Probiotics for the management of type 2 diabetes mellitus: A systematic review and meta-analysis
Introduction
Type 2 diabetes mellitus (T2DM), a metabolic disease characterised by hyperglycaemia, is associated with either insensitivity of insulin or lack of insulin secretion [1]. It is the leading cause of cardiovascular disorders, blindness, end-stage renal failure, amputations and hospitalisation [2]. The incidence of T2DM is increasing. In 2011, 366 million adults worldwide were estimated to suffer from diabetes mellitus. The number is projected to increase to 592 million by year 2035 [3]. In addition, the management of T2DM is costly. In 2010, the global estimation of diabetes expenditures was USD376 billion; the expenditure is predicted to increase to USD490 billion in the next 20 years [4]. Given its substantial health and socio-economic burden, identifying an optimal therapy for T2DM is important.
The underlying mechanisms of the abnormal rise of blood glucose level are complex and multi-factorial [5]. T2DM associated risk factors that have already been identified include age, genetic predisposition, sedentary lifestyle, diet patterns and stress [6]. Recently, emerging data suggested that gut microbiota may have an important role in progression and development of T2DM. It was reported that when the microbiome balance is shifted in favour of the unhealthy ones, the level of metabolic endotoxin will increase and potentially trigger a chronic, low-grade inflammation [7]. The release of inflammatory cytokines can cause oxidative stress [8], and ultimately, lead to destruction of β-cells in the pancreas. It was found that probiotic consumption could increase the amount of beneficial bacteria (i.e. Bifidobacteria) in the gut, which could in turn reduce intestinal permeability towards lipopolysaccharide (LPS) produced by unhealthy gut microorganisms, and altogether attenuate systemic inflammation responses [9]. As such, modulating gut microbiota through dietary interventions (e.g. probiotic intake) may be useful in the prevention and control of inflammatory metabolic disorders including T2DM.
Probiotics are live microorganisms that when administered in sufficient amounts can confer health benefit to their host [10]. Lactobacilli and bifidobacteria are the two most common types of probiotics [5]. The global probiotic market was estimated at USD33.19 billion in 2015 and it is projected to reach USD46.55 billion by 2020; dominated by Asia–Pacific market [11]. The applications of probiotics as alternative biotherapeutics have been successfully demonstrated in treatment of respiratory infection [12], inflammatory bowel disease [13], antibiotic associated diarrhoea [14] and ulcerative colitis [15]. In spite of the booming in vitro and in vivo probiotic studies against metabolic diseases such as T2DM, their application at clinical settings remains scarce [16], [17]. In fact, the findings from the very few clinical trials that have been conducted were inconsistent. The most recent systematic review and meta-analysis on probiotic use in glycaemic control comprised of 17 trials, involving a broad range of study populations [i.e. healthy participants, T2DM patients, patients with hypercholesterolaemia, non-alcoholic steatohepatitis or metabolic syndrome, obese populations and patients with gestational diabetes mellitus (GDM)]. The findings, however, were limited by substantial inter-study clinical heterogeneity [18]. In addition, the effects of probiotics against vital parameters like glycated haemoglobin (HbA1c), anti-inflammatory and anti-oxidative markers were not assessed [18]. This systematic review and meta-analysis focused mainly on clinical studies that have investigated the efficacy of probiotics in T2DM patients, highlighting areas that were not usually addressed by previous review (Supplementary Table 1): the effect of probiotic on HbA1c and fasting blood glucose (FBG), anti-inflammation and anti-oxidation.
Section snippets
Literature search strategy
A search of electronic databases, including EMBASE, PubMed/Medline, SpringerLink, the Cochrane Library and trial registry website (ClinicalTrials.gov) was performed. The final search was carried out in October 2015, using combinations of search terms which included ‘diabetes mellitus’, ‘probiotics’, ‘lactobacilli’, ‘bifidobacter’, ‘streptococcus’, ‘microbiota’, ‘microflora’, ‘microbiome’, ‘gut hormone’, ‘insulin sensitivity’, ‘anti-oxidant’ and ‘anti-inflammatory’. In addition, citations in
Description of included studies
Out of the 260 records that have been identified through the search (after removal of duplicates), 254 records were excluded based on the pre-specified criteria (Fig. 1). Table 1 outlines the details of all eligible studies and their findings. Whilst a total of six eligible studies that have investigated the use of probiotics in T2DM patients were included in the qualitative synthesis (systematic review) [8], [20], [21], [22], [23], [24], only five were included in quantitative synthesis
Discussion
The current meta-analysis is the first to examine the pooled estimate of probiotics on HbA1c. The use of HbA1c is a gold standard in clinical management of T2DM [25] and it permits comparability among the published studies. A 1% reduction in HbA1c has been associated with 21% risk reduction of diabetes related-end points and 37% risk reduction for microvascular complications [26]. Hence, a 1% reduction in HbA1c is considered to be clinically relevant. The findings from the current meta-analysis
Conclusion
The current meta-analysis suggested moderate beneficial hypoglycaemic effects of certain probiotics, with significantly lower FBG. Findings on HBA1c, anti-inflammatory and anti-oxidative effects of probiotics in the clinical setting, however, remain inconsistent, and thus, merits further investigations in future clinical studies. Based on the current literature, well designed, prospective clinical studies investigating the effects of probiotic administration on glycaemic control in T2DM
Declaration of interest
No competing interest declared by the authors.
Authors contribution
Each author contributed equally in this study.
Acknowledgements
The authors thank the Ministry of Education Malaysia for financial support under the Fundamental Research Grant Scheme [600-RMI/FRGS 5/3 (22/2014)].
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