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Background: the burden of diabetes mellitus
Diabetes mellitus is a complex metabolic disorder whose main clinical and diagnostic feature is hyperglycaemia. 1 Diabetes has reached epidemic proportions, affecting around 387 million people worldwide. Over the next 20 years, its prevalence is predicted to double, and more than half-a billion people will be affected. 2 Estimated regional diabetes prevalence ranges from 5.1% in Africa to 11.4% in North America and the Caribbean, with more than 75% of subjects living in low- and middle-income countries. 2 Moreover, the increase in prevalence is estimated to be greater in developing areas, 3 as many countries adopt Western lifestyle habits (sedentary behaviour, lack of physical activity and energy-dense diet) which are well-recognised risk factors for type 2 diabetes mellitus (T2DM). 4
Although much progress has been made in the identification of risk factors associated with diabetes, in particular T2DM, its health and socioeconomic impact is increasing, mainly because of its associated complications. 5 Diabetes (particularly T2DM) approximately doubles the risk of a wide range of cardiovascular diseases, including coronary heart disease and stroke. 6 Moreover, T2DM is also associated with a wide range of non-vascular diseases, including cancer, mental and nervous system disorders, infections and liver disease. 7 Similarly, type 1 diabetes mellitus (T1DM; ~10% of all diabetes cases) is associated with an increased risk of both vascular and non-vascular complications. 8 9 Therefore, a better understanding of the mechanisms that result in hyperglycaemia could help to identify potential therapeutic targets to curb diabetes and its related complications.
The aim of this review is to summarise historical developments in our understanding of the pathophysiology of T1DM and T2DM from epidemiological, clinical and biological studies, describing the extraordinary progress made in the last century.
Pathophysiology of diabetes mellitus
Initial discoveries
Initial discoveries in the pathophysiology of diabetes mellitus are intrinsically linked to polyuria, historically considered to be its main (and diagnostic) characteristic. The term 'diabetes' is derived from the ancient Greek word 'diabainen', meaning 'go through', to indicate the excessive passing of urine through the kidney. 10 It was not until the 1600s, however, that Willis added the term 'mellitus' ('sweet') to distinguish this condition from an excessive production of non-sweet urine (diabetes 'insipidus'). 10 Almost 200 years later (1776), Dobson...