Istituto di Ingegneria Biomedica     
Murphy R., Tura A., Clark P., Holst J. J., Mari A., Hattersley A. Glucokinase, the pancreatic glucose sensor, is not the gut glucose sensor. In: Diabetologia, vol. 52 (1) pp. 154 - 9. Springer, 2009.
AIMS/HYPOTHESIS: The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic peptide (GIP) are released from intestinal endocrine cells in response to luminal glucose. Glucokinase is present in these cells and has been proposed as a glucose sensor. The physiological role of glucokinase can be tested using individuals with heterozygous glucokinase gene (GCK) mutations. If glucokinase is the gut glucose sensor, GLP-1 and GIP secretion during a 75 g OGTT would be lower in GCK mutation carriers compared with controls. METHODS: We compared GLP-1 and GIP concentrations measured at five time-points during a 75 g OGTT in 49 participants having GCK mutations with those of 28 familial controls. Mathematical modelling of glucose, insulin and C-peptide was used to estimate basal insulin secretion rate (BSR), total insulin secretion (TIS), beta cell glucose sensitivity, potentiation factor and insulin secretion rate (ISR). RESULTS: GIP and GLP-1 profiles during the OGTT were similar in GCK mutation carriers and controls (p = 0.52 and p = 0.44, respectively). Modelled variables of beta cell function showed a reduction in beta cell glucose sensitivity (87 pmol min(-1) m(-2) [mmol/l](-1) [95% CI 66-108] vs 183 pmol min(-1) m(-2) [mmol/l](-1) [95% CI 155-211], p < 0.001) and potentiation factor (1.5 min [95% CI 1.2-1.8] vs 2.2 min [95% CI 1.8-2.7], p = 0.007) but no change in BSR or TIS. The glucose/ISR curve was right-shifted in GCK mutation carriers. CONCLUSIONS/INTERPRETATION: Glucokinase, the major pancreatic glucose sensor, is not the main gut glucose sensor. By modelling OGTT data in GCK mutation carriers we were able to distinguish a specific beta cell glucose-sensing defect. Our data suggest a reduction in potentiation of insulin secretion by glucose that is independent of differences in incretin hormone release.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18974968
Subject Beta cell function
Incretin hormones
Oral glucose tolerance test

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