Mechanisms Controlling Glucose-Induced GLP-1 Secretion in Human Small Intestine

被引：104

作者：

Sun, Emily W. ^{[1
,2
]}

de Fontgalland, Dayan ^{[3
]}

Rabbitt, Philippa ^{[3
]}

Hollington, Paul ^{[3
]}

Sposato, Luigi ^{[3
]}

Due, Steven L. ^{[3
]}

Wattchow, David A. ^{[3
]}

Rayner, Christopher K. ^{[4
,5
,6
]}

Deane, Adam M. ^{[4
,5
,7
]}

Young, Richard L. ^{[4
,5
,8
]}

Keating, Damien J. ^{[1
,2
,8
]}

机构：

[1] Flinders Univ S Australia, Discipline Human Physiol, Adelaide, SA, Australia

[2] Flinders Univ S Australia, Ctr Neurosci, Adelaide, SA, Australia

[3] Flinders Univ S Australia, Discipline Surg, Adelaide, SA, Australia

[4] Univ Adelaide, Adelaide Med Sch, Adelaide, SA, Australia

[5] Univ Adelaide, Natl Hlth & Med Res Council, Ctr Res Excellence Translating Nutr Sci Good Hlth, Adelaide, SA, Australia

[6] Royal Adelaide Hosp, Dept Gastroenterol & Hepatol, Adelaide, SA, Australia

[7] Royal Adelaide Hosp, Intens Care Unit, Adelaide, SA, Australia

[8] South Australian Hlth & Med Res Inst, Nutr & Metab, Adelaide, SA, Australia

来源：

DIABETES | 2017年 / 66卷 / 08期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

D O I：

10.2337/db17-0058

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Intestinal glucose stimulates secretion of the incretin hormone glucagon-like peptide 1 (GLP-1). The mechanisms underlying this pathway have not been fully investigated in humans. In this study, we showed that a 30-min intraduodenal glucose infusion activated half of all duodenal L cells in humans. This infusion was sufficient to increase plasma GLP-1 levels. With an ex vivo model using human gut tissue specimens, we showed a dose-responsive GLP-1 secretion in the ileum at 200 mmol/L glucose. In ex vivo tissue from the duodenum and ileum, but not the colon, 300 mmol/L glucose potently stimulated GLP-1 release. In the ileum, this response was independent of osmotic influences and required delivery of glucose via GLUT2 and mitochondrial metabolism. The requirement of voltage-gated Na+ and Ca2+ channel activation indicates that membrane depolarization occurs. K-ATP channels do not drive this, as tolbutamide did not trigger release. The sodium-glucose cotransporter 1 (SGLT1) substrate -MG induced secretion, and the response was blocked by the SGLT1 inhibitor phlorizin or by replacement of extracellular Na+ with N-methyl-d-glucamine. This is the first report of the mechanisms underlying glucose-induced GLP-1 secretion from human small intestine. Our findings demonstrate a dominant role of SGLT1 in controlling glucose-stimulated GLP-1 release in human ileal L cells.

引用

页码：2144 / 2149

页数：6

共 21 条

[1] Baggio L.L., Drucker D.J., Biology of incretins: GLP-1 and GIP, Gastroenterology, 132, pp. 2131-2157, (2007)
[2] D'Alessio D.A., Kahn S.E., Leusner C.R., Ensinck J.W., Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal, J Clin Invest, 93, pp. 2263-2266, (1994)
[3] Holst J.J., Madsbad S., Mechanisms of surgical control of type 2 diabetes: GLP-1 is key factor, Surg Obes Relat Dis, 12, pp. 1236-1242, (2016)
[4] Theodorakis M.J., Carlson O., Michopoulos S., Et al., Human duodenal enteroendocrine cells: Source of both incretin peptides, GLP-1 and GIP, Am J Physiol Endocrinol Metab, 290, pp. E550-E559, (2006)
[5] Tolhurst G., Reimann F., Gribble F.M., Nutritional regulation of glucagon-like peptide-1 secretion, J Physiol, 587, pp. 27-32, (2009)
[6] Reimann F., Habib A.M., Tolhurst G., Parker H.E., Rogers G.J., Gribble F.M., Glucose sensing in L cells: A primary cell study, Cell Metab, 8, pp. 532-539, (2008)
[7] Gorboulev V., Schurmann A., Vallon V., Et al., Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion, Diabetes, 61, pp. 187-196, (2012)
[8] Parker H.E., Adriaenssens A., Rogers G., Et al., Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion, Diabetologia, 55, pp. 2445-2455, (2012)
[9] Roder P.V., Geillinger K.E., Zietek T.S., Thorens B., Koepsell H., Daniel H., The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing, PLoS One, 9, (2014)
[10] Kuhre R.E., Frost C.R., Svendsen B., Holst J.J., Molecular mechanisms of glucosestimulated GLP-1 secretion from perfused rat small intestine, Diabetes, 64, pp. 370-382, (2015)

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