effects on metabolic health. Galectin-3 may protect against metabolic disorders such as type 2 diabetes by reducing chronic inflammation associated with a high fat diet and age [2,6]. Galectin-3's anti-inflammatory actions may also reduce insulin resistance and β-cell dysfunction by modulating NF-κB and the NLRP3 inflammasome [6], pathways that incite inflammation in adipose tissue and the pancreas [7]. Further, galectin-3 influences glucose homeostasis through inflammation-independent mechanisms, perhaps by reducing adipogenesis [2,6]. In animal models, galectin-3 deficiency increased inflammation and obesity related to a high-fat diet [8], and knock-out of the galectin-3 gene elevated adiposity, inflammation, and dysregulation of glucose metabolism [9].
Randomized controlled trials in humans reveal that intermittent fasting reduces hemoglobin A1c [10], homeostasis model assessment of insulin resistance (HOMA-IR) [11], and a metabolic syndrome score (MSS) [11]. Periodic fasting is also linked to a lower risk of type 2 diabetes and coronary artery disease (CAD) [12]. In almost 2000 patients, periodic fasting was associated with lower B-type natriuretic peptide (BNP), greater survival, and a profoundly lower risk of incident HF [13]. Given these and other data [[13], [14], [15], [16]], it was proposed [13] that fasting may influence HF risk through pathways similar to those impacted by SGLT-2 inhibitors, including by triggering the body to use ketones and fatty acids for energy in a low-glucose environment [17].
Notably, the anti-diabetic sodium-glucose cotransporter 2 (SGLT-2) inhibitor canagliflozin was associated with increased galectin-3 in a post hoc analysis of a randomized trial, while the medication also reduced BNP [but did not change soluble suppression of tumorigenicity 2 (sST2)] [18]. This increase of galectin-3 and concomitant decrease in BNP is important because SGLT-2 inhibitors are known to decrease heart failure (HF) risk [19], while in contrast substantial epidemiologic data show that galectin-3 is elevated in people with incident HF [20], patients with HF with preserved ejection fraction (HFpEF) [21,22], patients with myocardial infarction and atrial fibrillation [23], and patients with HF of inflammatory and fibrotic etiologies [24]. In those epidemiologic studies, whether galectin-3 is a causal factor or simply a marker of people with elevated HF risk is unknown and its use as a clinical biomarker for HF received only a class II recommendation [25]. It may be that in some etiologies that galectin-3 is elevated for the purpose of reducing inflammation and insulin resistance, which are also reduced by SGLT-2 inhibitors [17], and by fasting [4,5,10,11].
Galectin-3 has been implicated, though, in increased risk of fibrosis in mechanistic studies of cardiac, pulmonary, renal, and hepatic fibrosis [[26], [27], [28], [29], [30]]. It may also be involved in risk of some cancers [30]. Because the effects of galectin-3 may depend on tissue localization and etiology of disease [26,31], it is plausible that it can beneficially influence some conditions while negatively affecting others. Indeed, despite its many benefits in the human response to infection [[1], [2], [3]], a murine study of simultaneous infection by influenza A and Streptococcus pneumoniae suggested that galectin-3 was hijacked to cause worse outcomes [32]. Thus, while galectin-3 may be involved in risk-related actions in some conditions, its functions related to intermittent fasting such as effects on the metabolism may suggest that fasting will increase galectin-3. This study evaluated the effect of intermittent fasting on galectin-3 in a post hoc evaluation of a randomized controlled trial [11].
Section snippets
Methods
This study evaluated stored plasma samples from the Weekly ONe-Day watER-only Fasting interventionaL (WONDERFUL) trial (registration: clinicaltrials.gov, NCT02770313), a randomized controlled trial of a water-only intermittent fasting regimen versus an ad libitum diet control group in subjects with one or more metabolic syndrome factors and modestly-elevated low-density lipoprotein cholesterol (LDL-C) [11]. The original WONDERFUL findings included substantial reductions in HOMA-IR and MSS by
Results
As previously reported [11], 103 subjects were randomized and 71 subjects completed the final follow-up at 26 weeks. Of the 71 subjects, galectin-3 results were available for 67 (36 in the intermittent fasting arm and 31 in the control arm) and the other 4 with missing values (2 fasting, 2 control) were excluded from study analyses. Further, galectin-3 was available for 83 of the 88 subjects who had a week 4 visit and for 77 of the 80 subjects who had a week 13 visit. Baseline characteristics
Summary
Galectin-3 increased a median of 0.793 from baseline to 26 weeks in subjects undergoing an intermittent fasting intervention compared to a decline of 0.332 in controls who were eating ad libitum. The galectin-3 increase correlated with declines in HOMA-IR, insulin, glucose, and MSS, all of which are indicators of insulin sensitivity or risk of metabolic syndrome. The galectin-3 change was not significant at interim 4- and 13-week timepoints. Other HF-associated biomarkers such as BNP and sST2
Conclusions
A 24-h water-only intermittent fasting regimen increased galectin-3 over 26 weeks in a secondary analysis of the WONDERFUL Trial population. The galectin-3 change was negatively correlated with changes in HOMA-IR and MSS, but not with weight change. This fasting-triggered rise in galectin-3 may be an adaptive response that protects health by mollifying underlying etiologies of disease by reducing inflammation and decreasing insulin resistance. These novel findings require validation, including
Authors’ contributions
BDH and HTM had full access to all study data and take responsibility for the integrity of the data and the accuracy of the data analysis. BDH and JBM had authority over manuscript preparation and the decision to submit the manuscript for publication. Conception and design: BDH, JLA, HTM, SGD, JBM; acquisition, analysis, or interpretation of data: BDH, HTM, VTL, OG, TLB, KUK, JBM; drafting of the manuscript: BDH; critical revision for important intellectual content: JLA, HTM, VTL, OG, SGD, TLB,
Funding
This research was funded by the Intermountain Research and Medical Foundation grant number 759 (PI: BDH) and a supplemental grant from the Intermountain Research and Medical Foundation that was provided through the philanthropy of the Dell Loy Hansen Heart Foundation. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.
Data availability
The data underlying this article cannot be shared publicly due to United States privacy laws. The data will be shared on reasonable request to the corresponding author.
Declaration of competing interest
BDH is PI of other intermittent fasting-related grants from the Intermountain Research and Medical Foundation and a member of the scientific advisory boards of Opsis Health and Lab Me Analytics. The authors declare no other potential conflicts of interest.
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