Differential sensitivity of human islets from obese versus lean donors to chronic high glucose or palmitate.
human islets
insulin secretion
islet transplantation
nitric oxide synthase
obesity
一氧化氮合成酶
人胰岛
肥胖
胰岛移植
胰岛素分泌
Journal
Journal of diabetes
ISSN: 1753-0407
Titre abrégé: J Diabetes
Pays: Australia
ID NLM: 101504326
Informations de publication
Date de publication:
Jul 2020
Jul 2020
Historique:
received:
09
07
2019
revised:
15
01
2020
accepted:
19
02
2020
pubmed:
25
2
2020
medline:
15
5
2021
entrez:
25
2
2020
Statut:
ppublish
Résumé
Due to the shortage of multi-organ donors, human pancreatic islet transplantation has now been extended to islets originating from obese subjects. In this study, our aim is to compare the respective sensitivity of human islets from lean vs obese donors to chronic high glucose or high palmitate. Human islets were isolated from pancreases harvested from brain-dead multi-organ donors. Islets were cultured during 72 hours in the presence of moderate (16.7 mmol/L) or high (28 mmoL/L) glucose concentrations, or glucose (5.6 mmoL/L) and palmitate (0.4 mmoL/L), before measurement of their response to glucose. We first observed a greater insulin response in islets from obese donors under both basal and high-glucose conditions, confirming their hyperresponsiveness to glucose. When islets from obese donors were cultured in the presence of moderate or high glucose concentrations, insulin response to glucose remained unchanged or was slightly reduced, as opposed to that observed in lean subjects. Moreover, culturing islets from obese donors with high palmitate also induced less reduction in insulin response to glucose than in lean subjects. This partial protection of obese islets is associated with less induction of inducible nitric oxide synthase in islets, together with a greater expression of the transcription factor forkhead box O1 (FOXO1). Our data suggest that in addition to an increased sensitivity to glucose, islets from obese subjects can be considered as more resistant to glucose and fatty acid excursions and are thus valuable candidates for transplantation. 背景: 由于缺乏多器官供体, 人胰岛移植目前已衍生到肥胖者来源的胰岛移植。在这项研究中, 我们旨在比较瘦人和肥胖者的胰岛对慢性高糖或棕榈酸盐的敏感性。 方法: 从脑死亡的多器官捐赠者的胰腺中分离胰岛。胰岛在中等浓度(16.7 mmol/L)或高浓度(28 mmol/L)葡萄糖培养基中, 或是葡萄糖(5.6 mmol/L)和棕榈酸盐(0.4 mmol/L)存在下培养72h, 然后测定其对葡萄糖的反应。 结果: 我们首先观察到肥胖捐赠者的胰岛在基础和高糖条件下都有更大的胰岛素反应, 证实了其对葡萄糖的高反应性。但当来自肥胖捐赠者的胰岛在中高浓度葡萄糖存在的情况下继续培养时, 胰岛对葡萄糖的反应则保持不变或略有降低, 这与在瘦的捐赠者中观察到的相反。此外, 用高棕榈酸培养后的肥胖捐赠者胰岛也比瘦捐献者的对于葡萄糖的胰岛素反应减少得少。这种对肥胖者胰岛的部分保护作用, 与较少诱导一氧化氮合成酶有关, 以及转录因子FOXO1的较高表达相关。 结论: 我们的结果表明, 除了对葡萄糖的敏感性增加外, 肥胖者的胰岛可以被认为对葡萄糖和脂肪酸剧增更有抵抗力, 因此是有价值的移植候选者。.
Sections du résumé
BACKGROUND
BACKGROUND
Due to the shortage of multi-organ donors, human pancreatic islet transplantation has now been extended to islets originating from obese subjects. In this study, our aim is to compare the respective sensitivity of human islets from lean vs obese donors to chronic high glucose or high palmitate.
METHODS
METHODS
Human islets were isolated from pancreases harvested from brain-dead multi-organ donors. Islets were cultured during 72 hours in the presence of moderate (16.7 mmol/L) or high (28 mmoL/L) glucose concentrations, or glucose (5.6 mmoL/L) and palmitate (0.4 mmoL/L), before measurement of their response to glucose.
RESULTS
RESULTS
We first observed a greater insulin response in islets from obese donors under both basal and high-glucose conditions, confirming their hyperresponsiveness to glucose. When islets from obese donors were cultured in the presence of moderate or high glucose concentrations, insulin response to glucose remained unchanged or was slightly reduced, as opposed to that observed in lean subjects. Moreover, culturing islets from obese donors with high palmitate also induced less reduction in insulin response to glucose than in lean subjects. This partial protection of obese islets is associated with less induction of inducible nitric oxide synthase in islets, together with a greater expression of the transcription factor forkhead box O1 (FOXO1).
CONCLUSIONS
CONCLUSIONS
Our data suggest that in addition to an increased sensitivity to glucose, islets from obese subjects can be considered as more resistant to glucose and fatty acid excursions and are thus valuable candidates for transplantation.
背景: 由于缺乏多器官供体, 人胰岛移植目前已衍生到肥胖者来源的胰岛移植。在这项研究中, 我们旨在比较瘦人和肥胖者的胰岛对慢性高糖或棕榈酸盐的敏感性。 方法: 从脑死亡的多器官捐赠者的胰腺中分离胰岛。胰岛在中等浓度(16.7 mmol/L)或高浓度(28 mmol/L)葡萄糖培养基中, 或是葡萄糖(5.6 mmol/L)和棕榈酸盐(0.4 mmol/L)存在下培养72h, 然后测定其对葡萄糖的反应。 结果: 我们首先观察到肥胖捐赠者的胰岛在基础和高糖条件下都有更大的胰岛素反应, 证实了其对葡萄糖的高反应性。但当来自肥胖捐赠者的胰岛在中高浓度葡萄糖存在的情况下继续培养时, 胰岛对葡萄糖的反应则保持不变或略有降低, 这与在瘦的捐赠者中观察到的相反。此外, 用高棕榈酸培养后的肥胖捐赠者胰岛也比瘦捐献者的对于葡萄糖的胰岛素反应减少得少。这种对肥胖者胰岛的部分保护作用, 与较少诱导一氧化氮合成酶有关, 以及转录因子FOXO1的较高表达相关。 结论: 我们的结果表明, 除了对葡萄糖的敏感性增加外, 肥胖者的胰岛可以被认为对葡萄糖和脂肪酸剧增更有抵抗力, 因此是有价值的移植候选者。.
Autres résumés
Type: Publisher
(chi)
背景: 由于缺乏多器官供体, 人胰岛移植目前已衍生到肥胖者来源的胰岛移植。在这项研究中, 我们旨在比较瘦人和肥胖者的胰岛对慢性高糖或棕榈酸盐的敏感性。 方法: 从脑死亡的多器官捐赠者的胰腺中分离胰岛。胰岛在中等浓度(16.7 mmol/L)或高浓度(28 mmol/L)葡萄糖培养基中, 或是葡萄糖(5.6 mmol/L)和棕榈酸盐(0.4 mmol/L)存在下培养72h, 然后测定其对葡萄糖的反应。 结果: 我们首先观察到肥胖捐赠者的胰岛在基础和高糖条件下都有更大的胰岛素反应, 证实了其对葡萄糖的高反应性。但当来自肥胖捐赠者的胰岛在中高浓度葡萄糖存在的情况下继续培养时, 胰岛对葡萄糖的反应则保持不变或略有降低, 这与在瘦的捐赠者中观察到的相反。此外, 用高棕榈酸培养后的肥胖捐赠者胰岛也比瘦捐献者的对于葡萄糖的胰岛素反应减少得少。这种对肥胖者胰岛的部分保护作用, 与较少诱导一氧化氮合成酶有关, 以及转录因子FOXO1的较高表达相关。 结论: 我们的结果表明, 除了对葡萄糖的敏感性增加外, 肥胖者的胰岛可以被认为对葡萄糖和脂肪酸剧增更有抵抗力, 因此是有价值的移植候选者。.
Identifiants
pubmed: 32090456
doi: 10.1111/1753-0407.13026
doi:
Substances chimiques
Palmitates
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
532-541Subventions
Organisme : Centre Hospitalier Régional Universitaire de Montpellier
Organisme : University Montpellier
ID : BQR 2011
Organisme : Montpellier University Hospital
ID : AOI-2010/UF8687
Organisme : Juvenile Diabetes Research Foundation
ID : 3-RSC-2016-162-I-X
Pays : United States
Informations de copyright
© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
Références
Shapiro AM, Pokrywczynska M, Ricordi C. Clinical pancreatic islet transplantation. Nat Rev Endocrinol. 2017;13:268-277.
Collaborative Islet Transplant Registry. Ninth Annual Report; 2016. CITR www.citregistry.org.
Neidlinger NA, Odorico JS, Sollinger HW, Fernandez LA. Can 'extreme’ pancreas donors expand the donor pool? Curr Opin Organ Transplant. 2008;13:67-71.
Berney T, Johnson PR. Donor pancreata: evolving approaches to organ allocation for whole pancreas versus islet transplantation. Transplantation. 2010;90:238-243.
Lakey JR, Warnock GL, Rajotte RV, et al. Variables in organ donors that affect the recovery of human islets of Langerhans. Transplantation. 1996;61:1047-1053.
Matsumoto I, Sawada T, Nakano M, et al. Improvement in islet yield from obese donors for human islet transplants. Transplantation. 2004;78:880-885.
Humar A, Ramcharan T, Kandaswamy R, Gruessner RW, Gruessner AG, Sutherland DE. The impact of donor obesity on outcomes after cadaver pancreas transplants. Am J Transplant. 2004;4:605-610.
Badet L, Benhamou PY, Wojtusciszyn A. et al; GRAGIL GroupExpectations and strategies regarding islet transplantation: metabolic data from the GRAGIL 2 trial. Transplantation. 2007;84:89-96.
Emamaullee JA, Shapiro AMJ. Factors influencing the loss of beta-cell mass in islet transplantation. Cell Transplant. 2007;16:1-8.
Bhargava R, Senior PA, Ackerman TE, et al. Prevalence of hepatic steatosis after islet transplantation and its relation to graft function. Diabetes. 2004;53:1311-1317.
Toso C, Isse K, Demetris AJ, et al. Histologic graft assessment after clinical islet transplantation. Transplantation. 2009;88:1286-1293.
Lee Y, Ravazzola M, Park BH, Bashmakov YK, Orci L, Unger RH. Metabolic mechanisms of failure of intraportally transplanted pancreatic beta-cells in rats: role of lipotoxicity and prevention by leptin. Diabetes. 2007;56:2295-2301.
Eizirik DL, Korbutt GS, Hellerstrom C. Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function. J Clin Invest. 1992;90:1263-1268.
Mezghenna K, Pomies P, Chalancon A, et al. Increased neuronal nitric oxide synthase dimerisation is involved in rat and human pancreatic beta cell hyperactivity in obesity. Diabetologia. 2011;54:2856-2866.
Lajoix AD, Reggio H, Chardes T, et al. A neuronal isoform of nitric oxide synthase expressed in pancreatic beta-cells controls insulin secretion. Diabetes. 2001;50:1311-1323.
Eizirik DL, Leijerstam F. The inducible form of nitric oxide synthase (iNOS) in insulin-producing cells. Diabete Metab. 1994;20:116-122.
Henningsson R, Salehi A, Lundquist I. Role of nitric oxide synthase isoforms in glucose-stimulated insulin release. Am J Physiol Cell Physiol. 2002;283:C296-C304.
Meidute Abaraviciene S, Lundquist I, Galvanovskis J, Flodgren E, Olde B, Salehi A. Palmitate-induced beta-cell dysfunction is associated with excessive NO production and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms. PLoS One. 2008;3:e2182.
Bucher P, Mathe Z, Morel P, et al. Assessment of a novel two-component enzyme preparation for human islet isolation and transplantation. Transplantation. 2005;79:91-97.
Roomp K, Kristinsson H, Schvartz D, et al. Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism. PLoS One. 2017;12(4):e0176391.
Brajkovic S, Ferdaoussi M, Pawlowski V, et al. Islet brain 1 protects insulin producing cells against lipotoxicity. J Diabetes Res. 2016;2016:9158562.
Hart NJ, Powers AC. Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions. Diabetologia. 2019;62:212-222.
Brun T, Li N, Jourdain AA, et al. Diabetogenic milieus induce specific changes in mitochondrial transcriptome and differentiation of human pancreatic islets. Hum Mol Genet. 2015;24:5270-5284.
Maedler K, Sergeev P, Ris F, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110:851-860.
Welsh N, Cnop M, Kharroubi I, et al. Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes. 2005;54:3238-3244.
Zhang T, Kim DH, Xiao X, et al. FoxO1 plays an important role in regulating beta-cell compensation for insulin resistance in male mice. Endocrinology. 2016;57:1055-1070.
Ferrannini E, Camastra S, Gastaldelli A, et al. Beta-cell function in obesity: effects of weight loss. Diabetes. 2004;53(suppl 3):S26-S33.
Phillips MS, Liu Q, Hammond HA, et al. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet. 1996;13:18-19.
Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988;81:442-448.
Henquin JC. Influence of organ donor attributes and preparation characteristics on the dynamics of insulin secretion in isolated human islets. Physiol Rep. 2018;6:e13646.
Lyon J, Manning Fox JE, Spigelman AF, et al. Research-focused isolation of human islets from donors with and without diabetes at the Alberta diabetes institute IsletCore. Endocrinology. 2016;157:560-569.
Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of insulin resistance (EGIR). J Clin Invest. 1997;100:1166-1173.
Bensellam M, Laybutt DR, Jonas JC. The molecular mechanisms of pancreatic beta-cell glucotoxicity: recent findings and future research directions. Mol Cell Endocrinol. 2012;364:1-27.
Marshak S, Leibowitz G, Bertuzzi F, et al. Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose. Diabetes. 1999;48:1230-1236.
Muhammed SJ, Lundquist I, Salehi A. Pancreatic beta-cell dysfunction, expression of iNOS and the effect of phosphodiesterase inhibitors in human pancreatic islets of type 2 diabetes. Diabetes Obes Metab. 2012;14:1010-1019.
Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev. 2008;29:351-366.
Dubois M, Kerr-Conte J, Gmyr V, et al. Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration. Diabetologia. 2004;47:463-469.
Ostenson CG, Chen J, Sheu L, Gaisano HY. Effects of palmitate on insulin secretion and exocytotic proteins in islets of diabetic Goto-Kakizaki rats. Pancreas. 2007;34:359-363.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102-110.
Deng S, Vatamaniuk M, Huang X, et al. Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes. 2004;53:624-632.
Eizirik DL, Darville MI. Beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes. Diabetes. 2001;50(suppl 1):S64-S69.
Jimenez-Feltstrom J, Lundquist I, Salehi A. Glucose stimulates the expression and activities of nitric oxide synthases in incubated rat islets: an effect counteracted by GLP-1 through the cyclic AMP/PKA pathway. Cell Tissue Res. 2005;319:221-230.
Salehi A, Meidute Abaraviciene S, Jimenez-Feltstrom J, Ostenson CG, Efendic S, Lundquist I. Excessive islet NO generation in type 2 diabetic GK rats coincides with abnormal hormone secretion and is counteracted by GLP-1. PLoS One. 2008;3:e2165.
Bandyopadhyay A, Chakder S, Rattan S. Regulation of inducible and neuronal nitric oxide synthase gene expression by interferon-gamma and VIP. Am J Physiol. 1997;272:C1790-C1797.
Hajmrle C, Smith N, Spigelman AF, et al. Interleukin-1 signaling contributes to acute islet compensation. JCI Insight. 2016;1:e86055.
Segerstolpe A, Palasantza A, Eliasson P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab. 2016;24:593-607.
Kim MK, Shin HM, Jung H, et al. Comparison of pancreatic beta cells and alpha cells under hyperglycemia: inverse coupling in pAkt-FoxO1. Diabetes Res Clin Pract. 2017;131:1-11.
Kanao T, Sawada T, Davies SA, et al. The nitric oxide-cyclic GMP pathway regulates FoxO and alters dopaminergic neuron survival in drosophila. PLoS One. 2012;7:e30958.
Chan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR. Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in beta-cell gene expression and progression to diabetes. Diabetes. 2013;62:1557-1568.