Abstract
The discovery that glucagon-like peptide 1 (GLP-1) mediates a significant proportion of the incretin effect during the postprandial period and the subsequent observation that GLP-1 bioactivity is retained in type 2 diabetes (T2D) led to new therapeutic strategies being developed for T2D treatment based on GLP-1 action. Although owing to its short half-life exogenous GLP-1 has no use therapeutically, GLP-1 mimetics, which have a much longer half-life than native GLP-1, have proven to be effective for T2D treatment since they prolong the incretin effect in patients. These GLP-1 mimetics are a desirable therapeutic option for T2D since they do not provoke hypoglycaemia or weight gain and have simple modes of administration and monitoring. Additionally, over more recent years, GLP-1 action has been found to mediate systemic physiological beneficial effects and this has high clinical relevance due to the post-diagnosis complications of T2D. Indeed, recent studies have found that certain GLP-1 analogue therapies improve the cardiovascular outcomes for people with diabetes. Furthermore, GLP-1–based therapies may enable new therapeutic strategies for diseases that can also arise independently of the clinical manifestation of T2D, such as dementia and Parkinson’s disease. GLP-1 functions by binding to its receptor (GLP-1R), which expresses mainly in pancreatic islet beta cells. A better understanding of the mechanisms and signalling pathways by which acute and chronic GLP-1R activation alleviates disease phenotypes and induces desirable physiological responses during healthy conditions will likely lead to the development of new therapeutic GLP-1 mimetic–based therapies, which improve prognosis to a greater extent than current therapies for an array of diseases.
Highlights
Glucagon-like peptide 1 (GLP-1) was initially identified as a gut-derived incretin hormone that augments insulin secretion in a glucose-dependent manner from pancreatic islet beta cells during the postprandial period[1,2]
Summary In summary, abundant evidence has emerged over recent years to demonstrate that GLP-1 has multiple pancreatic effects and extrapancreatic targets and actions throughout the body, which likely play a significant role in maintaining metabolic homeostasis during healthy conditions and to label GLP-1 as just an ‘incretin hormone’ is outdated[1,2,7,12]
GLP-1 receptor (GLP-1R) agonists were thought to be limited to type 2 diabetes (T2D) treatment, but it has become clear that these drugs have the potential to treat other diseases such as obesity, cardiovascular disease (CVD), dementia and NAFLD2,7,12,77,103
Summary
Glucagon-like peptide 1 (GLP-1) was initially identified as a gut-derived incretin hormone that augments insulin secretion in a glucose-dependent manner from pancreatic islet beta cells during the postprandial period[1,2]. Studies have revealed that GLP-1 has multiple extrapancreatic targets and effects, which assists with inducing the desired physiological response during the postprandial period and has beneficial effects on alleviating pathology associated with certain tissues and organs systemically, which arises because of T2D manifestation or independently of T2D2,8,9,12 These findings are of clinical importance since there is demand for new therapeutic strategies that both reduce the prevalence and incidence of T2D post-diagnosis complications and provide better prognosis than current treatments for diseases such as dementia[2,7,8,9,12]. Abbreviations ALT, alanine aminotransferase; CNS, central nervous system; CVD, cardiovascular disease; DIO, diet-induced obesity; DPP-4, dipeptidyl peptidase 4; ER, endoplasmic reticulum; GIP, gastric inhibitory polypeptide; GIPR, gastric inhibitory polypeptide receptor; GIT, gastrointestinal tract; GLP-1, glucagon-like peptide 1; GLP-1R; glucagon-like peptide 1 receptor; GR, glucagon receptor; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PKA, protein kinase A; T2D, type 2 diabetes
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