Interactions between cholinergic agonists and enteric factors in the regulation of insulin secretion from isolated perifused rat islets

Zawalich, Walter S.; Zawalich, Kathleen C.; Rasmussen, Howard

doi:10.1530/acta.0.1200702

Cited by 21 publications

(4 citation statements)

References 16 publications

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“…These data demonstrate L-type Ca 2+ channels are required effectors for glucose-stimulated insulin secretion. In addition, influx of extracellular Ca 2+ as well as other secretagogues acetylcholine and cholecystokinin can potentiate insulin secretion through the release of intracellular Ca 2+ stores and activation of protein kinase C (Graves and Hinkle, 2003; Zawalich et al ., 1989). …”

Section: Section IImentioning

confidence: 99%

Chapter 16 Insulin Granule Biogenesis, Trafficking and Exocytosis

Hou

Min

Pessin

2009

Vitamins &Amp; Hormones

196

161

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It is becoming increasingly apparent that beta cell dysfunction resulting in abnormal insulin secretion is the essential element in the progression of patients from a state of impaired glucose tolerance to frank type 2 diabetes (Del Prato, 2003; Del Prato and Tiengo, 2001). Although extensive studies have examined the molecular, cellular and physiologic mechanisms of insulin granule biogenesis, sorting, and exocytosis the precise mechanisms controlling these processes and their dysregulation in the developed of diabetes remains an area of important investigation. We now know that insulin biogenesis initiates with the synthesis of preproinsulin in rough endoplastic reticulum and conversion of preproinsulin to proinsulin. Proinsulin begins to be packaged in the Trans-Golgi Network and is sorting into immature secretory granules. These immature granules become acidic via ATP-dependent proton pump and proinsulin undergoes proteolytic cleavage resulting the formation of insulin and C-peptide. During the granule maturation process, insulin is crystallized with zinc and calcium in the form of dense-core granules and unwanted cargo and membrane proteins undergo selective retrograde trafficking to either the constitutive trafficking pathway for secretion or to degradative pathways. The newly formed mature dense-core insulin granules populate two different intracellular pools, the readily releasable pools (RRP) and the reserved pool. These two distinct populations are thought to be responsible for the biphasic nature of insulin release in which the RRP granules are associated with the plasma membrane and undergo an acute calcium-dependent release accounting for first phase insulin secretion. In contrast, second phase insulin secretion requires the trafficking of the reserved granule pool to the plasma membrane. The initial trigger for insulin granule fusion with the plasma membrane is a rise in intracellular calcium and in the case of glucose stimulation results from increased production of ATP, closure of the ATP-sensitive potassium channel and cellular depolarization. In turn, this opens voltage-dependent calcium channels allowing increased influx of extracellular calcium. Calcium is thought to bind to members of the fusion regulatory proteins synaptogamin that functionally repressors the fusion inhibitory protein complexin. Both complexin and synaptogamin interact as well as several other regulatory proteins interact with the core fusion machinery composed of the Q- or t-SNARE proteins syntaxin 1 and SNAP25 in the plasmamembrane that assembles with the R- or v-SNARE protein VAMP2 in insulin granules. In this chapter we will review the current progress of insulin granule biogenesis, sorting, trafficking, exocytosis and signaling pathways that comprise the molecular basis of glucose-dependent insulin secretion.

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Section: Section IImentioning

confidence: 99%

Chapter 16 Insulin Granule Biogenesis, Trafficking and Exocytosis

Hou

Min

Pessin

2009

Vitamins &Amp; Hormones

196

161

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“…For example, the failure of the fuel molecule glucose to significantly activate PLC in mouse islets may be compensated for by receptor-mediated activation of the enzyme by cholinergic input to the islet. Moreover, other signaling molecules, such as cholecystokinin, which also activates PLC , and the incretins glucagonlike peptide or gastric inhibitory polypeptide that elevate cAMP, may augment the secretory response as well (Zawalich et al 1989c, Zawalich & Zawalich 1996b. These findings suggest caution in the extrapolation of signal transduction biochemical data between species unless accompanied by supporting insulin secretory responses as well.…”

Section: Figurementioning

confidence: 99%

Comparative effects of amino acids and glucose on insulin secretion from isolated rat or mouse islets

Zawalich

Yamazaki²,

Zawalich³

et al. 2004

Journal of Endocrinology

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Glucose and the combination of leucine and glutamine were used to stimulate insulin secretion from rat islets during a dynamic perifusion and the responses obtained were compared with those elicited from mouse islets under identical conditions. In rat islets, glucose (15 mM) or the amino acid combination of 10 mM glutamine plus 20 mM leucine were most efficacious and peak secondphase insulin release responses were 20-to 30-fold above prestimulatory rates. In contrast to rat islet responses, sustained second-phase insulin secretory responses to the same agonists were minimally increased 1-to 2-fold from mouse islets. Parallel studies demonstrated that phospholipase C (PLC) was markedly activated in rat, but not mouse, islets by both high glucose concentrations and the amino acid combination.Additional studies documented that glucose and amino acid responses of both rat and mouse islets were amplified by carbachol or forskolin. However, wortmannin, a phosphatidylinositol 3-kinase inhibitor, amplified only the responses to glucose leaving the responses to the amino acid mixture unaltered. These observations support the concept that mitochondrial metabolism alone is minimally effective in stimulating insulin secretion from islets. The activation of the supplementary second messenger systems (PLC and/or cAMP) appears essential for the emergence of their full secretory potential. The mechanism regulating the potency and specificity of wortmannin's impact on glucose-induced secretion remains to be identified; however a unique mechanism is supported by these findings.

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“…Previously, ACh had been shown to poten tiate the insulinotropic effect of CCK and GIP when infused together in perifused islets [26]. However, in that study the effect of GIP alone with ACh was not examined and the concentration of GIP used (10-8 M) was approximately 50 X that observed postprandially [18, 27,28].…”

Section: Discussionmentioning

confidence: 98%

Modulation of Acetylcholine-Stimulated Insulin Release by Glucose and Gastric Inhibitory Polypeptide

Verchere¹,

Kwok²,

Brown³

1991

Pharmacology

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The interactions of glucose, acetylcholine and gastric inhibitory polypeptide in the regulation of insulin secretion were examined using the in situ perfused rat pancreas. Acetylcholine (1 × 10^–6M) had no effect on the release of immunoreactive insulin in the presence of 2.2 × 10^–3M glucose. However, in the presence of 4.4, 6.6 or 8.9 × 10^–3M glucose, the same concentration of acetylcholine stimulated insulin secretion approximately fourfold. At the highest glucose concentration tested (17.8 × 10^–3M), the stimulatory effect of acetylcholine on insulin release was less pronounced. The insulin response to acetylcholine was potentiated by the presence of gastric inhibitory polypeptide. This potentiation was most marked when the peptide was present at a concentration of 1 × 10^–9M, whereas the effect of concomitant infusion of acetylcholine and 2 × 10^–10M gastric inhibitory polypeptide was only slightly greater than additive. Both atropine (1 × 10^–6M) and hexamethonium (1 × 10^–4M) inhibited the insulin response to acetylcholine. However, neither of these cholinergic antagonists had a significant effect on glucose- or gastric inhibitory polypeptide-stimulated insulin secretion. These results demonstrate that the insulinotropic action of acetylcholine is glucose-dependent. A synergistic interaction may exist between acetylcholine and gastric inhibitory polypeptide at the β-cell which does not involve glucose or gastric inhibitory polypeptide acting on cholinergic receptors in the pancreas. Cholinergic stimulation of insulin secretion in the perfused rat pancreas appears to be mediated by both muscarinic receptors on the β-cell and nicotinic receptors, presumably on intrapancreatic ganglia.

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Interactions between cholinergic agonists and enteric factors in the regulation of insulin secretion from isolated perifused rat islets

Cited by 21 publications

References 16 publications

Chapter 16 Insulin Granule Biogenesis, Trafficking and Exocytosis

Chapter 16 Insulin Granule Biogenesis, Trafficking and Exocytosis

Comparative effects of amino acids and glucose on insulin secretion from isolated rat or mouse islets

Modulation of Acetylcholine-Stimulated Insulin Release by Glucose and Gastric Inhibitory Polypeptide

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