Project description:Hyperglycemia commonly occurs during surgery due to a reaction to metabolic stress and trauma. It has been shown that improper glycemia control leads to impaired wound healing and a higher risk of other postoperative complications.
The primary aim of our project is to assess the feasibility of the use of continuous glucose monitoring in measuring blood glucose levels in patients undergoing colorectal cancer surgery. The secondary aim is to analyze changes in perioperative blood glucose levels to understand the effects of stress and intraoperative interventions on the blood glucose level. The tertiary goal is to assess the predictive value of hyperglycemia for surgical site infection.
Project description:While much is known about glucose metabolism in yeast, less is known about the receptors and signaling pathways that indicate glucose availability. Here we compared wildtype and 16 mutants in yeast glucose sensing pathway for their transcriptomics profiles in 0.05% glucose vs 10 min after glucose addition to 2% glucose. With these data, we were able to define various roles of glucose sensing pathway components. We demonstrated that the G protein-coupled receptor (Gpr1/Gpa2) directed early events in glucose utilization, the transceptors (SNF3/RGT2) regulated subsequent processes and downstream products of glucose metabolism. Whereas the large G protein transmits the signal from its cognate receptor, Ras2 (but not Ras1) integrates responses from both receptor pathways. We also determined the relative contributions of the Gα (Gpa2) and Gβ (Asc1) protein subunits to glucose-initiated processes in yeast. We determined that Gpa2 is primarily involved in regulating carbohydratesugar metabolism while Asc1 is primarily involved in amino acid metabolism. Both proteins are involved in regulating purine metabolism. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast.
Project description:We assessed the impact of glucose transporter Glut2 gene inactivation in adult mouse liver (LG2KO mice). This suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was normal early after Glut2 inactivation but intolerance developed at later time. This was caused by progressive impairment of glucose-stimulated insulin secretion even though beta-cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinate down-regulation of cholesterol biosynthesis genes in LG2KO mice. This was associated with reduced hepatic cholesterol in fasted mice and a 30 percent reduction in bile acid production. We showed that chronic bile acids or FXR agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from fxr-/- mice. Collectively, our data show that glucose sensing by the liver controls beta-cell glucose competence, through a mechanism that likely depends on bile acid production and action on beta-cells.
Project description:Saccharomyces cerevisiae developed elegant mechanisms to monitor nutrient availability and trigger adaptative responses to nutrient deficiency. Nutrient sensing requires close coordination of cell surface sensors with intracellular mechanisms. This yeast senses the presence of glucose by two modified hexose transporters, Rgt2 and Snf3 (regulating expression of genes encoding hexose transporters) and the G-protein coupled receptor Gpr1 (modulating Protein Kinase A (PKA) activity).. It has been difficult to differentiate between cellular responses mediated by cell surface and intracellular sensors, respectively. Using a strain that is devoid of glucose uptake, we show that the mere presence of glucose does not elicit any glucose-dependent transcriptional responses. This indicates that signals generated by surface sensors are not sufficient to mediate glucose-dependent transcriptional responses. Instead, intracellular glucose or metabolites derived from it are required for transcriptional changes associated with glucose exposure. We used microarrays from biological triplicate samples to measure the global transcriptional response to sudden addition of glucose to yeast cells growing at steady state on ethanol. The experiment was conducted using a strain that is devoid of glucose uptake and compared with an isogenic strain.