Physiology and Pathophysiology of Hormone Secretion from lslets of Langerhans
Abstract
Diabetes is a metabolic disorder stemming from the improper regulation of blood glucose levels by hormones secreted by pancreatic islets of Langerhans. Paper I describes the mechanism by which glucose can regulate glucagon secretion, independent of membrane potential, from pancreatic α-cells, via modulation of endoplasmic reticulum Ca2+ handling. Paper II shows that the GLP-1 metabolite GLP-1(9-36) acts directly on α-cells to inhibit glucagon secretion, via activation of Gi-coupled glucagon receptors. Paper III, shows that the islet autoantigen tetraspanin-7 regulates β-cell transmembrane Ca2+ influx and the Ca2+ sensitivity of exocytosis. Paper IV demonstrates that α-cells and their neighbouring δ-cells exhibit a novel paracrine signalling loop. δ-cells react to the activity of adjacent α-cells, secreting somatostatin, to prevent glucagon hypersecretion. This mechanism becomes sensitised following exposure to hypoglycaemia, leading to excessive intra-islet somatostatin secretion, impairing glucose counter-regulation. Together, these papers reveal novel mechanisms governing the regulation of islet hormone secretion, which may lead to improvements in therapies for diabetes.
Parts of work
1. Acreman, S., Ma, J., Denwood, G., Gao, R., Rorsman, P., Zhang, Q. The
endoplasmic reticulum plays a key role in α-cell intracellular Ca2+ dynamics
and glucose-regulated glucagon secretion. Manuscript 2. Gandasi, N.R., Gao, R., Kothegala, K., Pearce, A., Santos, C., Acreman, S.,
Basco, D., Benrick, A., Chibalina, M.V., Clark, A., Guida, C., Harris, M.,
Johnson, P.R.V., Knudsen, J.G., Ma, J., Miranda, C., Shigeto, M., Tarasov,
A.I., Yeung, H.Y., Thorens, B., Wernstedt Asterholm, I., Zhang, Q.,
Ramracheya, R., Ladds, G., Rorsman, P. GLP-1 metabolite GLP-1(9-36) is a
systemic inhibitor of mouse and human pancreatic islet glucagon secretion. Manuscript 3. McLaughlin, K., Acreman, S., Nawaz, S., Cutteridge, J., Clark, A., Knudsen,
J.G., Denwood, G., Spigelman, A.F., Manning Fox, J.E., Singh, S.P.,
MacDonald, P.E., Hastoy, B., Zhang, Q. Loss of tetraspanin-7 expression
reduces pancreatic β-cell exocytosis Ca2+ sensitivity but has limited effect on
systemic metabolism. Diabetic Medicine 2022; 39(12):e14984. http://doi.org/10.1111/dme.14984 4. Gao, R., Acreman, S., Ma, J., Miranda, C., Dou, H., Zhao, R., Maghera, J., Ellis, C., Dickerson, M., Tarasov, A., Clark, A., Yang, T., Gilon, P., Macdonald, P.E., Jacobson, D.A., Rorsman, P., Zhang, Q. A mechanism for rapid cross-talk between pancreatic α- and δ-cells and its role in hypoglycaemia-induced glucagon secretory failure. Manuscript
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Neuroscience and Physiology. Department of Physiology
Disputation
Fredagen den 17 november 2023, kl. 13.00, Sal 2119, Hus 2, Hälsovetarbacken, Arvid Wallgrens backe 5, Göteborg
Date of defence
2023-11-17
Samuel.acreman@gu.se
Date
2023-10-30Author
Acreman, Samuel
Keywords
Islet
diabetes
glucagon
insulin
somatostatin
incretin
pancreas
hypoglycaemia
tetraspanin
GLP-1
endoplasmic reticulum
Publication type
Doctoral thesis
ISBN
978-91-8069-485-8 (TRYCK)
978-91-8069-486-5 (PDF)
Language
eng