Glucokinase, the pancreatic glucose sensor, is not the gut glucose sensor.
OBJECTIVE
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
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.
Murphy
R
R
Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Tura
A
A
Clark
P M
PM
Holst
J J
JJ
Mari
A
A
Hattersley
A T
AT
D000293:Adolescent; D000328:Adult; D000368:Aged; D015374:Biosensing Techniques; D002096:C-Peptide / Q000032:analysis; D005260:Female; D005941:Glucokinase / Q000097:blood* / Q000235:genetics*; D005947:Glucose / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D007422:Intestines / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010179:Pancreas / Q000502:physiology*; D055815:Young Adult
D002096:C-Peptide; D054795:Incretins; D007328:Insulin; D005941:Glucokinase; D005947:Glucose