Increased insulin resistance and beta cell activity in patients with Crohn's disease

BACKGROUND: Pancreatitis and exocrine pancreatitic insufficiency have been described as extraintestinal manifestations of inflammatory bowel disease. In this study, we investigated whether the endocrine pancreatic function is also disturbed in patients with inflammatory bowel disease. METHODS: Seventeen patients with Crohn's disease and 13 healthy volunteers participated in the study. We analyzed the plasma insulin response in a 75-g oral glucose tolerance test. Glucose and insulin levels were determined at time 0 (fasting levels) and 30, 60, 90, 120, 180, 240, and 300 min after glucose uptake. Insulin resistance and beta cell function (BCF) were analyzed by calculating respective indices. RESULTS: Fasting and oral glucose-tolerance test glucose levels appeared to be similar in patients with Crohn's disease and in the controls. Impaired fasting glucose, impaired glucose tolerance, and/or overt diabetes mellitus were not observed in the volunteers. Insulin as well as the index for BCF were significantly increased in patients with Crohn's disease. In addition, insulin resistance was shown to be significantly elevated in Crohn's disease. CONCLUSIONS: Patients with Crohn's disease reveal an increased insulin secretion caused by an enhanced BCF, which may be induced by an up-regulated enteropancreatic axis. This hypersecretion may override the insulin resistance given by the chronic inflammatory state.     

Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia

Aims/hypothesis  

The postpartum phase following gestational diabetes (GDM) is characterised by subtle metabolic defects, including the beta cell dysfunction that is believed to mediate the increased future risk of type 2 diabetes in this patient population. Low circulating levels of adiponectin and increased leptin and C-reactive protein (CRP) have recently emerged as novel diabetic risk factors, although their relevance to GDM and subsequent diabetes has not been characterised. Thus, we sought to determine whether adiponectin, leptin and CRP levels during pregnancy relate to the postpartum metabolic defects linking GDM with type 2 diabetes.     

Effects of insulin and glucose on pulmonary insulin receptors in late gestation fetal rats.

The effects of high glucose and insulin concentrations on fetal lung insulin receptors and tyrosine kinase activity were studied in an in vitro system utilizing 19- or 20-d fetal rat lung explants. Exposure of the explants to 100 mM glucose and insulin (0.1 unit/mL) for 72 h resulted in a significant decrease in specific binding of insulin to partially purified receptors [5.78% +/- 0.66 (SEM) vs. 9.64% +/- 1.68; P less than .01] when compared with lung explants exposed to 10 mM glucose alone. When individual effects of high insulin and glucose were studied, down-regulation of specific insulin binding was also observed, but to a lesser extent than that observed using both high glucose and insulin. Differences in insulin receptor affinity were not noted. Insulin receptor tyrosine kinase activity was also significantly decreased (52% of control values) under high-glucose/high-insulin conditions. Total phosphatidylcholine and disaturated phosphatidylcholine concentrations were significantly decreased in explants grown under high-glucose/high-insulin conditions, consistent with delayed pulmonary maturation. High glucose and insulin levels thus result in down-regulation of fetal lung insulin receptors and insulin receptor tyrosine kinase activity late in gestation. These results may have implications for substrate availability in the developing fetal lung.     

Ethnic differences in beta cell adaptation to insulin resistance in obese children and adolescents

Aims/hypothesis The prevalence of altered glucose metabolism in obese children and adolescents is growing at a significant rate, especially in ethnic minorities. It is not clear whether young people of different ethnic backgrounds differ in their adaptive mechanisms to obesity-related insulin resistance. The aim of this study was to evaluate the early insulin response and insulin clearance in response to an oral glucose load in obese children and adolescents. Methods Seven hundred and nine obese children and adolescents underwent an OGTT. Indices of the early insulin response and insulin clearance were compared in participants of White European, African American and Hispanic origin. Results Participants of the three ethnic groups demonstrated similar mechanisms of adaptation to increasing insulin resistance, but with different magnitudes. African American subjects had a greater early insulin response and decreased insulin clearance than their White European and Hispanic counterparts. This happened regardless of whether the cohort was divided by glucose tolerance level or by level of insulin sensitivity. IGT across ethnic groups was characterised by a marked decline in the acute insulin response in the context of severe insulin resistance and very low insulin clearance. Conclusions/interpretation In obese children and adolescents, mechanisms of adaptation to obesity related to insulin resistance are similar across ethnic groups. The greater early insulin response needed to maintain glucose tolerance in young people of ethnic minorities may partially explain their greater tendency to develop type 2 diabetes.     

Mechanisms of hepatic and peripheral insulin resistance during acute infections in humans.

To examine mechanisms of insulin resistance, nine patients (age 33 +/- 4 yr, body mass index 22 +/- 1 kg/m2) with acute bacterial or viral infections and in six matched normal subjects were studied. Endogenous glucose appearance (Ra), glucose disappearance (Rd), and recycling, the percentage of plasma lactate originating from plasma glucose, total glucose oxidation, and whole body and forearm muscle Rd were measured after an overnight fast in the basal state and during physiological hyperinsulinemia (serum insulin approximately 215 pmol/L). Basally Ra, Rd, glucose recycling, and oxidation were similar in both groups. During hyperinsulinemia, insulin stimulated plasma Rd approximately 35% less (17.6 +/- 1.3 vs. 26.8 +/- 3.6 mumol/kg.min, P less than 0.01, patients vs. normal subjects), and inhibited endogenous Ra less in the patients (from 13.3 +/- 0.8 to 5.3 +/- 0.8 mumol/kg.min) than in the normal subjects (from 12.8 +/- 1.0 to 2.1 +/- 1.2 mumol/kg.min, P less than 0.01). The decrease in whole body Rd was largely explained by a approximately 75% reduction in muscle Rd (5.6 +/- 1.5 vs. 20.8 +/- 3.3 mumol/kg muscle.min, P less than 0.01, patients vs. normal subjects). The defect in Rd was confined to nonoxidative (4.8 +/- 1.1 vs. 11.0 +/- 3.0 mumol/kg.min, P less than 0.01, patients vs. normal subjects) but not to oxidative glucose metabolism. The percentage of plasma lactate derived from plasma glucose during hyperinsulinemia averaged 63 +/- 6% in the patients and 79 +/- 5% in the normal subjects, indicating that glycogenolysis did not excessively dilute glycolytic carbons in the patients. We conclude that during natural infections in humans, abnormal glucose metabolism is confined to the insulin-stimulated state and involves a marked defect in muscle glucose uptake and glycogen synthesis, as well as a less marked hepatic defect.     

Adiponectin expression in human fetal tissues during mid- and late gestation

Adiponectin (ApN), an adipocytokine expressed in adipocytes with antidiabetic and antiatherogenic actions, has been detected in cord blood, suggesting a putative role in intrauterine fetal development. The aim of this study was to confirm the presence of ApN in the fetal circulation and directly investigate ApN expression in fetal tissues. The study showed high ApN levels in umbilical venous blood from fetuses [n = 44; 31.2 +/- 14.1 (sd) mg/liter in umbilical vs. 8.4 +/- 4.0 in maternal circulation (P < 0.0001)] that positively correlated with gestational age. By using RT-PCR, Western blotting, and immunohistochemistry, ApN was detected in several fetal tissues at mid- and late gestation (from 14 to 36 wk) but not in the placenta. ApN was expressed in tissues of mesodermic origin, i.e. brown and white adipocytes, skeletal muscle fibers of diaphragm and iliopsoas, smooth muscle cells of small intestine and arterial walls, perineurium and renal capsule, and tissues of ectodermal origin, i.e. epidermis and ocular lens. The distribution of ApN expression in nonadipose tissues showed a general decline during the progression of gestation. The unexpected pattern of ApN expression in the human fetus may account for the high ApN levels in cord blood and predicts novel roles for ApN during fetal development.     

Hepatic and peripheral insulin resistance following streptozotocin-induced insulin deficiency in the dog

Insulin resistance and insulin deficiency are both present in many patients with diabetes mellitus. We tested the hypothesis that insulin resistance can evolve from a primary lesion of the beta-cell secretory function. Insulin-mediated glucose uptake (insulin clamp), endogenous glucose production, and glucose-stimulated insulin secretion (hyperglycemic clamp) were measured in awake dogs before and four to six weeks after streptozotocin-induced diabetes mellitus. Streptozotocin (30 mg/kg) resulted in a significant rise in the mean fasting plasma glucose concentration from 104 +/- 2 mg/100 mL to 200 +/- 34 mg/100 mL, (P less than 0.05), and a slight decrease in the mean fasting plasma insulin concentration (from 21 +/- 2 microU/mL to 15 +/- 2 microU/mL). Under conditions of steady-state hyperglycemia (+75 mg/100 mL hyperglycemic clamp, insulin secretion was reduced by 75% in the streptozotocin-treated dogs (P less than 0.025), and the total amount of glucose metabolized decreased from 13.56 +/- 1.04 to 4.74 +/- 0.70 mg/min X kg (P less than 0.001). In the postabsorptive state, endogenous glucose production was slightly, although not significantly, higher in the diabetic dogs (3.05 +/- 0.46 v 2.51 +/- 0.22 mg/min . kg), while the glucose clearance rate was 35% lower (P less than 0.001). When the plasma insulin concentration was increased to approximately 45 microU/mL (insulin clamp) while holding plasma glucose constant at the respective fasting levels (99 +/- 1 and 186 +/- 30 mg/100 mL), endogenous glucose production was completely suppressed in control dogs but suppressed by only 51% (1.46 +/- 0.37 mg/min . kg, P less than 0.025) in diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

非酒精性脂肪肝与肥胖及胰岛素抵抗的关系

探讨非酒精性脂肪肝 (NASH)的体脂含量和分布特征 ,血脂情况及与胰岛素抵抗的关系。对 87例观察对象分为NASH组 (30例 )和对照组 (5 7例 ) ,检测身高、体重、血脂、血糖、血胰岛素 ,计算胰鸟素敏感指数和体重指数 ;做腹部CT扫描以其配备软件计算腹内脂肪面积 (VA)和腹皮下脂肪面积 (SA)。 6 8例肥胖者发生NASH2 8人(41 18% ) ,19例体重正常者发生HASH2人 (10 5 3% )。 (x2 =6 175 ,P <0 0 2 5 )差异有显著性。不伴NASH的肥胖者VA(x±s,cm2 ) (男 :10 5 8± 2 9 6　女 :117 3± 33 1)与伴有NASH的肥胖者VA(男 :138 2± 5 3 7　女 :14 2 6± 31 2 )比较差异有显著性 (t =2 72 ,2 31　P <0 0 1,0 0 5 )。无NASH肥胖者与伴有NASH肥胖者比较IAI差异有显著性 (t =1 98　P <0 0 5 )。肥胖尤其是腹内型肥胖与NASH有密切的关系 ;肥胖者发生NASH ,胰岛素抵抗在其中起重要作用。     

Phasic respiratory activity in the fetal lamb during late gestation and labour

We quantified the respiratory activity of 9 fetal lambs using computer-analysis of the diaphragmatic electromyogram (EMG) obtained during 2 h recording sessions interspersed over the last 13 days of gestation. The fetuses delivered unassisted at an average gestational age of 145 days (term = 147 days). During the last 2 h of labour the number of phasic EMG bursts (breaths) averaged 3% of the peak recorded earlier in the study. This decline in breathing began at least 2 days before labour and resulted predominantly from the fetus spending an increasing proportion of time in apnoea. Respiratory rate within epochs of breathing also fell significantly 1 day before labour, and the proportion of time spent in the low voltage electrocortical state declined once labour commenced. No significant change occurred in arterial PO2, PCO2 or pH over the study period. We conclude that fetal respiratory activity falls well before the onset of labour, largely as a result of increased apnoea, and that the decline does not result from the development of a progressive hypoxaemia associated with labour.     

Fatty acids and insulin resistance in muscle and liver

Free fatty acids (FFAs) circulate round the body and represent important nutrients and the key oxidative fuel for the heart and resting skeletal muscle. In addition, FFAs are thought to be potent signalling molecules. Growing evidence indicates that FFAs may be involved in type 2 diabetes mellitus and obesity by mediating insulin resistance. In 1963, it was postulated that accumulated glucose-6-phosphate as a result of increased FFA oxidation leads to decreased glucose uptake. An alternative hypothesis is that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity, which appears to be a consequence of decreased insulin receptor substrate-1-associated phosphatidyl inositol 3 kinase activity. Moreover, FFAs can arise locally, and increased intramyocellular and hepatocellular lipids have been shown to be associated with insulin resistance. This paper reviews the main aspects of FFA metabolism in the development of insulin resistance in skeletal muscle and liver, as well as the role of ectopic lipid deposits as a local source of FFAs. Finally, the role of thiazolidinediones as modulators of FFA-induced insulin resistance will be discussed.     

Roles of insulin resistance and beta cell dysfunction in macrosomia among Chinese women with gestational diabetes mellitus

Aims

The aim was to examine associations of insulin resistance and beta cell dysfunction with macrosomia in Chinese women with gestational diabetes mellitus (GDM).

The relationship between pulse pressure,insulin resistance,and beta cell function in non-diabetic Korean adults

AimsThe present study was conducted to assess the association of pulse pressure (PP) with insulin resistance and beta cell function in Korean non-diabetic populations.MethodsThis study used the data from the 2015 Korean National Health and Nutrition Examination Survey including 4380 adults, aged 20 or older.ResultsA multivariate analysis revealed that systolic blood pressure (SBP) (β = 0.089, 95% confidence interval [CI], 0.004–0.011; p < 0.001), diastolic blood pressure (DBP) (β = ?0.057, 95% CI ?0.014 to ?0.003; p = 0.002), and PP (β = 0.069, 95% CI 0.004–0.011; p < 0.001) were significant factors determining the homeostasis model assessment of insulin resistance (HOMA-IR). SBP (β = 0.070, 95% CI, 0.113–0.420; p = 0.001), DBP (β = ?0.068, 95% CI ?0.676 to ?0.203; p < 0.001), and PP (β = 0.050, 95% CI 0.115–0.422; p = 0.001) were significant factors determining the homeostasis model assessment of beta cell function (HOMA-B). In the analysis of covariance test, after adjusting for related variables (except age), the quartiles of PP were not associated with HOMA-IR (p = 0.191) and were inversely associated with HOMA-B (p < 0.001). However, when further adjusting for age, the quartiles of PP were positively associated with both HOMA-IR (p < 0.001) and HOMA-B (p = 0.027).ConclusionPP was positively associated with insulin resistance and beta cell function in non-diabetic Korean adults.     

脂肪细胞因子与非酒精性脂肪性肝病胰岛素抵抗的初步探讨

目的探讨视黄醇结合蛋白4(RBP-4)及网膜素与非酒精性脂肪性肝病(NAFLD)患者胰岛素抵抗的关系。方法选择NAFLD患者50例(NAFLD组),无NAFLD患者50例(对照组)。测定2组空腹血糖、空腹胰岛素、HDL-C、LDL-C、TC、TG、天冬氨酸转氨酶、丙氨酸转氨酶、RBP-4及网膜素,同时计算体重指数、胰岛素抵抗指数,并进行多元逐步回归分析。结果 NAFLD组体重指数、丙氨酸转氨酶、TG、空腹胰岛素、胰岛素抵抗指数及RBP-4水平明显高于对照组,HDL-C、网膜素水平明显低于对照组(P<0.05,P<0.01)。Pearson相关分析,NAFLD组胰岛素抵抗指数与年龄、血压、体重指数、空腹血糖、空腹胰岛素、TC、TG、LDL-C、RBP-4呈正相关,与HDL-C、网膜素呈负相关(P<0.05,P<0.01)。多元线性逐步回归结果进入回归方程的有RBP-4、TG、体重指数、网膜素(P<0.05,P<0.01)。结论 RBP-4和网膜素与NAFLD患者胰岛素抵抗发生、发展有关。     

Correlation of insulin resistance, beta cell function and insulin sensitivity with serum sFas and sFasL in newly diagnosed type 2 diabetes

Pancreatic beta cell dysfunction and reduced insulin sensitivity are fundamental factors associated with glucotoxicity, lipotoxicity and oxidative stress in type 2 diabetic patients (T2DM). Diabetic milieu can induce apoptosis in several types of cells. The aim of present study was to compare circulating soluble apoptotic markers (sFas and sFas-L) with HOMA-IR, HOMA-%S, HOMA-%B in the serum of newly diagnosed T2DM and healthy subjects. For this study, 94 T2DM and 60 healthy subjects were enroled and evaluated for various parameters. Biochemical quantifications were performed with Syncron CX5 auto-analyzer. The levels of serum sFas-L, TNF-α and IL-6 were estimated by flowcytometry. The fasting serum insulin and sFas quantified by ELISA. HOMA-IR, HOMA-%S and HOMA-%B were calculated with HOMA calculator v2.2.2. The levels of TC, TG, LDL-C, VLDL-C were augmented and HDL declined significantly (P < 0.001) in diabetics. The levels of serum insulin, TNF-α, IL-6, sFas, HOMA-IR were raised (P < 0.001) and sFas-L, HOMA-%S and HOMA-%B were decreased significantly (P < 0.001) in T2DM subjects than healthy. In diabetics, serum sFas was positively correlated with HOMA-IR (r = 0.720, P < 0.001) and negatively with HOMA-%B (r = ?0.642, P < 0.001) significantly while serum sFasL was negatively correlated with HOMA-IR (r = ?0.483, P < 0.001) and positively with HOMA-%B (r = 0.466, P < 0.001) significantly. Further, the multivariate stepwise regression analysis shows that HOMA-IR contributes significantly to the variance of sFas and sFasL. Our findings suggest that the pancreatic beta cell dysfunction along with increased insulin resistance appears to be associated with apoptotic markers.     

肝脏胰岛素抵抗的机制和后果

肝脏作为胰岛素作用的主要靶器官,在维持空腹状态下内生性葡萄糖的产生和输出以及进食后葡萄糖的吸收、利用和存储等方面发挥重要作用.肝脏胰岛素抵抗主要是指胰岛素抑制肝脏葡萄糖输出能力下降,而细胞胰岛素抵抗则指细胞内胰岛素受体活化后参与细胞内信号传导的改变~([1]),可通过测定胰岛素刺激时的中间蛋白磷酸化、中介激酶活性改变和(或)调节靶基因表达或靶细胞功能改变来判断~([2]).     

不同糖代谢状态下游离脂肪酸与胰岛素抵抗和胰岛β细胞功能的相关性研究

目的　游离脂肪酸 (FFAs)水平在不同糖代谢状态下对胰岛素抵抗和胰岛 β细胞分泌功能的影响。 方法　选自2 0 0 1- 0 5 2 0 0 3- 11在中国医科大学附属第一医院住院的糖耐量正常 (NGT) 2 8例 ,空腹血糖异常 (IFG)患者 2 0例 ,糖耐量低减 (IGT)患者 2 3例 ,IFG/IGT患者 2 6例 ,2型糖尿病 (T2DM)患者 2 5例。测定各组FFAs水平 ,稳态模型评估胰岛素敏感性 ,HOMA IS及OGTT中糖负荷后 30分钟胰岛素增值与血糖增值的比值评估胰岛 (细胞分泌功能。结果　 (1)IGT组、IFG/IGT组及T2DM组患者FFAs水平明显高于NGT组 ;IFG/IGT组患者FFAs水平明显高于IFG组 ;T2DM组患者FFAs水平低于IGT组。 (2 )IGT组、IFG/IGT组及T2DM组患者HOMA IR均明显高于NGT组。(3)胰岛素分泌功能均以T2DM患者变化最显著。 (4)FFAs与HOMA -IR呈正相关 ;FFAs与胰岛素分泌指数呈负相关 ,FFAs与HOMA β细胞功能指数呈负相关。 结论　FFAs水平与胰岛素抵抗和胰岛素分泌缺陷密切相关     

Transuteroplacental metabolism of cortisol and cortisone during mid- and late gestation in the baboon

We measured uterine extraction (i.e. metabolism) and transuteroplacental interconversion of cortisol (F) and cortisone (E) to determine whether metabolism across the uterus changes during pregnancy and contributes to the MCR of these corticosteroids. On day 100 (n = 4) or 170 (n = 3) of pregnancy (term = day 184), baboons (Papio anubis; 14-18 kg) were sedated with ketamine, and a constant infusion (0.38 ml/min) of 8-12 microCi [3H]F and 9-15 microCi [14C]E in 80 ml 0.9% NaCl-1% ethanol was initiated (time zero) via a maternal antecubital vein. At 60 min, animals were laparotomized, and at 70, 80, and 90 min, blood samples were obtained from right and left uterine veins and from a maternal saphenous vein. At 95 min, a transverse incision was made in the uterus, the fetus was isolated, and blood samples were obtained from the umbilical vein and artery. The cord was then clamped, and the fetus was delivered. Radio-labeled F and E were extracted from serum and purified by sequential paper chromatography, and metabolic parameters were calculated. Endogenous F and E levels were determined by RIA. In the mother, the percent conversions of E to F at midgestation (mean +/- SE; 72 +/- 4) and late gestation (65 +/- 3) were similar and exceeded (P less than 0.01) respective values for oxidation of F to E (51 +/- 7 and 46 +/- 7, respectively), indicating that maternal corticosteroid metabolism favors F formation and is unchanged during the second half of gestation. In contrast, corticosteroid metabolism across the uterus and placenta (transuteroplacental) was altered during pregnancy. At midgestation, transuteroplacental conversion of E to F (37 +/- 9) exceeded (P less than 0.05) the reverse reaction (18 +/- 3), whereas oxidation of F to E at term (28 +/- 4) was 7-fold greater (P less than 0.05) than reduction of E to F (4 +/- 1). At midgestation, essentially all of the F and E in umbilical vein was derived from maternal F. This contrasts with that observed in near-term baboons in which only 41 +/- 9% of the F and 64 +/- 8% of the E entering the fetal circulation was of maternal origin. As a result of uterine, placental, and fetal metabolism, 30% of the F and 15% of the E in maternal circulation were extracted by the uterus at both mid- and late gestation. We conclude that transuteroplacental corticosteroid metabolism changes from reduction at midgestation to oxidation at term.(ABSTRACT TRUNCATED AT 400 WORDS)     

老年胰岛素抵抗与下肢动脉病变的相关性

目的 探讨老年胰岛素抵抗(IR)与下肢动脉病变(PAD)的相关性.方法 100例新诊断老年2型糖尿病(T2DM)患者,采用稳态模型计算胰岛素抵抗指数(HOMA-IR),并根据HOMA-IR值分3组,通过测量踝臂指数(ABI)评价患者PAD情况,观察IR与PAD的相关性.结果 随着HOMA-IR的升高,收缩压(SBP)、低密度脂蛋白胆固醇(LDL-C)、糖化血红蛋白(HbA1c)逐渐升高,ABI逐渐降低(F=9.115、21.954、24.9、7.524,P＜ 0.01);HOMA-IR与ABI呈负相关(r=-0.352,P＜0.01),与SBP、LDL-C、餐后2小时血糖(2 h PG)、HbA1c呈正相关(r=0.346、0.532、0.222、0.534、0.376,P＜0.05或P＜0.01).结论 老年IR与PAD有强相关性,是发生PAD的高危因素.