Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substan...Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substantial role in glucose metabolism.However,whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear.This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.Methods The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction.The mRNA and protein expression of the components in the insulin pathway,LRP6/β-catenin and mammalian target of rapamycin(mTOR)/S6 kinase(S6K)signaling,was determined.Liver tissues were immunostained for the expression of LRP6 andβ-catenin.LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.Results Compared with the control rats,CG-IUGR rats showed higher homeostasis model assessment for insulin resistance(HOMA-IR)index and fasting insulin level,decreased insulin signaling,reduced mTOR/S6K/insulin receptor substrate-1(IRS-1)serine307 activity,and decreased LRP6/β-catenin in the liver tissue.The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age(AGA)rats led to reductions in insulin receptor(IR)signaling and mTOR/S6K/IRS-1 serine307 activity.In contrast,LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.Conclusion LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways,IR and mTOR-S6K signaling.LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.展开更多
Background：A relationship between hyperthyroidism and insulin secretion in type 2 diabetes mellitus （T2DM） has been reported.Therefore,this study explored the use of first-phase insulin secretion in the differentia...Background：A relationship between hyperthyroidism and insulin secretion in type 2 diabetes mellitus （T2DM） has been reported.Therefore,this study explored the use of first-phase insulin secretion in the differential diagnosis of thyroid diabetes （TDM） and T2DM.Methods：In total,101 patients with hyperthyroidism were divided into hyperthyroidism with normal glucose tolerance （TNGT）,hyperthyroidism with impaired glucose regulation （TIGR）,and diabetes （TDM） groups.Furthermore,96 patients without hyperthyroidism were recruited as control groups （normal glucose tolerance [NGT],impaired glucose regulation [IGR],and T2DM）.The following parameters were evaluated：homeostasis model assessment （HOMA）-IR,HOMA-β,modified β-cell function index （MBCI）,peak insulin/fasting insulin （IP/I0）,AUCins-OGTT,and AUCins-OGTr/AUCglu-OGTT from the oral glucose tolerance test （OGTT） insulin release test were utilized to assess the second-phase insulin secretion,while the IP/I0,AIR0＇-10＇,and AUCins-IVGTT from the intravenous glucose tolerance test （IVGTT） insulin release test were used to assess the first-phase insulin secretion.Results：In the OGTT,the HOMA-β values of the TNGT and TDM groups were higher than those of the NGT and T2DM groups （all P 〈 0.05）.In the hyperthyroidism groups,the MBCI of the TDM group was lower than that of the TNGT and TIGR groups （all P 〈 0.05）.Among the control groups,the MBCI values of the IGR and T2DM groups were lower than that of the normal glucose tolerance （NGT） group （all P 〈 0.05）.In the IVGTT,insulin secretion peaked for all groups at 2-4 min,except for the T2DM group,which showed a low plateau and no secretion peak.The IPvalues of the TNGT,TIGR,and TDM groups were higher than those of the NGT,IGR,and T2DM groups （all P 〈 0.05）.The IP/I0,AIR0＇-10＇,and AUCins-IVGTT values of the TDM group were higher than those of the T2DM group but were lower than those of the TNGT,TIGR,NGR,and IGR groups （all P 〈 0.05）.Compared with the other five groups,the IP/I0 AIR0＇-10＇,and AUCins-IVGTT values of the T2DM group were significantly decreased （all P 〈 0.05）.The IP/I0 and AUCins-IVGTT values of the TNGT group were higher than those of the NGT group （all P 〈 0.05）.Conclusions：β-cell function in TDM patients is superior to that in T2DM patients.First-phase insulin secretion could be used as an early diagnostic marker to differentiate TDM and T2DM.展开更多
基金supported by the National Natural Science Foundation of China(No.82001651 and No.81660268).
文摘Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substantial role in glucose metabolism.However,whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear.This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.Methods The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction.The mRNA and protein expression of the components in the insulin pathway,LRP6/β-catenin and mammalian target of rapamycin(mTOR)/S6 kinase(S6K)signaling,was determined.Liver tissues were immunostained for the expression of LRP6 andβ-catenin.LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.Results Compared with the control rats,CG-IUGR rats showed higher homeostasis model assessment for insulin resistance(HOMA-IR)index and fasting insulin level,decreased insulin signaling,reduced mTOR/S6K/insulin receptor substrate-1(IRS-1)serine307 activity,and decreased LRP6/β-catenin in the liver tissue.The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age(AGA)rats led to reductions in insulin receptor(IR)signaling and mTOR/S6K/IRS-1 serine307 activity.In contrast,LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.Conclusion LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways,IR and mTOR-S6K signaling.LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.
文摘Background：A relationship between hyperthyroidism and insulin secretion in type 2 diabetes mellitus （T2DM） has been reported.Therefore,this study explored the use of first-phase insulin secretion in the differential diagnosis of thyroid diabetes （TDM） and T2DM.Methods：In total,101 patients with hyperthyroidism were divided into hyperthyroidism with normal glucose tolerance （TNGT）,hyperthyroidism with impaired glucose regulation （TIGR）,and diabetes （TDM） groups.Furthermore,96 patients without hyperthyroidism were recruited as control groups （normal glucose tolerance [NGT],impaired glucose regulation [IGR],and T2DM）.The following parameters were evaluated：homeostasis model assessment （HOMA）-IR,HOMA-β,modified β-cell function index （MBCI）,peak insulin/fasting insulin （IP/I0）,AUCins-OGTT,and AUCins-OGTr/AUCglu-OGTT from the oral glucose tolerance test （OGTT） insulin release test were utilized to assess the second-phase insulin secretion,while the IP/I0,AIR0＇-10＇,and AUCins-IVGTT from the intravenous glucose tolerance test （IVGTT） insulin release test were used to assess the first-phase insulin secretion.Results：In the OGTT,the HOMA-β values of the TNGT and TDM groups were higher than those of the NGT and T2DM groups （all P 〈 0.05）.In the hyperthyroidism groups,the MBCI of the TDM group was lower than that of the TNGT and TIGR groups （all P 〈 0.05）.Among the control groups,the MBCI values of the IGR and T2DM groups were lower than that of the normal glucose tolerance （NGT） group （all P 〈 0.05）.In the IVGTT,insulin secretion peaked for all groups at 2-4 min,except for the T2DM group,which showed a low plateau and no secretion peak.The IPvalues of the TNGT,TIGR,and TDM groups were higher than those of the NGT,IGR,and T2DM groups （all P 〈 0.05）.The IP/I0,AIR0＇-10＇,and AUCins-IVGTT values of the TDM group were higher than those of the T2DM group but were lower than those of the TNGT,TIGR,NGR,and IGR groups （all P 〈 0.05）.Compared with the other five groups,the IP/I0 AIR0＇-10＇,and AUCins-IVGTT values of the T2DM group were significantly decreased （all P 〈 0.05）.The IP/I0 and AUCins-IVGTT values of the TNGT group were higher than those of the NGT group （all P 〈 0.05）.Conclusions：β-cell function in TDM patients is superior to that in T2DM patients.First-phase insulin secretion could be used as an early diagnostic marker to differentiate TDM and T2DM.
