Endogenous Glucagon-Like Peptide-1 as a Potential Mediator of the Resolution of Diabetic Kidney Disease following Roux en Y Gastric Bypass: Evidence and Perspectives

Diabetic kidney disease in patients with type 2 diabetes strongly correlates with the incidence of major cardiovascular events and all-cause mortality. Pharmacological and lifestyle based management focusing on glycaemic, lipid, and blood pressure control is the mainstay of treatment but efficacy remains limited. Roux en Y gastric bypass is an efficacious intervention in diabetes. Emerging evidence also supports a role for bypass as an intervention for early diabetic kidney disease. This paper firstly presents level 1 evidence of the effects of bypass on hyperglycaemia and hypertension and then summarises emerging data on its effects on diabetic kidney disease. Glucagon-like peptide-1 is implicated as a central mediator of diabetes resolution following bypass through the incretin effect. It has been ascribed vasodilatory, pronatriuretic, and antioxidant properties and its exogenous administration or optimisation of its endogenous levels via dipeptidyl peptidase IV inhibition results in antioxidant and antiproteinuric effects in preclinical models of DKD. Some evidence is emerging of translation of coherent effects in the clinical setting. These findings raise the question of whether pharmacotherapy targeted at optimising circulating hormone levels may be capable of recapitulating some of the effects of bypass surgery on renal injury. 1. Diabetic Kidney Disease: Prevalence, Pathogenesis, and Treatment Options Type 2 diabetes (T2DM) and the consequences of its attendant complications are now a worldwide problem. World Health Organisation endorsed findings published in 2011 by the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose) revealed sex-specific prevalence rates of 9.8% and 9.2% for males and females, respectively. In high income regions, large increases in fasting plasma glucose levels were associated with increases in body mass index (BMI) attributable to overweight and obesity. Although 80% of individuals categorised as obese do not develop comorbid T2DM, up to 20% do and hence it may be the increased disease burden of “diabesity” in these individuals that is fuelling the global epidemic of diabetes. Subsequent chronic complications of T2DM, particularly diabetic kidney disease (DKD), increase morbidity, mortality [1], and healthcare costs [2]. More than 40% of patients with diabesity develop DKD. While nonprogressors and the increased risk of fatal cardiovascular events in patients with mild to moderate chronic kidney disease (CKD) restrict the absolute numbers progressing to end-stage renal disease