Regulation of Pancreatic Insulin and Glucagon Secretion

Gerich, John E.; Charles, M. Arthur; Grodsky, G M

doi:10.1146/annurev.ph.38.030176.002033

Cited by 306 publications

(151 citation statements)

References 68 publications

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“…The two phases are initiated by differing (although incompletely understood) upstream signaling pathways (28) and are characterized by recruitment of functionally distinct populations of secretory granules. It has been long hypothesized (49,50), and now experimentally supported (51), that first phase secretion represents fusion of predocked secretory granules (a readily releasable pool), whereas second phase necessitates recruit- ment of additional granules from a reserve pool. These processes are in a dynamic equilibrium because it has been shown that some predocked granules detach from the plasma membrane and retreat to the reserve pool (51).…”

Section: Discussionmentioning

confidence: 99%

Phospholipase D1 Regulates Secretagogue-stimulated Insulin Release in Pancreatic β-Cells

Hughes

Elgundi

Huang

et al. 2004

Journal of Biological Chemistry

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Phospholipase D (PLD) has been strongly implicated in the regulation of Golgi trafficking as well as endocytosis and exocytosis. Our aim was to investigate the role of PLD in regulating the biphasic exocytosis of insulin from pancreatic ␤-cells that is essential for mammalian glucose homeostasis. We observed that PLD activity in MIN6 pancreatic ␤-cells is closely coupled to secretion. Cellular PLD activity was increased in response to a variety of secretagogues including the nutrient glucose and the cholinergic receptor agonist carbamoylcholine. Conversely, pharmacological or hormonal inhibition of stimulated secretion reduced PLD activity. Most importantly, blockade of PLD-catalyzed phosphatidic acid formation using butan-1-ol inhibited insulin secretion in both MIN6 cells and isolated pancreatic islets. It was further established that PLD activity was required for both the first and the second phase of glucose-stimulated insulin release, suggesting a role in the very distal steps of exocytosis, beyond granule recruitment into a readily releasable pool. Visualization of granules using green fluorescent protein-phogrin confirmed a requirement for PLD prior to granule fusion with the plasma membrane. PLD1 was shown to be the predominant isoform in MIN6 cells, and it was located at least partially on insulin granules. Overexpression of wild-type or a dominant negative catalytically inactive mutant of PLD1 augmented or inhibited secretagogue-stimulated secretion, respectively. The results suggest that phosphatidic acid formation on the granule membrane by PLD1 is essential for the regulated secretion of insulin from pancreatic ␤-cells.

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Section: Discussionmentioning

confidence: 99%

Phospholipase D1 Regulates Secretagogue-stimulated Insulin Release in Pancreatic β-Cells

Hughes

Elgundi

Huang

et al. 2004

Journal of Biological Chemistry

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“…Regarding synchronous oscillations in response to glucose, studies using confocal microscopy in mouse islets indicate that only ␤-cells oscillate (42,43). Arginine-induced [Ca 2+ ] i effects could, on the other hand, be influenced by ␣-cell participation because this amino acid is a potent stimulator of glucagon secretion (41) and induces an increase in [Ca 2+ ] i in mouse islets (37,42). Note, however, that [Ca 2+ ] i responses to arginine tended to be higher rather than lower after high-glucose culture.…”

Section: Discussionmentioning

confidence: 99%

Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation.

2000

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“…Secretion of glucagon is stimulated by low blood glucose (Gorus et al 1984), amino acids (Pipeleers et al 1985), and a variety of hormones and neurotransmitters, such as adrenaline, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 Gromada et al 1997). Insulin, somatostatin, and fatty acids reduce glucagon secretion (Gerich et al 1976;Ding et al 1997). Whereas insulin levels are inadequately low in hyperglycaemic diabetic patients, glucagon levels are elevated, and this aggravates the disease (Unger 1971).…”

Section: Comparison Between Insulin-secreting B-cells and Glucagon-sementioning

confidence: 99%

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Barg

2003

Pharmacology & Toxicology

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In pancreatic B-and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca 2π -influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca 2π -influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (Ͻ1% in insulin-secreting B-cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further ''priming'' for release by several ATP-and Ca 2π -dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose-stimulated insulin secretion. Since this release pattern is altered in type-2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin-secreting B-cells and glucagon-secreting A-cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L-type Ca 2π -channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65-kDa sulfonylurea-binding protein.

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Regulation of Pancreatic Insulin and Glucagon Secretion

Cited by 306 publications

References 68 publications

Phospholipase D1 Regulates Secretagogue-stimulated Insulin Release in Pancreatic β-Cells

Phospholipase D1 Regulates Secretagogue-stimulated Insulin Release in Pancreatic β-Cells

Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation.

Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

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