TY  - JOUR
A1  - Parker, H. E.
A1  - Adriaenssens, A.
A1  - Rogers, G.
A1  - Richards, P.
A1  - Koepsell, H.
A1  - Reimann, F.
A1  - Gribble, F. M.
T1  - Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion
JF  - Diabetologia
N2  - Aims/hypothesis
Several glucose-sensing pathways have been implicated in glucose-triggered secretion of glucagon-like peptide-1 (GLP-1) from intestinal L cells. One involves glucose metabolism and closure of ATP-sensitive K\(^+\) channels, and another exploits the electrogenic nature of Na\(^+\)-coupled glucose transporters (SGLTs). This study aimed to elucidate the role of these distinct mechanisms in glucose-stimulated GLP-1 secretion.

Methods
Glucose uptake into L cells (either GLUTag cells or cells in primary cultures, using a new transgenic mouse model combining proglucagon promoter-driven Cre recombinase with a ROSA26tdRFP reporter) was monitored with the FLII\(_{12}\)Pglu-700μδ6 glucose sensor. Effects of pharmacological and genetic interference with SGLT1 or facilitative glucose transport (GLUT) on intracellular glucose accumulation and metabolism (measured by NAD(P)H autofluorescence), cytosolic Ca\(^{2+}\) (monitored with Fura2) and GLP-1 secretion (assayed by ELISA) were assessed.

Results
L cell glucose uptake was dominated by GLUT-mediated transport, being abolished by phloretin but not phloridzin. NAD(P)H autofluorescence was glucose dependent and enhanced by a glucokinase activator. In GLUTag cells, but not primary L cells, phloretin partially impaired glucose-dependent secretion, and suppressed an amplifying effect of glucose under depolarising high K\(^+\) conditions. The key importance of SGLT1 in GLUTag and primary cells was evident from the impairment of secretion by phloridzin or Sglt1 knockdown and failure of glucose to trigger cytosolic Ca\(^{2+}\) elevation in primary L cells from Sglt1 knockout mice.

Conclusions/interpretation
SGLT1 acts as the luminal glucose sensor in L cells, but intracellular glucose concentrations are largely determined by GLUT activity. Although L cell glucose metabolism depends partially on glucokinase activity, this plays only a minor role in glucose-stimulated GLP-1 secretion.
KW  - KATP channel
KW  - glucokinase
KW  - glucagon-like peptide-1 (GLP-1)
KW  - SGLT1
KW  - L cells
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125927
VL  - 55
IS  - 9
ER  -