Incretin Hormone Secretion - Studies in Human Subjects

Abstract: Several different hormones are released from the intestine following a meal. In this thesis we have focused on the so called incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). An important function of the incretin hormones is potentiation of insulin release from pancreatic beta-cells following a meal. This property has attracted a lot of interest in the hormones as a treatment for diabetes and GLP-1 in particular has proved effective in this aspect. GLP-1 also has several other interesting effects like decreasing glucagon secretion, weight reduction in obese subjects and positive effects on the heart and nervous system. GIP on the other hand is involved in lipid metabolism and the finding that GIP receptor knockout mice are resistant to weight gain following high-fat diet has led to the proposal that blocking GIP could be a way to treat or prevent obesity. As obese persons are often more insulin resistant than lean persons and therefore have to secrete more insulin to prevent elevated blood glucose and diabetes, the secretion and effects of incretin hormones are of great interest in obesity. In this thesis we have studied how single macronutrients and a mixed meal affect incretin secretion in healthy lean subjects, how this is affected by obesity and if secretion is affected by time of the day. We have also for the first time compared incretin hormone secretion following oral versus intravenous fat intake. The most important findings are that oral ingestion of the three major macronutrients, glucose, fat and protein are equally strong stimuli for incretin hormone secretion. GLP-1 secretion was found to be reduced in obese subjects following glucose and mixed meal but unaffected following fat and protein. GIP secretion is decreased in the obese subjects following protein, increased following glucose and unaffected following fat and mixed meal. Furthermore, we found that incretin hormone release is more rapid in the morning compared to the afternoon. Finally, we have found support for a similar incretin effect following oral versus intravenous fat intake as the well known incretin effect following glucose intake. In conclusion this thesis has expanded the knowledge of the regulation of incretin hormone secretion including how it is affected by obesity and found evidence for an incretin effect following fat ingestion.