Central nervous effects
A role for GLP-1 in the central nervous regulation of food intake has been inferred from the high density of GLP-1 receptors in the hypothalamus . Also, direct intracerebroventricular administration of GLP-1 has caused a significant reduction in food intake in rats, and these actions could be abolished by co-administration of the GLP-1 receptor antagonist exendin (9-39) . These initial effects have been confirmed and extended by several other groups. Some studies have also reported a reduction of fluid intake by GLP-1 at pharmacologic concentrations . Three potential sources of central nervous GLP-1 action have been suggested: (1) there is evidence for a local production of GLP-1 in the brainstem, from where the peptide is believed to be transported along axonal networks into the CNS ; (2) studies in humans have demonstrated that peripherally produced GLP-1 can access the brain through certain areas that lack a typical blood – brain barrier, such as the area postrema and the subfornical organs ; (3) receptors on peripheral nerve ends in the gut mucosa, the portal venous bed as well as the vagal nerve are held to project to certain areas within the hypothalamus to exert action on appetite regulation and glucose metabolism .
In humans with and without diabetes, significant reductions of appetite sensations and food intake has been demonstrated dur- ing the exogenous administration of supraphysiologic amounts of GLP-1 . These effects were found to be dose-dependent, and significant effects on food intake have only been observed with relatively high doses . It is therefore questionable whether the endogenous secretion of GLP-1 plays a major role for the postprandial induction of satiety.
Other potential GLP-1 effects of unknown physiologic relevance
Aside from the well-characterized action on islet hormone secretion, gastrointestinal motility, and appetite regulation, a number of potential extra-glycemic actions of GLP-1 have been suggested. Evidence for these actions has been derived primarily from experimental studies in rodents or in vitro models. The physiologic significance of these actions is therefore largely unclear.
Regulation of islet cell death and turnover
Induction of β-cell proliferation during incubation with GLP-1 was first observed in β-cell lines as well as in isolated rodent islets . Subsequently, these results have been confirmed in a large number of rodent studies, in which both islet neogenesis and replication of existing β cells have been described after treatment with GLP-1 or GLP-1 receptor agonists . It has also been suggested that GLP-1 treatment promotes transdifferentiation of exocrine ductal cells into insulin-secreting β cells and induces expression of Pdx-1 in the pancreas [71,72]. The fact that GLP-1 receptor knockout mice exhibit abnormalities in islet cell architecture indicates some physiologic relevance of these effects for normal islet formation . However, due to the inaccessibility of the human pancreas for biopsy sampling, it is as yet unclear whether GLP-1 also promotes β-cell proliferation in humans to a measurable extent. Furthermore, the vast majority of rodent studies demonstrating induction of β-cell proliferation with GLP-1 have been carried out in neonatal or infant rodent models, and more recent studies in adult mice and rats have called into question the stimulation of β-cell proliferation with GLP-1 receptor agonists, even at pharmacologic concentrations . There is also evidence that the proliferative capacity of human β cells is much lower compared to rodent islets. In addition to β-cell proliferation, effects on β-cell apoptosis have also been ascribed to GLP-1. In isolated human islets, apoptosis was significantly reduced during incubation with the peptide , and these effects have been reproduced in various animal and in vitro models [69,75]. Mechanistically, the reduction of β-cell apoptosis by GLP-1 is held to be mediated through a cAMP- and PI3K-dependent signaling pathway. The relevance of these preclinical findings for human physiology cannot be judged with certainty at present.
Cardiovascular effects of GLP-1
A potential cardioprotective role for GLP-1 has been initially suggested based on the indirect effects on various cardiovascular risk factors, such as glycemia, blood pressure, hyperlipidemia, and obesity . Interestingly, whereas numerous studies have consistently demonstrated significant reductions in blood pressure during therapeutic administration of various GLP-1 receptor agonists , initial experiments in rodents had demonstrated the opposite effect of GLP-1 to even raise blood pressure . GLP-1 receptors have also been identified directly on cardiomyocytes as well as on vascular smooth muscle cells . A number of experimental studies have examined the effects of GLP-1 in ischemia-reperfusion models. Most of these studies have reported significant reductions in myocardial necrosis along with preserved contractility after exogenous administration of pharmacologic doses of GLP-1 or GLP-1 receptor agonists . Furthermore, improved myocardial glucose uptake has been reported in dogs, and studies in experimental models of cardiomyopathy  or in humans with chronic heart failure have suggested a positive inotropic effect of GLP-1. There is also evidence for enhanced flow-mediated vasodilation after GLP-1 administration in humans. In rodent models of atherosclerosis, GLP-1 receptor activation has been shown to directly prevent the formation of atherosclerotic lesions . Mechanistically, these cardioprotective properties of GLP-1 have been largely attributed to binding of GLP-1 to cardiac receptors with subsequent activation of intracellular PI3-kinase-dependent pathways . More recently, the finding that cardioprotective GLP-1 effects were also observed in mice lacking a GLP-1 receptor as well as after administration of the GLP-1 metabolite (9-36) amine, which does not bind to the typical GLP-1 receptor, have led to speculation about a second GLP-1 receptor in the cardiovascular system . However, as yet no such receptor has been identified. In recent clinical trials examining the effects of pharmacologic doses of GLP-1 receptor agonists, increases in heart rate of ∼3 – 6 beats per min were reported . Overall, a large number of studies have demonstrated effects of GLP-1 in the cardiovascular system at supraphysiologic plasma concentrations. The importance of such effects in normal physiology is still largely unclear.
Mice with a GLP-1 receptor knockout are characterized by a learning deficit, which was found to be reversible after gene transfer of the GLP-1 receptor into the hippocampus, thereby suggesting a role for GLP-1 in learning processes . Various rodent studies have also demonstrated that neuronal cell damage can be partly prevented by the administration of GLP-1 or GLP-1 receptor agonists . Finally, neuroprotective effects as well as enhanced neurogenesis have been reported in rodent models of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. The physiologic relevance of these preclinical findings is difficult to judge at present .
Other effects of GLP-1 that have been suggested include enhanced diuresis and renal excretion of sodium chloride, increased skeletal muscle glucose uptake and enhanced liver glycogen storage, and enhanced bone formation .