Background and Purpose
Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined.

Experimental Approach
Apoptosis in pancreatic beta cell apoptosis was evaluated using Hoechst-33342 staining, TUNEL assays and Annexin-V-FITC/PI staining. Insulin secretion and second messenger production were monitored using ELISAs. Protein and phospho-protein levels were determined by Western blotting. A glucose tolerance test was carried out to examine the functions of CCK-8s in streptozotocin-induced diabetic mice.

Key Results
The sulfated carboxy-terminal octapeptide CCK26-33 amide (CCK-8s) activated CCK1 receptors and induced accumulation of both IP3 and cAMP. Whereas Gq-PLC-IP3 signalling was required for the CCK-8s-induced insulin secretion under low-glucose conditions, Gs-PKA/Epac signalling contributed more strongly to the CCK-8s-mediated insulin secretion in high-glucose conditions. CCK-8s also promoted formation of the CCK1 receptor/β-arrestin-1 complex in pancreatic beta cells. Using β-arrestin-1 knockout mice, we demonstrated that β-arrestin-1 is a key mediator of both CCK-8s-mediated insulin secretion and of its the protective effect against apoptosis in pancreatic beta cells. The anti-apoptotic effects of β-arrestin-1 occurred through cytoplasmic late-phase ERK activation, which activates the 90-kDa ribosomal S6 kinase-phospho–Bcl-2-family protein pathway.

Conclusions and Implications
Knowledge of different CCK1 receptor-activated downstream signalling pathways in the regulation of distinct functions of pancreatic beta cells could be used to identify biased CCK1 receptor ligands for the development of new anti-diabetic drugs.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13271

Different downstream signalling of CCK1 receptors regulates distinct functions of CCK in pancreatic beta cells

Insulin is a key metabolic regulator in health and diabetes In pancreatic beta cells, insulin release is regulated by the major second messengers Ca2+ and cAMP: exocytosis is triggered by Ca2+ and mediated by the cAMP/protein kinase A (PKA) signalling pathway However, the causal link between these two processes in primary beta cells remains undefined Time-resolved confocal imaging of fluorescence resonance energy transfer signals was performed to visualise PKA activity, and combined membrane capacitance recordings were used to monitor insulin secretion from patch-clamped rat beta cells Membrane depolarisation-induced Ca2+ influx caused an increase in cytosolic PKA activity via activating a Ca2+-sensitive adenylyl cyclase 8 (ADCY8) subpool Glucose stimulation triggered coupled Ca2+ oscillations and PKA activation ADCY8 knockdown significantly reduced the level of depolarisation-evoked PKA activation and impaired replenishment of the readily releasable vesicle pool Pharmacological inhibition of PKA by two inhibitors reduced depolarisation-induced PKA activation to a similar extent and reduced the capacity for sustained vesicle exocytosis and insulin release Our findings suggest that depolarisation-induced Ca2+ influx plays dual roles in regulating exocytosis in rat pancreatic beta cells by triggering vesicle fusion and replenishing the vesicle pool to support sustained insulin release Therefore, Ca2+ influx may be important for glucose-stimulated insulin secretion

/pdf/calcium-influx-activates-adenylyl-cyclase-8-for-sustained-xzyyacysts.pdf

Calcium influx activates adenylyl cyclase 8 for sustained insulin secretion in rat pancreatic beta cells

Somatostatin secretion from islet delta cells plays an important role in regulating islet function and is tightly controlled by environmental changes. Activation of the adrenergic system promoted somatostatin secretion from islet delta cells; however, the role of the adrenergic system in regulating somatostatin content and transcription has not been defined. An imbalance between the somatostatin content and its secretion may cause dysfunctions in the islet delta cells. We have investigated the role of the adrenergic system in the modulation of somatostatin content and transcription in pancreatic delta cells and the detailed underlying mechanisms of this regulation. The stress hormone adrenaline (epinephrine), specific adrenergic agonists or specific adrenergic antagonists were applied to islets from either wild-type or specific adrenergic receptor knockout mice and pancreatic delta cell lines to investigate their effects on somatostatin content and transcription. The GloSensor assay, quantitative real-time PCR, western blots and the dual luciferase assay were used to monitor the cAMP level, somatostatin expression, activations of kinases and transcriptional factors. Arrb1 knockout mice, specific Creb or Pax6 mutations and specific kinase inhibitors were used to dissect the signalling pathway. Adrenaline and isoprenaline increased somatostatin content and transcription through the activation of β1-/β2-adrenergic receptors (β1-/β2ARs). The somatostatin content in β1AR
 −/−
 /β2AR
 −/− (Adrb1/Adrb2 knockout) mice was 50% lower than in β1AR
 +/+
 /β2AR
 +/+ mice. Two parallel signalling pathways, Gs–cAMP–protein kinase A (PKA)–cAMP response element binding protein (CREB) and β-arrestin 1–extracellular signal-related kinase (ERK)–paired box protein 6 (PAX6), cooperatively regulated isoprenaline-induced somatostatin transcription. A stress pathway increased somatostatin content and transcription through β-adrenergic agonism. β-Arrestin1, ERK and PAX6 are important pancreatic delta cell regulators in addition to cAMP, PKA and CREB. Dysfunction of β-adrenergic agonism may impair pancreatic delta cell function.

https://link.springer.com/content/pdf/10.1007%2Fs00125-014-3290-0.pdf

A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and β-arrestin 1

Somatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion. Disruption of this circuit contributes to the development of diabetes. However, the precise mechanisms that control somatostatin secretion from islets remain elusive. Here, we found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets. Constitutive ablation of CUL4B, the core component of the CRL4B-PRC2 complex, in δ cells impaired glucose tolerance and decreased insulin secretion through enhanced somatostatin release. Moreover, mechanistic studies showed that the CRL4B-PRC2 complex, under the control of the δ cell-specific transcription factor hematopoietically expressed homeobox (HHEX), determines the levels of intracellular calcium and cAMP through histone posttranslational modifications, thereby altering expression of the Cav1.2 calcium channel and adenylyl cyclase 6 (AC6) and modulating somatostatin secretion. In response to high glucose levels or urocortin 3 (UCN3) stimulation, increased expression of cullin 4B (CUL4B) and the PRC2 subunit histone-lysine N-methyltransferase EZH2 and reciprocal decreases in Cav1.2 and AC6 expression were found to regulate somatostatin secretion. Our results reveal an epigenetic regulatory mechanism of δ cell paracrine interactions in which CRL4B-PRC2 complexes, Cav1.2, and AC6 expression fine-tune somatostatin secretion and facilitate glucose homeostasis in pancreatic islets.

/pdf/a-cullin-4b-ring-e3-ligase-complex-fine-tunes-pancreatic-d-59izh0t95k.pdf

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on β-cells plays an indispensable role. Recently, α-cell-derived glucagon but not intestine-derived GLP-1 has been proposed as the critical hormone that potentiates GSIS via GLP-1R. However, the function of glucagon receptors (GCGR) on β-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single β-cells, α-β cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via β-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse β-cells with RAB-ICUE (a genetically encoded cAMP fluorescence indicator) to monitor cAMP level after glucose stimulation and GCGR activation. Using specific inhibitors of different adenylyl cyclase (AC) family members, we revealed that high glucose concentration or GCGR activation independently evoked cAMP elevation via AC5 in β-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated β-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that β-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload.

Glucagon Potentiates Insulin Secretion Via β-Cell GCGR at Physiological Concentrations of Glucose.

While glucose-stimulated insulin secretion depends on Ca2+ influx through voltage-gated Ca2+ channels in the cell membrane of the pancreatic β-cell, there is also ample evidence for an important ro...

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00081.2011

Thiopental-induced insulin secretion via activation of IP3-sensitive calcium stores in rat pancreatic β-cells

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Thiopental-induced insulin secretion via activation of IP3-sensitive calcium stores in rat pancreatic β-cells