We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.

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The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity

Biology of Incretins: GLP-1 and GIP

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via Gq proteins to phospholipase C-β. The high-affinity receptor state requires both Mg2+ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has bee...

The Oxytocin Receptor System: Structure, Function, and Regulation

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

The Physiology of Glucagon-like Peptide 1

The biology of incretin hormones.

Amylin alters the biological action of the incretin hormone GLP-1(7-36)amide

The functional connection between the gut and pancreatic islets is described by the term "enteroinsular axis". A humoral factor of the gut that might enhance the glucose-induced secretion of insulin is named "incretin". For many years glucose-dependent insulin-releasing polypeptide (GIP) was the strongest incretin candidate. However, recent evidence suggests that glucagon-like peptide-1(7-36)amide represents a more potent physiological incretin. The sequence of GLP-1 is identical in various mammals including man. The 7-36 sequence of the original peptide is a potent insulin-releasing peptide in vitro and in vivo. GLP-1(7-36)amide was found in the human bowel; its circulating level rises in answer to oral glucose and after meals. Recently, specific high-affinity binding sites for GLP-1(7-36)amide were demonstrated on rat insulinoma-derived RINm5F cells. In this model system for B-cell studies the peptide has potent stimulatory effects on cAMP formation, insulin-mRNA transcript synthesis, and insulin release. Further studies in the insulinotropic action of GLP-1(7-36) amide in health and disease will be of great importance.

[The entero-insular axis: the new incretin candidate glucagon-like peptide-1(7-36)amide (GLP-1(7-36))amide].

Binding sites for peptide-histidine-isoleucine (PHI) on rat insulinoma-derived RINm5F cells

In May 1993, a first International Symposium on glucagon-like peptide 1 (GLP-1) has been held in Copenhagen (Denmark). While deciding to organize this meeting we were inspired by the imagination that a gettogether (fig. 1) of all leading experts in the field could be a milestone in the history of GLP-1. GLP-1 is actually a gut hormone that has a good chance to make its way from the basic science experiment into the field of clinical usage which is the treatment of type II diabetes melli-tus. This fact alone supports the scientific efforts gastrointestinal en-docrinologists and others have undertaken to understand its meaning. However, the meeting also showed that more work needs to be done before GLP-1 or a related synthetic analogue is ready for clinical applications. The Copenhagen meeting became a milestone for GLP-1 research since it has provided the state of the art about this hormone, its biological actions and its possible therapeutic perspective in the treatment of non-insulin-dependent diabetics. This is documented by the short communications presented here. One suggestion to simplify the nomenclature of the proglucagon-de-rived peptides, and here especially the GLPs, was approved by all participants. From now on the name GLP-1 should be reserved for the GLP-l(7-36)amide peptide, naturally occurring in the gut. Like other amidated peptides a Gly-extended form does also exist; this should be called Gly-extended GLP-1. Furthermore, processing intermediates exist, e.g. N-terminally extended GLP-1, which may correspond to proglucagon 72-107 and may exist in a Gly-extended form and in an amidated form. In cases of doubt one should refer to the peptide according to the positions of its terminal residues in proglucagon, e.g. for the major proglucagon fragment: proglucagon 72-158. The organizers wish to express their warmest thanks to Novo Nor-disk (Denmark) and Bayer AG (FRG) for their financial support.

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Rüdiger Göke

Papers

Amylin alters the biological action of the incretin hormone GLP-1(7-36)amide

[The entero-insular axis: the new incretin candidate glucagon-like peptide-1(7-36)amide (GLP-1(7-36))amide].

Binding sites for peptide-histidine-isoleucine (PHI) on rat insulinoma-derived RINm5F cells

Glucagon-Like Peptide 1: On Its Way to Clinical Application

Knock-down of Pdcd4 stimulates angiogenesis via up-regulation of angiopoietin-2