Schematic representation of the pathways to diabetes complications and how they fit into current paradigms

Susceptibility to diabetes complications is driven by a combination of environmental factors (eg, diet, lifestyle, microbiota, pathogen exposure) and genetic programming. With diabetes onset, many changes occur that are thought to be pathological, including involvement of pathways that have been explored recently and are highlighted in this review. These include the following: changes to the microbiome, potentially affecting substrate delivery and utilization, gastrointestinal inflammation and permeability, release of intestinal toxins, neuroendocrine signaling and the immune system; aberrant energy utilization, substrate delivery and nutrient flux, which can alter the metabolic pathways utilized by tissues affected by complications; mitochondrial dysfunction in the form of mitochondrial fission and fusion, decreased biogenesis, aberrant energy utilization and delivery and, potentially, ROS generation; epigenetic changes, which alter the regulation of genes associated with pathological pathways. All these factors are likely to be exacerbated by the presence of comorbidities (obesity, raised blood pressure, dyslipidemia, endothelial dysfunction), initiating a downstream cascade of interacting pathways ultimately resulting in microvascular and macrovascular complications. These pathways include post-translational modifications (AGE formation, oxidation of proteins and lipids and ER stress), inflammation and immune dysregulation (increases in inflammatory cytokines, chemoattractant molecules and ultimately immune cell infiltration), ROS production, and gene expression and transcription. Current therapeutic strategies include intensive blood glucose control and treatment of comorbidities, with the former appearing to be more effective early in disease development. The paucity of therapies that actually prevent or reverse complications once they are established remains one of the major challenges posed by the global diabetes pandemic. ECM=extracellular matrix, ER=endoplasmic reticulum, ROS=reactive oxygen species