Beginnings: a reflection on the history of gastrointestinal endocrinology.

The gut is the largest endocrine organ in the body. Gut hormones share some characteristics: Their structure groups hormones into families, each of which originate from a single gene. A hormone gene is often expressed in multiple peptides due to tandem genes, alternative splicing or differentiated posttranslational processing. By these mechanisms, more than 100 different hormonally active peptides are produced in the gastrointestinal tract. In addition, gut hormones are widely expressed outside the gut. The different cell types often express different products of the same gene and release the peptides in different ways. Consequently, the same peptide may act as a hormone, a local growth factor, or a neurotransmitter. This new biology suggests that gastrointestinal hormones should be conceived as intercellular messengers of major general impact. The following short review is a vignette on steps in the history of gastrointestinal endocrinology from classic studies of digestive juice secretion over peptide chemistry, immunochemistry, and molecular genetics to modern receptor pharmacology and drug development. From shadowy beginnings, gastrointestinal endocrinology has emerged as a central discipline in the understanding of multicellular life and its diseases.

Gut endocrine secretions and their relevance to satiety.

The three major regions of the gastrointestinal tract (stomach, upper small intestine, ileum/colon) are each the source of factors influencing food intake. These can enhance appetite or, conversely, inhibit it. The active factors include hormones, lipid mediators, nutrients and gastric distension. Vagal afferent neurons mediate the effects of some gut signals on the brain, but other gut hormones also act directly on the brain in areas where the blood-brain barrier can be penetrated. Many different interactions between these factors are now emerging. Collectively, this system presents an array of new potential targets in seeking to modify energy intake.

Primary structure of frog PYY: implications for the molecular evolution of the pancreatic polypeptide family.

A peptide belonging to the pancreatic polypeptide (PP) family was isolated in pure form from the intestine of the European green frog (Rana ridibunda). The primary structure of the peptide was established as: Tyr-Pro-Pro-Lys-Pro-Glu-Asn-Pro-Gly-Glu10-Asp-Ala- Ser-Pro-Glu-Glu-Met-Thr-Lys-Tyr20-Leu-Thr-Ala-Leu-Arg-His-Tyr-Ile- Asn-Leu30-Val - Thr-Arg-Gln-Arg-Tyr-NH2. This amino acid sequence shows moderate structural similarity to human PYY (75% identity) but stronger similarity to the PP family peptides isolated from the pancreas of the salmon (86%) and dogfish (83%). The data suggest that the two putative duplications of an ancestral PP family gene that have given rise to PP, PYY and NPY in mammals had already taken place by the time of the appearance of the amphibia. In fish, however, only a single duplication has occurred, giving rise to NPY in nervous tissue and a PYY-related peptide in both pancreas and gut.

Chemical messengers: a view from the gut.

The peptides usually called gastrointestinal hormones belong to a broader group of regulatory substances distributed in many parts of the body and delivered to their targets not only by the blood but also by neural and paracrine paths. The neural, endocrine, and paracrine cells as a group might be called "regulator cells" and the chemical messengers they produce might be called "regulins." Twenty peptides have been isolated from the alimentary tract and pancreas: 12 have been sequenced, 4 have been partially sequenced, and 4 more have been identified only by immunoreactivity. Gastrin, gastric inhibitory peptide, glucagon, insulin, and secretin can be regarded as established hormones that are released into the blood by identified stimuli and produce identified physiological responses. The evidence for the hormonal status of cholecystokinin, pancreatic polypeptide, and motilin is incomplete but suggestive. The possible physiological roles of the other 12 peptides remain to be determined. If specific antagonists of these peptides can be found, they will greatly assist in elucidating the peptides' physiological roles.