Journal
DIABETOLOGIA
Volume 55, Issue 9, Pages 2445-2455Publisher
SPRINGER
DOI: 10.1007/s00125-012-2585-2
Keywords
Glucagon-like peptide-1 (GLP-1); Glucokinase; K-ATP channel; L cells; SGLT1
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Funding
- Wellcome Trust [WT088357, WT084210]
- Deutsche Forschungsgemeinschaft [SFB 487/C1]
- MRC Centre for Obesity and Related Metabolic Diseases (Cambridge)
- Medical Research Council [G0600717B] Funding Source: researchfish
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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. 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-700 mu I ' 6 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 Ca2+ (monitored with Fura2) and GLP-1 secretion (assayed by ELISA) were assessed. 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 Ca2+ elevation in primary L cells from Sglt1 knockout mice. 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.
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