Glucokinase, the pancreatic glucose sensor, is not the gut glucose sensor

Diabetologia. 2009 Jan;52(1):154-9. doi: 10.1007/s00125-008-1183-9. Epub 2008 Oct 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biosensing Techniques
  • C-Peptide / analysis
  • Female
  • Glucokinase / blood*
  • Glucokinase / genetics*
  • Glucose / analysis*
  • Glucose / metabolism
  • Humans
  • Incretins / metabolism
  • Insulin / analysis
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology
  • Intestines / physiology*
  • Male
  • Middle Aged
  • Mutation
  • Pancreas / physiology*
  • Young Adult


  • C-Peptide
  • Incretins
  • Insulin
  • Glucokinase
  • Glucose