Intermittent fasting and changes in Galectin-3: A secondary analysis of a randomized controlled trial of disease-free subjects

Highlights

• The WONDERFUL Trial was a randomized controlled trial of intermittent fasting.

• This post hoc evaluation tested if intermittent fasting increased galectin-3.

• Galectin-3 was increased by intermittent fasting versus controls.

• Galectin-3 changes correlated inversely with declines in metabolic risk factors.

• Increased galectin-3 may be an adaptive response to protect human health.

Abstract

Background and aims

Intermittent fasting reduces risk of interrelated cardiometabolic diseases, including type 2 diabetes and heart failure (HF). Previously, we reported that intermittent fasting reduced homeostasis model assessment of insulin resistance (HOMA-IR) and Metabolic Syndrome Score (MSS) in the WONDERFUL Trial. Galectin-3 may act to reduce insulin resistance. This post hoc evaluation assessed whether intermittent fasting increased galectin-3.

Methods and results

The WONDERFUL Trial enrolled adults ages 21–70 years with ≥1 metabolic syndrome features or type 2 diabetes who were not taking anti-diabetic medication, were free of statins, and had elevated LDL-C. Subjects were randomized to water-only 24-h intermittent fasting conducted twice-per-week for 4 weeks and once-per-week for 22 weeks or to a parallel control arm with ad libitum energy intake. The study evaluated 26-week change scores of galectin-3 and other biomarkers. Overall, n = 67 subjects (intermittent fasting: n = 36; control: n = 31) completed the trial and had galectin-3 results. At 26-weeks, the galectin-3 change score was increased by intermittent fasting (median: 0.793 ng/mL, IQR: −0.538, 2.245) versus control (median: −0.332 ng/mL, IQR: −0.992, 0.776; p = 0.021). Galectin-3 changes correlated inversely with 26-week change scores of HOMA-IR (r = −0.288, p = 0.018) and MSS (r = −0.238, p = 0.052). Other HF biomarkers were unchanged by fasting.

Conclusion

A 24-h water-only intermittent fasting regimen increased galectin-3. The fasting-triggered galectin-3 elevation was inversely correlated with declines in HOMA-IR and MSS. This may be an evolutionary adaptive survival response that protects human health by modifying disease risks, including by reducing inflammation and insulin resistance.

Trial registration

Clinicaltrials.gov, NCT02770313 (registered on May 12, 2016; first subject enrolled: November 30, 2016; final subject's 26-week study visit: February 19, 2020).

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].