GLP-1 Obesity and Diabetes Gerald H Tomkin and Daphne Owens

Medical School did not teach us about lizards or if they did we failed to take notice. Now everyone is familiar with two venomous lizards, Heloderma suspectum (Gila monster) and close relative Heloderma horridium (Mexican bearded lizard). They live in the south of North America. The Gila monster is large, by lizard standards, being up to 700g and 22cm length. The venom is not fatal to adults but does cause severe pain, swelling, hypotension and lymphadenopathy. The venom contains more than a dozen peptides including serotonin and various vasoactive intestinal peptide (VIP)-like proteins (Exendins 1.2 and 3) which bind to VIP receptors. Exendin 3 binds to a VIP receptor to stimulate amylase release [1,2]. In 1992 Eng et al. [3] predicted a receptor for Exendin 4. They wrote ‘The presence of the exendin receptor, although functionally undefined at the present time, predicts the existence of an endogenous mammalian analog to the exendin peptides”. Cloning and functional expression of the human islet GLP-1 receptor was described in 1993 Thorens et al. [4]. In 1999 Xu et al. [5] showed that exendin-4 improved glucose tolerance in diabetic rats and increased betacell mass through both beta cell replication and neogenesis. Exendin 4 is a GLP-1 like protein with a 50% homology but with a much longer biological half-life. Szayna et al. [6] showed that exendin-4 reacts with the GLP-1 receptor to induce insulin release. Exendin -4 was found to be much more potent than GLP-1 with a much longer biological half-life. In Zucker fatty rats Exendin 4 was found to lower blood sugars but also to reduce food intake and reduce fat deposition. Edwards et al. [7] showed that GLP-1 reduced blood sugar and decreased energy intake in humans but the very short half-life due to rapid cleavage by the enzyme DPP-4 meant that the drug had to be given by intravenous infusion. Exendin -4 does not have this problem as the molecule is not disrupted by DPP-4 therefore the biological half-life is much longer, it was known that incretins are glucose dependent with regards to their insulin stimulation effect. Egan et al. [8] demonstrated that exendin 4 is a potent and long lasting insulinotropic agent in both non-diabetic and diabetic subjects using a glucose clamp method. In 2003 Exendin-4 given in bolus subcutaneous doses was shown to reduce blood sugars and HbA1c [9]. Exendin 4 was shown to delay gastric emptying and reduce post prandial blood sugars in Type 1 diabetic patients [10].