Physiology in Focus 2024 (Northumbria University, UK) (2024) Proc Physiol Soc 59,
PL03
Research Symposium: Endogenous physiological mechanisms as basis for treatment of obesity and type 2 diabetes
Jens Juul Holst1,
1NNF Center for Basic Metabolic Research and Department of Medical Sciences, University of Copenhagen Copenhagen Denmark,
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Since their discovery there has been an interest in the translational aspects of the gut hormones, starting in 1906 with attempts to treat diabetes with gut extracts, continuing with search for inhibitors of acid secretion to treat duodenal ulcer disease as well as inhibitors of appetite and food intake to treat obesity. For diabetes therapy the interest focused around the incretins, and GIP (glucose-dependent insulinotropic polypeptide) was found to potently stimulate insulin secretion, but had no effect in T2DM. Further research resulted in discovery of another incretin, glucagon-like peptide-1, a product of the enteroendocrine L-cells. This peptide was soon demonstrated to also inhibit glucagon secretion, gastrointestinal secretion and motility, and to inhibit appetite and food intake. Importantly, it retained activity in T2D. Most recently, GLP-1 receptor agonists for weekly or even oral administration, given either alone or as the main component of compounds with additional receptor activities (GIP, glucagon) have demonstrated weight losses of up to 25 % within 1.5-2 years in obese individuals and normalization of average glucose levels in T2DM patients (> 50 % reaching < 5.7 % glycated hemoglobin). Therapy is also associated with a reduced risk of stroke, cognitive impairment, occurrence of dementia and occurrence of or aggravation of diabetic kidney disease. But most importantly, therapy of individuals at risk, both with and without T2DM, has been shown to reduce risk of major adverse cardiovascular events, including mortality, by 14-20 %. The underlying mechanisms have not been clearly elucidated but seem to include anti-atherosclerotic and anti-inflammatory actions. The new GLP-1RAs are now changing our approach to therapy of both T2DM and obesity.
Where applicable, experiments conform with Society ethical requirements.
