Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

Quesada, Iván; Tudurí, Eva; Ripoll, Cristina; Nadal, Ángel

doi:10.1677/joe-08-0290

Cited by 336 publications

(383 citation statements)

References 158 publications

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“…For Ca 2ϩ imaging experiments utilizing cells isolated from islets we did not specifically identify ␤ cells, which comprise ϳ75% of the islet. However, for all cytosolic Ca 2ϩ measurements we selected cells that exhibited a positive response to glucose, which selected against ␣-glucagon cells that comprise ϳ20% of the islet and do not respond positively to high glucose stimulation (29).…”

Section: Methodsmentioning

confidence: 99%

Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin

Wang

McGrath

Kopp

et al. 2013

Journal of Biological Chemistry

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Background: A genetic deficiency in protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) in human and mice results in insulin-dependent diabetes. Results: Acute inhibition of PERK impairs insulin secretion, secretagogue-stimulated Ca 2ϩ influx, and sarcoplasmic endoplasmic reticulum Ca 2ϩ -ATPase activity through a calcineurin-dependent pathway. Conclusion: PERK and calcineurin regulates Ca 2ϩ dynamics underlying insulin secretion. Significance: Our findings provide insights into the intracellular mechanisms underlying stimulated insulin secretion.

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Section: Methodsmentioning

confidence: 99%

Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin

Wang

McGrath

Kopp

et al. 2013

Journal of Biological Chemistry

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“…[22][23][24] Notably, in humans not only islet a-cells but also β-cells express CADM1 on the cell membrane. 7 Therefore, CADM1 is likely to contribute to the establishment of GJIC not only among a-cells but also among β-cells via homophilic binding.…”

Section: Do Not Distributementioning

confidence: 99%

Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet α-cells and prevents their excessive secretion of glucagon

Ito

Ichiyanagi

Ikeda

et al. 2012

Islets

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Keywords: connexin, cell-cell interaction, Necl-2, hyperglucagonemia, diabetes mellitus, SynCAMCell adhesion molecule-1 (CADM1) is a recently identified adhesion molecule of pancreatic islet a-cells that mediates nerve-a-cell interactions via trans-homophilic binding and serves anatomical units for the autonomic control of glucagon secretion. CADM1 also mediates attachment between adjacent a-cells. Since gap junctional intercellular communication (GJIC) among islet cells is essential for islet hormone secretion, we examined whether CADM1 promotes GJIC among a-cells and subsequently participates in glucagon secretion regulation. Dye transfer assays using aTC6 mouse a-cells, which endogenously express CADM1, supported this possibility; efficient cell-to-cell spread of gap junction-permeable dye was detected in clusters of aTC6 cells transfected with nonspecific, but not with CADM1-targeting, siRNA. Immunocytochemical analysis of connexin 36, a major component of the gap junction among aTC6 cells, revealed that it was localized exclusively to the cell membrane in CADM1-non-targeted aTC6 cells, but diffusely to the cytoplasm in CADM1-targeted cells. Next, we incubated CADM1-targeted and non-targeted aTC6 cells in a medium containing 1 mM glucose and 200 mM arginine for 30 min to induce glucagon secretion, and found that the targeted cells secreted three times more glucagon than did the non-targeted. We conducted similar experiments using pancreatic islets that were freshly isolated from wild-type and CADM1-knockout mice, and expressed glucagon secretion as ratios relative to baseline values. The increase in ratio was larger in CADM1-knockout islets than in wild-type islets. These results suggest that CADM1 may serve as a volume limiter of glucagon secretion by sustaining a-cell attachment necessary for efficient GJIC.

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“…Glucose homeostasis is tightly regulated by insulin and glucagon secreted by pancreatic beta and alpha cells, respectively [1][2][3]. Accordingly, a proper ratio of beta and alpha cells is crucial to meet the challenges of metabolic stress.…”

Section: Introductionmentioning

confidence: 99%

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

Cai

Luk

et al. 2014

Diabetologia

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Aims/hypothesis Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagonlike peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action. Methods We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines. In vivo we examined pancreas-specific Rb knockout, whole-body p107 knockout and Rb/p107 doubleknockout mice.Results Rb, but not p107, was downregulated in response to the GLP-1 analogue, exendin-4, in both alpha and beta cells. Intriguingly, this resulted in opposite outcomes of cell cycle arrest in alpha cells but proliferation in beta cells. Overexpression of Rb in alpha and beta cells abolished or attenuated the effects of exendin-4 supporting the important role of Rb in GLP-1 modulation of cell cycling. Similarly, in vivo, Rb, but not p107, deficiency was required for the beta cell proliferative response to exendin-4. Consistent with this finding, Rb, but not p107, was suppressed in islets from humans with diabetes, suggesting the importance of Rb regulation for the compensatory proliferation that occurs under insulin resistant conditions. Finally, while p107 alone did not have an essential role in islet homeostasis, when combined with Rb deletion, its absence potentiated apoptosis of both alpha and beta cells resulting in glucose intolerance and diminished islet mass with ageing. Conclusions/interpretation We found a central role of Rb in the dual effects of GLP-1 in alpha and beta cells. Our findings highlight unique contributions of individual Rb family members to islet cell proliferation and survival.

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Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

Cited by 336 publications

References 158 publications

Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin

Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin

Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet α-cells and prevents their excessive secretion of glucagon

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

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