| 1. |
- Oduori, O. S., et al.
(author)
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Gs/Gq signaling switch in beta cells defines incretin effectiveness in diabetes
- 2020
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In: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:12, s. 6639-6655
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Journal article (peer-reviewed)abstract
- By restoring glucose-regulated insulin secretion, glucagon-like peptide-1-based (GLP-1-based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic beta cells. However, the reason why only GLP-1-based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K+ (K-ATP) channels play a crucial role in coupling the systemic metabolic status to beta cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of beta cells due to genetic cell-specific Kcnj11(-/-)mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the K-ATP channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse beta cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in beta cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.
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| 2. |
- Peterson, Q. P., et al.
(author)
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A method for the generation of human stem cell-derived alpha cells
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease progression and proper glucose control. Here we report on the generation of stem cell-derived human pancreatic alpha (SC-alpha) cells from pluripotent stem cells via a transient pre-alpha cell intermediate. These pre-alpha cells exhibit a transcriptional profile similar to mature alpha cells and although they produce proinsulin protein, they do not secrete significant amounts of processed insulin. Compound screening identified a protein kinase c activator that promotes maturation of pre-alpha cells into SC-alpha cells. The resulting SC-alpha cells do not express insulin, share an ultrastructure similar to cadaveric alpha cells, express and secrete glucagon in response to glucose and some glucagon secretagogues, and elevate blood glucose upon transplantation in mice. Deriving functional pancreatic cell types from human stem cells may have important clinical applications. Building on previous work, here the authors generate stem cell-derived alpha cells via a polyhormonal intermediate, which have a gene expression pattern similar to human islet alpha cells and behave as such when transplanted into mice.
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| 3. |
- Zhang, Q., et al.
(author)
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'Resistance is futile?' - paradoxical inhibitory effects of K-ATP channel closure in glucagon-secreting alpha-cells
- 2020
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In: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 598:21, s. 4765-4780
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Journal article (peer-reviewed)abstract
- By secreting insulin and glucagon, the beta- and alpha-cells of the pancreatic islets play a central role in the regulation of systemic metabolism. Both cells are equipped with ATP-regulated potassium (K-ATP) channels that are regulated by the intracellular ATP/ADP ratio. In beta-cells, K-ATP channels are active at low (non-insulin-releasing) glucose concentrations. An increase in glucose leads to K-ATP channel closure, membrane depolarization and electrical activity that culminates in elevation of [Ca2+](i) and initiation of exocytosis of the insulin-containing secretory granules. The alpha-cells are also equipped with K-ATP channels but they are under strong tonic inhibition at low glucose, explaining why alpha-cells are electrically active under hypoglycaemic conditions and generate large Na+- and Ca2+-dependent action potentials. Closure of residual K-ATP channel activity leads to membrane depolarization and an increase in action potential firing but this stimulation of electrical activity is associated with inhibition rather than acceleration of glucagon secretion. This paradox arises because membrane depolarization reduces the amplitude of the action potentials by voltage-dependent inactivation of the Na(+)channels involved in action potential generation. Exocytosis in alpha-cells is tightly linked to the opening of voltage-gated P/Q-type Ca2+ channels, the activation of which is steeply voltage-dependent. Accordingly, the inhibitory effect of the reduced action potential amplitude exceeds the stimulatory effect resulting from the increased action potential frequency. These observations highlight a previously unrecognised role of the action potential amplitude as a key regulator of pancreatic islet hormone secretion.
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