Somatostatin Receptors Shape Insulin and Glucagon Output within the Pancreatic Islet through Direct and Paracrine Effects
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Aims/Hypothesis
Pancreatic delta cells secrete somatostatin (SST), which can inhibit both alpha and beta cells of the pancreatic islet. By controlling insulin and glucagon release, delta cells play an important role in maintaining nutrient homeostasis. However, the mechanism by which a single inhibitory hormone inhibits both alpha and beta cells, which are often considered as functional antagonists in the counterregulatory control of blood glucose, has been a physiological riddle. Here, we solve this riddle through assessment of the contributions of alpha and beta cell specific somatostatin receptors to cell intrinsic behaviors and hormone release.
Methods
Islets from mice constitutively expressing fluorescent sensors reporting on cyclic AMP and Ca 2+ in both alpha and beta cells were imaged using stimuli to mimic the post-prandial state of a meal consisting of glucose and amino acids. This approach was coupled with cell specific somatostatin receptor antagonists to identify how somatostatin inhibits alpha and beta cell hormone output through modulation of cAMP and Ca 2+ secondary messengers and paracrine interactions.
Results
Our results support and extend prior observation that somatostatin receptor 2 (SSTR2) is the only somatostatin receptor expressed by alpha cells, while somatostatin receptor 3 (SSTR3) is the only receptor expressed by mouse beta cells. Interestingly, SSTR2 and SSTR3 regulate downstream cAMP and Ca 2+ signaling cascades differently within alpha and beta cells of intact islets. Stimulation of somatostatin receptors robustly inhibits cyclic AMP in alpha or beta cells. In contrast, stimulation of SSTR2 inhibits alpha cell Ca 2+ with significantly greater potency compared to inhibition of beta cell Ca 2+ via SSTR3. Despite the absence of SSTR2 on beta cells, blocking alpha cell SSTR2 during nutrient stimulation resulted in a significant increase in insulin release downstream of local release of glucagon.
Conclusions/Interpretation
Our observations address the physiological riddle of the delta cell’s role during the post-prandial phase where we demonstrate that somatostatin primarily inhibits alpha cell cAMP and Ca 2+ via SSTR2, preventing glucagon release. Blocking SSTR2 resulted in an increase in locally released glucagon, which coupled with muted ability for SSTR3 to inhibit beta cell calcium under strong nutrient stimulation, results in potentiation of glucose stimulated insulin secretion from the beta cell. We conclude that the role of delta cells under nutrient stimulation is to modulate the volume of insulin release by tuning the strength of intra-islet paracrine potentiation of insulin secretion by glucagon, mediated via beta cell GLP1R.
Research in Context
What is already known about this subject?
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Somatostatin released by delta cells can attenuate glucagon release from the alpha cells and insulin release from the beta cells of the islet through inhibitory somatostatin receptors.
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Somatostatin receptor 2 is a major receptor expressed on the mouse alpha cell surface, while mouse beta cells express SSTR3 on their primary cilia.
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Paracrine signaling by alpha cell glucagon potentiates insulin release through the engagement of stimulatory glucagon-like peptide 1 receptors on beta cells.
What are the key questions?
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How do the cell specific somatostatin receptors of the alpha cell (SSTR2) and beta cell (SSTR3) differentially regulate cell-intrinsic Ca2+ and cAMP signaling and the indirect paracrine pathways that shape insulin secretion in the post-prandial state?
What are the new findings?
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Alpha cells of the mouse islet express exclusively SSTR2 and not SSTR3.
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Somatostatin is a more potent inhibitor of cytosolic calcium activity via alpha cell SSTR2 compared to beta cell SSTR3.
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Preventing somatostatin inhibition of the alpha cell in the presence of elevated glucose and amino acids potentiates insulin release through the engagement of glucagon-like peptide 1 receptors on the beta cell by glucagon.
How might this impact on clinical practice in the foreseeable future?
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Our findings indicate that local feedback inhibition of beta cells is accomplished by tuning the strength of the paracrine potentiation of locally released glucagon. This is relevant in the context of developing treatments for hypoglycemia with alpha cell specific SSTR2-specific antagonists that could potentiate insulin release and potentially exacerbate hypoglycemic episodes.
