Somatostatin- and Epinephrine-Induced Modifications of 45Ca++ Fluxes and Insulin Release in Rat Pancreatic Islets Maintained in Tissue Culture

Wollheim, Claes B.; Kikuchi, Masatoshi; Renold, Albert E.; Sharp, Geoffrey W. G.

doi:10.1172/jci108869

Cited by 112 publications

(80 citation statements)

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“…To further explore this point, we monitored the ability of hormones normally capable of suppressing insulin secretion through the activation of cell-surface, G-protein-coupled receptors, to affect hormone secretion after overexpression of active or inactive forms of AMPK. As anticipated, either somatostatin ( Figure 7A) or the α2-adrenoreceptor agonist clonidine [58] (Figure 7B) completely blocked the release of transfected hGH elicited by 30 mM glucose, or release stimulated by co-transfection with AMPK DN. Neither agent exerted any detectable effect on hGH release at 3 mM glucose, nor release at 3 or 30 mM glucose in cells co-transfected with AMPK CA (Figures 7A and 7B).…”

Section: Effects Of Active and Inactive Ampk On Cell Viability And Apsupporting

confidence: 77%

“…Each of the above receptor agonists is likely to inhibit insulin (and transfected hGH) release through actions both to decrease intracellular [Ca# + ] c [58], and at a late exocytotic step [59]. By contrast, the K ATP channel opener diazoxide [5] is predicted to act largely by hyperpolarizing the cell, thus suppressing [Ca# + ] c increases.…”

Section: Effects Of Active and Inactive Ampk On Cell Viability And Apmentioning

confidence: 99%

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Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

Xavier

Leclerc

Váradi

et al. 2003

Biochemical Journal

246

239

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AMP-activated protein kinase (AMPK) has recently been implicated in the control of preproinsulin gene expression in pancreatic islet β-cells [da Silva Xavier, Leclerc, Salt, Doiron, Hardie, Kahn and Rutter (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 4023–4028]. Using pharmacological and molecular strategies to regulate AMPK activity in rat islets and clonal MIN6 β-cells, we show here that the effects of AMPK are exerted largely upstream of insulin release. Thus forced increases in AMPK activity achieved pharmacologically with 5-amino-4-imidazolecarboxamide riboside (AICAR), or by adenoviral overexpression of a truncated, constitutively active form of the enzyme (AMPKα1.T172D), blocked glucose-stimulated insulin secretion. In MIN6 cells, activation of AMPK suppressed glucose metabolism, as assessed by changes in total, cytosolic or mitochondrial [ATP] and NAD(P)H, and reduced increases in intracellular [Ca2+] caused by either glucose or tolbutamide. By contrast, inactivation of AMPK by expression of a dominant-negative form of the enzyme mutated in the catalytic site (AMPKα1.D157A) did not affect glucose-stimulated increases in [ATP], NAD(P)H or intracellular [Ca2+], but led to the unregulated release of insulin. These results indicate that inhibition of AMPK by glucose is essential for the activation of insulin secretion by the sugar, and may contribute to the transcriptional stimulation of the preproinsulin gene. Modulation of AMPK activity in the β-cell may thus represent a novel therapeutic strategy for the treatment of type 2 diabetes mellitus.

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Section: Effects Of Active and Inactive Ampk On Cell Viability And Apsupporting

confidence: 77%

Section: Effects Of Active and Inactive Ampk On Cell Viability And Apmentioning

confidence: 99%

Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

Xavier

Leclerc

Váradi

et al. 2003

Biochemical Journal

246

239

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“…45 Ca ++ loading of the islets Pancreatic islets were isolated by the collagenase digestion technique (34) (29) . In parallel determinations, the extracellular space was 1.1 ± 0.11 nl/islet (n = 19) for islets maintained at 1 mM phosphate and 2.1 ± 0.25 (n = 18) for islets maintained at 5 mM phosphate.…”

Section: Isolation Andmentioning

confidence: 99%

“…The islets were perifused using 40 islets/chamber, as described in detail previously (4,29,37). The perifusate consisted of Krebs-Ringer bicarbonate buffer (KRB) containing 1.0 mM CaCh (except when stated), 0.5% dialyzed bovine serum albumin, and 2.8 mM glucose.…”

Section: Perifusion Of the Islets And Measurement Of Insulin Releasementioning

confidence: 99%

“…Thus, it seems possible that the biphasic insulin release is a reflection of a biphasic change in the concentration of cytosol Ca++ (23). In considering this possibility, it has been demonstrated that the effect of high glucose to increase the uptake of extracellular ca++ by islets (24)(25)(26)(27)(28)(29)(30)(31)(32)(33) is necessary for second phase release but plays no part in the first phase response (23). If increased cytosol Ca++ is required for insulin release, it follows that intracellular Ca ++ must play the major role in the genesis of first phase release.…”

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confidence: 99%

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Biphasic Insulin Release in Rat Islets of Langerhans and the Role of Intracellular Ca⁺⁺Stores*

et al. 1979

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ABSTRACT. The role of extracellular Ca++ in the development of biphasic insulin release has been studied previously by using Verapamil to block the glucose-induced stimulation of Ca++ uptake. It was found that glucose-stimulated uptake of ca++ from the extracellular fluid was important for the second phase of insulin release but had no role in the first phase. In the current study, the role of intracellular ca++ stores in biphasic insulin release has been studied.Isolated rat islets were maintained in tissue culture for 46 h with normal (1 mM) or high (5 mM) phosphate concentrations. The intracellular calcium content of islets maintained in high phosphate was 50 times greater than the content of control islets. Insulin release was studied by perifusion, and the Ca ++ concentration in the medium was decreased to 0.1 mM during stimulation with high glucose to minimize the effect of extracellular S TIMULATION of insulin release from the B cells of islets of Langerhans by a rapid increase in glucose concentration is characterized by a two-phase response (1-4). Characteristically, a rapid peak of release (first phase) is followed by a period of slowly increasing release (second phase). The mechanism responsible for this biphasicity has not been elucidated. It has been suggested that the first phase is due to 1) a small labile pool of insulin-containing granules distinct from the majority of granules in that they are more susceptible to release, perhaps by their sensitivity to fusion with the plasma membrane or by close apposition to structures critical to the release process (5-7); 2) individual B cells that have differential sensitivity to glucose (8); 3) an initial burst of insulin release which then causes a transient feedback inhibition of subsequent release (9, 10); 4) effects such as the concomitant release of somatostatin (11); or 5) a biphasic change in the concentration of an intracellular mediator of release (12). As Ca++ is known to be required for (13,14) and can alone stimulate (15)(16)(17)(18)(19)(20) insulin release, a rise in intracellular Ca ++ concentration is now considered to be a major controlling influence in stimu- Received September 11, 1978. • This work was supported by the Swiss National Science Foundation (Grant 3.774-0.76SR).t To whom requests for reprints should be addressed. 1013Ca++. The islets maintained in normal phosphate responded with a transient subnormal first phase insulin release. In contrast, 16.7 mM glucose elicited a 3.5-fold greater first phase release from the ca++_loaded islets. This release was quantitatively similar to the first phase response of islets perifused with 1 mM ca++ throughout. ca++ loading also increased the rate of second phase insulin release, but this was less marked than that observed for the first phase.It is concluded that the handling of intracellular ca++ is primarily responsible for the first phase of insulin release, whereas both intracellular ca++ and increased uptake of ca++ from the extracellular compartment are involved in the genesis and de...

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Significance of γ‐glutamyl transpeptidase and thiols in amino acid uptake by rat pancreatic islets: Studies with glutamine and leucine

Ammon

Fuss

Verspohl

1988

Cell Biochemistry & Function

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The importance of gamma-glutamyl transpeptidase, the key enzyme of the gamma-glutamyl cycle and of thiols for the uptake of amino acids into rat pancreatic islets was investigated. Both serine-borate, an inhibitor of gamma-glutamy transpeptidase, and serine which does not inhibit this enzyme, but probably is a competitive inhibitor of amino acid uptake, inhibited the uptake of glutamine. The inhibitory effect of serine-borate was not greater than that of serine alone. The uptake of glutamine was not affected by either GSH (reduced glutathione) or diamide (a thiol oxidant). Neither substances affected the uptake of leucine. The results indicate that the uptake of glutamine by rat pancreatic islets is not dependent on the functioning of gamma-glutamyl transpeptidase and that thiols are not important for the uptake of the amino acids glutamine and leucine.

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Somatostatin- and Epinephrine-Induced Modifications of 45Ca++ Fluxes and Insulin Release in Rat Pancreatic Islets Maintained in Tissue Culture

Cited by 112 publications

References 56 publications

Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

Biphasic Insulin Release in Rat Islets of Langerhans and the Role of Intracellular Ca⁺⁺Stores*

Significance of γ‐glutamyl transpeptidase and thiols in amino acid uptake by rat pancreatic islets: Studies with glutamine and leucine

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Somatostatin- and Epinephrine-Induced Modifications of 45Ca++ Fluxes and Insulin Release in Rat Pancreatic Islets Maintained in Tissue Culture

Cited by 112 publications

References 56 publications

Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression

Biphasic Insulin Release in Rat Islets of Langerhans and the Role of Intracellular Ca++Stores*

Significance of γ‐glutamyl transpeptidase and thiols in amino acid uptake by rat pancreatic islets: Studies with glutamine and leucine

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Biphasic Insulin Release in Rat Islets of Langerhans and the Role of Intracellular Ca⁺⁺Stores*