Physiological and pathophysiological signalling between the gut and the kidney: role in diabetic kidney disease

Physical and chemical stimuli secondary to the presence of nutrients in the lumen of the gastrointestinal tract provoke integrated downstream responses in order to generate a co-ordinated response to feeding. A focus of physiological research has therefore been to identify the mediators and mechanisms that control the transit, digestion and absorption of nutrients, direct their optimal utilization and dictate the activation of central pathways involved in the regulation of ingestive behaviour. Neural circuits and the actions of enteroendocrine hormones are implicated in all of the above. Many examples can be drawn upon to illustrate the actions of enteroendocrine hormones, but the incretin effect, in which an oral glucose load elicits a stronger insulin secretory response than an isoglycaemic parenteral bolus, typifies enteroendocrine hormone-based organ–system level co-ordination between pre-absorptive and postabsorptive events (McIntyre et al. 1965). A sound rationale exists for exploring the extent to which co-ordination exists between events in the gastrointestinal tract and the kidney. Studies revealing the existence of direct communication between the gut and the kidney in relation to ion homeostasis (e.g. sodium, phosphate) have substantiated the existence of a gut–kidney axis in normal physiology (Michell et al. 2008). The current series of four review articles arise from a symposium entitled Physiological and pathophysiological signalling between the gut and the kidney: role in diabetic kidney disease held at Experimental Biology 2014 in San Diego on Wednesday 30 April 2014. The session provided a platform for investigators interested in the gut–kidney axis in health and disease to discuss how increased understanding of the axis may be most optimally exploited in the refinement of pharmacological and surgical approaches to treat diabetic kidney disease (DKD). Volker Vallon and Neil Docherty (Vallon & Docherty, 2014) describe how hyperglycaemia acts as a pathophysiological stimulus for compensatory growth of the renal proximal tubule targeted towards increasing renal tubular glucose-handling capacity. The mechanisms are described through which this initial compensatory response becomes maladaptive via enhancement of proximal tubular sodium reclamation and the promotion of early glomerular hyperfiltration. The paper subsequently discusses how the incretin hormone glucagon-like peptide 1 (GLP-1) may be renoprotective in DKD through mechanisms beyond the enhancement of first-phase insulin secretion and improved glycaemic control. A description of the direct and indirect natriuretic effects of GLP-1 which target early tubular sodium reabsorption follows, along with reference to emerging data demonstrating that GLP-1 can exert direct anti-inflammatory and antioxidant effects in the kidney. As circulating GLP-1 levels are restricted by enzymatic degradation mediated by dipeptidyl peptidase 4 (DPP-4), the potential for DPP-4 inhibitors in current clinical use to have GLP-1-dependent and -independent renoprotective effects is also discussed. In randomized controlled trials, Roux-en-Y gastric bypass (RYGB) shows superior efficacy to both standard and intensified medical therapy in relation to the treatment of type 2 diabetes in patients with obesity (Mingrone et al. 2012; Schauer et al. 2014). Accumulating evidence points to the importance of an early and sustained weight-loss-independent effect of incretin as a key mediator of the diabetes-resolving effect of surgery. Neil Docherty and Carel le Roux (Docherty & le Roux, 2014) present a review that starts by describing how anatomical alterations involved in RYGB surgery lead to increases in incretin hormone release and subsequently details how the benefits of RYGB reach beyond