黑棘皮病与青少年肥胖

黑棘皮病是青少年肥胖患者中常见的皮肤病变,是青少年肥胖患者体内严重胰岛素抵抗的皮肤标志.在肥胖患者中,高胰岛素血症、炎性反应因子、异常分泌的脂肪细胞因子可促进皮肤组织内的成纤维细胞及角蛋白细胞的增殖,从而促进黑棘皮病的发生.另外,基因多态性同样在这一过程中发挥重要作用.然而青少年肥胖患者黑棘皮病的治疗尚无特效方法,通过饮食、运动及药物改善内胰岛素敏感性可能有效.     

肥胖儿童黑棘皮病严重程度与胰岛素抵抗的相关性研究

目的探究肥胖儿童的各项指标尤其是胰岛素抵抗随着黑棘皮病（AN）程度加重的变化情况,分析黑棘皮病严重程度预测胰岛素抵抗的能力。 方法回顾性分析2018年3月到2020年1月在天津医科大学总医院儿科就诊的88例肥胖儿童的临床资料,收集一般资料：身高、体重、腰围、收缩压及舒张压,检测儿童的葡萄糖、胰岛素、谷丙转氨酶、谷草转氨酶、尿酸、总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白、糖化血红蛋白和25羟维生素D等指标,分析肥胖儿童黑棘皮病严重程度与一般资料、生化指标的关系以及其预测胰岛素抵抗的能力。 结果4组肥胖儿童中中度AN组的BMI、腰围、收缩压和生化指标UA的值最高,并未随着黑棘皮病的加重而逐步升高;肥胖儿童非AN组的HOMA-IR随着黑棘皮病的加重而升高,IAI随着黑棘皮病的加重而降低,非AN组的HOMA-IR、IAI与任何程度的AN组均存在统计学意义;肥胖儿童黑棘皮病严重程度预测胰岛素抵抗的曲线下面积为0.791,当黑棘皮病严重程度大于1分（即存在AN）时,敏感性为61.43%,特异性为94.44%。 结论肥胖儿童的胰岛素抵抗程度随着黑棘皮病的加重而加重,黑棘皮病可作为筛查胰岛素抵抗的临床表型特征。     

二甲双胍对IGT伴黑棘皮病肥胖青少年体重、血糖、血脂及胰岛素水平的影响

二甲双胍是已经有 6 0年应用历史的降血糖药物 ,近年来英国糖尿病前瞻性研究 (ＵＫＰＤＳ)证明其除降血糖外 ,还是改善 2型糖尿病患者长期临床转归的药物。本研究利用该药不增加体重 ,不发生低血糖的特点 ,观察二甲双胍对ＩＧＴ伴黑棘皮病肥胖青少年体重、血糖、血脂及胰岛素水平和黑棘皮病本身的影响。一、对象和方法1.1996年 8月至 1998年 12月间在我院门诊就诊、体重指数 (ＢＭＩ)≥ 30的肥胖青少年共 87例 ,其中伴不同程度的黑棘皮病者 32例 (男性 17例 ,女性 15例 ) ,占 36 .8% ,黑棘皮病诊断按标准〔1〕。本研究把仅有腋窝部轻度色素…     

黑棘皮病伴高胰岛素血症7例报告

黑棘皮病 (AN)系以色素增生、角化过度、疣状增殖为特征的少见皮肤病 ,多见于腋下、腹股沟、颈部、乳晕、肛周和暴露部位。临床上分为五型 ,包括 :真性良性型、假性 AN、药物型、综合征性良性型、恶性型。本组病例均属于良性 AN型。一、临床资料本组 7例其中男 4例 ,女 3例。年龄 11～ 2 6岁 ,平均 18岁。体重指数 2 8.1～ 32 .3kg/ m2 ,平均 30 .0 kg/ m2 ,家族中无类似病人。所有患者都具有以上皮肤病临床特征 ,且均经皮肤活检证实为AN。 7例病人血清胰岛素水平均高于正常值 2～ 5倍 ,其中 1例伴2型 DM,1例伴 IGT,3例女性均伴继发性…     

二甲双胍对高胰岛素血症儿童假性黑棘皮病的疗效观察

对88例高胰岛素血症假性黑棘皮病(AN)肥胖儿童给予二甲双胍治疗3个月和6个月后,对空腹胰岛素、葡萄糖耐量试验2 h胰岛素和AN评分等进行评价,结果表明二甲双胍可改善假性AN肥胖患儿高胰岛素血症状态,AN分级方法可作为病情变化的无创监测手段.     

二甲双胍对假性黑棘皮病胰岛素抵抗及高胰岛素血症的作用

假性黑棘皮病 (ａｃａｎｔｈｏｓｉｓｎｉｇｒｉｃａｎｓ,ＡＮ)是一种胰岛素抵抗、高胰岛素血症、高雄激素血症的皮肤特征性改变 ,在不同的胰岛素抵抗综合征中常常伴有假性ＡＮ。胰岛素抵抗和代偿性高胰岛素血症已被证明对糖尿病、肥胖、高血压、高脂血症等疾病的发生起着重要的促进作用。及早发现和识别高胰岛素血症并给予早期干预治疗是目前临床研究的重点。二甲双胍除降低血糖外 ,可改善机体对胰岛素的敏感性 ,增加细胞的胰岛素受体数目 ,从而改善高胰岛素血症。本研究旨在观察二甲双胍对假性ＡＮ中胰岛素抵抗及高胰岛素血症、高雄激素血…     

儿童、青少年肥胖者2型糖尿病和高危者筛查

目的　调查儿童、青少年肥胖者 2型糖尿病 (DM )及其高危者的发生率 ,探讨高危因素。方法　对 13 5例肥胖者 ( 7～ 2 0岁 )进行口服葡萄糖耐量试验 ,测定空腹和 2h血糖、胰岛素水平及计算胰岛素抵抗值 (Homa IR)及胰岛 β细胞功能 (Homa β)并对糖代谢异常者中的 14例进行干预治疗。 结果 ( 1)在 13 5例肥胖者中发现 2型DM 3例 ( 2 .2 % ) ,糖耐量异常 (IGT) 18例 ( 13 .3 % ) ,高胰岛素血症 72例 ( 5 3 .3 % ) ;( 2 )青少年肥胖组其 2h血糖、胰岛素水平、2h胰岛素与葡萄糖之比、Homa IR及Homa β显著高于儿童肥胖组及非肥胖组 ,且糖代谢异常的发生率显著高于儿童组 (P <0 .0 5～P <0 .0 0 1) ;( 3 )糖代谢异常者各指标明显高于单纯性肥胖者 (P <0 .0 5～P <0 .0 0 1) ;( 4 ) 93例糖代谢异常中 44例 ( 4 7.3 % )有 2型DM家族史 ,3 2例 ( 3 4.4% )有黑棘皮病样表现 ;( 5 ) 14例患者经药物治疗 ( 2 .9± 1.7)个月 ,糖代谢指标显著改善 (P <0 .0 5～P <0 .0 1)。结论　学龄期应开始肥胖干预、糖尿病筛查 ,以降低青少年 2型DM发生率。     

肥胖患者运动血压与血糖、血浆胰岛素水平的关系

目的探讨肥胖患者运动血压与血糖、血浆胰岛素水平的关系.方法选取完成次极量踏车运动试验的49例肥胖患者(Obesity)及45例体重正常的对照组(Control),比较其静态血压(RBP)、运动血压(PBP)及空腹和口服75克葡萄糖2小时后血糖、血浆胰岛素水平.并分析肥胖组中合并运动性高血压(PBP1)与运动血压正常者(PBP2)的血糖、胰岛素水平.结果静态下两组血压无显著差异,负荷试验后达到运动性高血压标准者,肥胖组21/49例(42.8%),对照组8/45例(17.8%),P<0.01;运动后肥胖组的收缩压与舒张压均较对照组升高,特别是收缩压升高更明显;两组空腹血糖无显著差异,肥胖组的空腹胰岛素、餐后2小时血糖及胰岛素均明显高于对照组;肥胖组中伴运动性高血压者的餐后2小时血糖、胰岛素水平均高于不伴运动性高血压的肥胖患者.结论肥胖患者血压、血糖升高可能与胰岛素水平升高有关.     

肥胖和非肥胖糖耐量受损患者胰岛素敏感性和1相胰岛素分泌研究

目的研究肥胖和非肥胖糖耐量受损(IGT)患者的胰岛素敏感性和β细胞1相胰岛素分泌功能,以探讨在IGT患者中肥胖对胰岛素抵抗和1相胰岛素分泌的影响。方法共有99位受试者(包括正常对照者32名,肥胖IGT44例,非肥胖IGT23例)接受了口服75 g葡萄糖耐量试验(OGTT)和胰岛素改良的减少样本数(采血样12次)的Bergman微小模型技术结合静脉葡萄糖耐量试验(FSIGTT)。胰岛素抵抗由FSIGTT中胰岛素敏感性指数(SI)加以评估,而OGTT中糖负荷后30 min胰岛素增值与血糖增值之比值[ΔI30/ΔG30=(I30 min-I0 min) /(G30 min-G0 min)]和FSIGTT中急性胰岛素分泌反应(AIRg)则用以评价胰岛β细胞分泌功能。处理指数(DI =AIRg×SI)用于评价AIRg是否代偿机体的胰岛素抵抗。结果与正常对照组[(7.52±10.89)×10-4]相比,二组IGT患者之SI明显降低,而肥胖IGT组的SI[(1.72±1.11)×10-4]较非肥胖组[(3.15±1.49)×10-4]更低(均P<0.01); AIRg和ΔI30/ΔG30在正常组(412±191,14.45±8.47)和肥胖IGT组(378±235,17.02±11.30)之间差异无统计学意义,但均大于非肥胖组(196±160,8.93±6.69,均P<0.01);与正常组(2 851±1 180)相比,DI指数在二组IGT显著降低(595±485,584±517),但后二组间此值差异无统计学意义。SI与2 h胰岛素、体重指数、尿酸和胆固醇呈显著的负相关性(校正r2=0.603,P<0.01);而AIRg与ΔI30/ΔG30显著正相关,与空腹血糖负相关(校正r2=0.479,P<0.01)。结论IGT患者存在胰岛素抵抗和β细胞功能异常。与非肥胖IGT患者相比,肥胖IGT患者胰岛素抵抗程度更为严重,但胰岛β细胞胰岛素1相分泌相对充分。     

蛋白酪氨酸磷酸酶1B的普遍激活:胰岛素抵抗和瘦素抵抗可能的共同发病机制

近年研究发现蛋白酪氨酸磷酸酶1B(PTP1B)是胰岛素信号转导和瘦素信号转导的负性调控因子;肥胖相关胰岛素抵抗及瘦素抵抗中均存在PTP1B的过度表达。PTP1B活化可能是胰岛素抵抗和瘦素抵抗的共同机制。因此,抑制PTP1B为治疗2型糖尿病和肥胖开辟了新的途径。     

Insulin and phorbol ester stimulate conductive Na+ transport through a common pathway.

Insulin stimulates Na+ transport across frog skin, toad urinary bladder, and the distal renal nephron. This stimulation reflects an increase in apical membrane Na+ permeability and a stimulation of the basolateral membrane Na,K-exchange pump. Considerable indirect evidence has suggested that the apical natriferic effect of insulin is mediated by activation of protein kinase C. However, no direct information has been available documenting that insulin and protein kinase C indeed share a common pathway in stimulating Na+ transport across frog skin. In the present work, we have studied the interaction of insulin and phorbol 12-myristate 13-acetate (PMA), a documented activator of protein kinase C. Preincubation of skins with 1,2-dioctanoylglycerol, another activator of protein kinase C, increases baseline Na+ transport and reduces the subsequent natriferic response to PMA. Preincubation with PMA markedly reduces the subsequent natriferic action of insulin. This effect does not appear to primarily reflect PMA-induced internalization of insulin receptors. The insulin receptors are localized on the basolateral surface of frog skin, but the application of PMA to this surface is much less effective than mucosal treatment in reducing the response to insulin. Preincubation with D-sphingosine, an inhibitor of protein kinase C, also reduces the natriferic action of insulin. The current results provide documentation that insulin and protein kinase C share a common pathway in stimulating Na+ transport across frog skin. The data are consistent with the concept that the natriferic effect of insulin on frog skin is, at least in part, mediated by activation of protein kinase C.     

Phospholipase C-ε links Epac2 activation to the potentiation of glucose-stimulated insulin secretion from mouse islets of Langerhans

Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is potentiated by cAMP-elevating agents, such as the incretin hormone glucagon-like peptide-1 (GLP-1), and cAMP exerts its insulin secretagogue action by activating both protein kinase A (PKA) and the cAMP-regulated guanine nucleotide exchange factor designated as Epac2. Although prior studies of mouse islets demonstrated that Epac2 acts via Rap1 GTPase to potentiate GSIS, it is not understood which downstream targets of Rap1 promote the exocytosis of insulin. Here, we measured insulin secretion stimulated by a cAMP analog that is a selective activator of Epac proteins in order to demonstrate that a Rap1-regulated phospholipase C-epsilon (PLC-ε) links Epac2 activation to the potentiation of GSIS. Our analysis demonstrates that the Epac activator 8-pCPT-2'-O-Me-cAMP-AM potentiates GSIS from the islets of wild-type (WT) mice, whereas it has a greatly reduced insulin secretagogue action in the islets of Epac2 (-/-) and PLC-ε (-/-) knockout (KO) mice. Importantly, the insulin secretagogue action of 8-pCPT-2'-O-Me-cAMP-AM in WT mouse islets cannot be explained by an unexpected action of this cAMP analog to activate PKA, as verified through the use of a FRET-based A-kinase activity reporter (AKAR3) that reports PKA activation. Since the KO of PLC-ε disrupts the ability of 8-pCPT-2'-O-Me-cAMP-AM to potentiate GSIS, while also disrupting its ability to stimulate an increase of β-cell [Ca2+]i, the available evidence indicates that it is a Rap1-regulated PLC-ε that links Epac2 activation to Ca2+-dependent exocytosis of insulin.     

Role of atypical protein kinase C in activation of sterol regulatory element binding protein-1c and nuclear factor kappa B (NFκB) in liver of rodents used as a model of diabetes, and relationships to hyperlipidaemia and insulin resistance

Aims/hypothesis  Previous findings in rodents used as a model of diabetes suggest that insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but, unexpectedly, conserved in liver, despite impaired hepatic protein kinase B (PKB/Akt) activation. Moreover, aPKC at least partly regulates two major transactivators: (1) hepatic sterol receptor binding protein-1c (SREBP-1c), which controls lipid synthesis; and (2) nuclear factor kappa B (NFκB), which promotes inflammation and systemic insulin resistance. Methods  In Goto–Kakizaki rats used as a model of type 2 diabetes, we examined: (1) whether differences in hepatic aPKC and PKB activation reflect differences in activation of IRS-1- and IRS-2-dependent phosphatidylinositol 3-kinase (PI3K); (2) whether hepatic SREBP-1c and NFκB are excessively activated by aPKC; and (3) metabolic consequences of excessive activation of hepatic aPKC, SREBP-1c and NFκB. Results  In liver, as well as in muscle, IRS-2/PI3K activation by insulin was intact, whereas IRS-1/PI3K activation by insulin was impaired. Moreover, hepatic IRS-2 is known to control hepatic aPKC during insulin activation. Against this background, selective inhibition of hepatic aPKC by adenoviral-mediated expression of mRNA encoding kinase-inactive aPKC or short hairpin RNA targeting Irs2 mRNA and partially depleting hepatic IRS-2 diminished hepatic SREBP-1c production and NFκB activities, concomitantly improving serum lipids and insulin signalling in muscle and liver. Similar improvements in SREBP-1c, NFκB and insulin signalling were seen in ob/ob mice following inhibition of hepatic aPKC. Conclusions/interpretation  In diabetic rodent liver, diminished PKB activation may largely reflect impaired IRS-1/PI3K activation, while conserved aPKC activation reflects retained IRS-2/PI3K activity. Hepatic aPKC may also contribute importantly to excessive SREPB-1c and NFκB activities. Excessive hepatic aPKC-dependent activation of SREBP-1c and NFκB may contribute importantly to hyperlipidaemia and systemic insulin resistance. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Phospholipase C-ε links Epac2 activation to the potentiation of glucose-stimulated insulin secretion from mouse islets of Langerhans

Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is potentiated by cAMP-elevating agents, such as the incretin hormone glucagon-like peptide-1 (GLP-1), and cAMP exerts its insulin secretagogue action by activating both protein kinase A (PKA) and the cAMP-regulated guanine nucleotide exchange factor designated as Epac2. Although prior studies of mouse islets demonstrated that Epac2 acts via Rap1 GTPase to potentiate GSIS, it is not understood which downstream targets of Rap1 promote the exocytosis of insulin. Here, we measured insulin secretion stimulated by a cAMP analog that is a selective activator of Epac proteins in order to demonstrate that a Rap1-regulated phospholipase C-epsilon (PLC-ε) links Epac2 activation to the potentiation of GSIS. Our analysis demonstrates that the Epac activator 8-pCPT-2’-O-Me-cAMP-AM potentiates GSIS from the islets of wild-type (WT) mice, whereas it has a greatly reduced insulin secretagogue action in the islets of Epac2 (-/-) and PLC-ε (-/-) knockout (KO) mice. Importantly, the insulin secretagogue action of 8-pCPT-2’-O-Me-cAMP-AM in WT mouse islets cannot be explained by an unexpected action of this cAMP analog to activate PKA, as verified through the use of a FRET-based A-kinase activity reporter (AKAR3) that reports PKA activation. Since the KO of PLC-ε disrupts the ability of 8-pCPT-2’-O-Me-cAMP-AM to potentiate GSIS, while also disrupting its ability to stimulate an increase of β-cell [Ca2+]i, the available evidence indicates that it is a Rap1-regulated PLC-ε that links Epac2 activation to Ca2+-dependent exocytosis of insulin.     

Insulin-like Growth Factors as Regulators of Cell Motility Signaling Mechanisms.

Accumulating evidence indicates that the insulin-like growth factors (IGFs) function not only as mitogenic factors, but also as promoters of cell motility. In this article we review the current knowledge concerning the biochemical mechanisms whereby the IGFs activate cell motility. A key aspect of IGF-stimulated cell motility is the ability of IGFs to promote actin polymerization at the leading edge of the cell. This effect of the IGFs is mediated by activation and autophosphorylation of the type I IGF receptor, followed by docking of insulin receptor substrate-1 (IRS-1), stimulation of phosphatidylinositol (PI) 3-kinase, and possibly activation of the small GTPase Rac. IGF-stimulated cell motility also requires the formation of new adhesions, a process associated with tyrosine phosphorylation of paxillin and focal adhesion kinase. Determining the biochemical mechanisms by which IGFs regulate cell motility should allow for a better understanding of bone remodeling, neurite outgrowth, tumor metastasis, placental formation, and skin and blood vessel repair. (c) 1997, Elsevier Science Inc. (Trends Endocrinol Metab 1997;8:1-6).     

Increasing cAMP attenuates activation of mitogen-activated protein kinase.

Activation of the mitogen-activated protein kinase (MAP kinase) isoforms ERK1 and ERK2 was investigated in rat adipocytes. Kinase activities were measured by using myelin basic protein as substrate after the isoforms were resolved by Mono Q chromatography or by immunoprecipitation with specific antibodies. Insulin increased the activity of both isoforms by 3- to 4-fold. The beta-adrenergic agonist isoproterenol was without effect in the absence of insulin but markedly reduced the increases in ERK1 and ERK2 activities produced by the hormone. MAP kinase activation was also attenuated by forskolin and glucagon, which increase intracellular cAMP, and by dibutyryl-cAMP, 8-bromo-cAMP, and 8-(4-chlorophenylthio)-cAMP. Thus, increasing cAMP is associated with decreased activation of MAP kinase by insulin. Forskolin also inhibited activation of MAP kinase by several agents (epidermal growth factor, phorbol 12-myristate 13-acetate, and okadaic acid) that act independently of insulin receptors. Moreover, forskolin did not inhibit insulin-stimulated tyrosine phosphorylation of the insulin receptor substrate IRS-1. Therefore, the inhibitory effect on MAP kinase did not result from compromised functioning of the insulin receptor. The inhibitory effect was not confined to adipocytes, as forskolin and dibutyryl-cAMP inhibited the increase in MAP kinase activity by phorbol 12-myristate 13-acetate in wild-type CHO cells. In contrast, these agents did not inhibit MAP kinase activity in mutant CHO cells (line 10248) that express a cAMP-dependent protein kinase resistant to activation by cAMP. Our results suggest that activation of cAMP-dependent protein kinase represents a general counter-regulatory mechanism for opposing MAP kinase activation.     

Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance

The mammalian target of rapamycin (mTOR) pathway integrates insulin and nutrient signaling in numerous cell types. Recent studies also suggest that this pathway negatively modulates insulin signaling to phosphatidylinositol 3-kinase/Akt in adipose and muscle cells. However, it is still unclear whether activation of the mTOR pathway is increased in obesity and if it could be involved in the promotion of insulin resistance. In this paper we show that basal (fasting state) activation of mTOR and its downstream target S6K1 is markedly elevated in liver and skeletal muscle of obese rats fed a high fat diet compared with chow-fed, lean controls. Time-course studies also revealed that mTOR and S6K1 activation by insulin was accelerated in tissues of obese rats, in association with increased inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser636/Ser639 and impaired Akt activation. The relationship between mTOR/S6K1 overactivation and impaired insulin signaling to Akt was also examined in hepatic cells in vitro. Insulin caused a time-dependent activation of mTOR and S6K1 in HepG2 cells. This was associated with increased IRS-1 phosphorylation on Ser636/Ser639. Inhibition of mTOR/S6K1 by rapamycin blunted insulin-induced Ser636/Ser639 phosphorylation of IRS-1, leading to a rapid (approximately 5 min) and persistent increase in IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation. These results show that activation of the mTOR pathway is increased in liver and muscle of high fat-fed obese rats. In vitro studies with rapamycin suggest that mTOR/S6K1 overactivation contributes to elevated serine phosphorylation of IRS-1, leading to impaired insulin signaling to Akt in liver and muscle of this dietary model of obesity.