Glucose-dependent insulinotropic polypeptide as a regulator of beta cell function and fate.

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that is secreted in response to food intake and modulates beta cell function. It may also regulate beta cell fate. Released from the nutrient-sensing K-cells of the upper intestine, GIP acts on various tissues, including pancreatic beta cells, via interaction with its G-protein-coupled receptor. Perhaps the most important effect of GIP is its potentiation of insulin secretion. Indeed, pharmacological blockade or genetic knockout of its receptor delays glucose-dependent insulin secretion. Exposure to GIP also enhances the beta cell response to future nutrient stimulation and upregulates transcription of key beta cell genes. There is emerging evidence that like the related hormone glucagon-like peptide-1, GIP may function as a beta cell growth factor and anti-apoptotic agent, further supporting a role for this hormone in balancing beta cell function to changing metabolic conditions. Overproduction of GIP in response to increased nutrient loads may, however, contribute to the pathophysiology of obesity. Interestingly, its insulinotropic effect is lost in type 2 diabetes, perhaps because of hyperglycemia-induced receptor desensitization. A better understanding of GIP's effects on the beta cell under normal and pathological conditions may facilitate the design of GIP derivatives for the treatment of metabolic disorders.

Thermodynamics of denaturation of hisactophilin, a beta-trefoil protein.

Hisactophilin is a histidine-rich pH-dependent actin-binding protein from Dictyostelium discoideum. The structure of hisactophilin is typical of the beta-trefoil fold, a common structure adopted by diverse proteins with unrelated primary sequences and functions. The thermodynamics of denaturation of hisactophilin have been measured using fluorescence- and CD-monitored equilibrium urea denaturation curves, pH-denaturation, and thermal denaturation curves, as well as differential scanning calorimetry. Urea denaturation is reversible from pH 5.7 to pH 9.7; however, thermal denaturation is highly reversible only below pH approximately 6.2. Reversible denaturation by urea and heat is well fit using a two-state transition between the native and the denatured states. Urea denaturation curves are best fit using a quadratic dependence of the Gibbs free energy of unfolding upon urea concentration. Hisactophilin has moderate, roughly constant stability from pH 7.7 to pH 9.7; however, below pH 7.7, stability decreases markedly, most likely due to protonation of histidine residues. Enthalpic effects of histidine ionization upon unfolding also appear to be involved in the occurrence of cold unfolding of hisactophilin under relatively mild solution conditions. The stability data for hisactophilin are compared with data on hisactophilin function, and with data for two other beta-trefoil proteins, human interleukin-1beta, and basic fibroblast growth factor.