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Commentaries

Species-Dependent Mechanisms Regulating Glucose-Dependent GLP-1 Secretion?

  1. Patricia L. Brubaker⇑
  1. Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada
  1. Corresponding author: Patricia L. Brubaker, p.brubaker{at}utoronto.ca.
Diabetes 2017 Aug; 66(8): 2063-2065. https://doi.org/10.2337/dbi17-0020
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Since the discovery of glucagon-like peptide 17–36NH2 (GLP-1) as an “incretin” hormone (1), numerous GLP-1 receptor agonists and incretin hormone degradation (dipeptidyl peptidase 4) inhibitors have been developed for the treatment of patients with type 2 diabetes (2). The success of these therapeutics in reducing HbA1c levels, as well as decreasing body weight and exerting cardioprotective actions in the case of the agonists, has been well established, and incretin-based drugs are now recommended for dual-therapy management of type 2 diabetes (3). However, considerable interest has been engendered in a third possible approach to GLP-1–based therapy, that being enhancement of endogenous secretion, either alone or with a degradation inhibitor (4). GLP-1 is secreted by the endocrine L cell of the intestinal epithelium in rodents and humans (5). GLP-1 release is stimulated by ingested nutrients, including glucose, although neural and hormonal secretagogues have also been described (4). However, a thorough understanding of the molecular underpinnings of human L-cell secretory responses is critical if GLP-1 secretagogues are to be considered for therapeutic use.

L cells are diffusely scattered through the gut epithelium, providing a major challenge to their study (5). Furthermore, although the advent of techniques to fluorescently label murine L cells has enabled their isolation, purified L cells fail to survive in vitro (6). Consequently, the cellular mechanisms underlying GLP-1 secretion by the primary murine L cell are now commonly studied using heterogeneous cultures derived from isolated crypts (6,7). Such in vitro models have been generated from all regions of the mouse intestine, although most reports have focused on the proximal 50% of the small intestine and the colon. These studies have elucidated the major signaling pathways that underlie the regulation of GLP-1 release by the murine L cell, including, most notably, the response to glucose (Fig. 1) (6,7). Although similar approaches have been used to culture human crypt cells, the majority of such studies have focused on the colon, a relatively accessible site for tissue sampling (8). The article by Sun et al. (9) in this issue of Diabetes presents novel insight into the cellular mechanisms underlying glucose-stimulated GLP-1 secretion by the human L cell, using biopsies obtained from not only the colon but also the duodenum and ileum.

Figure 1
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Figure 1

Signaling pathways regulating glucose-stimulated GLP-1 secretion in primary human ileal mucosal biopsy samples as compared with primary murine upper small intestinal (SI; proximal 50%) and colonic crypt cultures. Marked differences in sensitivity to glucose are apparent, as well as in some of the downstream pathways. Solid lines indicate demonstrated significant pathways in the L-cell secretory response to glucose, whereas dashed lines indicate pathways that appear to be of lesser importance. VDCC, voltage-dependent calcium channel; VGNaC, voltage-gated sodium channel.

In the first part of the study, healthy subjects received an intraduodenal glucose infusion followed by collection of duodenal biopsies after 30 min for immunostaining; plasma was also obtained to determine circulating GLP-1 levels (9). Consistent with findings in rats (10), luminal glucose induced a 70% increase in the number of human duodenal L cells expressing phosphorylated calcium calmodulin–dependent kinase II, an enzyme that links extracellular glucose to insulin secretion in the β-cell (11). A parallel increase was also observed in plasma GLP-1 levels, although the exact source of this GLP-1 cannot be identified, as the rate of infusion and single time point of sampling almost certainly would have permitted glucose activation of the more abundant jejunal L cells (5,12). Consistent with this possibility, GLP-1 release is much greater following intrajejunal as compared with intraduodenal infusion of glucose in normal humans (13).

In the second part of the study, ileal and colonic mucosal biopsies were collected from patients at the time of intestinal surgery (9). These samples, as well as those from the duodenum, were examined acutely for their GLP-1 secretory responses to glucose. Interestingly, the results indicate both similarities to and differences from the murine L cell (Fig. 1). First, as expected based on the mouse studies (6,7), glucose stimulated GLP-1 release from human small intestinal (duodenal and ileal) L cells; however, in contrast to the mouse, human colonic L cells did not respond to glucose. Analysis of the mechanisms underlying ileal L cell glucose sensing demonstrated additional species-dependent intracellular responses. Hence, the human L cell was markedly less sensitive to glucose than that of the mouse (human ileal ≥200 mmol/L vs. mouse proximal ≥1 mmol/L and colonic ≥0.1 mmol/L [Fig. 1]). Both species use the sodium–glucose transporter 1 (SGLT1) as a key mediator of glucose-induced GLP-1 release, translocating one glucose with two Na+; the latter causes depolarization (at least in the murine L cell), leading to opening of voltage-dependent calcium channels and activation of calcium-induced exocytosis. As the Km for Na+ transport by murine SGLT1 is 2–7 times lower than that for human SGLT1 (14,15), these differences may account, in part, for the differential sensitivities of the small intestinal L cells to glucose. In addition, although human small intestinal L cells are known to express SGLT1 (16), it has not been determined that this is the case for human colonic L cells. Furthermore, recent studies have demonstrated that proximal L cells in mice and humans differ markedly from distal L cells in their polyhormonal expression of several other gut endocrine peptides (17,18). As glucose is normally absorbed by the proximal gut, the physiological relevance of any glucose sensing by the distal L cell remains unclear. Nonetheless, as GLP-1 serves as an “ileal brake” to delay intestinal transit (4), such responses may enable feedback in the setting of an overload of proximal absorptive capacity. Indeed, one possible advantage of this distal sensing capacity is observed following malabsorptive bariatric surgery, which directs unusually large volumes of nutrients into the distal small intestine, thereby increasing GLP-1 secretion in association with improved glycemic tolerance (19). Finally, although other subtle differences found between the human and murine L cells relate to roles for the glucose transporter GLUT2, glucose metabolism, the KATP channel, and the taste receptors T1R2/R3, none of these appear to be primary regulators of glucose sensing in either species (Fig. 1).

It must be recognized that there are also experimental differences between the study by Sun et al. (9) and those examining the mouse L cell, including the site of origin (ileal vs. proximal and colonic), the method of ex vivo analysis (explants vs. culture), the use of whole mucosal biopsies containing villus and crypt L cells vs. isolated crypts only, and the limited amount of human tissue available, which precluded testing of multiple complementary inhibitors. Nonetheless, the study by Sun et al. represents a first attempt to systematically analyze the intracellular mechanisms underlying glucose sensing by the human L cell. Ultimately, although similarities between the murine and human L cell will suggest potential therapeutic targets for GLP-1 secretagogues, it is the differences between these cells that will be the key to success.

Article Information

Funding. P.L.B. is supported by the Canada Research Chairs program. Research studies in the Brubaker laboratory are supported by an operating grant from the Canadian Institutes of Health Research (PJT-148530).

Duality of Interest. P.L.B. has received operating funds from Novo Nordisk and GLyPharma Therapeutic. No other potential conflicts of interest relevant to this article were reported.

Footnotes

  • See accompanying article, p. 2144.

  • © 2017 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

References

  1. ↵
    1. Kreymann B,
    2. Williams G,
    3. Ghatei MA,
    4. Bloom SR
    . Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 1987;2:1300–1304pmid:2890903
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Campbell JE,
    2. Drucker DJ
    . Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013;17:819–837pmid:23684623
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    Chamberlain JJ, Herman WH, Leal S, et al. Pharmacologic therapy for type 2 diabetes: synopsis of the 2017 American Diabetes Association Standards Of Medical Care in Diabetes. Ann Intern Med 2017;166:572–578
  4. ↵
    1. Dong CX,
    2. Brubaker PL
    . Ghrelin, the proglucagon-derived peptides and peptide YY in nutrient homeostasis. Nat Rev Gastroenterol Hepatol 2012;9:705–715pmid:23026903
    OpenUrlCrossRefPubMed
  5. ↵
    1. Eissele R,
    2. Göke R,
    3. Willemer S, et al
    . Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest 1992;22:283–291pmid:1499644
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    1. Reimann F,
    2. Habib AM,
    3. Tolhurst G,
    4. Parker HE,
    5. Rogers GJ,
    6. Gribble FM
    . Glucose sensing in L cells: a primary cell study. Cell Metab 2008;8:532–539pmid:19041768
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Parker HE,
    2. Adriaenssens A,
    3. Rogers G, et al
    . Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion. Diabetologia 2012;55:2445–2455pmid:22638549
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Habib AM,
    2. Richards P,
    3. Rogers GJ,
    4. Reimann F,
    5. Gribble FM
    . Co-localisation and secretion of glucagon-like peptide 1 and peptide YY from primary cultured human L cells. Diabetologia 2013;56:1413–1416pmid:23519462
    OpenUrlCrossRefPubMed
  9. ↵
    1. Sun EW,
    2. de Fontgalland D,
    3. Rabbitt P, et al
    . Mechanisms controlling glucose-induced GLP-1 secretion in human small intestine. Diabetes 2017;66:2144–2149pmid:28385801
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Lee J,
    2. Cummings BP,
    3. Martin E, et al
    . Glucose sensing by gut endocrine cells and activation of the vagal afferent pathway is impaired in a rodent model of type 2 diabetes mellitus. Am J Physiol Regul Integr Comp Physiol 2012;302:R657–R666pmid:22160540
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Easom RA
    . CaM kinase II: a protein kinase with extraordinary talents germane to insulin exocytosis. Diabetes 1999;48:675–684pmid:10102681
    OpenUrlAbstract
  12. ↵
    1. Worsøe J,
    2. Fynne L,
    3. Gregersen T, et al
    . Gastric transit and small intestinal transit time and motility assessed by a magnet tracking system. BMC Gastroenterol 2011;11:145pmid:22206545
    OpenUrlCrossRefPubMed
  13. ↵
    1. Wu T,
    2. Thazhath SS,
    3. Marathe CS, et al
    . Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut-incretin axis response in healthy males. Nutr Diabetes 2015;5:e156pmid:25985092
    OpenUrlPubMed
  14. ↵
    1. Díez-Sampedro A
    . Involvement of amino acid 36 in TM1 in voltage sensitivity in mouse Na+/glucose cotransporter SGLT1. J Membr Biol 2009;227:57–66pmid:19122974
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    1. Sala-Rabanal M,
    2. Hirayama BA,
    3. Loo DD,
    4. Chaptal V,
    5. Abramson J,
    6. Wright EM
    . Bridging the gap between structure and kinetics of human SGLT1. Am J Physiol Cell Physiol 2012;302:C1293–C1305pmid:22159082
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Vrhovac I,
    2. Balen Eror D,
    3. Klessen D, et al
    . Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch 2015;467:1881–1898pmid:25304002
    OpenUrlCrossRefPubMed
  17. ↵
    1. Habib AM,
    2. Richards P,
    3. Cairns LS, et al
    . Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 2012;153:3054–3065pmid:22685263
    OpenUrlCrossRefPubMedWeb of Science
  18. ↵
    1. Egerod KL,
    2. Endelstoft MS,
    3. Grunddal KV, et al
    . A major lineage of enteroendocrine cells co-express CCK, GLP-1, GIP, PYY, neurotensin, and secretin but not somatostatin. Endocrinology 2012;153:5782–5795pmid:23064014
    OpenUrlCrossRefPubMedWeb of Science
  19. ↵
    1. Romero F,
    2. Nicolau J,
    3. Flores L, et al
    . Comparable early changes in gastrointestinal hormones after sleeve gastrectomy and Roux-En-Y gastric bypass surgery for morbidly obese type 2 diabetic subjects. Surg Endosc 2012;26:2231–2239pmid:22302537
    OpenUrlCrossRefPubMed
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Species-Dependent Mechanisms Regulating Glucose-Dependent GLP-1 Secretion?
Patricia L. Brubaker
Diabetes Aug 2017, 66 (8) 2063-2065; DOI: 10.2337/dbi17-0020

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Species-Dependent Mechanisms Regulating Glucose-Dependent GLP-1 Secretion?
Patricia L. Brubaker
Diabetes Aug 2017, 66 (8) 2063-2065; DOI: 10.2337/dbi17-0020
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