On the role of the incretin hormones GIP and GLP-1 in the pathogenesis of Type 2 diabetes mellitus.

BACKGROUND In 1906, extracts of mucosa from the porcine upper small intestine were used by Moore et al. as a treatment for diabetes, hoping that “the pancreas secretion might be stimulated by the substance of the nature of a hormone yielded by the duodenal mucosa membrane” (1). In 1932, La Barre named the unidentified substance thought to exert this effect “incretin” (2). Thirty years later, McIntyre et al. demonstrated that gut derived factors have a potentiating effect on insulin secretion after ingestion of glucose (3). Some years later, a polypeptide was discovered and named gastric inhibitory polypeptide (GIP) because of its inhibitory effect on gastric acid secretion in dogs (4). Eventually, it was shown to be insulinotropic at elevated glucose concentrations (5-7). Its gastric inhibitory effects were weak (8, 9) and it was, therefore, suggested that GIP should be renamed “glucose-dependent insulinotropic polypeptide” (5-7). Today, both names are still in use. Later, experimental and clinical studies suggested that the gut produces more than a single insulinotropic hormone (10, 11). In 1983, the gene encoding the human pancreatic hormone, glucagon, was cloned, and the structure of its precursor, proglucagon, was deduced and shown to include the sequence of two glucagon-like peptides, in addition to glucagon itself (12). The gene was found to be expressed in both the pancreatic α-cells and the intestinal L-cells. The primary transcripts and translation products of the gene in the two types of cells are identical (13), but the post-translational processing differs markedly in these two tissues (14-16). In the pancreas proglucagon is cleaved to glucagon, glicentin-related pancreatic peptide (GRPP) and a major proglucagon fragment (14). Apart from glucagon, all of these fragments seem to be biologically inactive (17). In contrast, in the intestinal L-cells, the molecule is processed to GLP-1 (glucagon-like peptide-1), GLP-2 (glucagon-like peptide-2) (18) and glicentin (19) (Figure 1). GLP-1 was found to be strongly insulinotropic (20, 21) and GLP-2 to be a key regulator of small bowel growth (22). Today, therefore, we have two major incretin hormones: glucosedependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which together are thought to be responsible for the incretin effect. The incretin effect is quantitated by comparison of the insulin response after oral and intravenous glucose, administered in such a way that identical blood glucose concentrations are obtained (23-26) .