Vascular insulin/insulin-like growth factor-1 resistance in female obese Zucker rats

Because insulin resistance/diabetes may cause inordinate vascular complications in females, we have investigated the effects of insulin and insulin-like growth factor (IGF-1) on vascular reactivity in 12-week-old female Zucker obese (Ob) rats, a rodent model of insulin resistance and its lean (Ln) age-matched counterpart. Endothelium intact aortic rings from Ob animals and their Ln littermates (12 weeks of age) were subjected to contractile concentration responses to phenylephrine (PE) followed by relaxation to isoproterenol (Iso), with and without preincubation for 2 hours with cholera toxin (CTX; 1 microg/mL) or pertussis toxin (PTX; 2 microg/mL) and before and after incubation with either insulin or IGF-1 (100 nmol/L) for 1 hour. Systolic blood pressure was higher (138 +/- 3 v. 109 +/- 4 mm Hg; P <.0001) in the 12-week-old Ob rats. Contractile responses to PE were similar in both groups; however, both insulin and IGF-1 induced a paradoxical increase (P <.001) in contraction in Ob vasculature (929 +/- 92 v. 679 +/- 25 mg, respectively). CTX alone decreased contraction in the Ob (P <.02) and PTX in the Ln (P <.02), but there were no interactions between either IGF-1 or insulin and the toxins. Marked impairment of relaxation to Iso was seen in aortic rings of these female Ob rats (ED(50) = 2.6 micromol/L v. 418 nmol/L, P =.0002), an effect exacerbated by preincubation with either insulin or IGF-1 (P =.0001). Again, no role for G-proteins could be demonstrated. Insulin-dependent glucose uptake was severely impaired (P <.05) in aortic segments of the Ob insulin-resistant rats. Insulin receptor binding, tyrosine kinase activity (TKA), and abundance of several G-protein alpha subunits (inhibitory and stimulatory) in solubilized arterial membrane preparations (assessed by Western blot) were comparable in the 2 groups. These results indicate that resistance to the vascular actions of insulin/IGF-1 in female Ob rats is a postreceptor event that parallels glucose uptake resistance and is independent of G-proteins.     

Enhanced cyclooxygenase 2-mediated vasorelaxation in coronary arteries from insulin-resistant obese Zucker rats

Objective

The expression of p53 has been associated with DNA damage, cell senescence, proliferation and apoptosis in human atherosclerotic plaques. However, it is largely unknown whether p53 expression is related to the stability and clinical manifestations of atherosclerotic plaques in humans. In the present study, we examined whether p53 expression is related to clinical symptoms and plaque integrity in patients with carotid atherosclerosis (n = 62). We also investigated p53 expression and its relation to apoptosis and apoptosis-related cathepsin L and ferritin in the carotid lesions.

Methods and results

We found that smooth muscle cells often had nuclear p53 in the shoulder region of carotid lesions while CD68-positive macrophages, which had both nuclear and cytoplasmic p53, frequently appeared in the surrounding areas of necrotic cores or plaque cap regions. Quantitative image analysis of immunohistochemistry showed that p53 expression was significantly increased in plaques with necrotic core formation or cap rupture and lesions from patients with transient ischemic attacks (TIAs). The levels of p53 expression was significantly increased in more severe stenosed lesions but decreased with prolonged time between symptom onset and carotid endarterectomy. Furthermore, p53 expression was significantly correlated with the expression of ferritin, lysosomal cathepsin L, and apoptosis.

Conclusion

The increased p53 expression, particularly macrophage p53 levels, is associated with the enlargement of necrotic cores, plaque rupture and clinical manifestations of carotid plaques. Concomitant increases of lysosomal cathepsin, ferritin, and p53 levels may promote the apoptosis and atheroma progression in patients with carotid atherosclerosis.     

Altered pressure-natriuresis in obese Zucker rats.

It has not been examined whether the pressure-natriuresis response is altered in the insulin-resistant condition. Furthermore, despite an important role of nitric oxide (NO) in modulating pressure-natriuresis, no investigations have been conducted assessing the renal interstitial NO production in insulin resistance. The present study examined whether pressure-natriuresis was altered in insulin-resistant obese Zucker rats (OZ) and assessed the cortical and medullary nitrate/nitrite (NOx) levels with the use of the renal microdialysis technique. In OZ, serum insulin/glucose ratio (23.0+/-4.0x10(-8), n=9) and blood pressure (119+/-3 mm Hg) were greater than those in lean Zucker rats (LZ; 7.0+/-1.9x10(-8) and 103+/-4 mm Hg, n=9). The pressure-natriuresis curve in OZ was shifted to higher renal perfusion pressure (RPP), and the slope was blunted compared with that in LZ (0.073+/-0.015 vs 0.217+/-0.047 microEq/min kidney weight/mm Hg, P<0.05). The basal renal NOx level was reduced in OZ (cortex, 4.032+/-0.331 micromol/L; medulla, 4. 329+/-0.515 micromol/L) compared with that in LZ (cortex, 7.315+/-1. 102 micromol/L; medulla: 7.698+/-0.964 micromol/L). Furthermore, elevating RPP increased the medullary NOx in LZ, but this pressure-induced response was lost in OZ. Four-week treatment with troglitazone, an insulin-sensitizing agent, improved hyperinsulinemia, systemic hypertension, and basal renal NOx levels (cortex, 5.639+/-0.286 micromol/L; medulla, 5.978+/-0.284 micromol/L), and partially ameliorated the pressure-natriuresis curves; the slope of pressure-natriuresis curves and elevated RPP-induced NOx, however, were not corrected. In conclusion, our study suggests that insulin resistance is closely associated with abnormal pressure-natriuresis and hypertension. These deranged renal responses to insulin resistance are most likely attributed to impaired medullary NO production within the medulla.     

Altered renal microvascular response in Zucker obese rats

Although available evidence demonstrates that obesity manifests insulin resistance and causes glomerular sclerosis, it has not been determined whether insulin resistance alters the renal microvascular reactivity. This study examined whether insulin- and acetylcholine (ACH)-induced vasodilation was impaired in Zucker obese rats, and attempted to clarify the change in myogenic afferent arteriolar constriction, a determinant of glomerular pressure. Isolated perfused hydronephrotic rat kidneys were used to visualize the renal microcirculation. In Zucker lean rats, insulin (10 to 300 microU/mL) inhibited norepinephrine (NE)-induced afferent and efferent arteriolar constriction in a dose-dependent manner, with 112 % +/- 8% and 98% +/- 8% reversal at 300 microU/mL Similarly, ACH elicited dose-dependent dilation of these vessels. In Zucker obese rats, by contrast, afferent and efferent arterioles failed to dilate in response to insulin, and manifested diminished vasodilator responses to acetylcholine In the presence of nitro-L-arginine methylester (LNAME; 100 micromol/L), ACH (10 micromol/L) induced transient afferent arteriolar dilation (121% +/- 9% reversal) in Zucker lean rats, whereas this response was blunted in obese rats (72% +/- 8% reversal) Furthermore, myogenic afferent arteriolar constriction by elevating renal arterial pressure to 180 mm Hg was diminished in Zucker obese rats (-14% +/- 3% decrement in diameter), compared with that in lean rats (-23% +/- 2% decrement) Finally, the impairment in these vasodilator and vasoconstrictor responses was partially prevented by troglitazone, an insulin-sensitizing agent. Collectively, in insulin resistance, renal microvessels are refractory to the vasodilator action of insulin. Furthermore, "renal insulin resistance" is associated with the impaired vasodilator responses to ACH-induced nitric oxide (NO) and the diminished vasoconstrictor responses to pressure. The blunted myogenic afferent arteriolar constriction would allow glomerular hypertension, and in concert with the impaired endothelium-dependent vasodilation, could be responsible for the development of glomerular injury in obesity.     

Low plasma insulin-like growth factor-1 concentrations predict worsening of insulin-mediated glucose uptake in older people

OBJECTIVE: The relationship among insulin action, advancing age, and insulin like growth factor-1 (IGF-1) is poorly understood. To gain further insight, the predictive role that low plasma IGF-1 concentration may have on insulin- mediated glucose uptake in older persons was investigated. DESIGN: The study was designed as a longitudinal, observational trial. PARTICIPANTS: Fifty-eight healthy aged (73.1+/-9.4 years) subjects (31 males/27 females) were followed up for 12 months. MEASUREMENTS: At baseline and at the end of the follow-up, insulin-mediated glucose uptake was assessed by euglycemic glucose clamp and plasma total IGF-1 and IGF-binding protein 3 (IGF-BP-3) in each subject, and concentrations were determined. RESULTS: At baseline, plasma IGF-1 concentrations correlated with whole body glucose uptake (WBGD) (r = 0.39, P < .003), insulin-stimulated glucose oxidation (GOX) (r = 0.35, P < .009), and non-oxidative glucose metabolism (r = 0.37, P < .007). Such correlations were also independent of age, sex, body fat, and waist/hip ratio. Fasting plasma total IGF-1 concentrations (84+/-56 vs 63+/-44 microg/L, P < .040), plasma IGF-1/IGF-BP3 molar ratio (0.13+/-0.05 vs 0.10+/-0.03 P < .050), and WBGD (34.8+/-5.0 vs 23.1+/-4.6 micromol/kg x min, P < .010) were more elevated at baseline than at the end of the follow-up. Low baseline fasting plasma IGF-1 concentration (RR = 1.5, 95%CI = 1.3-1.7) and plasma IGF-1/IGFBP-3 molar ratio (RR = 1.4, 95% CI = 1.3-1.8) predicted a decline in WBGD. The predictive role of plasma IGF-1 on age-related decline in WBGD was independent of age, sex, body fat, waist/hip ratio, and degree of physical activity (model 1), or of fasting plasma free fatty acid and triglyceride concentrations, LDL/HDL ratio, and basal adjusted respiratory quotient (model 2). Finally, low plasma IGF-1 concentration predicts a decline in WBGD independent of body fat, free fatty acids, waist/hip ratio, and basal adjusted respiratory quotient (model 3). CONCLUSION: Our study demonstrates that fasting plasma IGF-1 concentration may have a modulatory role on insulin action in older people. This finding might prompt an evaluation of the direct effect of IGF-1 administration on insulin sensitivity in older adults.     

Intracerebroventricular insulin-like growth factor-1 decreases feeding in diabetic rats

Insulin-like growth factor-1 (IGF-1) is a hormone that is important in the regulation of growth processes and additionally has been demonstrated to modulate metabolic and autonomic responses. Some of its effects are mediated by the central nervous system (CNS), and there are IGF-1 receptors dispersed throughout the CNS. Both IGF-1 and insulin alter peripheral metabolic and autonomic nervous activity by a central mechanism, and the well-defined role of insulin in the regulation of feeding, especially in diabetes, led us to investigate the effect of chronic central administration of IGf-1 on metabolic and feeding parameters in normal and diabetic rats. Normal and diabetic rats with intracere-broventricular cannulas were given IGF-1, insulin (0.5 nmol/animal), or artificial cerebrospinal fluid via cannula twice daily for 4 d. Blood samples were collected on d 2 and 4, and the body weights and food intake were recorded daily. IGF-1 administered intracere-breventricularly did not alter plasma glucose, insulin, body weight, or food intake in normal rats. However, in diabetic animals, IGF-1 decreased food intake but did not alter blood glucose or plasma insulin. In correlated studies, intracerebroventricular insulin decreased food intake in both normal and diabetic animals. From these studies, we conclude that IGF-1 may act centrally to decrease food intake in the hyperphagic diabetic animals but not in normal animals. This suggests that diabetic animals have an increased sensitivity to CNS IGF-1.     

Altered insulin-like growth factor-1 and nitric oxide sensitivities in hypertension contribute to vascular hyperplasia

Vascular medial thickening, a hallmark of hypertension, is associated with vascular smooth muscle cell (VSMC) hypertrophy and hyperplasia. Although the precise mechanisms responsible are elusive, we have shown that strain induced regulation of autocrine insulin-like growth factor-1 (IGF-1) and nitric oxide (NO) reciprocally modulate VSMC proliferation. Therefore, we investigated potential IGF-1 and NO abnormalities in young (10-week-old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and their respective VSMC ex vivo. The SHR had increased mean arterial pressure (173 ± 2 v 128 ± 3 mm Hg, n = 24, P < .05) but similar pulse pressures (31 ± 2 v 30 ± 3 mm Hg; P > .05) v WKY. The SHR exhibited increased aortic wall thickness in comparison with WKY (523 ± 16 v 355 ± 17μm; P < .05). No differences were seen in plasma combined NO₂ and NO₃ (NO_x) (0.48 ± 0.11 mmol/L for WKY v 0.58 ± 0.18 mmol/L for SHR) or plasma IGF-1 (1007 ± 28 ng/mL for WKY v 953 ± 26 ng/mL for SHR). Aortic VSMC from SHR displayed enhanced proliferation in comparison with WKY (P < .05). Underlying this enhanced proliferation was altered SHR VSMC sensitivity to the antiproliferative NO donor 2,2"[Hydroxynitrosohydrazono] bis-ethanimine (DETA-NO) (ID₅₀: 270 ± 20 mmol/L for SHR; 150 ± 11 mmol/L for WKY; P < .05). Basal cyclic guanosine monophosphate (cGMP) secretion from SHR VSMC was 65-fold greater than that seen from WKY (P < .001). In response to DETA-NO, cGMP secretion from SHR VSMC increased modestly (1.5-fold; P < .01), whereas treatment of WKY VSMC resulted in a 26-fold (P < .001) increase in cGMP. The SHR VSMC did not respond to exogenous IGF-1, whereas WKY VSMC exhibited a dose dependent increase in proliferation with IGF-1 (10⁻¹⁰ to 10⁻⁷ mol/L). These data suggest that VSMC hyperplasia in early hypertension is not reflected by imbalances in plasma IGF-1 or NO. Rather, altered SHR VSMC sensitivity to NO is likely responsible in part for the observed hyperproliferation seen in early stages of hypertension.     

Functional insulin-like growth factor-1/insulin-like growth factor-1 receptor-mediated circuit in human and murine thymic epithelial cells

Interactions between thymocytes and thymic epithelial cell (TEC) can be modulated by growth hormone via insulin-like growth factor-1 (IGF-1). In this study, we showed IGF-1 and IGF-1 receptor mRNA expression by human and murine TEC and thymocytes. Functionally, IGF-1 stimulates extracellular matrix production by human TEC. Moreover, pretreatment of murine TEC with IGF-1 increases their adhesion to thymocytes. Interestingly, we observed an increase in the frequency of CD4-CD8-CD90+ T cells which adhered to pretreated TEC, supporting the concept that IGF-1 may also act indirectly on intrathymic T cell differentiation and migration through the thymic epithelium.     

过敏性紫癜患儿血清胰岛素样生长因子及胰岛素样生长因子结合蛋白-3的变化

目的 探讨胰岛素样生长因子(IGF)-1及胰岛素样生长因子结合蛋白(IGFBP)-3在过敏性紫癜(HSP)中的作用.方法 采用放射免疫法方法测定45例HSP患儿不同时期的血清IGF-1及IGFBP-3、C反应蛋白(CRP)水平.采用t检验和直线相关关系.结果 HSP急性发作组血清IGF-1[(452±183)μg/L]、IGFBP-3[(13 897±3124)μg/L]及CRP[(20±8)mg/L]水平升高,与健康对照组和缓解组比较,差异均有统计学意义(t值分别为3.42、4.10、11.17、11.63、8.59、9.86.P均<0.01);HSP缓解组血清IGF-1、IGFBP-3及CRP与健康对照组比较,差异无统计学意义(t=0.3,4、0.34、0.52,P均>0.05).HSP急性期并发肾损害组血清IGF-1[(621±253)μg/L]、IGFBP-3[(18 763±3173)μg/L]水平升高,与无肾损害组比较,差异有统计学意义(t值分别为4.21、7.26,P均<0.01),有胃肠道症组血清IGF-1[(479±192)μg/L]、IGFBP-3[(13 986±3162)μg/L]水平与无胃肠道症状组比较,差异无统计学意义(t值分别为0.83、0.16,P均>0.05);血清CRP水平在肾损害组与非肾损害组及胃肠道症组与无胃肠道症状组问差异均无统计学意义(t值分别为0.56、0.32.P均>0.05).HSP急性期患儿血IGF-1、IGFBP-3与CRP浓度之间呈直线正相关(r值分别为0.624,0.672,JP均<0.01).结论 IGF-1、IGFBP-3参与了HSP疾病的病理生理过程,血清IGF-1、IGFBP-3测定对紫癜性肾损害的诊断、病情监测及预后判断有一定帮助.

Abstract：

Objecfive To investigate the role of serum Insulin-like growth factor(IGF)-1,insulinlike growth factor-binding potein(IGFBP)-3 in children with Henoch-Schonlein purpura(HSP).Methods The serum concentration of IGF-1,1GFBP-3 was measured by enzyme-linked immunosorbent assay(ELISA)method in 45 acute SHP patients,40 recoverv patients and 30 healthy controls.Results The serum levels of IGF-1 [(452±183)μg/L],IGFBP-3 [(13 897±3124)μg/L] and C-reactive protein(CRP)[(20±8)mg/L]in acute phase were significantly higher than those in healthy controls(P<0.0 1)and higher than those during recovery period.The serum level of IGF-1,IGFBP-3 for the HSP patients dropped back slowly and their levels during recovery period were the same as those in healthy controls(P>0.05).The serum levels of IGF-1[(621±253)μg/L] and IGFBP-3[(18 763±3173)μg/L] were higher in the renal damage group than in the non-renal damage group(P<0.01).and the same in patients with gastrointestinal symptoms group as in patients without gastrointestinal symptoms group(P>0.05).whereas the serum level of CRP was not significantly different(P>0.05).The serum levels of IGF-1,IGFBP-3 showed positive correlation with the level of CRP(r=0.624,0.672,P<0.01).Conclusion The IGF-1 and IGFBP-3 may play an important role in the pathological mechanism of HSP.The level of IGF-1 may be used as an indicator for HSP disease activity and progression.IGF-1 mav have a close relation with the damage"of renaJ system in HSP.     

Sleeve gastrectomy prevents lipoprotein receptor-1 expression in aortas of obese rats

AIM: To investigate the effects of sleeve gastrectomy on adipose tissue infiltration and lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) expression in rat aortas. METHODS: Twenty-four rats were randomized into three groups: normal chow (control), high fat diet (HD) and high fat diet with sleeve gastrectomy (SG). After surgery, the HD and SG groups were fed a high fat diet. Animals were sacrificed and plasma high density lipoprotein (HDL) and low density lipoprotein (LDL) levels were determin...     

Testosterone stimulates growth of tibial epiphyseal growth plate and insulin-like growth factor-1 receptor abundance in hypophysectomized and castrated rats

Puberty is associated with an increased in the plasma concentration of sex steroids, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Gonadal steroid hormones are important for the normal pubertal growth spurt and skeletal growth. The mechanism by which gonadal steroids induces skeletal growth is still not fully understood. To study the GH-independent effect of testosterone on growth, we investigated the effect of testosterone injections on the tibial epiphyseal growth plate (EGP) in an in vivo model of hypophysectomized and castrated male rats. Four groups (six animals each) of 28-d-old male rats were studied. Groups A, B, and C were hypophysectomized and castrated and received 500 μg/(kg·d) of hydrocortisone and 15 μg/(kg·d) of levothyroxine sodium. Groups A and B were also treated with daily sc injections of 10 μg of testosterone/100 g of body wt, and 100 μg of testosterone/100 g of body wt, respectively, for 7 d. Group C was injected with vehicle alone. Group D were intact animals injected with saline (controls). Animals were sacrificed on 8 d. As expected, serum GH levels were found to be very low (1.13±0.1 ng/mL) in the hypophysectomized animals (group C, hypopit), and testosterone treatment did not change them significantly. Serum IGF-1 decreased from 502.9± 13 ng/mL in group D to 167±41.4 ng/mL in group C (p<0.001). Testosterone therapy had no stimulatory effect on serum IGF-1 levels in the hypopit + low-dose group (A) (220±94.8 ng/mL) and had an inhibitory effect in the hypopit + high-dose group (B) (39.3±17.5). Histomorphometric determinations demonstrated an EGF width of 472.3±39 μm in the intact animals but only 336.9±1.6 μm in the hypopit group (C) (p<0.01). High-dose testosterone treatment (group B) significantly increased the EGP width (to 438.8±27.8), (p<0.001), whereas low-dose testosterone (group A) did not. Immunohistochemistry studies revealed that the levels of IGF-1 in the EGP of the control animals were almost negligible and that testosterone did not change them. However, testosterone increased in a dose-dependent manner the abundance of IGF-1 receptor EGP. We conclude that testosterone has a direct, local, GH-independent effect on the EGP growth and IGF-1 receptor abundance.     

Altered triiodothyronine metabolism in Zucker fatty rats

Genetically obese Zucker fatty rats require two autosomal recessive genes (fa/fa) to express the obese phenotype. The obese Zucker rat (fa/fa) has decreased total and free serum T3 concentrations, but normal serum T4 concentrations, compared to those in their lean littermates. To elucidate the mechanism of these differences, we measured the MCR and production rate (PR) of T4 and T3 in the three genotypes of 4-month-old male Zucker rats (Fa/Fa, Fa/fa, and fa/fa). In addition, 5'-deiodinase activity in liver, kidney, and brown adipose tissue homogenates was determined. T4 MCRs were equivalent in all three genotypes, but a decreased T3 MCR was seen in Fa/fa and fa/fa rats. An additive effect of the fa gene was noted with respect to the decrease in T3 MCR (Fa/Fa, 42.0 +/- 1.5; Fa/fa, 38.7 +/- 2.4; fa/fa, 34.7 +/- 3.4 ml/h; P less than 0.05). Whole body T4 PRs were equal in all three genotypes, but the T3 PR was decreased in the fa/fa rat by 25% compared to that in the homozygous lean rats (15.7 +/- 2.1 vs. 21.2 +/- 2.4 ng/h; P less than 0.005). Liver and kidney 5'-deiodinase activities were decreased in the fa/fa rat by 34% (P less than 0.005) and 20% (P less than 0.01), respectively. Brown adipose tissue and pituitary 5'-deiodinase activity were similar in all three genotypes. These results show a reduction in T3, but not T4, MCR in obese Zucker rats. Whole body T3 production and type I 5'-deiodinase activity were decreased in the obese (fa/fa) rats. These results suggest that decreased T4 to T3 conversion is responsible for the decreased T3 production rate in the fatty rat and may contribute to its obesity.     

Preserved insulin vasorelaxation and up-regulation of the Akt/eNOS pathway in coronary arteries from insulin resistant obese Zucker rats

Obesity is associated with insulin resistance in the peripheral vasculature and is an important risk factor for coronary artery disease. The current study assessed whether the vascular effects and the signaling pathways of insulin are impaired in coronary arteries from a rat model of genetic obesity. Intramyocardial arteries from obese Zucker rats (OZR) and lean Zucker rats (LZR) were mounted in microvascular myographs to assess insulin vasoactive effects and the proteins of the insulin pathway were determined by Western blotting. The endothelium-dependent and nitric oxide (NO)-mediated vasorelaxant effect of insulin was similar in arteries from LZR and OZR and blunted by inhibition of phosphatidylinositol 3-kinase (PI3K) and endothelial NO synthase (eNOS), but unaltered by either mitogen activated protein kinase (MAPK) or endothelin (ET) receptor blockade. Basal levels of phospho-eNOS Ser(1177) and phospho-Akt Ser(473) were up-regulated in OZR, and insulin increased phosphorylation of eNOS and Akt in both LZR and OZR. Moreover, insulin enhanced Akt expression in LZR. Basal and insulin-stimulated levels of phospho-MAPK p42/p44 were lower in OZR and palmitic acid reduced these levels in LZR. Coronary arteries are protected from vascular IR. The results underscore the fact that preservation of insulin-mediated vasorelaxation along with an up-regulation of the Akt/eNOS pathway and an impairment of the MAPK cascade account for this protection.     

Insulin and insulin-like growth factor-1 action on human skeletal muscle: preferential effects of insulin-like growth factor-1 in type 2 diabetic subjects

The metabolic actions of insulin and insulin-like growth factor-1 (IGF-1) were compared in cultured skeletal muscle cells from nondiabetic (ND) and type 2 diabetic subjects. Insulin stimulated glucose uptake with comparable sensitivity in ND (EC(50) = 2.0 +/- 0.7 nmol/L) and diabetic (1.3 +/- 0.4) cells. IGF-1 sensitivity for uptake stimulation was similar in ND (EC(50) = 0.30 +/- 0.06 nmol/L) and type 2 cells (0.37 +/- 0.01). In ND cells, insulin and IGF-1 were equally potent for stimulation of glucose uptake and glycogen synthase (GS) activity. However, in diabetic cells, maximal insulin stimulation of both responses was only half of the increases due to IGF-1. Final absolute activities after IGF-1 stimulation were still lower in diabetic cells compared with cells from ND subjects. Hormonal stimulation of Akt phosphorylation exhibited the same behavior as metabolic responses; comparable for insulin and IGF-1 in ND muscle, while IGF-1 was significantly more effective in diabetic cells. Both insulin receptor (IR) binding and receptor protein expression were similar in ND and diabetic cells. IGF-1 binding and receptor protein expression were not significantly different in diabetic compared with ND cells. The expression of IGF-binding proteins (IGFBP) 3, 5, and 6 were similar in ND and diabetic cells; IGFBP-4 was slightly, but significantly higher, in diabetic cells. While insulin and IGF-1 are equally effective on metabolic responses in ND muscle, diabetic muscle cells are markedly more resistant to insulin than IGF-1. The greater metabolic activity of IGF-1 in type 2 diabetic muscle may provide new insights into the mechanisms of insulin resistance in skeletal muscle.     

Metabolic imbalance of the insulin-like growth factor-I axis in Zucker diabetic fatty rats

In healthy conditions, insulin-like growth factor-I (IGF-I) acts in a coordinated fashion with insulin to lower glycemia, mainly by increasing insulin sensitivity in peripheral tissues. The aim of this study was to explore the relationship between glucose homeostasis and the endocrine IGF-I axis in Zucker diabetic fatty (ZDF) rats. The plasma levels of glucose, insulin, growth hormone, free IGF-I, total IGF-I (associated to insulin-like growth factor binding proteins plus free), and corticosterone were measured in 13-week-old ZDF rats and in age-matched controls under fasting and postprandial conditions. The plasma IGF-I binding capacity was measured by radioligand binding. In ZDF rats, fasting total and free IGF-I levels were reduced by 22% and 92%, respectively, compared with controls. Postprandial free IGF-I was reduced by 35%, whereas total IGF-I was unaffected. The plasma IGF-I binding capacity in ZDF rats was reduced by 24% after fasting and by 13% under postprandial conditions. A clear correlation between free IGF-I and insulin was observed in postprandial controls but not in ZDF rats. A principal component analysis clearly separated ZDF and control rats into 2 main components under both fasting and postprandial conditions. The first component was determined equally by total IGF-I, bound IGF-I, the free to total IGF-I ratio, and the IGF-I binding capacity. The second component was determined mostly by glucose and insulin. Our results show a marked alteration of the plasma IGF-I levels and of the capacity of plasma to bind IGF-I, and a disturbed relationship between IGF-I and postprandial insulinemia in a rat model of type 2 diabetes mellitus.     

胰岛素样生长因子-1在类风湿关节炎血管炎发病中的作用

目的研究血清胰岛素样生长因子(IGF)-1在类风湿关节炎(RA)血管炎发病中的作用。方法应用双抗体夹心酶联免疫吸附试验(ELISA)法测定62例RA患者,30名正常对照组血清IGF-1及肿瘤坏死因子(TNF)-α水平。进一步按外周血血小板计数分为血小板升高组和血小板正常组;按呼吸系统检查情况分为伴肺间质改变及不伴肺间质改变组;并与同时检测的其他免疫学指标进行相关分析。结果RA血小板升高组血清IGF-1为(132±81)ng/ml,血清TNF-α(1.34±0.30)ng/ml;血小板正常组血清IGF-1为(75±79)ng/ml,血清TNF-α(0.96±0.46)ng/ml;伴肺间质改变组血清IGF-1为(155±99)ng/ml,血清TNF-α(1.22±0.57)ng/ml,无肺间质改变组血清IGF-1为(81±62)ng/ml,血清TNF-α(1.09±0.37)ng/ml;正常对照组血清IGF-1及TNF-α水平分别为(37±74)ng/ml和(0.27±0.10)ng/ml。RA组血清IGF-1、TNF-α与正常对照组相比差异有显著性,且两者存在相关关系,血小板升高、伴肺间质改变组血清IGF-1均较血小板正常组及正常对照组增高且有统计学意义。结论提示血清IGF-1在RA伴有血管炎患者中明显升高特别在肺间质性疾病中起重要作用。     

瘦素、胰岛素生长因子-1与OSAHS关联性的研究

目的探讨肥胖相关的血清因子瘦素(LEP)、胰岛素生长因子-1(IGF-1)与阻塞性睡眠呼吸暂停低通气综合征(OSAHS)的关联性,为指导OSAHS临床诊治和预防提供科学依据。方法将华北理工大学附属医院呼吸科睡眠室和唐山协和医院耳鼻喉科睡眠室就诊并经过PSG(多导睡眠监测)确诊的131例重度OSAHS患者作为病例组;健康查体的90例非OSAHS者作为正常非肥胖组,其中45例BMI=25的为正常肥胖组,另45例BMI25的为正常非肥胖组。所有入选对象均使用统一调查表收集患者的一般情况、临床特征等资料填表登记;并对每位入选对象,清晨空腹采血捡测瘦素、胰岛素生长因子-1(IGF-1)。结果在本研究中,LEP水平在正常对照组最低,肥胖对照组次之,病例组最高,3组间差异无统计学意,LEP暴露水平与OSAHS的关联有统计学意义。LEP水平升高,OSAHS危险性增高(χ~2=6.45,OR 2.47)。而上述3个组间的IGF-1水平比较(P=0.00)。两两比较,各项指标均以病例组最低,肥胖组次之,正常对照组最高,组间差异均有统计学意义。(OR=6.94)。结论 LEP、IGF-1水平与OSAHS均有关联,LEP水平升高,OSAHS危险性增高,IGF-1暴露水平低的肥胖者,OSAHS的危险性升高。