title: Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective.
abstract: Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin-dependent' (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with 'insulin-dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and β-cell insulin secretion in 'type II' diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between 'type I' and 'type II' diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in a better patient phenotyping and therapeutic approach.
authors.affiliation: Diabetes Research Centre, University of Leicester, Leicester, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zaccardi
authors.affiliation: Diabetes Research Centre, University of Leicester, Leicester, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Webb
authors.affiliation: Diabetes Research Centre, University of Leicester, Leicester, UK NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Unit, Leicester, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Yates
authors.affiliation: Diabetes Research Centre, University of Leicester, Leicester, UK.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Davies
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D015190:Blood Glucose Self-Monitoring; D048909:Diabetes Complications / Q000266:history / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000266:history / Q000276:immunology / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000266:history / Q000276:immunology / Q000503:physiopathology*; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D007004:Hypoglycemic Agents / Q000266:history / Q000627:therapeutic use*; D018836:Inflammation Mediators; D007328:Insulin / Q000378:metabolism* / Q000627:therapeutic use; D007333:Insulin Resistance / Q000276:immunology*; D009369:Neoplasms / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D012307:Risk Factors; D012959:Socioeconomic Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D007328:Insulin
keywords: DIABETES & ENDOCRINOLOGY; HISTORY (see Medical History)