Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity

RATIONALE AND OBJECTIVES: Although many clinical physiology and epidemiology studies show an association between obstructive sleep apnea (OSA) and markers of insulin resistance, no causal pathway has been established. The purpose of the current study was to determine if the intermittent hypoxia (IH) stimulus that characterizes OSA causes insulin resistance in the absence of obesity. Furthermore, we assessed the impact of IH on specific metabolic function in liver and muscle. Finally, we examined the potential mechanistic role of the autonomic nervous system (ANS) in mediating insulin resistance in response to IH. METHODS AND RESULTS: Hyperinsulinemic euglycemic clamps were conducted and whole-body insulin sensitivity, hepatic glucose output, and muscle-specific glucose utilization assessed in conscious, chronically instrumented adult male C57BL/6J mice exposed to (1) IH (achieving a nadir of Fi(O(2)) = 5-6% at 60 cycles/h for 9 h), (2) intermittent air as a control, (3) IH with ANS blockade (hexamethonium), or (4) IA with ANS blockade. IH decreased whole-body insulin sensitivity compared with intermittent air (38.8 +/- 2.7 vs. 49.4 +/- 1.5 mg/kg/min, p < 0.005) and reduced glucose utilization in oxidative muscle fibers, but did not cause a change in hepatic glucose output. Furthermore, the reduction in whole-body insulin sensitivity during IH was not restored by ANS blockade. CONCLUSION: We conclude that IH can cause acute insulin resistance in otherwise lean, healthy animals, and that the response is associated with decreased glucose utilization of oxidative muscle fibers, but that it occurs independently of activation of the ANS.     

Melatonin reduces ventricular arrhythmias and preserves capillary perfusion during ischemia-reperfusion events in cardiomyopathic hamsters

Earlier studies showed that melatonin has powerful antioxidative effects on ischemia-reperfusion (I/R) injury in healthy hamsters. In the present study, the possible protective effects of melatonin in 10-month-old cardiomyopathic (CM) hamsters were evaluated in a model of I/R in the cheek pouches observed by intravital microscopy. In CM (BIO 14.6) hamsters diameter, red blood cell (RBC) velocity and flow in arterioles as well as lipid peroxide and nitrite/nitrate concentrations in the systemic blood, perfused capillary length, vascular permeability, and leukocyte adhesion were measured after melatonin injection (6 mg/kg intraperitoneally daily for 3 weeks), and after I/R. The influence of melatonin on the incidence of postischemic-reperfusion-induced ventricular tachycardia (VT) and ventricular fibrillation (VF) were also measured. Changes in the arteriolar response to NG-monomethyl-L-arginine (L-NMMA), a nitric oxide inhibitor, norepinephrine (NE), and angiotensin II (ANG II) were studied before and after melatonin injection (10 mg/kg intravenously). In CM hamsters, melatonin restored normal arteriolar responses to L-NMMA, NE, and ANG II. I/R elevated lipid peroxide and nitrate/nitrite levels, and vascular permeability while arteriolar diameter, RBC velocity, flow and capillary perfusion were reduced. These effects were more marked in CM versus healthy hamsters. During I/R melatonin reduced oxidative and nitrosative stress, vasoconstriction, leukocyte adhesion, and vascular permeability and increased capillary perfusion. Melatonin reduced the incidence of VT while VF during reperfusion disappeared totally. In conclusion, melatonin prevents both microvascular injury and ventricular arrhythmias during postischemic reperfusion by modulating the lipid peroxide overproduction and nitrative stress which are involved in the development of cardiomyopathy.     

Loss of insulin‐mediated microvascular perfusion in skeletal muscle is associated with the development of insulin resistance

Aim: The aetiology of the development of type 2 diabetes remains unresolved. In the present study, we assessed whether an impairment of insulin‐mediated microvascular perfusion occurs early in the onset of insulin resistance. Materials and methods: Hooded Wistar rats were fed either a normal diet (ND) or a high‐fat diet (HFD) for 4 weeks. Anaesthetized animals were subjected to an isoglycaemic hyperinsulinaemic clamp (3 or 10 mU/min/kg × 2 h), and measurements were made of glucose infusion rate (GIR), hindleg glucose uptake, muscle glucose uptake by 2‐deoxy‐d ‐glucose (R′g), glucose appearance (Ra), glucose disappearance (Rd), femoral blood flow (FBF) and hindleg 1‐methylxanthine disappearance (1‐MXD, an index of microvascular perfusion). Results: Compared with ND‐fed animal, HFD feeding led to a mild increase in fasting plasma glucose and plasma insulin, without an increase in total body weight. During the clamps, HFD rats showed an impairment of insulin‐mediated action on GIR, hindleg glucose uptake, R′g, Ra, Rd and FBF, with a greater loss of insulin responsiveness at 3 mU/min/kg than at 10 mU/min/kg. The HFD also impaired insulin‐mediated microvascular perfusion as assessed by 1‐MXD. Interestingly, 1‐MXD was the only measurement that remained unresponsive to the higher dose of 10 mU/min/kg insulin. Conclusions: We conclude that the early stage of insulin resistance is characterized by an impairment of the insulin‐mediated microvascular responses in skeletal muscle. This is likely to cause greater whole body insulin resistance by limiting the delivery of hormones and nutrients to muscle.     

Effects of central administration of insulin or l-NMMA on rat skeletal muscle microvascular perfusion

Aim: Intracerebroventricular (ICV) administration of a nitric oxide synthase (NOS) inhibitor to rats has been reported to raise blood pressure (BP) and cause insulin resistance, suggestive of a central effect of insulin that is NO dependent. Herein we test whether ICV insulin has peripheral haemodynamic and metabolic effects and whether peripheral effects of systemic insulin are affected by the ICV administration of the NOS inhibitor N^G‐methyl‐l ‐arginine (l ‐NMMA). Methods: Anaesthetized rats were fitted with an ICV cannula for insulin, artificial cerebrospinal fluid (aCSF) or l ‐NMMA infusion. Rats receiving ICV l ‐NMMA (500 µg) underwent systemic insulin clamp (10 mU/min/kg) or saline treatment for 70 min and were compared with animals receiving an equal amount of l ‐NMMA infused systemically. Results: ICV aCSF or insulin (135 mU/min/kg brain) for 70 min or systemic l ‐NMMA (500 µg) had no effect on BP, heart rate (HR), femoral blood flow (FBF), glucose infusion rate, muscle 2‐deoxyglucose uptake, microvascular perfusion or plasma insulin. However, ICV l ‐NMMA reduced systemic insulin‐mediated increases in FBF (2.05 ± 0.08 to 1.55 ± 0.15 ml/min), 2‐deoxyglucose uptake (17.7 ± 0.15 to 10.0 ± 0.03 µg/g/min) and microvascular perfusion (10.5 ± 0.5 to 6.6 ± 1.1 mol/min) (each mean ± SE, p < 0.05); plasma insulin, HR and BP were unaffected. Conclusions: Central insulin administration had no effect on skeletal muscle haemodynamics or glucose metabolism. However, systemic insulin‐mediated increases in limb blood flow, muscle microvascular perfusion and glucose uptake may be regulated by a central pathway that is NO dependent.     

Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia (IH) during sleep. There is growing evidence from animal models of OSA that IH is independently associated with metabolic dysfunction, including dyslipidemia and insulin resistance. The precise mechanisms by which IH induces metabolic disturbances are not fully understood. Over the last decade, several groups of investigators developed a rodent model of IH, which emulates the oxyhemoglobin profile in human OSA. In the mouse model, IH induces dyslipidemia, insulin resistance and pancreatic endocrine dysfunction, similar to those observed in human OSA. Recent reports provided new insights in possible mechanisms by which IH affects lipid and glucose metabolism. IH may induce dyslipidemia by up-regulating lipid biosynthesis in the liver, increasing adipose tissue lipolysis with subsequent free fatty acid flux to the liver, and inhibiting lipoprotein clearance. IH may affect glucose metabolism by inducing sympathetic activation, increasing systemic inflammation, increasing counter-regulatory hormones and fatty acids, and causing direct pancreatic beta-cell injury. IH models of OSA have improved our understanding of the metabolic impact of OSA, but further studies are needed before we can translate recent basic research findings to clinical practice.     

间歇低氧对大鼠胰岛素抵抗及骨骼肌细胞GLUT4、Akt2的影响

目的 检测不同间歇低氧暴露时间对骨骼肌葡萄糖转运蛋白(GLUT)4与蛋白激酶B(PKB/Akt)2表达的影响,探讨二者在间歇低氧导致胰岛素抵抗中的作用.方法 选取健康雄性Sprague-Dawley大鼠40只,按照随机数字表法分为5组:常氧对照组(NC组),间歇低氧2周组(IH2组),间歇低氧4周组(IH4组),间歇低氧6周组(IH6组),间歇低氧8周组(IH8组),每组8只.IH2组、IH4组、IH6组、IH8组每天给予8h间歇低氧暴露(9:00～17:00),NC组室内环境正常饲养.检测各组空腹血糖和空腹胰岛素水平,计算稳态模型评估-胰岛素抵抗指数(HOMA-IR).采用免疫组织化学法检测大鼠骨骼肌GLUT4及Akt2蛋白的表达,蛋白表达量用平均灰度值表示,并分析GLUT4与Akt2的相关性.结果 与NC组相比,IH2组、IH4组、IH6组、IH8组空腹血糖、HOMA-IR升高,骨骼肌GLUT4与Akt2灰度值升高,并且随间歇低氧暴露时间的延长而升高明显(F =87.67～288.63,P均＜0.05);与NC组相比,IH2组、IH4组、IH6组、IH8组空腹胰岛素升高,其中IH2组、IH4组、IH6组,随间歇低氧暴露时间的延长而升高明显,IH8组较IH6组下降(F=86.04,P＜0.01).Pearson相关分析显示GLUT4与Akt2的表达呈正相关(r=0.895,P ＜0.05).结论 随着间歇低氧暴露时间的延长胰岛素抵抗程度增加,GLUT4与Akt2蛋白表达水平下降,二者在间歇低氧导致胰岛素抵抗的过程中起协同作用.     

Melatonin ameliorates endothelial dysfunction,vascular inflammation,and systemic hypertension in rats with chronic intermittent hypoxia

The pathogenesis of hypertension in patients with obstructive sleep apnea (OSA) is associated with endothelial dysfunction induced by chronic intermittent hypoxia (IH). Studies have shown that administration of melatonin ameliorates oxidative injury and inflammation. This study examined the effect of melatonin on the oxidative stress, endothelial dysfunction, and inflammation during the pathogenesis of hypertension in chronic IH. Adult Sprague‐Dawley rats that had received a daily injection of melatonin or vehicle were exposed to IH treatment mimicking a severe OSA condition for 14–21 days. Systolic pressure was significantly higher in the vehicle‐treated (144 ± 2.7 mmHg) but not in the melatonin‐treated rats (123 ± 5.1 mmHg) by 21–day IH treatment when compared with the normoxic control. Levels of malondialdehyde and the expressions of NADPH oxidase, pro‐inflammatory mediators (TNF‐α, inducible NO synthase, COX‐2), and adhesion molecules (ICAM‐1, VCAM‐1, and E‐selectin) of the thoracic aorta were markedly increased by 14‐day IH treatment preceding the hypertensive response. Also, levels of nitric oxide (NO˙), endothelial‐dependent relaxation, and the expressions of endothelial NO synthase (eNOS) and antioxidant enzymes (GPx, CAT, and Cu/Zn SOD) were significantly lowered in the IH rats. Melatonin treatment significantly mitigated the increased expression of NADPH oxidase, pro‐inflammatory mediators, and adhesion molecules. Moreover, melatonin prevented the endothelial dysfunction with ameliorated levels of NO˙, endothelial‐dependent relaxation, and expressions of eNOS and antioxidant enzymes. These results suggest that melatonin is protective against IH‐induced hypertension and endothelial dysfunction via an antioxidant and anti‐inflammatory mechanism.     

Short‐term melatonin consumption protects the heart of obese rats independent of body weight change and visceral adiposity

Chronic melatonin treatment has been shown to prevent the harmful effects of diet‐induced obesity and reduce myocardial susceptibility to ischaemia‐reperfusion injury (IRI). However, the exact mechanism whereby it exerts its beneficial actions on the heart in obesity/insulin resistance remains unknown. Herein, we investigated the effects of relatively short‐term melatonin treatment on the heart in a rat model of diet‐induced obesity. Control and diet‐induced obese Wistar rats (fed a high calorie diet for 20 wk) were each subdivided into three groups receiving drinking water with or without melatonin (4 mg/kg/day) for the last 6 or 3 wk of experimentation. A number of isolated hearts were perfused in the working mode, subjected to regional or global ischaemia‐reperfusion; others were nonperfused. Metabolic parameters, myocardial infarct sizes (IFS), baseline and postischaemic activation of PKB/Akt, ERK42/44, GSK‐3β and STAT‐3 were determined. Diet‐induced obesity caused increases in body weight gain, visceral adiposity, fasting blood glucose, serum insulin and triglyceride (TG) levels with a concomitant cardiac hypertrophy, large postischaemic myocardial IFSs and a reduced cardiac output. Melatonin treatment (3 and 6 wk) decreased serum insulin levels and the HOMA index (P < 0.05) with no effect on weight gain (after 3 wk), visceral adiposity, serum TG and glucose levels. It increased serum adiponectin levels, reduced myocardial IFSs in both groups and activated baseline myocardial STAT‐3 and PKB/Akt, ERK42/44 and GSK‐3β during reperfusion. Overall, short‐term melatonin administration to obese/insulin resistant rats reduced insulin resistance and protected the heart against ex vivo myocardial IRI independently of body weight change and visceral adiposity.     

The effects of insulin and short-term hyperglycaemia on myocardial blood flow in young men with uncomplicated Type I diabetes

AIMS/HYPOTHESIS: Insulin enhances coronary vasodilation in healthy subjects. We tested whether insulin is able to induce coronary vasodilation in Type I (insulin-dependent) diabetic mellitus patients. Additionally, the effect of short-term hyperglycaemia on myocardial perfusion was studied. METHODS: Myocardial blood flow was quantitated basally and during adenosine infusion (140 microg/kg per min i.v.) with or without simultaneous insulin infusion (1 mU/kg per min for 60 min) in nine non-smoking Type I diabetic males (HbA(1c) 7.4+/-1.0%) without diabetic complications and 10 healthy non-diabetic otherwise matched males using positron emission tomography and (15)O-water. Diabetic patients were studied on two occasions, once during normoglycaemia (plasma glucose ~6 mmol/l) and once during hyperglycaemia (approximately 10 mmol/l) induced by reducing the dose of insulin for two days. RESULTS: Resting myocardial blood flow was similar in the studied groups (NS). Hyperaemic adenosine stimulated flow was 23% lower in diabetic than in non-diabetic subjects (3.09+/-0.72 vs 4.0+/-1.13 ml x g(-1) x min(-1), p<0.05). Insulin increased significantly adenosine stimulated flow by 23% in diabetic and 17% in non-diabetic subjects (NS between the groups). Hyperglycaemia for two days had no effect on flow values when compared to the values during normoglycaemia (NS). CONCLUSION/INTERPRETATION: Insulin has similar vasodilative effects on coronary arteries in diabetic and non-diabetic subjects. Short-term hyperglycaemia does not alter myocardial blood flow or abolish insulin induced vasodilation in these patients. Insulin induced coronary vasodilation might contribute to the known beneficial effect of intensive insulin therapy on myocardial ischaemia in diabetic patients.     

间歇低氧大鼠肝细胞GLUT-2、GCK表达与胰岛素抵抗的相关性研究

目的 检测葡萄糖转运蛋白-2(GLUT-2)、葡萄糖激酶(GCK)在间歇低氧大鼠模型肝细胞中表达的变化,探讨间歇低氧引起胰岛素抵抗的相关机制.方法 24只6周龄健康雄性SpragueDawley(SD)大鼠按照随机数字表法分为对照组、间歇低氧4周组(IH4组)和间歇低氧8周组(IH8组),每组8只.间歇低氧组按预设通气模式每天给予间歇低氧暴露8h,对照组给予间歇压缩空气,暴露时间同IH4组.实验结束后测定各组大鼠空腹血糖、空腹胰岛素,计算稳态模型评估-胰岛素抵抗指数(HOMA-IR)及胰岛素敏感性指数(ISI).免疫组织化学染色观察肝细胞GLUT-2、GCK蛋白表达变化,并利用平均灰度值对蛋白进行定量分析.结果 与对照组相比,IH4组及IH8组空腹血糖、空腹胰岛素、HOMA-IR均升高,ISI均降低,且IH8组更明显(F=161.92、51.46、126.99、83.87,P均＜0.05).与对照组相比,IH4组及I-H8组肝细胞GLUT-2、GCK蛋白表达均降低,且IH8组更显著(F=184.91、240.85,P均＜0.05).Pearson相关分析显示,GLUT-2、GCK平均灰度值与ISI呈负相关(r=-0.886、-0.906,P均＜0.05),与HOMA-tR呈正相关(r=0.894、0.869,P均＜0.05).结论 间歇低氧暴露使大鼠肝细胞GLUT-2、GCK蛋白表达下调,可能参与间歇低氧条件下胰岛素抵抗的发生.     

Obesity is associated with impaired endothelial function in the postprandial state

Adequate microvascular perfusion is essential for the regulation of tissue metabolism. Therefore, defects in microvascular function may play a role in obesity-associated insulin resistance. Steady-state hyperinsulinemia during a euglycemic hyperinsulinemic clamp stimulates endothelium-dependent vasodilation and capillary recruitment, which contribute to increased glucose uptake. These phenomena have been shown to be blunted in obesity. If insulin's effects on microcirculatory function indeed play a physiological role in regulating insulin-mediated glucose uptake, such effects should be demonstrable not only during steady-state hyperinsulinemia, but also after meal ingestion. We investigated whether similar responses occur after ingestion of a glucose load or a mixed meal. We examined the effects of a glucose drink, a mixed meal drink, or a control drink (water) on skin capillary density (i.e. baseline capillary density, hyperemic capillary recruitment, and density during venous congestion, using capillaroscopy) and skin endothelium-(in)dependent vasodilation (using laser-Doppler flowmetry with iontophoresis of acetylcholine and sodium nitroprusside) in 20 lean and 19 obese individuals. In lean individuals, neither the glucose nor the mixed meal drink induced a significant effect on capillary density or endothelium-(in)dependent vasodilation. Possibly this is related to the modest plasma insulin levels as compared to the insulin clamp. In obese individuals, the mixed meal drink, compared to the control drink, decreased baseline skin perfusion (P < 0.05) and acetylcholine-mediated vasodilation (P < 0.05), while no effect of the drinks on capillary density was found. Compared to lean individuals, obese individuals had impaired acetylcholine-mediated vasodilation after meal ingestion (P = 0.02). The latter findings are consistent with impaired postprandial microvascular function in obesity.     

Melatonin improves metabolic syndrome induced by high fructose intake in rats

Abstract: In this study, we examined whether melatonin improves metabolic syndrome induced by high fructose intake in male Wistar rats. Feeding of a diet containing 60% fructose (HFD) for 4 or 6 wk caused increased serum insulin, triglyceride, total cholesterol, free fatty acids, uric acid, leptin, and lipid peroxide concentrations as well as hepatic triglyceride and cholesterol concentrations, and relative intra‐abdominal fat and liver weights. The 4‐ or 6‐wk HFD feeding reduced serum high‐density lipoprotein cholesterol and adiponectin concentrations. The 6‐wk HFD feeding increased serum tumor necrosis factor‐α concentration and hepatic lipid peroxide concentration and lowered hepatic reduced glutathione concentration. Daily intraperitoneal administration of melatonin (1 or 10 mg/kg body weight), starting at 4‐wk HFD feeding, attenuated these changes at 6‐wk HFD feeding more effectively at its higher dose than at its lower dose. In an oral glucose tolerance test, rats with 4‐ or 6‐wk HFD feeding showed higher serum insulin response curve and normal serum glucose response curve when compared with the corresponding animals that received the control diet. The 4‐ or 6‐wk HFD feeding caused insulin resistance, judging from the scores of HOMR‐IR and QUICKI, which are indices of insulin resistance. The daily administered melatonin (1 or 10 mg/kg body weight) ameliorated the higher serum insulin response curve in the oral glucose tolerance test and insulin resistance at 6‐wk HFD feeding more effectively at its higher dose than at its lower dose. These results indicate that melatonin improves metabolic syndrome induced by high fructose intake in rats.     

Long‐term enteral administration of melatonin reduces plasma insulin and increases expression of pineal insulin receptors in both Wistar and type 2‐diabetic Goto‐Kakizaki rats

Abstract: This paper represents an essential aspect of recent investigations into the functional and clinical implications of insulin–melatonin interrelationships. The aim of the study was to analyze whether melatonin reduces insulin secretion in an animal in a manner comparable to the pattern observed in previous in vitro experiments; to this end, we used two models: Wistar and type 2‐diabetic Goto‐Kakizaki (GK) rats. Thirty‐two Wistar and 32 GK rats were divided into two subgroups of 16 rats each; each subgroup was treated either with or without melatonin. The daily administration of melatonin, starting in 8‐ wk‐old rats, was adjusted to 2.5 mg/kg body weight. Melatonin was given daily during the dark period for 12 hr. After 9 wk of treatment, the rats were sacrificed in the middle of the dark period. Melatonin administration strongly enhanced the plasma melatonin level and diminished the expression of pancreatic melatonin receptor‐mRNA, whereas the expression of pineal AA‐NAT and HIOMT was unchanged. Furthermore, the experiments showed in agreement with recent in vitro results of pancreatic islets that plasma insulin levels were diminished after melatonin treatment. However, the pineal insulin receptor expression was increased after melatonin administration. The pancreatic expression of glucagon, GLUT2, and glucokinase was decreased in GK rats, whereas the glucose levels, as well as the parameters of glucose sensing, GLUT2‐mRNA, and glucokinase‐mRNA, were unchanged after melatonin administration in both Wistar and GK rats. In summary, the results show that melatonin administration decreases plasma insulin levels in vivo and, furthermore, that an insulin–melatonin antagonism exists.     

Melatonin improves oxidative stress parameters measured in the blood of elderly type 2 diabetic patients

Abstract: An elevated oxidative status in the aging organism may be involved in the development of non‐insulin dependent diabetes mellitus (NIDDM). Melatonin, a potent antioxidant agent, is essential for glucose homeostasis and regulation. The aim of this study was to determine the influence of melatonin supplementation on the oxidative stress parameters in elderly NIDDM patients. The malondialdehyde (MDA) concentration, Cu‐Zn superoxide dismutase (SOD‐1) activity in erythrocytes, the level of nitrate/nitrite in plasma and morning melatonin concentration and oxidase activity of ceruloplasmin (Cp) in serum in 15 elderly NIDDM patients at baseline and after the 30 days of melatonin supplementation (5 mg daily) in comparison with levels in 15 healthy elderly volunteers were determined. A significant increase of MDA level and decrease of SOD‐1 activity and melatonin concentration were observed in NIDDM patients. Cp oxidase activity and nitrate/nitrite level were similar in both examined groups. Melatonin administration in NIDDM patients resulted in a significant increase in the morning melatonin concentration and SOD‐1 activity, and a reduction in the MDA level and Cp oxidase activity. Statistically significant alterations in nitrate/nitrite levels were not observed. These results indicate an improvement of antioxidative defense after melatonin supplementation in the NIDDM individuals and suggest melatonin supplementation as an additional treatment for the control of diabetic complications.     

Obesity is associated with impaired endothelial function in the postprandial state

Adequate microvascular perfusion is essential for the regulation of tissue metabolism. Therefore, defects in microvascular function may play a role in obesity-associated insulin resistance. Steady-state hyperinsulinemia during a euglycemic hyperinsulinemic clamp stimulates endothelium-dependent vasodilation and capillary recruitment, which contribute to increased glucose uptake. These phenomena have been shown to be blunted in obesity. If insulin's effects on microcirculatory function indeed play a physiological role in regulating insulin-mediated glucose uptake, such effects should be demonstrable not only during steady-state hyperinsulinemia, but also after meal ingestion. We investigated whether similar responses occur after ingestion of a glucose load or a mixed meal. We examined the effects of a glucose drink, a mixed meal drink, or a control drink (water) on skin capillary density (i.e. baseline capillary density, hyperemic capillary recruitment, and density during venous congestion, using capillaroscopy) and skin endothelium-(in)dependent vasodilation (using laser-Doppler flowmetry with iontophoresis of acetylcholine and sodium nitroprusside) in 20 lean and 19 obese individuals. In lean individuals, neither the glucose nor the mixed meal drink induced a significant effect on capillary density or endothelium-(in)dependent vasodilation. Possibly this is related to the modest plasma insulin levels as compared to the insulin clamp. In obese individuals, the mixed meal drink, compared to the control drink, decreased baseline skin perfusion (P < 0.05) and acetylcholine-mediated vasodilation (P < 0.05), while no effect of the drinks on capillary density was found. Compared to lean individuals, obese individuals had impaired acetylcholine-mediated vasodilation after meal ingestion (P = 0.02). The latter findings are consistent with impaired postprandial microvascular function in obesity.     

Circulating vascular endothelial growth factor is unaffected by acute hyperglycemia and hyperinsulinemia in type 1 diabetes mellitus

BACKGROUND: Circulating levels of vascular endothelial growth factor (VEGF) may predict microvascular complications in type 1 diabetes mellitus and are elevated when metabolic control is poor. We tested whether serum VEGF is influenced by prevailing glucose and insulin levels. METHODS: In 15 type 1 diabetic patients, serum VEGF, plasma von Willebrand factor antigen (vWF-Ag), and serum soluble intercellular adhesion molecule-1 (s-ICAM) levels were measured after 210 min of hyperglycemia (blood glucose target 12.0 mmol/l) and hyperinsulinemia (insulin infused at 120 mU/kg/h), alone and in combination. These were then compared with the levels obtained at the end of a 210-min normoglycemic (blood glucose target 5.0 mmol/l) standard insulin clamp (insulin infused at 30 mU/kg/h). RESULTS: VEGF (p>0.60) as well as vWF-AG (p>0.80) and s-ICAM (p>0.20) remained unchanged at the end of the three intervention periods. CONCLUSION: These findings suggest that no special precautions, in terms of concurrent measurement of glucose or timing of insulin administration, are necessary when interpreting circulating VEGF in this patient category.     

Dual effect of melatonin as proinflammatory and antioxidant in collagen-induced arthritis in rats

Abstract:  The aim of this study was to determine the effects of melatonin on proinflammatory status of rats with collagen-induced arthritis (CIA). CIA was induced in male Wistar rats with an emulsion of type II collagen in Freund's Incomplete Adjuvant (C-II/FIA). For 14 days, control and pinealectomized rats received a subcutaneous injection of 100  μ L melatonin (30  μ g) or vehicle (saline on 1% ethanol). Levels of cytokines interleukin (IL)-1 β and IL-6 were determined in the serum, peripheral blood mononuclear cells, and joints. Levels of anti-type II collagen antibody, nitrite/nitrate, and lipid peroxidation (LPO) were determined in the serum, joints, and brain. Treatment with melatonin significantly increased the levels of IL-1 β , IL-6, nitrite/nitrate and LPO in joints. However, melatonin significantly reduced the levels of nitrite/nitrate and LPO in serum and brain. Moreover, CIA in pinealectomized rats presented significantly reduced levels of IL-1 β and IL-6, titers of anti-type II collagen antibodies, levels of nitrite/nitrate, and LPO in joints but elevated levels in serum and brain. Melatonin has been described as a proinflammatory and antioxidant agent. In a process of inflammation as CIA, melatonin acts with a markedly proinflammatory effect at local and peripheral levels maintaining its antioxidant effect only at peripheral level.     

The investigation of insulin resistance in patients with idiopathic hirsutism

Hirsutism, which is characterized by excessive growth of terminal hair in a male pattern, is a common clinical condition in women. It may result from various causes including polycystic ovary syndrome, nonclassic adrenal hyperplasia, adrenal or ovarian tumors, or it may be idiopathic. Idiopathic hirsutism (IH) is considered to be one of the most common forms of hirsutism. Although not universal, insulin resistance and hyperinsulinemia have been demonstrated in women with polycystic ovary syndrome. Because there are not enough data showing whether patients with IH also have insulin resistance, we intended to investigate the presence/absence of insulin resistance in women with IH. Thirty-two women with IH [mean age, 24.8 +/- 1.2 yr; body mass index (BMI), 24.6 +/- 0.8 kg/m2] and 17 healthy women (mean age, 25.8 +/- 0.6 yr; BMI, 22.5 +/- 0.6 kg/m2) were included in the study. Eight of 32 patients with IH had BMI higher than 30 kg/m2. The presence of insulin resistance was investigated by using basal insulin levels, the oral glucose tolerance test, the i.v. insulin tolerance test, and the homeostasis model assessment (HOMA) score in both groups. Six (18.7%) patients had impaired glucose tolerance (IGT). Overall, patients with IH had significantly (P < 0.05) higher basal insulin levels (10.5 +/- 1.1 mU/liter vs. 5.7 +/- 0.9 mU/liter) and HOMA scores (2.0 +/- 0.2 vs. 1.1 +/- 0.2) and lower plasma glucose disappearance rate values (5.2 +/- 0.2 vs. 6.0 +/- 0.3) than control subjects. However, patients with IGT were notably more obese than the patients with a normal glucose tolerance test. Analyses after omitting the patients with IGT showed that there was still a significant (P < 0.05) difference in terms of basal insulin levels and HOMA scores. Six of eight (75%) obese patients with IH showed IGT. These data suggest that IH is associated with insulin resistance and an increased prevalence of IGT in obese patients.