Microvascular disease beyond diabetes: a metabolic continuum with implications for early detection and diabetes care

Microvascular disease has traditionally been regarded as a defining complication of diabetes, responsible for major clinical outcomes including retinopathy, nephropathy, neuropathy, and limb amputation. Existing frameworks have largely attributed microvascular injury to chronic hyperglycaemia, mediated through pathways such as advanced glycation end product formation, protein kinase C activation, and oxidative stress. While these mechanisms are well established, a predominantly glucose-centric paradigm may incompletely capture the complexity of microvascular pathology. Accumulating evidence indicates that microvascular abnormalities are also prevalent in individuals without diabetes and may arise across a continuum of metabolic dysfunction. Epidemiological studies and clinical trials further suggest that intensive glucose lowering alone does not fully eliminate the risk of microvascular complications, highlighting the importance of non-glycaemic contributors, including hypertension, dyslipidaemia, insulin resistance, adiposity, and chronic inflammation. Notably, these metabolic disturbances may precede overt hyperglycaemia and provide earlier signals of vascular vulnerability. These observations have direct clinical relevance for diabetologists, as they suggest that microvascular injury may develop during prediabetes or earlier stages of metabolic dysfunction, with important implications for early screening and risk stratification in diabetes-oriented clinical practice. In this review, we propose the concept of metabolic microvascular disease (MMD), which reframes microvascular pathology as a systemic consequence of metabolic dysregulation rather than a complication confined to diabetes. We synthesise evidence of microvascular disease across populations with and without diabetes, summarise shared and distinct pathogenic mechanisms, and outline a pragmatic framework to support early clinical recognition and research stratification. Finally, we discuss the clinical and public health implications of adopting a metabolic perspective, emphasising the need for prevention strategies that extend beyond glucose-lowering to include comprehensive metabolic risk management.