Insulin Secretagogues, But Not Glucose, Stimulate an Increase in [Ca2+]iin the Fetal Human and Porcine β-Cell

Weinhaus, Anthony J.; Tabiin, Muhammad T; Poronnik, Philip; Palma, Catalina A; Cook, David I.; Tuch, Bernard E.

doi:10.1210/jc.2002-021542

Cited by 16 publications

(11 citation statements)

References 37 publications

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“…At 15 weeks of gestation, K ATP channel subunits did not co-localise with glucagon or somatostatin [16]. K ATP channels are functional as early as 14 weeks of gestation in humans but do not respond to glucose [17]. Thus, any defect in K ATP channels may affect pancreas development after pancreas organogenesis.…”

Section: Discussionmentioning

confidence: 99%

Human Pancreas Endocrine Cell Populations and Activating ABCC8 Mutations

Busiah¹,

Verkarre²,

Cavé³

et al. 2014

Horm Res Paediatr

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Background/Aims: Activating mutations in the ABCC8 gene encoding the K_ATP channel subunit SUR1 cause β-cell dysfunction with non-autoimmune diabetes mellitus in neonates or infants. We investigated whether activating ABCC8 mutations affect endocrine pancreas development. Methods: We studied a male infant with compound heterozygous ABCC8 mutations (p.Arg826Trp/p.Ile93Thr) causing neonatal diabetes mellitus. He died of ketoacidosis. Postmortem pancreas specimens were evaluated by fluorescent microscopy after immunostaining for insulin, glucagon, somatostatin, and PCNA, and Hoechst 33342 nuclear staining. We compared the findings to those in 5 age-matched controls. Results: The number of islets was decreased and the number of single or small clusters of insulin cells increased in the patient compared to the age-matched controls. The islets in the patient had an insulin-cell core surrounded by intermingled glucagon and somatostatin cells. The insulin/Hoechst surface ratio was decreased and the glucagon/Hoechst surface ratio increased in the patient (4.3 and 8.8%, respectively) versus the controls (8.2 and 3.1%, respectively). Somatostatin surface staining was similar in the patient and controls (4 vs. 4.7%). PCNA staining was increased 3- to 3.5-fold, indicating increased insulin-cell proliferation compared to controls. Conclusion: Activating ABCC8 mutations impaired the balance between β and α cells in the patient, suggesting an effect on β-cell mass development.

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Section: Discussionmentioning

confidence: 99%

Human Pancreas Endocrine Cell Populations and Activating ABCC8 Mutations

Busiah¹,

Verkarre²,

Cavé³

et al. 2014

Horm Res Paediatr

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“…Procedures for calcium imaging experiments were modifi ed and performed as previously reported [19][20][21]. Briefl y, the attached ICCs were loaded with 1.5 μM of the fl uorescent intracellular dye fura-2 AM (Invitrogen) in KRBB plus 0.02% (wt/vol) Pluronic F-127 solution and 2.5 mM probenecid (Sigma Aldrich) at 37°C for 45 min in the dark.…”

Section: Measurement Of the Ca 2+ Infl Ux In Iccs By Calcium Imaging mentioning

confidence: 99%

PDZ-Domain Containing-2 (PDZD2) Drives the Maturity of Human Fetal Pancreatic Progenitor-Derived Islet-Like Cell Clusters With Functional Responsiveness Against Membrane Depolarization

Leung

Suen

Lau

et al. 2009

Stem Cells and Development

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We recently reported the isolation and characterization of a population of pancreatic progenitor cells (PPCs) from early trimester human fetal pancreata. The PPCs, being the forerunners of adult pancreatic cell lineages, were amenable to growth and differentiation into insulin-secreting islet-like cell clusters (ICCs) upon stimulation by adequate morphogens. Of note, a novel morphogenic factor, PDZ-domain containing-2 (PDZD2) and its secreted form (sPDZD2) were ubiquitously expressed in the PPCs. Our goals for this study were to evaluate the potential role of sPDZD2 in stimulating PPC differentiation and to establish the optimal concentration for such stimulation. We found that 10(-9)M sPDZD2 promoted PPC differentiation, as evidenced by the upregulation of the pancreatic endocrine markers (PDX-1, NGN3, NEURO-D, ISL-1, NKX 2.2, NKX 6.1) and INSULIN mRNA. Inhibited endogenous production of sPDZD2 suppressed expression of these factors. Secreted PDZD2 treatment significantly elevated the C-peptide content of the ICCs and increased the basal rate of insulin secretion. However, they remained unresponsive to glucose stimulation, reflected by a minimal increase in GLUT-2 and GLUCOKINASE mRNA expression. Interestingly, sPDZD2 treatment induced increased expression of the L-type voltage-gated calcium channel (Ca(v)1.2) in the ICCs, triggering calcium ion influx under KCl stimulation and conferring an ability to secrete insulin in response to KCl. Pancreatic progenitor cells from 10- and 13-week fetal pancreata showed peak expression of endogenous sPDZD2, implying that sPDZD2 has a specific role in islet development during the first trimester. In conclusion, our data suggest that sPDZD2 promotes functional maturation of human fetal PPC-derived ICCs, thus enhancing its transplanting potentials.

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“…Target(s) of Leucine-Recently, the role of amino acids in regulating protein translation by metabolism-linked signaling pathways rather than their well known role in serving as precursors for protein synthesis has become the subject of extensive studies (16,18,19,41). Leucine has been reported to mediate the phosphorylation of eukaryotic initiation factor 4-Ebinding protein-1 (eIE-E-BP1), which is also designated as phosphorylated heat-and acid-stable protein regulated by insulin (PHAS-1).…”

Section: Role Of ␤-Cell Mitochondria In Fuel Sensing-pancreaticmentioning

confidence: 99%

Leucine Culture Reveals That ATP Synthase Functions as a Fuel Sensor in Pancreatic β-Cells

Yang

Wong

Wang

et al. 2004

Journal of Biological Chemistry

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Our goal was to investigate whether leucine culture affects ␤-cell glucose sensing. One-day culture of rat islets with 10 mM leucine had no effect on glucose-induced insulin secretion. One-week leucine culture decreased the threshold for glucose-induced insulin secretion and increased maximal insulin secretion at 30 mM glucose. Glucose-induced cytosolic free Ca 2؉ was increased at 1 week but not at 1 day of leucine culture. Glucose is the main secretagogue of insulin secretion from pancreatic ␤-cells. The mechanisms of glucose-induced insulin secretion have been studied extensively. Through glycolysis and oxidation, glucose increases pancreatic ␤-cell ATP/ADP ratio, which closes ATP-sensitive potassium (K ATP ) channels and depolarizes the cell membrane. This results in an influx of extracellular Ca 2ϩ and increase of free cytosolic [Ca 2ϩ ] that stimulates exocytosis of insulin granules (1-5). Another mechanism is K ATP channel-independent and involves increased effectiveness of [Ca 2ϩ ] (6, 7). In pancreatic ␤-cells, most of the intracellular ATP comes from the oxidation of glucose-derived pyruvate and oxidation of NADH in the mitochondria via the electron transport chain. Damage or inhibition of ATP synthesis results in ␤-cell dysfunction and impairs glucose-stimulated insulin secretion (8, 9). Some recent publications indicate that superoxide produced by hyperglycemia activates uncouplingprotein-2 (UCP2) and destroys the proton gradient between inner and outer mitochondrial membranes. This negatively affects the activity of ATP synthase, decreases ATP production, and impairs glucose-stimulated insulin secretion of pancreatic ␤-cells resulting in diabetes (8, 9). More recently, it is shown that mitochondrial metabolism sets the maximal limit of fuel stimulated-insulin secretion in ␤-cells (10). These findings imply that mitochondrial ATP synthesis may play a vital role in fuel-stimulated insulin secretion of pancreatic ␤-cells.Some amino acids, particularly leucine and its non-metabolizable analogue 2-amino-2-norbornanecarboxylic acid, have been known to stimulate insulin secretion from pancreatic ␤-cells by activation of glutamate dehydrogenase (11-15). More recently, the branched-chain amino acids, including leucine, isoleucine, and valine, have been reported to activate the mammalian target of rapamycin (mTOR) 1 signaling pathway (16 -19) in ␤-cells. Leucine stimulates protein synthesis and pancreatic ␤-cell proliferation via the mTOR signaling pathway at physiological concentrations (16). These studies indicate a new role of branched-chain amino acids in pancreatic ␤-cell biology in addition to serving as fuels or residues for protein synthesis.As the rate-limiting enzyme of glucose metabolism, it is believed that glucokinase sets a strict control on glucose metabolism in pancreatic ␤-cells. However, overexpression of glucokinase or hexokinase I fails to increase the maximal insulin output induced by glucose, although it decreases the threshold for glucose-induced insulin secretion in pancreatic ␤-cel...

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Insulin Secretagogues, But Not Glucose, Stimulate an Increase in [Ca²⁺]_iin the Fetal Human and Porcine β-Cell

Cited by 16 publications

References 37 publications

Human Pancreas Endocrine Cell Populations and Activating <b><i>ABCC8</i></b> Mutations

Human Pancreas Endocrine Cell Populations and Activating <b><i>ABCC8</i></b> Mutations

PDZ-Domain Containing-2 (PDZD2) Drives the Maturity of Human Fetal Pancreatic Progenitor-Derived Islet-Like Cell Clusters With Functional Responsiveness Against Membrane Depolarization

Leucine Culture Reveals That ATP Synthase Functions as a Fuel Sensor in Pancreatic β-Cells

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