The effect of exogenous glucose-dependent insulinotropic polypeptide in combination with glucagon-like peptide-1 on glycemia in the critically ill

OBJECTIVE Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have additive insulinotropic effects when coadministered in health. We aimed to determine whether GIP confers additional glucose lowering to that of GLP-1 in the critically ill. RESEARCH DESIGN AND METHODS Twenty mechanically ventilated critically ill patients without known diabetes were studied in a prospective, randomized, double-blind, crossover fashion on 2 consecutive days. Between T₀ and T₄₂₀ minutes, GLP-1 (1.2 pmol/kg • min−1) was infused intravenously with either GIP (2 pmol/kg • min⁻¹) or 0.9% saline. Between T₆₀ and T₄₂₀ minutes, nutrient liquid was infused into the small intestine at 1.5 kcal/min. RESULTS Adding GIP did not alter blood glucose or insulin responses to small intestinal nutrient. GIP increased glucagon concentrations slightly before nutrient delivery (P = 0.03), but not thereafter. CONCLUSIONS The addition of GIP to GLP-1 does not result in additional glucose-lowering or insulinotropic effects in critically ill patients with acute-onset hyperglycemia.Michael Y. Lee, Jonathan D. Fraser, Marianne J. Chapman, Krishnaswamy Sundararajan, Mahesh M. Umapathysivam, Matthew J. Summers, Antony V. Zaknic, Christopher K. Rayner, Juris J. Meier, Michael Horowitz, Adam M. Dean

Regulation of GIP and GLP1 Receptor Cell Surface Expression by N-Glycosylation and Receptor Heteromerization

In response to a meal, Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) are released from gut endocrine cells into the circulation and interact with their cognate G-protein coupled receptors (GPCRs). Receptor activation results in tissue-selective pleiotropic responses that include augmentation of glucose-induced insulin secretion from pancreatic beta cells. N-glycosylation and receptor oligomerization are co-translational processes that are thought to regulate the exit of functional GPCRs from the ER and their maintenance at the plasma membrane. Despite the importance of these regulatory processes, their impact on functional expression of GIP and GLP-1 receptors has not been well studied. Like many family B GPCRs, both the GIP and GLP-1 receptors possess a large extracellular N-terminus with multiple consensus sites for Asn-linked (N)-glycosylation. Here, we show that each of these Asn residues is glycosylated when either human receptor is expressed in Chinese hamster ovary cells. N-glycosylation enhances cell surface expression and function in parallel but exerts stronger control over the GIP receptor than the GLP-1 receptor. N-glycosylation mainly lengthens receptor half-life by reducing degradation in the endoplasmic reticulum. N-glycosylation is also required for expression of the GIP receptor at the plasma membrane and efficient GIP potentiation of glucose-induced insulin secretion from the INS-1 pancreatic beta cell line. Functional expression of a GIP receptor mutant lacking N-glycosylation is rescued by co-expressed wild type GLP1 receptor, which, together with data obtained using Bioluminescence Resonance Energy Transfer, suggests formation of a GIP-GLP1 receptor heteromer

The FOOTPRINT software tools: pesticide risk assessment and management in the EU at different spatial scales.

Original paper can be found at: http://www.ask-eu.com/default.asp?Menue=149&AnbieterID=586 [Full text of this paper is not available in the UHRA]In the EU-project FOOTPRINT three pesticide risk assessment and management tools were developed, for use at different spatial scales. The three FOOTPRINT tools share the same underlying science, based on the consistent identification of environmental characteristics driving the fate of agriculturally applied pesticides and their interpretation to parameterise state of the art modelling applications thus providing an integrated solution to pesticide risk assessment and management in the EU