Pancreatic effects of GLP-1

Glucagon-like peptide-1 (GLP-1) is a key hormone for regulation of blood glucose and satiety in humans. It is produced by L-cells of the gut epithelium and is particularly known as an incretin hormone that reduces post prandial blood glucose levels by stimulation of insulin secretion in a glucose-dependent manner. But perhaps equally importantly, GLP-1’s glucose lowering effects are attributable to a strong inhibition of glucagon secretion, and, thereby, a reduction of hepatic glucose output. The effects of GLP-1 on insulin secretion are mediated by binding of the hormone to the receptor (GLP-1r) on the pancreatic β-cell, which increases intracellular cAMP levels and sets in motion a plethora of events that lead to secretion. In contrast, the inhibitory effect of GLP-1 on the α-cell may be indirect, involving paracrine intra-islet regulation by somatostatin and possibly also insulin, although GLP-1 also inhibits glucagon secretion in patients with type 1 diabetes mellitus. Besides these acute effects on the endocrine pancreas, GLP-1 also appears to have a positive effect on β-cell mass. In the following we will review GLP-1’s pancreatic effects with particular focus on its effects on pancreatic islets hormone secretion.

Effects of GLP-1 on the endocrine pancreas

GLP-1 stimulates glucose-dependent insulin secretion

GLP-1 is secreted upon meal intake by nutrient-specific activation of different secretory pathways (see; Incretin secretion: direct mechanisms). At the level of the pancreas, GLP-1 acts to potentiate glucose-stimulated insulin secretion, in healthy subjects accounting for 25-70% of the total postprandial release when the additive effect of the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP) is also taken into account. This action is accomplished by binding of GLP-1 to its Gαs-coupled receptor (GLP-1r), consequently increasing intracellular cAMP levels by activation of adenylate cyclase.

Subsequent activation of protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factor II (cAMP-GEFII, also known as Epac2) leads to a plethora of events that stimulates secretion. These events involve 1) PKA-mediated phosphorylation of ATP-sensitive potassium channels (KATP), acting synergistically with glucose to cause channel closure and cell membrane depolarization; 2) antagonistic effects of GLP-1 on the delayed rectifying K-channels (K+), which are responsible for cell repolarization, causing increased excitability and prolongation of action potential duration in the beta cells; 3) an influx of calcium (through voltage-gated calcium channels, activated by 1) and 2) ) which mobilizes intra-cellular calcium from ER stores by calcium-induced calcium release and by PKA-dependent (IP3 mediated) mechanisms, leading to secretion 4) Calcium mobilization from intra-cellular stores may then stimulate mitochondrial ATP synthesis, potentiating the secretory response by delaying repolarization further. 5) Finally, the events above are potentiated by PKA- and Epac2-dependent recruitment of secretory granules to the pool of rapid releasable vesicles. Indeed, this last mechanism is believed to be quantitatively the most important for GLP-1’s potentiating effects on glucose-stimulated insulin secretion.

Importantly, none of the GLP-1-mediated effects alone appears to be able to trigger insulin secretion; the potentiation of insulin secretion by GLP-1 is strictly glucose-dependent and relies on a combination of glucose metabolism to provide the substrate for KATP channel closure and cAMP formation. Therefore, when blood glucose concentrations increase, GLP-1 acts to augment glucose-stimulated insulin secretion in a potentiating manner; in contrast, during fasting state the effect of GLP-1 is lost [1]. These effects have made GLP-1 an attractive drug for type-2-diabetes treatment as overdosing or inadequate timing of intake is unlikely to result in hypoglycemic events, as often observed in patients treated with sulphonylurea and exogenous insulin. GLP-1’s glucose-dependent mode of action may, however, be uncoupled if administered together with sulfonylurea compounds (e.g. glimepiride), which bind directly the KATP channel subunit and lower their opening probability. This causes depolarization and intracellular Ca2+ increases, processes that GLP-1 will potentiate and which results in insulin release, even at low blood glucose concentrations[1].

GLP-1 inhibits glucagon secretion, but how?

Although most studies and descriptions of the pancreatic effects of GLP-1 concerns the insulinotropic effects, its glucagonostatic effect (inhibition of glucagon secretion) is also important for GLP-1s anti-diabetic effect because it contributes to a reduced hepatic glucose production[2]. Thus, pancreatic clamp studies in humans, which allow discrimination between alpha- and beta-cell mediated effects, showed that the glucagonostatic and insulinotropic effects of GLP-1 contribute equally to its blood glucose lowering actions [3]. For GLP-1 to exert direct effects on the alpha cell, presence of its receptor (GLP-1r) would be required, but the current data on this is inconclusive, as some studies show that the receptor is present while others conclude that it is not [4]. Part of the explanation for this may be that the commercially available antibodies against this receptor are unspecific [5], meaning that a reliable localization of GLP-1r expression is currently difficult to achieve by immunohistochemistry. Substantial efforts are, however, devoted to the generation of improved antibodies[6]; in addition , generation of transgenic mice showing cell specific expression of receptor-linked fluorescent markers has enabled anti-body free detection of GLP-1r [7].

Given absence of GLP-1r expression on alpha cells, the glucagonostatic effects of GLP-1 may involve stimulation of somatostatin secretion from the pancreatic delta-cell, which then would inhibit glucagon secretion in a paracrine manner. In favor of this hypothesis, studies on isolated perfused rat pancreas have demonstrated that small molecule antagonist of the somatostatin receptor (subtype 2) abolished the effects of GLP-1 on glucagon secretion; similarly, antibody neutralization of somatostatin actions increased alpha cell secretory output [8][9]. Other studies, employing different somatostatin neutralizing antibodies, showed no effect of somatostatin on glucagon secretion [10], but immunoneutralization is critically dependent on the affinity and concentration of the antibodies employed, and negative results do not carry significant weight[11].

It was previously believed that the microvasculature of the rat pancreatic islets directs flow from beta- to alpha- to delta-cells [12][13], meaning that increased somatostatin secretion would not be detected by the alpha cells. However, more recent studies with improved techniques do not support this view[14].

Again it should be emphasized that in Type 1 Diabetic individuals with no residual beta cell function, GLP-1 still powerfully inhibits glucagon secretion, excluding at least insulin from the equation. Assuming that human alpha cells do not, whereas the somatostatin cells clearly do express GLP-1 receptors[15], a role for intra-islet somatostatin currently seems most likely to explain why type 2 diabetic patients treated with GLP-1 analogues have significant reductions in plasma glucagon concentrations[16][17].

Effects of GLP-1 on beta-cell mass

Studies in rodents have indicated that expansion of the beta-cell mass allows them to adapt adequately to increased insulin demands, e.g. under pregnancy and in states of insulin resistance.Whether these adaptive changes may be caused by beta-cell proliferation, inhibition of apoptosis or both is, however, not fully understood. Could GLP-1 play a role in these processes? Indeed, some studies show an effect of GLP-1 on both proliferation and apoptosis while others only demonstrate an effect on one of these[18]. Based on these observations it could be speculated that GLP-1 may play a role for beta-cell expansion in humans, but as beta-cell mass only can be reliable determined post mortem, no direct data exist to support this. However, as human beta-cells are not thought to proliferate after birth, the current balance of data does not favor that GLP-1 may enhance β-mass by proliferation.

Nevertheless, GLP-1 based treatments may improve beta-cell function (and perhaps beta-cell health) in type-2-diabetic subjects, since 3 years of treatment with Exenatide resulted in completely preserved beta cell function; a decreased would have expected over this time span as indicated by the UKPDS study, but if anything, a small improvement was observed. However, there were no clear functional signs of beta cell expansion.


  1. ^ de Heer, J. and J.J. Holst, Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1. Diabetes, 2007. 56(2): p. 438-443.

  2. ^ Hvidberg, A., et al., Effect of glucagon-like peptide-1 (proglucagon 78-107amide) on hepatic glucose production in healthy man. Metabolism, 1994. 43(1): p. 104-108.

  3. ^ Hare, K.J., et al., The Glucagonostatic and Insulinotropic Effects of Glucagon-Like Peptide 1 Contribute Equally to Its Glucose-Lowering Action. Diabetes, 2010. 59(7): p. 1765-1770.

  4. ^ Drucker, D.J., Incretin Action in the Pancreas: Potential Promise, Possible Perils, and Pathological Pitfalls. Diabetes, 2013. 62(10): p. 3316-3323.

  5. ^ Pyke , C. and L.B. Knudsen, The Glucagon-Like Peptide-1 Receptor—or Not? Endocrinology, 2013. 154(1): p. 4-8.

  6. ^ Pyke, C., et al., GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology, 2014. 155(4): p. 1280-90.

  7. ^ Richards, P., et al., Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes, 2014. 63(4): p. 1224-33.

  8. ^ Heer, J., et al., Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas, in Diabetologia. 2008, Springer-Verlag. p. 2263-2270.

  9. ^ Cejvan, K., D.H. Coy, and S. Efendic, Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats. Diabetes, 2003. 52(5): p. 1176-1181.

  10. ^ Samols, E. and J.I. Stagner, Islet somatostatin--microvascular, paracrine, and pulsatile regulation. Metabolism, 1990. 39(9 Suppl 2): p. 55-60.

  11. ^ Brand, C.L., et al., Role of glucagon in maintenance of euglycemia in fed and fasted rats. Am J Physiol, 1995. 269(3 Pt 1): p. E469-77.

  12. ^ Samols, E., et al., The order of islet microvascular cellular perfusion is B----A----D in the perfused rat pancreas. The Journal of Clinical Investigation, 1988. 82(1): p. 350-353.

  13. ^ Jansson, L., The regulation of pancreatic islet blood flow. Diabetes/Metabolism Reviews, 1994. 10(4): p. 407-416.

  14. ^ Bosco, D., et al., Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes, 2010. 59(5): p. 1202-10.

  15. ^ Waser, B., et al., Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol, 2014.

  16. ^ Drucker, D.J., et al., Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet, 2008. 372(9645): p. 1240-50.

  17. ^ Zander, M., et al., Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet, 2002. 359(9309): p. 824-30.

  18. ^ Wajchenberg, B.L., beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev, 2007. 28(2): p. 187-218.


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