Adiponectin and Lipoprotein Particle Size

OBJECTIVE

Adiponectin has been postulated to affect lipid and insulin signal transduction pathways. We evaluated the relationships of plasma adiponectin with lipoprotein mean particle size and subclass concentrations, independent of obesity and insulin sensitivity.

RESEARCH DESIGN AND METHODS

A cross-sectional analysis of 884 young Israeli adults who participated in the population-based Jerusalem Lipid Research Clinic (LRC) study was conducted. Lipoprotein particle size was assessed using proton nuclear magnetic resonance.

RESULTS

In multivariable linear regression models that included sex, BMI, waist circumference, homeostasis model assessment of insulin resistance, and leptin, adiponectin was associated with mean LDL size (standardized regression coefficient B = 0.20; P < 0.001), VLDL size (B = −0.12; P < 0.001), and HDL size (B = 0.06; P = 0.013). Adiponectin was inversely related to large VLDL (P < 0.001) but positively to small VLDL (P = 0.02), inversely related to small LDL (P < 0.006) but positively to large LDL (P < 0.001), and positively related to large HDL (P < 0.001) subclass concentrations.

CONCLUSIONS

Adiponectin is favorably associated with lipoprotein particle size and subclass distribution independent of adiposity and insulin sensitivity.Adiponectin is a fat-derived adipocytokine (1,2) that is strongly associated with insulin sensitivity and favorable cardiovascular outcomes. Given that insulin resistance is associated with reduced adiponectin levels (3), we hypothesized that adiponectin may have a direct role in hepatic lipoprotein metabolism. Thus, the aim of this study was to evaluate the relationships of adiponectin with lipoprotein particle size, independent of the degree of obesity and insulin sensitivity, in a population-based sample of healthy young adults.     

Minimal Model–Derived Insulin Sensitivity Index Underestimates Insulin Sensitivity in Black Americans

OBJECTIVETo examine the ethnic differences in insulin sensitivity (S_I) as measured by the minimal model approach (S_I-MM) and the reference method, the euglycemic-hyperinsulinemic clamp (EHC).RESEARCH DESIGN AND METHODSIn a prospective study design, thirty Black Americans (BA) were age, sex, and BMI matched with non-Hispanic Whites (NHW). Participants underwent frequently sampled intravenous tolerance test (FSIVGTT) and EHC on 2 separate days during a single visit.RESULTSS_I-MM values were significantly lower in BA when compared with NHW (0.035 ± 0.025 vs. 0.058 ± 0.036 [dL/min]/[μU/mL]; P = 0.003). However, there were no ethnic differences in S_I measured by EHC (0.028 ± 0.012 vs. 0.035 ± 0.019 [dL/min]/[μU/mL]; P = 0.18).CONCLUSIONSS_I-MM systematically underestimates S_I in BA when compared with NHW. These findings suggest that studies inferring lower S_I in BA based on FSIVGTT and S_I-MM should be interpreted cautiously.     

Effects of an Intravenous Lipid Challenge and Free Fatty Acid Elevation on In Vivo Insulin Sensitivity in African American Versus Caucasian Adolescents

OBJECTIVE—African American youth have lower insulin sensitivity than their Caucasian peers, but the metabolic pathways responsible for this difference remain unknown. Free fatty acids (FFAs) are associated with insulin resistance through the Randle cycle. The present investigation determined whether elevating FFA is more deleterious to insulin sensitivity in African American than in Caucasian adolescents.RESEARCH DESIGN AND METHODS—Insulin sensitivity (3-h hyperinsulinemic-euglycemic clamp) was evaluated in 22 African American and 21 Caucasian adolescents on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid.RESULTS—During intralipid infusion, fasting insulin and C-peptide concentrations increased while fasting glucose and basal glucose turnover did not change in either group. Insulin sensitivity decreased similarly in African American (normal saline 7.65 ± 0.61 vs. intralipid 5.15 ± 0.52 μmol · kg⁻¹ · min⁻¹ per pmol/l) and Caucasian subjects (normal saline 8.97 ± 0.85 vs. intralipid 5.96 ± 0.56 μmol · kg⁻¹ · min⁻¹ per pmol/l) (P < 0.001).CONCLUSIONS—African American and Caucasian adolescents respond to FFA elevation similarly through increased fasting insulin secretion to maintain fasting glucose homeostasis and reduced peripheral glucose uptake and insulin resistance. Thus, African American adolescents are not more susceptible to FFA-induced insulin resistance than Caucasian youth.Free fatty acids (FFAs) are implicated in insulin resistance development through the Randle cycle (1,2). In adults, elevating plasma FFA by infusing lipid emulsion inhibits glucose disposal and oxidation in normal-weight, obese, and type 2 diabetic patients (3–5). The only pediatric study was performed in Caucasian children and demonstrated that intralipid infusion decreased insulin sensitivity in pubertal adolescents, with no such effect in prepubertal children (6). Such data support that pubertal insulin resistance is driven by the Randle cycle/substrate competition (7,8).Insulin sensitivity is lower in African American children than in their Caucasian peers (9,10), but the metabolic pathways responsible for this contrast remain unknown. Lower insulin sensitivity correlates inversely with an increased fat-to-carbohydrate ratio in the diet of African American children (10,11). Thus, FFAs may be detrimental to insulin sensitivity in African American children. If race-related differences in the susceptibility to FFA-induced insulin resistance exist, then this is of increased importance during puberty when increased FFAs decrease glucose disposal (6). The present investigation, therefore, aimed to compare the effects of FFA elevation on fasting and insulin-stimulated glucose metabolism in African American and Caucasian adolescents. We hypothesized that increased concentrations of circulating FFAs result in a greater decrement in insulin sensitivity in African American than in Caucasian adolescents.     

Inhibition of In Vivo Insulin Secretion by Prostaglandin E1

To determine the effect of prostaglandin E(1) (PGE(1)) infusion upon in vivo insulin secretion, serum insulin responses after an intravenous glucose pulse (2 g) were measured before and during an intravenous infusion of PGE(1) (10 mug/min) in 11 anesthetized dogs. Circulating insulin decreased significantly during PGE(1) infusion were significantly less than control responses. Three dogs received PGE(1) infusions into the thoracic aorta to preclude pulmonic and hepatic degradation of PGE(1) before its arrival at the pancreatic artery; inhibition of insulin secretion was again seen. Inhibition of insulin secretion could not be related to the degree of arterial hypotension induced by intravenous PGE(1), and despite alpha adrenergic blockade with intravenous phentolamine, PGE(1)-induced inhibition of glucose-stimulated insulin responses persisted. Significant increments in systemically circulating PGE levels during intravenous PGE(1) infusions were documented by radioimmunoassay. These studies demonstrate that systemic PGE(1) infusion inhibits insulin secretion and that this effect could not be shown to be dependent upon alpha adrenergic activity.     

Sleep Status and Low-Density Lipoprotein Particle Size in a General Japanese Female Population: The Mima Study

Objective

This study investigated the relationship between sleep adequacy and small dense low-density lipoprotein (sdLDL) in a Japanese population.

Subjects and Methods

Clinical data, including atherosclerotic risk factors, in addition to the mean LDL particle size (LDL-PS) measured by gel electrophoresis, were evaluated in 136 community-dwelling female subjects (40-80 years old). The sleep status was self-reported and the subjects were divided into those who had inadequate sleep (≤6 or ≥9 h of sleep) and had adequate sleep (7-8 h).

Results

The mean LDL-PS was significantly smaller in subjects with inadequate sleep [n = 68, 26.4 ± 0.4 (SD) nm] than in those with adequate sleep (n = 68, 26.6 ± 0.4 nm, p < 0.05). This difference remained significant and independent after adjusting for confounders (β = 0.15-0.19, p < 0.05).

Conclusion

Sleep adequacy was associated with the presence of sdLDL, while the influence of the sleep status on LDL-PS was minor in this population. Further research on the associations among sleep, sdLDL and cardiovascular disease prevention is warranted.Key Words: Atherosclerosis, Small dense low-density lipoprotein, Sleep hygiene     

Therapeutic Ultrasound-Induced Insulin Release in Vivo

The tolerability and efficacy of low-frequency, low-intensity therapeutic ultrasound-induced insulin release was investigated in a pre-clinical in vivo murine model. The treatment groups received a single 5-min continuous sonication at 1 MHz and 1.0 W/cm². Insulin and glucagon levels in the serum were determined using enzyme-linked immunosorbent assay. The pancreas was excised and sectioned for histologic analysis. In terminal studies, we observed a moderate (∼50 pM) but significant increase in blood insulin concentration in vivo immediately after sonication compared with a decrease of approximately 60 pM in sham animals (n < 6, p < 0.005). No difference was observed in the change in glucose or glucagon concentrations between groups. Comparisons of hematoxylin and eosin-stained terminal and survival pancreatic tissue revealed no visible differences or evidence of damage. This study is the first step in assessing the translational potential of therapeutic ultrasound as a treatment for early stages of type 2 diabetes.     

Insulin Sensitivity and Insulin Binding to Monocytes in Maturity-Onset Diabetes

Tissue sensitive to insulin and insulin binding to monocytes were evaluated in 15 nonobese maturity-onset diabetics and in 16 healthy controls. Insulin sensitivity was determined by the insulin clamp technique in which the plasma insulin is acutely raised and maintained 100 muU/ml above the fasting level and plasma glucose is held constant at fasting levels by a variable glucose infusion. The amount of glucose infused is a measure of overall tissue sensitivity to insulin.In the diabetic group, the fasting plasma glucose concentration (168+/-4 mg/dl) was 85% greater than controls (P < 0.01) whereas the plasma insulin level (15+/-1 muU/ml) was similar to controls. During the insulin clamp study, comparable plasma insulin levels were achieved in the diabetics (118+/-5) and the controls (114+/-5 muU/ml). However, the glucose infusion rate in the diabetics (4.7+/-0.4 mg/kg.min) was 30% below controls (P < 0.01). Among the diabetics, the glucose infusion rate correlated directly with the fasting plasma glucose level (r = 0.57, P < 0.05). In five diabetic subjects, glucose metabolism was similar to controls, and these diabetics had the highest fasting glucose levels. When they were restudied after prior normalization (with insulin) of the fasting plasma glucose (100+/-1 mg/dl), the glucose infusion rate during the insulin clamp was 30% lower than observed in association with hyperglycemia (P < 0.01). Studies that employed tritiated glucose to measure endogenous glucose production indicated comparable 90-95% inhibition of hepatic glucose production during hyperinsulinemia in the diabetic and control subjects.(125)I-insulin binding to monocytes in the diabetics (5.5+/-0.6%) was 30% below that in controls (P < 0.01). Insulin binding to monocytes and insulin action as determined with the insulin clamp were highly correlated in both control (r = 0.67, P < 0.01), and diabetic subjects (r = 0.88, P < 0.001).We conclude that (a) tissue sensitivity to physiologic hyperinsulinemia is reduced in most maturity-onset diabetics; (b) this decrease in sensitivity is located, at least in part, in extrahepatic tissues; (c) the resistance to insulin may be mediated by a reduction in insulin binding; and (d) in maturity-onset diabetics with normal tissue sensitivity to insulin, hyperglycemia may be a contributing factor to the normal rates of insulin-mediated glucose uptake.     

Monodisperse versus Polydisperse Ultrasound Contrast Agents: In Vivo Sensitivity and safety in Rat and Pig

Recent advances in the field of monodisperse microbubble synthesis by flow focusing allow for the production of foam-free, highly concentrated and monodisperse lipid-coated microbubble suspensions. It has been found that in vitro, such monodisperse ultrasound contrast agents (UCAs) improve the sensitivity of contrast-enhanced ultrasound imaging. Here, we present the first in vivo study in the left ventricle of rat and pig with this new monodisperse bubble agent. We systematically characterize the acoustic sensitivity and safety of the agent at an imaging frequency of 2.5 MHz as compared with three commercial polydisperse UCAs (SonoVue/Lumason, Definity/Luminity and Optison) and one research-grade polydisperse agent with the same shell composition as the monodisperse bubbles. The monodisperse microbubbles, which had a diameter of 4.2 μm, crossed the pulmonary vasculature, and their echo signal could be measured at least as long as that of the polydisperse UCAs, indicating that microfluidically formed monodisperse microbubbles are stable in vivo. Furthermore, it was found that the sensitivity of the monodisperse agent, expressed as the mean echo power per injected bubble, was at least 10 times higher than that of the polydisperse UCAs. Finally, the safety profile of the monodisperse microbubble suspension was evaluated by injecting 400 and 2000 times the imaging dose, and neither physiologic nor pathologic changes were found, which is a first indication that monodisperse lipid-coated microbubbles formed by flow focusing are safe for in vivo use. The more uniform acoustic response and corresponding increased imaging sensitivity of the monodisperse agent may boost emerging applications of microbubbles and ultrasound such as molecular imaging and therapy.     

Threshold Methotrexate Concentration for In Vivo Inhibition of DNA Synthesis in Normal and Tumorous Target Tissues

The suppression of DNA synthesis in host and tumor tissues by methotrexate has been monitored in mice by determining the in vivo incorporation of tritium-labeled deoxyuridine ([(3)H]UdR) into DNA. The duration of inhibition of [(3)H]UdR incorporation in normal tissues was related to the dose of methotrexate and was a direct function of plasma drug concentration. [(3)H]UdR incorporation recovered to 50% of pretreatment levels in bone marrow when plasma methotrexate concentration was 10(-8) M or less, irrespective of the dose administered, while 50% recovery of DNA synthesis in intestinal epithelium was not observed until plasma methotrexate levels were 5 x 10(-9) M or less. Ascitic L1210 leukemia cells did not fully return to pretreatment levels of [(3)H]UdR incorporation at any time, although a partial recovery of incorporation was noted at methotrexate ascitic fluid concentrations of approximately 10(-8) M.Methotrexate did not suppress the incorporation of tritium-labeled thymidine ([(3)H]TdR) into bone marrow and duodenal mucosa, confirming the specificity of its action in inhibiting thymidylate synthesis in host tissues. In the ascites tumor a gradual decline in [(3)H]TdR incorporation was seen after methotrexate, indicating that the tumor tissue depression of [(3)H]UdR incorporation is not solely due to inhibition of thymidylate synthesis.These studies indicate that host tissues are inhibited by extremely low concentrations of methotrexate, and indicate the importance of the slow final phase (t((1/2))=12 h) of drug elimination from plasma in producing a prolonged exposure of sensitive host tissues to inhibitory drug concentrations.     

Long-term Physiologically Regulated Expression of the Low-density Lipoprotein Receptor In Vivo Using Genomic DNA Mini-gene Constructs

Familial hypercholesterolemia (FH) is a condition caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Expression of LDLR is highly regulated and excess receptor expression is cytotoxic. To incorporate essential gene regulation into a gene therapy vector for FH, we generated vectors in which the expression of therapeutic human LDLR gene, or luciferase reporter gene, is driven by 10 kb of human LDLR genomic DNA encompassing the promoter region including elements essential for physiologically regulated expression. Using luciferase expression and specific LDL binding and internalization assays, we have shown in vitro that the genomic promoter element confers long-term, physiologically regulated gene expression and complementation of receptor deficiency in culture for 240 cell-generations. This was demonstrated in the presence of sterols or statins, modifiers of LDLR promoter activity. In vivo, we demonstrate efficient liver-specific delivery and expression of luciferase following hydrodynamic tail-vein injection and confirm that expression from the LDLR promoter element is sensitive to statin administration. We also demonstrate long-term LDLR expression from the 10-kb promoter element up to 9 months following delivery. The vector system that we describe provides the efficient delivery, long-term expression, and physiological regulation required for a successful gene therapy intervention for FH.     

Radiofrequency Catheter Ablation: The Effect of Electrode Size on Lesion Volume In Vivo

Radiofrequency current is a promising alternative to high voltage direct current defibrillator discharges for catheter ablation of arrhythmias. However, lesions produced with radiofrequency current are relatively small and use of high power is limited by the impedance rise that occurs with desiccation of tissue and coagulum formation. The effect of electrode size on radiofrequency ablation was assessed by comparing results of radiofrequency application using a standard 6 French electrode catheter (distal electrode 2 mm in length) to those using catheters modified with longer distal electrodes (3, 4, 6, 8, and 10 mm in length). Radiofrequency ablation was performed at 47 left ventricular endocardial sites in 20 anesthetized dogs. A constant power of 13.3 +/- 1.3 watts at 550 kHz was applied between the distal catheter electrode and a skin electrode until a total of 500 joules had been delivered or a rise in impedance occurred. Increasing electrode length from 2 to 4 mm more than doubled lesion volume from a mean of 143 to 326 mm3 (P = 0.025). Increasing electrode length beyond 4 mm produced progressively smaller lesions (157 mm3, 155 mm3, and 67 mm3 for 6-, 8-, and 10-mm electrode lengths, respectively). Impedance rise was significantly less likely with larger electrodes and took longer to occur. Increasing the size of electrodes used for radiofrequency ablation allows application of higher power without an impedance rise. Optimizing electrode size (3 or 4 mm in this study) results in larger lesions and may improve the effectiveness of radiofrequency ablation of arrhythmias.     

Attrition in nursing among Black and White nurses

Fundamental to dealing with the problems associated with attracting and retaining nurses during a tight labour market are issues centreing upon attrition from the field. In the United States, attrition has become such a significant issue that efforts to attract individuals to the field and recruit them to positions in the health care industry are not adequate to offset the flow of individuals from the field, much less bring in the additional nurses who are needed for an ageing population with increasing health care needs. As an example of the seriousness of the problem, it is probably safe to say that of the students who graduate from nursing schools each year and who enter the field of nursing, a significant number will no longer be practicing after 5 years in the profession. In a high attrition environment, even if many individuals were entering nursing, these losses will potentially offset any gains that are made. From the perspective of this study, it is important to know what is leading nurses to leave their careers. Do all nurses face the same challenges in the course of their careers, or is the pattern of turnover somewhat different for different groups of nurses or those in different stages of their careers? In this study, we consider what career differences may exist between the two major groups of nurses in the USA today – Black and White nurses – and ask whether there are differences between the two groups in terms of ‘whether’ and ‘why’ they may be leaving the field. Our primary purpose was to determine if differences in attrition exist between Black and White nurses, and if so, where in the career process are those differences most pronounced. Based on our analysis of data from the National Science Foundation, we do find significant differences in patterns of attrition for the two groups and we suggest what we believe may be their implications for policy.     

In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate,Artemether, or OZ78

Triclabendazole resistance is continually documented from livestock, and hence new treatment strategies for Fasciola hepatica infections are needed. We investigated the effect of triclabendazole combined with artesunate, artemether, or OZ78 compared to that of monotherapy against adult and juvenile F. hepatica in rats. In vitro experiments with triclabendazole and its sulfoxide and sulfone metabolites, each in combination with the peroxides, complemented our study. F. hepatica-infected rats were subjected to single drugs or drug combinations 3 to 4 weeks (juvenile flukes) and >8 weeks (adult flukes) postinfection. Negative binomial regressions of worm and egg counts were used to analyze dose-response relationships and whether the effects of drug combinations were synergistic or antagonistic. The in vitro assays were evaluated by means of viability scales based on fluke motility. Fifty percent effective dose values of 113.0, 77.7, 22.9, and 2.7 mg/kg of body weight were calculated for monotherapy with artesunate, artemether, OZ78, and triclabendazole, respectively, against adult F. hepatica. Likelihood ratio tests revealed synergistic interactions (P < 0.05) of combinations of triclabendazole (2.5 mg/kg) plus artesunate or artemether on adult worm burden. Antagonistic effects on the adult burden and egg output were observed when a lower triclabendazole dose (1.25 mg/kg) was combined with the artemisinins. No significant interactions (P = 0.07) were observed for OZ78 and triclabendazole combinations and between the triclabendazole effect and the effects of the other partner drugs on juvenile worms. Our in vitro studies of adult worms agreed with the in vivo results, while the in vitro analysis of juvenile worms revealed greater interactions than observed in vivo. In conclusion, single-agent triclabendazole demonstrated a more potent in vivo and in vitro fasciocidal activity than the experimental drugs artesunate, artemether, and OZ78. When combined, synergistic but also antagonistic effects depending on the doses administered were observed, which should be elucidated in more detail in future studies.The food-borne trematodes Fasciola hepatica and F. gigantica are the causative agents of fascioliasis (fasciolosis). Fasciola hepatica parasitizes a wide spectrum of domestic and wild animals (e.g., sheep, cattle, rats, and deer), and it causes a huge economic loss of $3 billion annually to the agriculture sector worldwide through losses of milk and meat yields (26, 31). In addition, an estimated 90 million people are at risk of fascioliasis and up to 17 million individuals are infected (20).Due to its excellent safety profile and the high activity against both juvenile and adult liver flukes, triclabendazole (Fasinex, Egaten) is the drug of choice for the treatment of human and veterinary fascioliasis. It is worrying, however, that triclabendazole resistance has been documented from Australian sheep farms since the mid-1990s and recently also from several western European countries (10). Furthermore, F. hepatica strains resistant to three alternative fasciocidal drugs (rafoxanide, closantel, and luxabendazole) have been isolated (11). Due to the rapid spread of resistance, the small arsenal of fasciocidal drugs, and the absence of effective vaccines in field conditions, there is a pressing need for the discovery and development of novel drugs or drug combinations (27). The use of drug combinations is an excellent strategy to avoid or delay drug resistance, since different drug targets are attacked simultaneously. Furthermore, drug combinations often are characterized by an increased activity and tolerability compared to that of monotherapy. Therefore, drug combinations are widely used in the treatment of infectious diseases (e.g., malaria, HIV, and tuberculosis), cancer, and chronic disorders (e.g., cardiovascular disease, diabetes, and pain management) (5, 8, 12, 30, 39). Combination chemotherapy has been tested in experimental studies using triclabendazole-susceptible and -resistant strains of F. hepatica. The combined treatment of triclabendazole plus clorsulon or luxabendazole was found to act synergistically. For example, the combination of triclabendazole and clorsulon, administered at one-fifth their recommended dosages, was highly effective against triclabendazole-resistant F. hepatica in sheep. This combination reduced 95% of the worms, while the single drugs achieved a worm burden reduction (WBR) of only approximately 30% (11, 28).Recently, the semisynthetic artemisinins artemether and artesunate and the synthetic peroxide OZ78 were described to have excellent fasciocidal properties in rats (19, 21). Importantly, artemether and OZ78 cured a triclabendazole-resistant F. hepatica infection in the rat model (22). Contradictory results were obtained in sheep. While OZ78 failed to cure a chronic F. hepatica infection in sheep (16), artemether and artesunate achieved high worm burden reductions in naturally F. hepatica-infected sheep (18, 23).The aim of the present investigation was to study the potential of the combined treatment of triclabendazole with artesunate, artemether, or OZ78 in F. hepatica-infected rats harboring juvenile or adult infections. Comparisons were made to monotherapies, and negative binomial regression was used for the analysis of egg burden and worm counts. In vitro studies complemented our work. We investigated the in vitro effect of triclabendazole and its sulfoxide and sulfone metabolites, each combined with the three peroxidic drugs (artesunate, artemether, and OZ78) against juvenile and adult F. hepatica flukes.     

Insulin Metabolism,Insulin Sensitivity and Hormonal Responses to Insulin Infusion in Patients Taking Oral Contraceptive Steroids

Abstract. The metabolism of unlabelled human monocomponent insulin was studied in a group of six patients being treated with combined oestrogen-progestogen oral contraceptives (OC) and compared with a group of ten normal subjects. The parameters of insulin metabolism were determined by a priming dose - continuous infusion technique which enabled measurements of metabolic clearance rate (MCR) of insulin to be made at four separate steady state hormone concentrations spanning the physiological range. In normal subjects MCR was greatest at low insulin concentrations, falling from 24.7 ml/kg/min. at 16 μU/ml to 11.4 ml/kg/min. at a mean concentration of 280 μU/ml. In the OC group, MCR averaged 20.5 ml/kg/min. and did not change with increasing plasma insulin concentration. The plasma half-disappearance time (T 1/2) was longer than normal in the OC group (5·6 vs. 4·4 min., p < 0·05) despite a higher MCR. The prolonged T 1/2 indicated that the apparent distribution space was increased in those on OC (166·6 vs. 82·7 ml/kg., p < 0·0025). The results are interpreted as indicating increased capillary permeability to insulin and increased peripheral degradation. The fact that MCR did not fall in the OC group with increasing plasma insulin concentrations whereas it did in normal subjects, suggested that OC leads to the loss of saturable component of insulin degradation that is present in normal subjects. Insulin sensitivity (as judged by induced hypoglycaemia) was reduced in the OC group while growth hormone responses were within the normal range. Plasma cortisol was increased in those taking OC but the response to insulin induced hyperglycaemia was less marked than normal. The results indicate a significant alteration in insulin metabolism in these subjects, which may contribute to the impairment of carbohydrate tolerance seen in some women taking combined OC.     

Insulin Metabolism, Insulin Sensitivity and Hormonal Responses to Insulin Infusion in Patients Taking Oral Contraceptive Steroids

Abstract. The metabolism of unlabelled human monocomponent insulin was studied in a group of six patients being treated with combined oestrogen-progestogen oral contraceptives (OC) and conroared with a group of ten normal subjects. The parameters of insulin metabolism ware determined by a priming dose - continuous infusion technique which enabled measurements of metabolic clearance rate (MCR) of insulin to be made at four separate steady state hormone concentrations spanning the physiological range. In normal subjects MCR was greatest at low insulin concentrations, falling from 24. 7 ml/kg/min. at 16 μU/ml to 11. 4 ml/kg/min. at a mean concentration of 280 μU/ml. In the OC group, MCR averaged 20.5 ml/kg/min. and did not change with increasing plasma insulin concentration. The plasma half-disappearance time (T 1/2) was longer than normal in the OC group (5. 6 vs. 4. 4 min., p < 0. 05) despite a higher MCR. The prolonged T 1/2 indicated that the apparent distribution space was increased in those on OC (166. 6 vs. 82. 7 ml/kg., p < 0. 0025). The results are interpreted as indicating increased capillary permeability to insulin and increased peripheral degradation. The fact that MCR did not fall in the OC group with increasing plasma insulin concentrations whereas it did in normal subjects, suggested that OC leads to the loss of saturable component of insulin degradation that is present in normal subjects. Insulin sensitivity (as judged by induced hypoglycaemia) was reduced in the OC group while growth hormone responses were within the normal range. Plasma Cortisol was increased in those taking OC but the response to insulin induced hyperglycaemia was less marked than normal. The results indicate a significant alteration in insulin metabolism in these subjects, which may contribute to the impairment of carbohydrate tolerance seen in some women taking combined OC.     

氯化钾、维生素C及胰岛素浓度对胰岛素吸附的影响

为了研究什么因素可影响胰岛素的吸附 ,应用放射免疫测定的方法 ,将临床上经常与胰岛素 (RI)滴注配伍的氯化钾和维生素C对胰岛素吸附影响进行了初步研究 ,并在高浓度RI液体输入时 ,对RI的影响进行了初步的观察 ,结果表明 :①在胰岛素溶液中加入氯化钾或维生素C后 ,在输液初始阶段胰岛素浓度高于对照组 (P <0 .0 5 ) ,从第 10 0ml至第 35 0ml液体输入过程中 ,胰岛素浓度波动比对照组小 ,接近参照浓度。②高浓度的胰岛素液体可最大限度地减少输液器吸附对胰岛素输入的干扰 ,可使胰岛素实际输入浓度迅速达到平衡     

超敏C-反应蛋白和胰岛素敏感指数在儿童阻塞性睡眠呼吸暂停综合征中的变化

目的研究超敏C-反应蛋白(hypersensitive3 C-reactive protein,hs-CRP)和胰岛素敏感指数(Insulin sensitivity index,ISI)在儿童阻塞性睡眠呼吸暂停综合征(Obstructive sleep apnea syndrome,OSAS)中的变化。方法选择2011年2月~2014年2月在我院接受诊治的打鼾及睡眠呼吸异常患儿102例作为研究对象。根据疾病情况将患儿分成OSAS者51例(观察组)和原发性鼾症者51例(对照组)。对比两组患儿多导睡眠监测结果,两组患儿hs-CRP、ISI各相关指标及ISI水平,分析观察组患儿hs-CRP水平与睡眠监测各指标水平的相关性。结果观察组的AHI水平显著高于对照组,LSa O2水平显著低于对照组,差异均有统计学意义(均P<0.05)。两组的平均心率相比,差异无统计学意义(P>0.05)。观察组的hs-CRP水平显著高于对照组,差异有统计学意义(P<0.05)。但两组在FPG、UA、TG、TC、LDL-C、INS及ISI等指标水平方面对比,差异均无统计学意义(均P>0.05)。根据Pearson法分析相关性可知,患儿hs-CRP水平与LSa O2呈负相关,与平均心率、AHI、BMI、INS及ISI无明显的相关性。结论 OSAS患儿机体的hs CRP水平上升,但胰岛素敏感指数无明显变化,临床上应对此加以关注,并进行尽早干预治疗,以免诱发心血管类病症。     

Insulin Sensitivity of Forearm Tissues in Prediabetic Man

In genetic prediabetic subjects (the glucose tolerant offspring of two diabetic parents or the identical twin of a known diabetic) serum insulin concentrations after glucose administration are subnormal. Maintenance of glucose tolerance in this setting is apparently paradoxical, suggesting increased tissue insulin sensitivity. Accordingly, forearm tissue insulin sensitivity in nine genetic prediabetic males was compared with that of seven males without familial diabetes. Diabetes was excluded in all subjects by preliminary oral glucose tolerance testing.On the preliminary 3 h oral glucose tolerance test (OGTT) the sum of increments in blood glucose above fasting was greater in prediabetic than in control subjects. Conversely, the sum of increments in serum insulin was subnormal for the first 2 h. The insulin index (the sum of increments in insulin divided by the sum of increments in glucose) was significantly lower in prediabetics throughout the test. High physiologic levels of insulin were produced in the forearm by intrabrachial arterial insulin infusion (100 muU/kg per min for 26 min). Balances of glucose and amino acids across forearm muscle became more positive, as did balances of glucose and free fatty acids across adipose tissue plus skin. There were no differences in response between prediabetic and normal subjects.Hence, the insulin sensitivity of peripheral tissues is normal in genetic prediabetes. Increased tissue insulin sensitivity is not essential to explain coexisting euglycemia and insulinopenia in prediabetes because blood glucose values on the OGTT are, in fact, elevated although still within the range considered normal.     

Influence of Adiposity on Insulin Resistance and Glycemia Markers Among U.K. Children of South Asian,Black African-Caribbean,and White European Origin: Child Heart and Health Study in England

OBJECTIVE

Ethnic differences in type 2 diabetes risk between South Asians and white Europeans originate before adult life and are not fully explained by higher adiposity levels in South Asians. Although metabolic sensitivity to adiposity may differ between ethnic groups, this has been little studied in childhood. We have therefore examined the associations among adiposity, insulin resistance, and glycemia markers in children of different ethnic origins.

RESEARCH DESIGN AND METHODS

Cross-sectional study of 4,633 9- to 10-year-old children (response rate 68%) predominantly of South Asian, black African-Caribbean, and white European origin (n = 1,266, 1,176, and 1,109, respectively) who had homeostasis model assessments of insulin resistance (HOMA-IR), glycemia markers (HbA_1c and fasting glucose), and adiposity (BMI, waist circumference, skinfold thicknesses, and bioimpedance [fat mass]).

RESULTS

All adiposity measures were positively associated with HOMA-IR in all ethnic groups, but associations were stronger among South Asians compared to black African-Caribbeans and white Europeans. For a 1-SD increase in fat mass percentage, percentage differences in HOMA-IR were 37.5% (95% CI 33.3–41.7), 29.7% (25.8–33.8), and 27.0% (22.9–31.2), respectively (P interaction < 0.001). All adiposity markers were positively associated with HbA_1c in South Asians and black African-Caribbeans but not in white Europeans; for a 1-SD increase in fat mass percentage, percentage differences in HbA_1c were 0.04% (95% CI 0.03–0.06), 0.04% (0.02–0.05), and 0.02% (−0.00 to 0.04), respectively (P interaction < 0.001). Patterns for fasting glucose were less consistent.

CONCLUSIONS

South Asian children are more metabolically sensitive to adiposity. Early prevention or treatment of childhood obesity may be critical for type 2 diabetes prevention, especially in South Asians.The prevalence of type 2 diabetes has been rising, both in the U.K. population (1) and worldwide (2,3). In the U.K., there are marked ethnic differences in the risks of type 2 diabetes, which are particularly high among South Asians and to a lesser extent black African-Caribbeans (4); increased type 2 diabetes risks are also apparent in these ethnic groups in the U.S. (5,6). Recent evidence suggests that ethnic differences in risks of type 2 diabetes are apparent in childhood, with higher levels of insulin resistance (a key precursor of type 2 diabetes), glycated hemoglobin (HbA_1c), and (less consistently) fasting blood glucose concentrations observed in U.K. South Asians and to a lesser extent black African-Caribbeans compared with white Europeans by the age of 10 years (7).Excess body fat (adiposity) is an important independent risk factor for the development of type 2 diabetes and insulin resistance both in adults (8,9) and children (10). However, the role of adiposity in these ethnic differences in type 2 diabetes is complex. In South Asian adults, it is well-recognized that BMI underestimates adiposity (11) and that body fat levels (particularly of central body fat) are higher than those of white Europeans (10,12–14). However, in most studies, adjusting for the higher body fat levels (usually assessed using skinfold thickness or waist and hip circumferences) has not accounted for the higher risks of diabetes and insulin resistance observed in South Asians (13,15–17). It has also been observed that the risks of diabetes, insulin resistance, and cardiovascular disease emerge at lower levels of adiposity (particularly BMI) in South Asian populations and that their associations with adiposity are stronger than those in white Europeans (13,17). We have previously shown in U.K. South Asian children that higher insulin and HbA_1c levels do not appear to be explained by higher adiposity levels (7,18). In a preliminary study, we also showed that insulin resistance in U.K. South Asian children may be more sensitive to adiposity than in white Europeans (18). However, this latter observation needs to be substantiated in larger scale studies in which insulin resistance, glycemia marker levels, and a range of adiposity markers are assessed in children from the relevant ethnic groups.We have therefore examined the cross-sectional associations among adiposity, insulin resistance, and glycemia markers in a study of ∼5,000 children of South Asian and white European origin aged 9 to 10 years; we also report on associations among children of black African-Caribbean origin. We hypothesized that metabolic sensitivity to adiposity would be greater in South Asians than white Europeans. Several adiposity markers were assessed, including measures based on skinfold thickness and bioimpedance, which provide robust measures of adiposity in this multiethnic population (19), as well as BMI and waist circumference. We have also included data on leptin, an adipokine with circulating levels that are strongly correlated with total body fat percentage (20). Because other studies have suggested that lower lean mass may be an important determinant of insulin resistance in young South Asian men (21), we also report on the influence of fat-free mass (FFM) on insulin resistance and glycemia.