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Pituitary adenomas(PAs) are the most common types of central nervous system tumors. Although most of them are benign tumors, aggressive PAs are resistant to conventional treatments and thus increase morbidity and mortality. Immunotherapy is a promising treatment and has been applied in treatment of kinds of neoplasms, including aggressive PAs. This review summarizes recent advances of immune checkpoint inhibitors in PAs.
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Objective To study the changes and mechanism of the function of islet βcells and insulin signal transduction molecules in rats after long-term period lipid infusion.Methods Thirty SpragueDawley (SD) rats were randomly divided into free fatty acid (FFA) and normal saline (NS) groups.Catheters were implanted under pentobarbital anesthesia in the right atrium via the jugular vein and the left carotid artery.A technique for a 72-h infusion in unrestrained rats was used for triglyceride and heparin or saline infusion.The infusion period was started on day 2 after surgery.After 72-h infusion,fasting serum insulin (Ins) and FFA in the blood were determined.The glucose infusion rat (GIR) was measured by hyperinsulinemia euglycemic clamp to evaluate the peripheral insulin resistance.The intravenous glucose tolerance test (ivgtt) and islet cell perifusion was conducted to evaluate the function of islet β-cell.The rats in two groups were sacrificed,and the pancreatic islets were isolated and collected.The levels of malondialdehyde (MDA) and reduced glutathione hormone (GSH) were detected in pancreatic tissues.The expressions of insulin receptor substrate-1 (IRS-1),insulin receptor substrate-2 (IRS-2),and glucose transporter-2 (Glut2)gene in islets were detected by real-time polymerase chain reaction (PCR).Results (1)The serum FFA concentration in the FFA group was higher than in NS group [(1.56 ± 0.21) mmol/L vs (0.65 ± 0.12)mmol/L,P ＜0.01].(2)The GIR was decreased significantly in FFA group compared with NS group(P ＜0.01).(3)The glucose that stimulated insulin secretion was decreased in the FFA group.(4)The levels of MDA were significantly higher in FFA group [(1.62 ± O.18) mmol/mg prot vs (0.76 ± 0.15) mmol/mg prot,P ＜0.01].The levels of GSH were lower in FFA group [(22.54 ±2.66) mg/g prot vs (36.58 ± 3.02) mg/g prot,P ＜ 0.01].(5) The gene cxprcssion of IRS-1 in islets was significantly decreased by [(36.8±1.8)％,P ＜0.01],and the expression of IRS-2 and Glut-2 was decreased by [(29.6±1.2) ％] and [(58.7 ± 2.1) ％] in FFA group,respectively(all P ＜0.01).Conclusions Lipid infusion in long time decreased the secretion of insulin and impaired the expression of insulin signal transduction molecules in islet βcells.
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ObjectivesTo evaluate the effect of combination of liraglutide,a glucagon-like peptide-1 analogue and pioglitazone,an insulin sensitizer,on diabetic db/db mice.MethodsThirty-five 8-week old male db/db mice were divided into control group (n = 8 ),pioglitazone group (n =9 ),liraglutide group (n =9) and combined therapeutic group (n =9),which was given normal saline 0.1 ml,2/d,pioglitazone 24 mg· kg-1 · d-1 (feed contained 0.02％ pioglitazone) + normal saline 0.1 ml,2/d,liraglutide 300 mg/kg,2/d,and pioglitazone 20 mg · kg-1 · d -1 ( feed contained 0.02％ pioglitazone) +liraglutide 300 mg/kg,2/d,respectively.Liraglutide were given at 8:00 and 16:00 via subcutaneous injection after having been diluted with sterilized normal saline.Effect on glucose,lipid metabolism and islet β-cell preservation were assessed after 4 weeks.Oneway ANOVA was adopted for statistical analysis.Results Combination therapy displayed promising anti-hyperglycemic[glycosylated hemoglobin Alc: (4.5 ± 0.6)％vs.(7.3 ±0.4)％,P ＜ 0.001].Glucose tolerance were improved assessed by area under curve(AUC) of glucose by intraperitoneal glucose tolerance test (IPGTT)[(1814 ±91 ) mmol · min · L-1 vs.(4042 ±183) mmol · min · L-1,P ＜0.001];insulin release response to glucose were also preserved as AUC of insulin by IPGTT was higher[( 1639 ±372) μg · min · L-1 vs.(834 ±201 )μg · min · L-1].Combination therapy also reduced circulated free fatty acids and TG[( 202.0 ± 20.4 ) μmol/L vs.( 272.5 ± 21.7 )μmol/L,(0.81 ± 0.28) mmol/L vs.( 1.35 ± 0.21 ) mmol/L],and increased plasma adiponectin [(16.7±2.0)mg/L vs.(10.2±1.8)mg/L].All P value ＜0.05.Islet immunohistochemistry showed that combination therapy significantly increased insulin positive area were[( 59.5 ± 1.5 ) ％ vs.( 22.4 ±1.5) ％]and ratio of Brdu positive β-cells was three folds than vehicle-treated mice[( 2.4 ± 0.5 ) ％ vs.(0.8 ±0.3)％],both greater than each single treatment.Combined therapy significantly improved islet β cell/α cell distribution,which led to islet recovery.ConclusionsCombined therapy improves glucose and lipid metabolism,preserves islet β-cell function and stimulates β-cell proliferation,greater than either liraglutide or pioglitazone treatment alone.
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Pancreatic stellate cell (PSC) activation in islet fibrosis of insulin-resistant rats induced by high-fat diet was investigated. After 20 weeks, the glucose infusion rate and glucose-stimulated insulin secretion in high-fat group were significantly decreased while fasting plasma glucose, fasting serum insulin, free fatty acid and the basal glucagon secretion were significantly increased compared with those parameters of the control rats (P< 0.05 or P<0.01). Activated PSC and collagen fiber ( type Ⅰ and Ⅲ) were found in islets of rats fed with high-fat. The result suggests that PSC activation, proliferation and migration to islet may contribute to islet fibrosis in insulin-resistant rats.
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Objective To explore whether an excessive accumulation of lipids is involved in the suppression of β cell proliferation and to determine the role of glucose in this experiment. Methods The proliferation of the Ins-1E cells was studied by 3H-thymidine incorporation. The accumulation of fatty acids in beta cells was studied by 3H-palmitate incorporation. Using Taqman real-time RT-PCR, we measured the expression of carnitine palmitoyltransferase-1 (CPT-1) gene. Results As compared with 3.3 mmol/L glucose, the 6.6 mmol/L and 11 mmol/L glucose increased the cell proliferation by 2.27 and 3.04 folds (P<0.05), and the supplemented 0.4 mmol/L palmitate blunted the glucose-induced cell proliferation (1.1 and 0.86 fold, at 6.6 and 11 mmol/L glucose, respectively). With increasing glucose levels, the incorporation of palmitate was augmented,which ranged from 15% to 92%. Wy 14 643 and Triacsin C alleviated the palmitate-induced inhibition of cell proliferation and reduced the incorporation of palmitate. Glucose did not change the expression of CPT-1 gene, but inhibited the palmitate-induced expression in a dose dependent manner. Conclusions The FA-stimulated CPT-1 gene expression is inhibited by glucose, which increases the FA accumulation in β cells and inhibits their proliferation. This could be underlying the mechanism of glucose-dependent lipotoxicity.
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Objective To investigate the changes of peripheral insulin resistance after lipid infusion and the effect of N-acetylcystein(NAC) intervention.Methods Thirty-seven normal male SD rats,eight weeks old,were randomly divided into three groups,FFA group,NS group and NAC group(using into NAC 300 mg/(kg?d) two weeks before infusion).Catheters were implanted into right atrium via the jugular vein and left carotid artery.A technique for a 48-h infusion in unrestrained rats was used for triglyceride and heparin or saline infusion.The infusion period started on day 2 after surgery.48-h after infusion,we determined free fat acid(FFA),nitrotyrosine,malonaldehyde(MDA),reduced glutathione hormone(GSH) level in plasma.The glucose infusion rat(GIR) was measured by hyperinsulinemia euglycemic clamp to evaluated the perpherial insulin resistance.The expressions of IRS-1,IRS-2 gene in muscle were detected by real time PCR.Results(1)The FFA,nitrotyrosine and MDA con-centrations in FFA group were higher than that in NS group,but GSH level in plasma was lower.NAC intervention could reverse these effects.(2)GIR was decreased significantly in FFA group as compared with NS group[(8.34?1.8)mg/(min?kg)] vs[(13.56?1.7)mg/(min?kg)],(P
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-4.88) and relative insulin resistant group (IAI≤-4.88), and 42 healthy normal persons were selected as control. Results The frequency of Trp 64Arg mutation of ? 3 AR gene was higher in the resistant group than that in the sensitive group (28.0% vs 15.7%, P