scholarly journals Islet adaptations in fetal sheep persist following chronic exposure to high norepinephrine

2017 ◽  
Vol 232 (2) ◽  
pp. 285-295 ◽  
Author(s):  
Xiaochuan Chen ◽  
Amy C Kelly ◽  
Dustin T Yates ◽  
Antoni R Macko ◽  
Ronald M Lynch ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Infusion ◽  
Inhibitory Concentration ◽  
Initial Assessment ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Intracellular Calcium Signaling ◽  
Glucose Stimulated Insulin Secretion ◽  
Lower Expression

Complications in pregnancy elevate fetal norepinephrine (NE) concentrations. Previous studies in NE-infused sheep fetuses revealed that sustained exposure to high NE resulted in lower expression of α2-adrenergic receptors in islets and increased insulin secretion responsiveness after acutely terminating the NE infusion. In this study, we determined if the compensatory increase in insulin secretion after chronic elevation of NE is independent of hyperglycemia in sheep fetuses and whether it is persistent in conjunction with islet desensitization to NE. After an initial assessment of glucose-stimulated insulin secretion (GSIS) at 129 ± 1 days of gestation, fetuses were continuously infused for seven days with NE and maintained at euglycemia with a maternal insulin infusion. Fetal GSIS studies were performed again on days 8 and 12. Adrenergic sensitivity was determined in pancreatic islets collected at day 12. NE infusion increased (P < 0.01) fetal plasma NE concentrations and lowered (P < 0.01) basal insulin concentrations compared to vehicle-infused controls. GSIS was 1.8-fold greater (P < 0.05) in NE-infused fetuses compared to controls at both one and five days after discontinuing the infusion. Glucose-potentiated arginine-induced insulin secretion was also enhanced (P < 0.01) in NE-infused fetuses. Maximum GSIS in islets isolated from NE-infused fetuses was 1.6-fold greater (P < 0.05) than controls, but islet insulin content and intracellular calcium signaling were not different between treatments. The half-maximal inhibitory concentration for NE was 2.6-fold greater (P < 0.05) in NE-infused islets compared to controls. These findings show that chronic NE exposure and not hyperglycemia produce persistent adaptations in pancreatic islets that augment β-cell responsiveness in part through decreased adrenergic sensitivity.

Reduced glucose-stimulated insulin secretion following a one-week IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect

2021 ◽  
Author(s):  
Alicia White ◽  
Jane Stremming ◽  
Brit H Boehmer ◽  
Eileen Chang ◽  
Sonnet S. Jonker ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Plasma Insulin ◽  
Cell Function ◽  
Late Gestation ◽  
Igf Binding Proteins ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Glucose Stimulated Insulin Secretion ◽  
Fetal Islets

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for one week into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n=8), an analogue of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n=9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n=8; CON, n=7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n=8; CON, n=7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared to CON (P=0.0135 and P=0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared to CON (P=0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P=0.0447). In summary, IGF-1 LR3 infusion for one week into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for one week. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in β-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.

scholarly journals Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

2014 ◽  
Vol 306 (1) ◽  
pp. E58-E64 ◽  
Author(s):  
Xiaochuan Chen ◽  
Alice S. Green ◽  
Antoni R. Macko ◽  
Dustin T. Yates ◽  
Amy C. Kelly ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Chronic Exposure ◽  
Uncoupling Protein ◽  
Adrenergic Blockade ◽  
Protein Subunit ◽  
Β Cell ◽  
Fetal Sheep ◽  
Isolated Pancreatic Islets ◽  
Glucose Stimulated Insulin Secretion

Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and β-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances β-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater ( P < 0.05) plasma NE concentrations and exhibited hyperglycemia ( P < 0.01) and hypoinsulinemia ( P < 0.01) compared with controls. GSIS during the NE infusion was also reduced ( P < 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater ( P < 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (α1D, α2A, α2C, and β1), G protein subunit-αi-2, and uncoupling protein 2 were lower ( P < 0.05) compared with controls, but β-cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets.

scholarly journals Dietary oxidised frying oil causes oxidative damage of pancreatic islets and impairment of insulin secretion, effects associated with vitamin E deficiency

2010 ◽  
Vol 105 (9) ◽  
pp. 1311-1319 ◽  
Author(s):  
Ya-Fan Chiang ◽  
Huey-Mei Shaw ◽  
Mei-Fang Yang ◽  
Chih-Yang Huang ◽  
Cheng-Hsien Hsieh ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Vitamin E ◽  
Oxidative Damage ◽  
Pancreatic Islets ◽  
Glucose Intolerance ◽  
Basal Diet ◽  
Frying Oil ◽  
Glucose Stimulated Insulin Secretion ◽  
High Level ◽  
Vitamin E Supplementation

We previously reported that, in rodents, a diet with a high oxidised frying oil (OFO) content leads to glucose intolerance associated with a reduction in insulin secretion. The present study aimed at investigating the impairment of pancreatic islets caused by dietary OFO. C57BL/6J mice were divided into three groups to receive a low-fat basal diet containing 5 g/100 g of fresh soyabean oil (LF group) or a high-fat diet containing 20 g/100 g of either fresh soyabean oil (HF group) or OFO (HO group). After 8 weeks, mice in the HO group showed glucose intolerance and hypoinsulinaemia, and their islets showed impaired glucose-stimulated insulin secretion (P < 0·05; HO group v. LF and HF groups). Significantly higher oxidative stress and a lower mitochondrial membrane potential were observed in the islets in the HO group compared with the LF and HF groups. Immunoblots showed that the reduction in insulin levels in HO islets was associated with activation of the c-Jun NH2-terminal kinase and a reduction in levels of pancreatic and duodenal homeobox factor-1. In a second study, when dietary OFO-induced tissue vitamin E depletion was prevented by large-dose vitamin E supplementation (500 IU(1·06 mmol all-rac-α-tocopherol acetate)/kg diet; HO+E group), the OFO-mediated reduction in islet size and impairment of glucose tolerance and insulin secretion were significantly attenuated (P < 0·05; HO group v. HO+E group). We conclude that a high level of dietary OFO ingestion impairs glucose metabolism by causing oxidative damage and compromising insulin secretion in pancreatic islets, and that these effects can be prevented by vitamin E supplementation.

scholarly journals Regulation of glucokinase in pancreatic islets by prolactin: a mechanism for increasing glucose-stimulated insulin secretion during pregnancy

2007 ◽  
Vol 193 (3) ◽  
pp. 367-381 ◽  
Author(s):  
Anthony J Weinhaus ◽  
Laurence E Stout ◽  
Nicholas V Bhagroo ◽  
T Clark Brelje ◽  
Robert L Sorenson
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Pancreatic Islets ◽  
Glucose Transporter ◽  
Β Cells ◽  
Glucose Transporter 2 ◽  
Underlying Mechanisms ◽  
Glucose Stimulated Insulin Secretion ◽  
Induced Changes

Glucokinase activity is increased in pancreatic islets during pregnancy and in vitro by prolactin (PRL). The underlying mechanisms that lead to increased glucokinase have not been resolved. Since glucose itself regulates glucokinase activity in β-cells, it was unclear whether the lactogen effects are direct or occur through changes in glucose metabolism. To clarify the roles of glucose metabolism in this process, we examined the interactions between glucose and PRL on glucose metabolism, insulin secretion, and glucokinase expression in insulin 1 (INS-1) cells and rat islets. Although the PRL-induced changes were more pronounced after culture at higher glucose concentrations, an increase in glucose metabolism, insulin secretion, and glucokinase expression occurred even in the absence of glucose. The presence of comparable levels of insulin secretion at similar rates of glucose metabolism from both control and PRL-treated INS-1 cells suggests the PRL-induced increase in glucose metabolism is responsible for the increase in insulin secretion. Similarly, increases in other known PRL responsive genes (e.g. the PRL receptor, glucose transporter-2, and insulin) were also detected after culture without glucose. We show that the upstream glucokinase promoter contains multiple STAT5 binding sequences with increased binding in response to PRL. Corresponding increases in glucokinase mRNA and protein synthesis were also detected. This suggests the PRL-induced increase in glucokinase mRNA and its translation are sufficient to account for the elevated glucokinase activity in β-cells with lactogens. Importantly, the increase in islet glucokinase observed with PRL is in line with that observed in islets during pregnancy.

scholarly journals The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells

2020 ◽  
Vol 117 (45) ◽  
pp. 28307-28315
Author(s):  
Baile Wang ◽  
Huige Lin ◽  
Xiaomu Li ◽  
Wenqi Lu ◽  
Jae Bum Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Adaptor Protein ◽  
Hek293 Cells ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Actin Remodeling ◽  
Actin Depolymerization ◽  
Glucose Stimulated Insulin Secretion

Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in β-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic β-cells. β-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic β-cells.

Maturation of Glucose-Stimulated Insulin Secretion in Fetal Sheep

Neonatology ◽  
1998 ◽  
Vol 73 (6) ◽  
pp. 375-386 ◽  
Author(s):  
Peter W. Aldoretta ◽  
Thomas D. Carver ◽  
William W. Hay Jr.
Keyword(s):  
Insulin Secretion ◽  
Fetal Sheep ◽  
Glucose Stimulated Insulin Secretion

Reduced sensitivity to dexamethasone of pancreatic islets from obese (fa/fa) rats

1992 ◽  
Vol 70 (11) ◽  
pp. 1518-1522 ◽  
Author(s):  
Catherine Chan ◽  
Jeffrey Lejeune
Keyword(s):  
Insulin Secretion ◽  
Minimum Inhibitory Concentration ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Inhibitory Concentration ◽  
Insulin Response ◽  
Zucker Rat ◽  
Direct Effects ◽  
Inhibitory Effects ◽  
Higher Doses

The direct effects of dexamethasone exposure on insulin secretion from islets of fa/fa rats and their lean littermates (Fa/?) were compared. After 72 h culture in 1 nM dexamethasone, glucose (27.5 mM)-stimulated insulin secretion over 90 min from islets of lean rats was significantly decreased compared with islets cultured without dexamethasone (12.9 ± 1.4 vs. 5.7 ± 1.0% of total islet content, p < 0.05). Higher doses of dexamethasone for 24–48 h culture produced similar effects. For islets of fa/fa rats, the minimum inhibitory concentration of dexamethasone was 10-fold higher, and islets required at least 48 h exposure for inhibitory effects to be observed. Dexamethasone also decreased the insulin response by islets to glybenclamide, indicating that dexamethasone effects were not specific to glucose transport or metabolism. The results suggest that islets of fa/fa rats may be less sensitive to direct inhibitory effects of glucocorticoids on glucose-stimulated insulin release than islets of lean animals.Key words: obesity, glucocorticoid, insulin, Zucker rat.

scholarly journals Menaquinone-4 Amplified Glucose-Stimulated Insulin Secretion in Isolated Mouse Pancreatic Islets and INS-1 Rat Insulinoma Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 1995 ◽  
Author(s):  
Hsin-Jung Ho ◽  
Hitoshi Shirakawa ◽  
Keisukei Hirahara ◽  
Hideyuki Sone ◽  
Shin Kamiyama ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Vitamin K2 ◽  
Cell Dysfunction ◽  
Mouse Pancreatic Islets ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulinoma Cells ◽  
Camp Levels ◽  
Dependent Pathway

Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, β-cell dysfunction following insulin secretion has been found to decrease in patients with type 2 diabetes mellitus. To elucidate the physiological function of MK-4 in pancreatic β-cells, we studied the effects of MK-4 treatment on isolated mouse pancreatic islets and rat INS-1 cells. Glucose-stimulated insulin secretion significantly increased in isolated islets and INS-1 cells treated with MK-4. It was further clarified that MK-4 enhanced cAMP levels, accompanied by the regulation of the exchange protein directly activated by the cAMP 2 (Epac2)-dependent pathway but not the protein kinase A (PKA)-dependent pathway. A novel function of MK-4 on glucose-stimulated insulin secretion was found, suggesting that MK-4 might act as a potent amplifier of the incretin effect. This study therefore presents a novel potential therapeutic approach for impaired insulinotropic effects.

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