BackgroundThe glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity.Scope of reviewIn this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases.Major conclusionsSince its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders

Diabetes is a disease of increasing prevalence in the general population and of unknown cause. Diabetes is manifested as hyperglycemia due to a relative deficiency of the production of insulin by the pancreatic beta-cells. One determinant in the development of diabetes is an inadequate mass of beta-cells, either absolute (type 1, juvenile diabetes) or relative (type 2, maturity-onset diabetes). Earlier, we reported that the intestinal hormone glucagon-like peptide I (GLP-I) effectively augments glucose-stimulated insulin secretion. Here we report that exendin-4, a long-acting GLP-I agonist, stimulates both the differentiation of beta-cells from ductal progenitor cells (neogenesis) and proliferation of beta-cells when administered to rats. In a partial pancreatectomy rat model of type 2 diabetes, the daily administration of exendin-4 for 10 days post-pancreatectomy attenuates the development of diabetes. We show that exendin-4 stimulates the regeneration of the pancreas and expansion of beta-cell mass by processes of both neogenesis and proliferation of beta-cells. Thus, GLP-I and analogs thereof hold promise as a novel therapy to stimulate beta-cell growth and differentiation when administered to diabetic individuals with reduced beta-cell mass.

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The homeodomain protein IPF1 (also known as IDX1, STF1 and PDX1; see Methods) is critical for development of the pancreas in mice and is a key factor for the regulation of the insulin gene in the beta-cells of the endocrine pancreas. Targeted disruption of the Ipf1 gene encoding IPF1 in transgenic mice results in a failure of the pancreas to develop (pancreatic agenesis). Here, we report the identification of a single nucleotide deletion within codon 63 of the human IPF1 gene (13q12.1) in a patient with pancreatic agenesis. The patient is homozygous for the point deletion, whereas both parents are heterozygotes for the same mutation. The deletion was not found in 184 chromosomes from normal individuals, indicating that the mutation is unlikely to be a rare polymorphism. The point deletion causes a frame shift at the C-terminal border of the transactivation domain of IPF1 resulting in the translation of 59 novel codons before termination, aminoproximal to the homeodomain essential for DNA binding. Expression of mutant IPF1 in Cos-1 cells confirms the expression of a prematurely terminated truncated protein of 16 kD. Thus, the affected patient should have no functional IPF1 protein. Given the essential role of IPF1 in pancreas development, it is likely that this autosomal recessive mutation is the cause of the pancreatic agenesis phenotype in this patient. Thus, IPF1 appears to be a critical regulator of pancreas development in humans as well as mice.