Reappraisal of GIP Pharmacology for Metabolic Diseases

GIP, like GLP-1, is one of the predominant incretin hormones produced in the alimentary tract in response to food intake that function to lessen postprandial glucose excursions. Unlike GLP-1, promoting GIP action has been discredited as a viable therapeutic strategy for T2D, primarily because of its reported resistance in certain human subjects and its presumed obesogenic propensity, as deduced from rodent loss-of-function phenotypic analyses. The use of refined GIPR agonists, transgenic rodent models, and observations from conditional GIPR knockout models suggest that promoting GIP action is beneficial for T2D. Combining GIP and GLP-1 pharmacology provides enhanced potency and efficacy for treating T2D, including improvements in glycemia, body weight, and tolerability. Glucagon-like peptide-1 (GLP-1) analogs are considered the best current medicines for type 2 diabetes (T2D) and obesity due to their actions in lowering blood glucose and body weight. Despite similarities to GLP-1, glucose-dependent insulinotropic polypeptide (GIP) has not been extensively pursued as a medical treatment for T2D. This is largely based on observations of diminished responses of GIP to lower blood glucose in select patients, as well as evidence from rodent knockout models implying that GIP promotes obesity. These findings have prompted the belief in some, that inhibiting GIP action might be beneficial for metabolic diseases. However, a growing body of new evidence – including data based on refined genetically modified models and improved pharmacological agents – suggests a paradigm shift on how the GIP system should be manipulated for metabolic benefits. Glucagon-like peptide-1 (GLP-1) analogs are considered the best current medicines for type 2 diabetes (T2D) and obesity due to their actions in lowering blood glucose and body weight. Despite similarities to GLP-1, glucose-dependent insulinotropic polypeptide (GIP) has not been extensively pursued as a medical treatment for T2D. This is largely based on observations of diminished responses of GIP to lower blood glucose in select patients, as well as evidence from rodent knockout models implying that GIP promotes obesity. These findings have prompted the belief in some, that inhibiting GIP action might be beneficial for metabolic diseases. However, a growing body of new evidence – including data based on refined genetically modified models and improved pharmacological agents – suggests a paradigm shift on how the GIP system should be manipulated for metabolic benefits. a protein hormone produced by adipocytes modulating glucose and lipid regulation. family of lipoprotein particles responsible for transporting lipids throughout the body. a cell-surface serine peptidase responsible for cleaving N-terminal dipeptides from many substrates, including GLP-1, GIP, and glucagon. cells dispersed throughout the gastrointestinal tract that produce factors and hormones with endocrine function. being involved in the gastrointestinal regulation of hormonal secretion from the endocrine pancreas. blood glucose within the normal physiological range. a stable 39amino acid reptilian paralog of GLP-1. reduced response of pharmacological GIP to enhance insulin secretion and reduce blood glucose. ability to induce the secretion of glucagon. organ damage that is brought on by the effects of excessive glucose and lipids. ability to induce the secretion of insulin. enteroendocrine cells responsible for the secretion of GIP, along with other gut hormones. reduced response of leptin to regulate systemic metabolism, including, but not limited to, reducing food intake. a mutation in the nucleotide sequence that results in an alteration in the amino acid sequence of a protein. T2D mouse model that is rendered hyperglycemic and obese due to a mutation in the leptin gene resulting in the absence of leptin. ability to promote fat mass gain. secreted protein primarily involved in bone metabolism but bearing many other diverse actions. protein secreted by adipocytes in rodents that negatively modulates insulin sensitivity.