The metabolic-microvascular dysregulation syndrome☆

Microvascular and metabolic physiology are inextricably linked. Thus, metabolic dysfunction impairs microvascular function and microvascular dysfunction impairs normal metabolism. The relationship is therefore reciprocal, justifying the concept of a ‘Metabolic-Microvascular Dysregulation Syndrome’. For example, metabolic dysregulation (hyperglycaemia) causes microvascular dysfunction, diabetic retinopathy and diabetic nephropathy. Conversely, microvascular dysregulation impairs insulin-mediated glucose disposal, i.e. causes insulin resistance, impairs insulin secretion, and is associated with onset of type 2 diabetes in prospective studies. Obesity is a key driver of the Metabolic-Microvascular Dysregulation Syndrome, as it impairs insulin signal transduction in endothelial cells through adverse changes in adipokines such as adiponectin, free fatty acids and tumour necrosis factor-α. Microvascular dysfunction in obesity appears reversible by diet-induced weight loss. Next to obesity, other factors are also likely to play a role. Examples are microvascular dysfunction of adipose tissue as a primary cause of adipose tissue dysfunction; early life exposures, both antenatal and postnatal; and large artery stiffening. Large artery stiffening is unquestionably important for microvascular function in susceptible organs such as the brain, the eye and the kidney but whether it can cause microvascular dysfunction in metabolically crucial tissues such as skeletal muscle, pancreas and adipose tissue has not been studied. It is therefore not clear that arterial stiffening in and of itself is sufficient to cause the Metabolic-Microvascular Dysregulation Syndrome.