The effect of vanadyl treatment on vascular responsiveness of streptozotocin-diabetic rats

Summary Vanadyl sulphate has been demonstrated to possess insulin-like effects in streptozotocin (STZ) diabetic rats, including the normalization of hyperglycaemia and the prevention of diabetes-induced cardiac dysfunction. However, the effectiveness of vanadyl sulphate on diabetes-related vascular aberrations has not been questioned. Hence, in the present work, we have specifically addressed the question of whether chronic oral vanadyl sulphate treatment has any beneficial effect on diabetes-induced changes in vascular reactivity. Male albino rats were injected with a single intravenous dose of STZ (55 mg/kg). Vanadyl sulphate was administered in the drinking water at a concentration of 1 mg/ml from 7 days after the STZ injection and treatment was maintained for 10 weeks. Vanadyl intake was accompanied by decreased blood glucose and serum insulin levels. The effects of diabetes on vascular smooth muscle function were assessed by the responsiveness of aortae to noradrenaline and KCl. Contractile responses of the diabetic aortae were found to be significantly increased as compared with controls. However, there were no significant differences in pD₂ values of the agonists in either of the groups. Treatment of diabetic rats with vanadyl sulphate completely prevented the increases in responsiveness of aortae to noradrenaline and KCl. The effect of diabetes on the fast and slow components of noradrenaline-induced contraction was also examined. Both components of the response to noradrenaline were significantly increased in diabetic aortae. These changes were also prevented by vanadyl sulphate treatment. The data demonstrate that 10-week vanadyl sulphate treatment results in improved vascular reactivity of diabetic rats.Abbrevations STZ streptozotocin - VST vanadyl sulphate trihydrate     

Effect of exercise-training on the metabolic manifestations of streptozotocin-induced diabetes in the rat

Summary Streptozotocin-induced insulin deficiency of a moderate degree was produced in exercise-trained and sedentary young rats, and determinations made of subsequent changes in plasma glucose, triglyceride, and insulin concentrations. Exercise-training attenuated the rise in both plasma glucose and triglyceride concentrations associated with insulin deficiency. Plasma insulin levels were, if anything, lower in exercise-trained rats. Thus, the beneficial effects of exercise-training on plasma glucose and triglyceride concentrations could not be due to the preservation of endogenous insulin secretion, and appear to be secondary to enhanced insulin sensitivity.     

蜕皮甾酮对2型糖尿病大鼠肝细胞IR S-2蛋白表达的影响

目的：探讨蜕皮甾酮对2型糖尿病大鼠肝细胞胰岛素受体底物2（ IRS-2）蛋白表达的影响。方法选择42只大鼠,14只作为正常组,常规饲料喂养,余下28只先以高脂喂养加小剂量STZ注射诱导2型糖尿病大鼠模型,造模成功后,随机分为模型组和治疗组,分别给予高脂饲料喂养、高脂饲料喂养＋蜕皮甾酮灌胃治疗。5周后取大鼠肝组织标本,应用免疫组化和RT-PCR技术检测IRS-2蛋白和mRNA含量。结果正常组和治疗组肝细胞IRS-2蛋白及mRNA含量均明显高于模型组（ P＜0．05或＜0．01）。结论蜕皮甾酮可提高2型糖尿病大鼠肝细胞IRS-2蛋白和mRNA含量,这可能是蜕皮甾酮改善2型糖尿病大鼠胰岛素抵抗的机制之一。     

Impaired insulin binding to isolated adipocytes in experimental diabetic ketoacidosis

Summary Insulin sensitivity in vivo and insulin binding in vitro to adipocytes have been studied in streptozotocin diabetic rats with ketoacidosis. Insulin sensitivity in vivo measured as the acute (20 min) fall in blood glucose in response to an insulin infusion of 1 U/kg body weight per hour correlated positively with arterial blood pH (r=0.92, p < 0.01: n=38). At pH < 6.9 there was no fall in blood glucose. For studies of insulin binding to adipocytes ketoacidotic animals were divided into a group with moderate ketoacidosis (pH > 7.0) and a second group with severe ketoacidosis (pH < 6.9). Insulin binding to adipocytes was maximal in cells from both ketoacidotic and from normal rats at pH 7.6–7.8. Total binding was decreased in the diabetic rats (p < 0.01) and this was more marked in the severely diabetic group (p < 0.001) at all pHs studied. At pH 7.4, ¹²⁵I-insulin binding was decreased in diabetics compared with normal rats (0.89±0.14 versus 2.0±0.24% with 2×10⁵ cells/ml: n=6; p < 0.01) and also in the severe compared with the moderate ketoacidotic rats (0.5± 0.08%/2×10⁵ cells; n=6, p < 0.05). Equilibrium binding studies showed that there was a small decrease in apparent affinity in adipocytes from both groups of diabetics (K_D = 2.8±0.2×10^-9 mol/l, n =6 in moderate ketoacidosis; 2.5±0.3×10^-9 mol/l, n=6 in severe ketoacidosis) compared with control animals (K_D = 1.8±0.15×10^-9 mol/l, n= 6). Scatchard analysis revealed that there was also a decrease in receptor concentration which was greater in the severely ketoacidotic group. These findings may explain in part the insulin resistance of severe ketoacidosis.     

Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with Type 1 diabetes.

AIMS: To compare quality of life (QoL) and treatment satisfaction in patients with Type 1 diabetes receiving the rapid-acting insulin analogue, insulin aspart (IAsp), with that in patients receiving soluble human insulin (HI). METHODS: In this 6-month, multinational, randomized, open-label trial, 424 patients from German-speaking countries were subjected to psychometric assessment before and after randomization (ratio 2 : 1) to basal-bolus treatment with either IAsp (n = 283) or HI (n = 141). Patients on HI were advised to keep an injection-meal interval of 30 min, whereas patients on IAsp were advised to inject immediately before meals. Treatment satisfaction and diabetes-related QoL were assessed using validated instruments to measure the domains of patients' individual treatment goals, physical complaints, worries about the future, social relations, leisure time flexibility, daily hassles, diet restrictions, burdens and fear of hypoglycaemia, blood glucose fluctuations, self-efficacy, and fear of insulin analogues. RESULTS: After 6 months, IAsp was associated with significantly greater improvement in treatment satisfaction than HI in two different scales (P < 0.01), and in QoL with respect to diet restrictions (P < 0.01). Improved satisfaction was mainly due to increased dietary and leisure time flexibility (P < 0.0001). Twenty-three percent of the IAsp group vs. 14% of the HI group achieved small but important improvements of total QoL (between-group difference, P < 0.06). The number needed to treat (NNT) with IAsp for an important increase in QoL was calculated to be 10. Regression analyses of potential predictors of improvement in QoL highlighted patients intensely striving for physical strength (P < 0.01; NNT = 7) and patients feeling less protected against hypoglycaemia (P < 0.005; NNT = 8) as being the most likely to benefit from IAsp. CONCLUSIONS: Under these study conditions, IAsp improved treatment satisfaction and quality of life regarding diet restrictions when compared with human insulin. The 'numbers needed to treat' for important quality of life benefits indicate that the effect of IAsp in this regard is not trivial.     

Prevention of diabetic glomerulopathy in streptozotocin diabetic rats by insulin treatment

Summary A quantitative morphological study of the mesangial regions has been performed on the kidneys of two groups of insulin treated diabetic rats 6 months after the induction of diabetes. In one group reasonably good control of plasma glucose levels (182±20 (SD) mg/l00ml at 0800 h; 95±35 mg/100 ml at 2300 h) was achieved. This group showed no mesangial changes when compared to a non-diabetic control group. In the second diabetic group poor control was intended (plasma glucose 452±41mg/100 ml and 555±86mg/100 ml respectively). The following differences were noted when this group was compared to the non-diabetic controls and to the rats in which the blood glucose was well-controlled: 1. Increase in total mesangial volume per glomerulus by 42% and 38% (2p = 0.025 and 0.037); 2. Increase in the total amount of basement membrane-like material (BMLM) per glomerulus by 30 and 27% (2p = 0.030 and 0.046); 3. Increase in the total mesangial cell volume per glomerulus by 46 and 43% (2p = 0.033 and 0.048); 4. Increase in volume of electron dense material in the BMLM by about 200% compared to both groups (2p = 0.001 and 0.0003). The study has shown that the mesangial regions also are involved in the diabetic glomerulopathy of experimental diabetes. The morphological changes including increased amounts of basement membrane material are prevented by proper glycaemic control.     

Decreased capacity to inhibit platelet hyperactivity and to stabilize prostacyclin of high-density lipoproteins in experimental diabetes

Twenty-eight male Sprague Dawley rats were divided into two groups: a control group (C) of 15 animals and a streptozotocin-induced diabetes group mildly balanced by insulin (D) of 13 animals. After 15 weeks, plasma and high-density lipoprotein (HDL) lipids were determined in each group. Apoprotein A-I concentration was evaluated in HDL fractions. The capacity of the HDL fraction to inhibit thrombin and ADP-induced aggregation of normal platelets was determined for each rat, and in an additional experiment the relation dose-effect of HDL was established. The effect of HDL of the two groups on the stabilization of prostacyclin was compared by aggregation bioassay. After 15 weeks, HDL cholesterol (free+esterified) tended to increase in group D compared with group C (P<0.08). By contrast, apoprotein A-I was very significantly decreased in HDL-D compared with HDL-C (P<0.001). These alterations were accompanied by a significantly decreased capacity of HDL (60 g/ml platelet suspension) to inhibit ADP-induced aggregation (P<0.0001) in group D compared with group C. Furthermore, HDL-D incubated 45 or 90 min with prostacyclin showed a significantly decreased capacity to stabilize prostacyclin compared with HDL-C (P<0.04;P<0.03, respectively). These alterations in HDL could be involved in thrombosis and atheromatous complications associated with this disease.     

Increase in circulating basement membrane antigens in diabetic rats and effects of insulin treatment

Summary The serum concentrations of two recently discovered antigens derived from basement membranes (7-S collagen and laminin P2) were assayed in streptozotocin-diabetic rats as possible indicators of basement membrane metabolism. The concentrations of both increased significantly after 8 weeks of diabetes, and that of 7-S collagen at least remained elevated up to 24 weeks. Treatment with insulin, which did not correct the metabolic disturbances, inhibited the increase in the concentration of 7-S collagen in serum, but did not completely normalize that of laminin P2.     

短期强化胰岛素治疗对高血糖毒性作用的影响

本试验对41例空腹血糖≥15mmol／L，餐后血糖≥16．8mmol／L的2型糖尿病患者进行短期胰岛素强化治疗(IIT)，治疗前后行糖负荷试验，并以放免法测胰岛素原、C肽。结果表明IIT降低空腹及餐后胰岛素原水平，改善β细胞功能。     

Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment

Summary The changes in insulin response to a 100 g glucose tolerance test after treatment by diet, sulphonylurea and insulin were compared in non-ketotic diabetic patients who had fasting blood glucose concentrations higher than 160 mg/100 ml. Patients were selected so that their pre-treatment and post-treatment blood glucose levels were comparable between different treatment groups. Their insulin responses were poor initially but increased significantly when the diabetic state was improved by each treatment. The degree of improvement of insulin response was similar between different treatment groups, when their fasting blood glucose decreased below 140 mg/100 ml and the glucose tolerance curves were improved to a similar extent. Preand post-treatment IRI values (sum of insulin values during glucose tolerance test, mean±SD) were 102±50 and 200±37 U/ml in diet-treated group (n = 28), 90±40 and 195±53 U/ml in sulphonylurea-treated-group (n=48), and 83±28 and 193±38 U/ml in insulin-treated group (n = 13), respectively. The data suggest that the poor insulin response in overt diabetes results not only from an inherent insensitivity of B-cells to glucose but also from the metabolic derangement of diabetes. Poor insulin response and overtly diabetic metabolism seems to form a vicious cycle.     

Peripheral nerves in early experimental diabetes

Summary The aim of the present study was to examine whether the nerve water content and the Schwann cell cytoplasm are increased in early experimental diabetes, as suggested in the sorbitol theory. The sciatic nerves of streptozotocin diabetic rats were found to have an increased wet weight. The amount of Schwann cell cytoplasm was reduced by 30%. The increased wet weight was paralleled by enlargement of the cross sectional area of the nerve which was explained by an expansion of the endoneurial space. The findings indicate the existence of endoneurial oedema and are in part in conflict with the sorbitol theory. Extension of the space surrounding the nerve fibres may explain the increased resistance to ischaemia in diabetic patients.     

Influence of glucose,insulin and sera from diabetic patients on the prostacyclin synthesis in vitro in cultured human endothelial cells

Summary The effects of glucose, insulin and sera from Type 1 (insulin-dependent) diabetic patients on the synthesis of prostacyclin in vitro were studied in confluent primary cultures of human endothelial cells. The stable metabolite, 6-keto-prostaglandin F₁, was measured in growth medium after 24 h of incubation with endothelial cells in a buffer incubated with the cells for 10 min on a rocker platform, and in a buffer solution of ruptured cells. Glucose (11, 15, 20 or 25 mmol/l) and glucose (11 mmol/l) plus insulin (10³, 10⁴ or 10⁶ mU/l) in growth medium did not have any effects on the prostacyclin synthesis. The prostacyclin synthesis was significantly reduced in cell cultures incubated with medium supplemented with 10% serum from patients with Type 1 diabetes (p<0.01) compared with cultures incubated with pooled serum from healthy blood donors. These data suggest that diabetic sera inhibit the prostacyclin synthesis in cultured endothelial cells unrelated to the glucose and insulin levels.     

Use of a prostacyclin analogue in cholesterol crystal embolism

The prognosis of cholesterol embolism is often poor, and no treatment is presently available. We report the use of a stable prostacyclin analogue in treating cholesterol embolism in a diabetic patient with arteriopathy. As a sole therapy, it improved cutaneous manifestations and pain, in parallel with an increased transcutaneous oxymetry. We think that prostacyclin analogues are novel candidates for the treatment of cholesterol embolism. © 1998 John Wiley & Sons, Ltd.     

慢性应激和增龄对糖尿病易感小鼠胰岛素敏感性的影响

目的研究慢性应激和增龄对小剂量链脲佐菌素诱导的糖尿病易感小鼠胰岛素敏感性的影响,并从胰岛素受体水平探讨其机理。方法取15月龄(幼年)、15月龄(成年)和20月龄(老年)昆明小鼠,用小剂量链脲佐菌素多次腹腔内注射,诱导其糖尿病易感状态后,分为应激组和对照组共6组,各20只。应激组分别给予6周实验性应激源刺激(限制、旋转、拥挤),检测空腹血糖(FBG)和空腹胰岛素(FINS)水平,计算胰岛素敏感指数(ISI),用Scatchard图分析肝细胞膜胰岛素受体高、低和平均亲和常数(K1、K2和K),高、低亲和力(R1、R2),以及每mg膜蛋白胰岛素受体数目(R),用ELISA方法测定10-7mol/L胰岛素刺激的肝细胞磷酸化胰岛素受体数(PINSR)。结果经6周实验性应激,FBG水平随增龄增高,幼年组(103±62)mol/L,成年组(152±36)mol/L,老年组(189±29)mol/L(P<005);FINS水平随增龄下降,幼年组(20±6)mIU/L,成年组(13±5)mIU/L,老年组(10±7)mIU/L(P<005);应激组ISI分别较同龄对照组降低〔幼年组(-51±07)对(-46±06),成年(-50±04)对(-48±08),老年组(-56±09)对(-45±12),P<005〕;成年和老年应激组肝细胞膜R1、R2和R均较同龄对照组上升,且老年应激组较成年应激组明显升高(P均<005);各应激组PINSR均较同龄对照组下降,老年应激组下降更明显,幼年组13±     

Prevention of weight gain in type 2 diabetes requiring insulin treatment

Background: Patients with type 2 diabetes who are failing on oral agents will generally gain a large amount of body fat when switched to insulin treatment. This adverse effect may be related to chronic hyperinsulinism induced by long-acting insulin compounds.
Aim: To test the concept that regain of glycaemic control can be achieved without causing weight gain, using a regimen free of long-acting insulin.
Methods: In a 3-month open-label pilot study including 25 patients with moderate overweight and secondary failure, we investigated whether nocturnal glycaemic control could be achieved with glimepiride administered at 20:00 hours. The starting dose was 1–2 mg, with subsequent titration up to a maximum of 6 mg. Rapid-acting insulin analogues were used three times daily to regain postprandial glucose control.
Results: Glycaemic control at 3 months was established with glimepiride in a dose of 4.4 ± 0.3 mg/day (mean ± standard error of the mean), and a total daily insulin dose of 24.1 ± 2.6 IU. Fasting glucose levels decreased from 12.7 ± 0.6 mmol/l to 8.1 ± 0.3 mmol/l (p  <  0.001), and target levels were reached in 14 of 25 patients (56%). Mean HbA1c decreased from 10.5 ± 0.4 to 7.7 ± 0.2% (p  <  0.001). Symptomatic nocturnal hypoglycaemia was not reported. Body weight did not change (85.7 ± 3.6 kg vs. 85.7 ± 3.3 kg, p = 0.99).
Conclusion: The data suggest that this new approach may be useful in about 50% of type 2 diabetes patients presenting with failure on maximal oral treatment.     

Prevention of diabetic glomerulopathy in streptozotocin diabetic rats by insulin treatment

Summary A single antibody radioimmunoassay has been used to measure albumin excretion in 3 groups of female Wistar rats. Two groups had Streptozotocin diabetes and were treated daily with insulin for 6 months. In one of the diabetic groups good glycaemic control was attempted and throughout the 6 months plasma glucose levels were fairly close to normal (92 ± 33 mg/100 ml at 2300 h and 186 ± 9 mg/100 ml at 0800 h). In the other diabetic group poor control was intended and the group had consistent high plasma glucose levels (576 ± 89 mg/100 ml and 460 ± 43 mg/100 ml). The third group was a non-diabetic control group. — Albumin excretion was measured on two occasions: before the induction of diabetes and after 6 months of diabetes. The geometric mean albumin excretion increased from 0.38 to 2.56 mg/24 h in the 18 non-diabetic controls. In the 20 diabetic rats in good control the geometric mean albumin excretion increased from 0.37 to 1.58 mg/ 24 h (NS compared with controls) and in the group of 22 rats in poor control albumin excretion increased from 0.35 to 6.54 mg/24 h. — The increase in albumin excretion in rats in poor control differed significantly both from that of the non-diabetic controls (2p = 0.023) and from that of the well-controlled diabetic rats (2p = 0.00011).     

老年早期糖尿病性心肌病变患者血糖强化治疗前后氧化应激水平的变化

目的评价老年早期糖尿病性心肌病（DCM）患者胰岛素泵强化治疗前后氧化应激水平的变化。方法对2009年2月至2011年10月确诊的30例老年早期DCM患者采用胰岛素泵强化治疗,治疗达标前后分别测定超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH．PX）、丙二醛（MDA）水平,进行比较。结果胰岛素泵强化治疗后,患者血浆中的SOD[（118．40±25．41）VS（171．16±27．76）U／ml]和GsH-PX[（120．53±46．26）vs（175．58±52．37）u]明显上升（P〈0．01）,MDA明显下降[（49．53±14．42）vs（22．65±12．54）nmol／ml,P〈0．01]。空腹血糖[（5．64±0．53）vs（10．96±2．63）mmol／L]、餐后2小时血糖[（7．74±1．46）vs（18．50±3．24）mmol／L]、胰岛素抵抗指数[（2．50±1．12）vs（5．90±1．82）mmol／L]、总胆固醇[（4．40±0．45）．kS（8．44±0．90）mmol／L]、甘油三酯[（2．80±1．01）vs（6．84±1．83）mmoi／L]、低密度脂蛋白胆固醇[（3．01±0．73）vs（5．11±1．35）mmol／L]、游离脂肪酸[（0．34±0．11）vs（0．73±0．10）mmol／L]明显降低（P〈0．05）,胰岛素分泌功能指数明显上升[（73．32±12．20）vs（11．80±5．50）mmol／L,P〈0．05]。心脏舒张功能（E／A）明显改善[（0．74±0．35）vs（1．09±0．23）,P〈0．01]。结论老年早期DCM患者使用胰岛紊泵强化治疗可明显降低氧化应激水平,改善心脏舒张功能。     

Absence of effects of ketanserin on renal prostacyclin and thromboxane A2 in essential hypertension

The anti-hypertensive effect of ketanserin, a new antagonist of 5-HT2-serotonergic receptors, was evaluated in 10 patients with uncomplicated essential hypertension. At the end of 2 weeks of placebo wash-out and following 2 and 4 weeks of treatment with ketanserin (20 mg twice daily), blood pressure and heart rate were measured both in the supine and standing position. In addition, before and at the end of treatment, plasma renin activity (PRA), plasma concentration of aldosterone and the nocturnal urinary excretion of 6-keto-PGF1 alpha and TXB2, the two metabolites that largely reflect the renal synthesis of prostacyclin and thromboxane, respectively, were determined. The study was carried out in a metabolic ward where the intake of sodium was adjusted to 100-120 mmol day-1. Ketanserin significantly reduced blood pressure both in the supine and standing position with no significant change of heart rate. The treatment did not produce any variation of PRA, aldosterone, urinary excretion of 6-keto-PGF1 alpha or TXB2. These results indicate that ketanserin reduces blood pressure without interfering with the renin-angiotensin-aldosterone system or the renal synthesis of prostacyclin and thromboxane.