Paracrinology of islets and the paracrinopathy of diabetes

Unger, Roger H; Orci, Lelio

doi:10.1073/pnas.1006639107

Cited by 239 publications

(242 citation statements)

References 32 publications

(30 reference statements)

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“…The endocrine pancreas is indispensable for adequately orchestrated insulin and glucagon release to maintain the body's energy homeostasis (1,71) and to protect it from noxious metabolic stress (72)(73)(74). Our knockout analysis focused on adult animals because both CB 1 R −/− and MAGL −/− mice are lean (7,8,52) and resistant to high-fat diet-induced obesity or diabetes (4,(7)(8)(9).…”

Section: Discussionmentioning

confidence: 99%

“…These data cumulatively link α cells infiltrating the core of pancreatic islets to enhanced α/β cell interplay and hormonal responsiveness. Therefore, we formulate the hypothesis that the increased number of α and β cell contacts drives paracrine signaling in the endocrine pancreas (19,73), possibly with insulin and glucagon secretion serving as a dual feedback mechanism for α and β cells, respectively (56,75,76).…”

Section: Discussionmentioning

confidence: 99%

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Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Malenczyk

Keimpema

Piscitelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB 1 cannabinoid receptor (CB 1 R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB 1 Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB 1 R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB 1 R −/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.A nandamide (AEA) and 2-arachydonoylglycerol (2-AG), major endocannabinoids (eCBs), are involved in the regulation of energy homeostasis through coordinated actions in peripheral organs (adipose tissue, liver, and pancreas) and brain (hypothalamus, ventral striatum) (1). eCB signals are particularly significant to coordinate the regulated release of insulin and glucagon from mature pancreatic islets (2-6). Genetic evidence from CB 1 cannabinoid receptor −/− (CB 1 R −/− ) mice supports these findings because CB 1 R −/− mice are lean, resistant to high fat diet-induced obesity and diabetes (4, 7-9). Whether eCBs impact the formation of the endocrine pancreas and predispose it to long-lasting changes in hormone release postnatally remains unknown.Because eCBs broadly affect cell proliferation, fate, motility, and differentiation (e.g., in sperm, hematopoietic and T cells, and neurons) (10-13), it is likely that they play a role in the cellular organization of developing pancreatic islets, possibly by affecting the spatial segregation of α and β cells. A contribution of eCBs to cell diversification and positioning in the developing pancreas is supported by the temporal control of their levels in fetal tissues (14) and circulation (15). Moreover, α and β cells in mature pancreatic islets express the molecular machinery for eCB metabolism together with CB 1 Rs and transient receptor potential cation channels, particularly subfamily V member 1 (TRPV1) (2,16,17). Understanding these developmental processes is also relevant to po...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Malenczyk

Keimpema

Piscitelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…It is not clear, however, whether β cells release insulin exclusively at the homologous cell-cell contact (β-β) or if they can also secrete hormone at the heterologous cell-cell contact (e.g., β-α). Answers to this question may become important in investigating the cellular organization of secretory machinery in islets and in understanding paracrine and/ or autocrine signaling among islet cells (31). As the initial step to address this question, we performed immunohistochemistry after ZIMIR imaging to identify α and β cells.…”

Section: Tration ([Znmentioning

confidence: 99%

Imaging dynamic insulin release using a fluorescent zinc indicator for monitoring induced exocytotic release (ZIMIR)

Chen

Bellomo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

145

176

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Current methods of monitoring insulin secretion lack the required spatial and temporal resolution to adequately map the dynamics of exocytosis of native insulin granules in intact cell populations in three dimensions. Exploiting the fact that insulin granules contain a high level of Zn 2+ , and that Zn 2+ is coreleased with insulin during secretion, we have developed a fluorescent, cell surface-targeted zinc indicator for monitoring induced exocytotic release (ZIMIR). ZIMIR displayed a robust fluorescence enhancement on Zn 2+ chelation and bound Zn 2+ with high selectivity against Ca 2+ and Mg 2+ . When added to cultured β cells or intact pancreatic islets at low micromolar concentrations, ZIMIR labeled cells rapidly, noninvasively, and stably, and it reliably reported changes in Zn 2+ concentration near the sites of granule fusion with high sensitivity that correlated well with membrane capacitance measurement. Fluorescence imaging of ZIMIR-labeled β cells followed the dynamics of exocytotic activity at subcellular resolution, even when using simple epifluorescence microscopy, and located the chief sites of insulin release to intercellular junctions. Moreover, ZIMIR imaging of intact rat islets revealed that Zn 2+ /insulin release occurred largely in small groups of adjacent β cells, with each forming a "secretory unit." Concurrent imaging of ZIMIR and Fura-2 showed that the amplitude of cytosolic Ca 2+ elevation did not necessarily correlate with insulin secretion activity, suggesting that events downstream of Ca 2+ signaling underlie the cell-cell heterogeneity in insulin release. In addition to studying stimulation-secretion coupling in cells with Zn 2+ -containing granules, ZIMIR may find applications in β-cell engineering and screening for molecules regulating insulin secretion on high-throughput platforms.probe development | zinc imaging | hormone secretion assay

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“…Consistently, in insulin-withdrawn diabetic patients, the glycaemic response to hyperglucagonaemia is 5 to 15 times greater than in nondiabetic controls [5]. This suggests that, in diabetic individuals, abnormalities in the secretion of not only glucagon but also insulin, along with the alteration in the glucagon-toinsulin ratio, leads to hyperglucagonaemia [1,9].…”

Section: Introductionmentioning

confidence: 52%

“…Particularly, in the absence of insulin signalling, insulin cannot suppress hepatic glucose production in liver-specific insulin receptor knockout (LIRKO) mice [50]. The Mck/Gcgr mice have both elevated glucagon and insulin, thus maintaining an appropriate ratio of glucagon to insulin, which represents an important mechanism for maintaining glycaemic stability, particularly in extremes of glucose influx or efflux [9] (Fig. 6).…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

et al. 2012

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Aims/hypothesis Excessive secretion of glucagon partially contributes to the development of diabetic hyperglycaemia. However, complete blocking of glucagon action will lead to adverse effects, since glucagon exerts certain beneficial effects via its receptor in many organs. We aimed to study the effects of a 'decoy receptor' for circulating glucagon on modulating beta cell function and glucose homeostasis in mice by over-producing the glucagon receptor (GCGR) in skeletal muscles. Methods We generated transgenic mice in which the expression of Gcgr is driven by the muscle specific creatine kinase (Mck) promoter, and assessed the effects of glucagon on the modulation of glucose homeostasis under conditions of extremes of glucose influx or efflux.Results Mck/Gcgr mice showed increased circulating levels of glucagon and insulin, resulting in an unchanged ratio of glucagon-to-insulin. The levels of hepatic glucose-6-phosphatase (G6PC) and fructose-1,6-bisphosphatase (F1,6P2ase) were significantly decreased, whereas the phosphorylation level of pancreatic cAMP-response-element-binding-protein (CREB) was significantly increased in these transgenic mice. Under basal conditions, the mice displayed normal blood glucose levels and unchanged glucose tolerance and insulin sensitivity when compared with their age-matched wild-type (WT) littermates. However, following multiple lowdose streptozotocin injections, Mck/Gcgr mice exhibited a delay in the onset of hyperglycaemia compared with the WT controls. This was associated with preserved beta cell mass and beta cell secretory capacity in response to glucose challenge.A. Maharaj and L. Zhu contributed equally to this study. Electronic supplementary material The online version of this article

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Paracrinology of islets and the paracrinopathy of diabetes

Cited by 239 publications

References 32 publications

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Imaging dynamic insulin release using a fluorescent zinc indicator for monitoring induced exocytotic release (ZIMIR)

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

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