Diabetes mellitus is the leading cause of new blindness in working-age people and the leading cause of end-stage renal disease. More than 60% of diabetic patients are affected by neuropathy, which includes distal symmetrical polyneuropathy, mononeuropathies, and a variety of autonomic neuropathies that cause erectile dysfunction, urinary incontinence, gastroparesis, and nocturnal diarrhea. Diabetic neuropathy, in conjunction with accelerated lower extremity arterial disease, accounts for more than 50% of all non-traumatic amputations in the USA. Diabetes and impaired glucose tolerance increase cardiovascular disease risk three to eightfold.

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

A sequential approach to the management of patients with diabetic gastroparesis needs to be considered on the basis of the severity of the symptoms and the efficacy and safety of the intervention. Starting at the base, frequent but mild complications can be treated with simple approaches such as dietary modifications. As the severity of symptoms increases, a more aggressive approach needs to be considered. The peak of the pyramid represents the minority of patients with diabetic gastroparesis that fails to respond to more conventional approaches; in these patients therapeutic options are limited and not necessarily evidence based.

Insulin secretion from the β-cells in the pancreas normally reduces glucose output by the liver and increases glucose uptake by skeletal muscle and adipose tissue. Once β-cell dysfunction in the pancreas and/or insulin resistance in the liver, skeletal muscle or adipose tissue occur, hyperglycemia develops, leading to an excessive amount of glucose circulating in the blood. The various factors listed at the top affect insulin secretion and insulin action.

An overview of neuroendocrine, inflammatory and autonomic pathways and their impact on diabetes-related processes is shown.

The increased risk of diabetic complications for patients with chronic kidney disease (CKD) means that the management of CKD in diabetes is never only focused on the kidney, but must also involve the proactive prevention, early detection and effective treatment of all diabetic complications.

Several mechanisms have been proposed to be responsible for the development of diabetic nephropathy. None of these are mutually exclusive, and it is likely that interactions among many of these factors contribute to diabetic nephropathy. An understanding of these mechanisms is essential for producing appropriate therapies to prevent both the development and progression of diabetic nephropathy. A number of existing therapies, as well as treatments currently in development or in clinical trials, are based on altering one or more of the mechanisms shown in this figure.

Autoreactive B cells in the blood and peripheral lymphoid organs can lose anergy and become activated through a variety of potential mechanisms. Collaboration with CD4+ helper T cells leads to the proliferation and differentiation of B cells that secrete inflammatory cytokines and the development of plasma cells that secrete autoantibodies, which can form immune complexes. The localization of this response is not yet fully understood; however, we hypothesize that these immune complexes, together with complement, can infiltrate the glomeruli, leading to mesangial expansion and thickening of the glomerular basement membrane. The presence of immune complexes in the glomerulus also induces macrophage accrual, promoting inflammation. The release of damage-associated molecular patterns following damage to the extracellular matrix, can lead to further B cell activation, leading to further cytokine production.

Morphological and functional alterations to renal glomeruli are one of the hallmarks of diabetic kidney disease.

The spectra of clinical neuropathic syndromes described in patients with diabetes mellitus include dysfunction of almost every segment of the somatic peripheral and autonomic nervous systems. Each syndrome can be distinguished by its pathophysiologic, therapeutic, and prognostic features. Initial neurologic evaluation should be directed toward detection of the specific part of the nervous system affected by diabetes. Diabetes may damage small fibers, large fibers, or both. Small nerve-fiber dysfunction usually, but not always, occurs early and often is present before objective signs or electrophysiologic evidence of nerve damage is found. Small nerve-fiber dysfunction is manifested first in the lower limbs by pain and hyperalgesia. Loss of thermal sensitivity follows, with reduced light touch and pinprick sensation. Large-fiber neuropathies may involve sensory or motor nerves or both. The neuropathies are manifested by reduced vibration (often, the first objective evidence of neuropathy) and position sense, weakness, muscle wasting, and depressed tendon reflexes. Most patients with distal sensory polyneuropathy have a mixed variety, with both large and small nerve-fiber involvement. In the case of distal sensory polyneuropathy, a “glove and stocking” distribution of sensory loss is almost universal. Early in the course of the neuropathic process, multifocal sensory loss may also be found. Diabetic peripheral symmetric polyneuropathy is thought to be a dying-back disorder, with prevailing effects on the axons and consequent demyelination. There is an early functional phase in which metabolic abnormalities are responsible for the clinical symptoms and signs. Later structural changes occur in the nerves so that treatment strategies have been developed to arrest or slow the rate of progression. When neuronal cell death occurs, little can be done to induce recovery. Clearly, all attempts at treating neuropathy should be oriented toward the reversible phase of the disorder.

Impairments in glucose and insulin metabolism have indirect and direct effects on bone quality in individuals with diabetes. Impaired glucose/insulin metabolism may indirectly affect bone by altering skeletal muscle signalling. Furthermore, in metabolic disease, the accumulation of advanced glycation end-products may trigger pathways that promote collagen cross-linking (altering bone biomechanics) and impact on bone remodelling. Furthermore, the bone vasculature is disturbed with dysregulation in glucose and insulin metabolism, so that the delivery of nutrients and signalling factors (eg, that regulate vasodilation) to the bone is impaired. The changes in bone vasculature in diabetes results in decreased remodelling activity in the bone. Impairments in glucose and insulin metabolism also directly impact on osteoblast and osteoclast activity, resulting in decreased bone formation and bone resorption. Ultimately, the indirect and direct effects of impaired glucose/insulin metabolism on bone lead to decreased bone remodelling/turnover, decreased bone quality and increased risk of fractures.

Schematic representation of the main pathogenetic events in the development and progression of diabetic retinopathy (DR) depicted from healthy (left) to advanced-stage DR (right). Non-proliferative DR is characterized by vascular changes such as thickening of the basement membrane, endothelial injury that leads to the disruption of the tight junctions and pericyte loss, resulting in dot haemorrhages, microaneurysms and hard exudates. Vascular endothelial growth factor (VEGF) and pro-inflammatory cytokine production (IL-1β, tumour necrosis factor, IL-6, IL-8 and monocyte chemoattractant protein 1) by the retinal pigment epithelium (RPE), glial cells and macrophages also contribute to the vascular changes. Endothelial damage leads to vasoconstriction owing to vasoconstrictor release (endothelin 1 and thromboxane A2) and hypoxia in pre-proliferative DR, which is aggravated owing to the capillary occlusion. The severe hypoxia in end-stage DR leads to neovascularization. These new blood vessels tend to grow into the vitreous body and are prone to rupture.