Long-term administration of highly purified eicosapentaenoic acid ethyl ester improves blood coagulation abnormalities and dysfunction of vascular endothelial cells in Otsuka Long-Evans Tokushima fatty rats

We investigated the effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E) on blood coagulation abnormalities and dysfunction of vascular endothelial cells in spontaneously diabetic Otsuka Long-Evans Tokushima Fatty rats. The animals were treated with either EPA-E or lard at a daily dose of 0.3 g/kg/day for 52 weeks by gavage, and their coagulation/fibrinolytic parameters, platelet aggregation, and functions of the vascular endothelial cells were examined. EPA-E significantly improved coagulation-related parameters including prothrombin time, activated partial thromboplastin time, fibrinogen level, and activities of factor II, V, VII, VIII, IX, X, XI, and XII, and antithrombin III, and fibrinolysis-related parameters including plasminogen, tissue-type plasminogen activator, alpha(2)-plasmin inhibitor, and plasminogen activator inhibitor. It also suppressed ADP- or collagen-induced platelet aggregation and the cholesterol/phospholipid molar ratio in platelet membranes at a dose of 0.3 g/kg. In addition, it significantly increased the migration activity of vascular endothelial cells, and decreased the binding of vascular endothelial cells to vascular endothelial growth factor. In contrast, lard had no effect on hypercoagulation, hypofibrinolysis, and platelet hyperaggregation but significantly aggravated the dysfunction of vascular endothelial cells. These data demonstrate that EPA-E beneficially altered certain factors known to promote thrombosis and atherosclerosis in this animal model.     

Long-term administration of highly purified eicosapentaenoic acid ethyl ester improves the dysfunction of vascular endothelial and smooth muscle cells in male WBN/Kob rats

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid, on the dysfunction of the endothelium and smooth muscle cells in male WBN/Kob rats, a model of spontaneous diabetes mellitus. After oral 8-month treatment with EPA-E, the agent significantly and dose-dependently increased the migration activity of vascular endothelial cells and also decreased 5-bromodeoxyuridine (BrdU) uptake by vascular smooth muscle cells at a dose of 0.1 g/kg or higher. In addition, there were significant correlations between the endothelial cell migration or smooth muscle cell proliferation and the 4-hour fasting glucose level. These findings suggest that EPA-E has a suppressive effect on thrombosis and atherosclerosis.     

Mechanism of the blunted glucagon response to insulin-induced hypoglycemia in diabetics

It has been widely reported that dysfunctions of pancreatic A-cell occur in diabetics. Since these pancreatic A-cell dysfunctions are not normalized by conventional insulin injection treatment, they were thought to be a primary defect of diabetes mellitus. Recently it was found that paradoxic glucagon secretion to oral glucose and excessive glucagon response to i.v. arginine could be perfectly normalized if strict blood glucose regulations were achieved with appropriate insulin treatment. However, there has been no report on the perfect normalization of glucagon secretion in response to insulin-induced hypoglycemia in diabetics. In this report, to elucidate the precise significance of A-cell function in hypoglycemia in diabetics, the effect of long-term strict glycemic regulations and the importance of intact autonomic nerve function on hypoglycemia-induced glucagon secretion were studied. In experiments on hypoglycemia-induced glucagon secretion in diabetics, 0.2 to 0.3 U/kg of regular insulin injection were usually employed to overcome the hyperglycemia and insulin resistance. However, hyperinsulinemia has been demonstrated to suppress A-cell function in experiments using the euglycemic clamp technique. Therefore, the effect of plasma insulin concentrations after insulin injections was first studied in 7 healthy volunteers by injecting insulin at doses of 0.1 U/kg and 0.3 U/kg. In this experiment with 0.3 U/kg of insulin, the rate of fall in glycemia and the nadir of blood glucose were made similar to that with 0.1 U/kg of insulin by using glucose clamp technique with artificial endocrine pancreas. The plasma glucagon response after 0.3 U/kg of insulin was significantly suppressed as compared to that after 0.1 U/kg of insulin. From these experiments, it was concluded that not only hypoglycemic stimuli but also plasma insulin concentrations are important factors for demonstrating significant glucagon secretion in response to insulin-induced hypoglycemia. Second, the effects of strict glycemic control and autonomic nerve function on hypoglycemia-induced glucagon secretion were studied. Regular insulin at a dose of 0.1 U/kg was injected in an i.v. bolus form into 21 insulin-dependent (IDDM) and 22 noninsulin-dependent (NIDDM) diabetics before and one to three months after strict glycemic control with multiple insulin injection therapy or continuous subcutaneous insulin infusion therapy. To reduce fasting blood glucose level and to obtain the same hypoglycemic stimuli, overnight insulin infusion at a basal dose was undertaken in IDDM who showed hyperglycemia before strict glycemic regulations.(ABSTRACT TRUNCATED AT 400 WORDS)     

Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans

RATIONALE: Acute lung injury and pneumonia are associated with pulmonary activation of coagulation and suppression of fibrinolysis, resulting in fibrin deposition in the lung. Activated protein C (APC) has systemic anticoagulant effects in patients with sepsis. OBJECTIVE: To determine the effect of systemic administration of recombinant human APC on endotoxin-induced hemostatic alterations in the bronchoalveolar space in humans. METHODS: Healthy humans received intravenous APC (24 microg/kg/hour; n = 8) or vehicle (n = 7); all subjects were administered saline in one lung subsegment and endotoxin (4 ng/kg) into the contralateral lung. Bronchoalveolar lavage was performed 16 hours after saline and endotoxin administration. MEASUREMENTS AND MAIN RESULTS: Endotoxin induced local activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes (1.9 +/- 0.1 ng/ml) and soluble tissue factor (15.0 +/- 0.6 pg/ml) in bronchoalveolar lavage fluid, which was inhibited by APC (1.4 +/- 0.1 ng/ml and 12.3 +/- 0.4 pg/ml, respectively; both p < 0.01). Concurrently, endotoxin suppressed fibrinolysis, as indicated by reduced bronchoalveolar levels of plasminogen activator activity accompanied by elevated levels of plasminogen activator inhibitor type I activity. APC diminished the rise in plasminogen activator inhibitor type I activity (from 3.9 +/- 0.1 to 3.0 +/- 0.2 ng/ml, p = 0.002), while not significantly influencing plasminogen activator activity levels. Endotoxin reduced bronchoalveolar protein C concentrations, which was prevented by APC. Protein C did not influence the endotoxin-induced rise in local soluble thrombomodulin levels. CONCLUSION: APC exerts an anticoagulant effect in the human lung challenged with endotoxin.     

Effects of mealtime insulin aspart and bedtime neutral protamine Hagedorn insulin on postprandial coagulation and fibrinolysis in patients with type 2 diabetes

Aim: Acute hyperglycaemia induces coagulation activation in diabetes patients. We hypothesized that rapid‐acting insulin has a beneficial postprandial effect on coagulation and fibrinolysis compared with intermediate‐acting insulin because of its ability to lower postprandial hyperglycaemia. Methods: This was tested in a parallel controlled study in well‐controlled patients with type 2 diabetes assigned to bedtime neutral protamine Hagedorn (NPH) insulin (n = 41) or mealtime insulin aspart (n = 37). They were served standard diabetic meals for breakfast (8:00 hours) and lunch (12:00 hours). Blood samples were collected at 7:40 hours (fasting), 9:30, 11:30, 13:30 and 15:30 hours and analysed for glucose, activated factor VII (FVIIa), D‐dimer, prothrombin fragment 1+2 (F1+2), tissue plasminogen activator antigen (t‐PA) and plasminogen activator inhibitor activity (PAI). Results: The postprandial glucose response differed significantly between insulin regimens with a postprandial increase on NPH insulin and a decrease on insulin aspart. There was a significant postprandial decrease in F1+2, PAI and t‐PA, and no changes in FVIIa and D‐dimer, on both insulin regimens, but with no differences between insulin treatment groups. Conclusions: The rapid‐acting insulin analogue aspart and the intermediate‐acting insulin NPH had similar postprandial effects on markers of coagulation activation and fibrinolysis despite different effects on postprandial glucose response.     

Hyperglycaemic siblings of Type II (non-insulin-dependent) diabetic patients have increased PAI-1, central obesity and insulin resistance compared with their paired normoglycaemic sibling

AIMS/HYPOTHESIS: First-degree relatives of Type II (non-insulin-dependent) diabetic patients in cross-sectional studies have increased insulin resistance, associated cardiovascular risk factors and abnormalities of fibrinolysis and coagulation. To minimise between-family genetic and environmental confounders, we investigated within-family relationships between early hyperglycaemia and risk factors. METHODS: Thirteen age and gender matched sibling pairs of Type II (non-insulin-dependent) diabetic patients, one hyperglycaemic, one normoglycaemic (fasting plasma glucose at screening 6.0-7.7 mmol.l(-1) and < 6.0 mmol.l(-1), respectively) were assessed for plasminogen activator inhibitor antigen (PAI-1), tissue plasminogen activator antigen (t-PA), fibrinogen, Factor VII and Factor VIII/von Willebrand factor antigen. Fasting lipid profiles, blood pressure and HOMA insulin sensitivity (%S) were also measured in siblings and in matched subjects without family history of diabetes. RESULTS: Hyperglycaemic and normoglycaemic siblings (7 female, 6 male) were aged, mean (SD) 56.8 (8.7) and 55.8 (8.4) years. Hyperglycaemic siblings had increased PAI-1 antigen, geometric mean (i.q.r.): 26.3 (15.1-45.6) vs 11.1 (2.1-23.3) ng/ml, p=0.0002, similar t-PA antigen, mean (SD) 9.5 (4.3) vs 7.4 (2.5) ng/ml, p=0.2 and fibrinogen 2.2 (0.3) vs 2.3 (0.6) g/l, p=0.5, and reduced %S 66.3 (30.5) vs 82.9 (25), p=0.04. PAI-1 correlated negatively with %S ( r=-0.55, p=0.005). No significant differences were found in blood pressure or fasting lipids. CONCLUSION/INTERPRETATION: A minor increase in plasma glucose in non-diabetic sibling pairs of Type II (non-insulin-dependent) diabetic patients was associated with reduced insulin sensitivity, increased central adiposity and a doubling of PAI-1 antigen concentration, suggesting impaired fibrinolysis. It is possible that this could contribute to increased cardiovascular risk in these subjects.     

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

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

C-peptide exerts antithrombotic effects that are repressed by insulin in normal and diabetic mice

Aims/hypothesis Diabetic macro- and microangiopathy are associated with a high risk of vascular complications. The diabetic patient exhibits a pathological coagulation state, with an increased synthesis of coagulation factors and plasminogen activator inhibitor 1 (PAI-1) as well as an enhanced aggregation of platelets. Previous studies have shown that C-peptide can reduce leucocyte-endothelial cell interaction and improve microvascular blood flow in patients with type 1 diabetes. In the present study, we examined in vivo whether C-peptide is able to reduce platelet activation and through that microvascular thrombus formation. Materials and methods In the microvessels of cremaster muscle preparations taken from normal and diabetic mice, ferric chloride-induced thrombus formation was analysed using intravital fluorescence microscopy. Results I.V. administration of C-peptide in high dose (70 nmol/kg), but not in low dose (7 nmol/kg), caused a significant delay in arteriolar and venular thrombus growth in normal and diabetic mice. This effect was repressed by cremaster muscle superfusion with insulin (100 μU/ml) in diabetic animals, but particularly in normal animals. In parallel, immunohistochemistry demonstrated a higher number of PAI-1-expressing vessels in cremaster muscle tissue from control animals and from animals treated with C-peptide and insulin compared with tissue from animals with C-peptide treatment application alone. Conclusions/interpretation We conclude that C-peptide possesses antithrombotic actions in vivo. A causal role of PAI-1 in this scenario needs to be further addressed. However, the reversal of C-peptide action by insulin may invalidate the use of this peptide as a treatment option to improve rheology and microcirculation in diabetic patients.     

A novel oral form of salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese rats

Aim: To investigate the effects of acute and chronic administration of a novel oral formulation of salmon calcitonin (sCT) on glycaemic control, glucose homeostasis and body weight regulation in diet‐induced obese (DIO) rats—an animal model of obesity‐related insulin resistance and type 2 diabetes. Methods: DIO rats were acutely given a single dose of oral sCT (0.5 and 2 mg/kg), its oral vehicle N‐(5‐chlorosalicyloyl)‐8‐aminocaprylic acid (5‐CNAC) or injectable sCT (5 and 10 µg/kg) (n = 8), followed by oral glucose tolerance test (OGTT). Other DIO rats were chronic treated twice daily with oral vehicle 5‐CNAC (n = 6), oral sCT (0.5 and 2 mg/kg) or injectable sCT (10 µg/kg) (n = 8). Fasting and postprandial glucose and pancreatic hormones, body weight and insulin sensitivity were assessed. Results: A single dose of oral sCT acutely reduced glucose and insulin area under the curve during OGTT by approximately 65 and 85%, respectively, compared with vehicle (p < 0.001). Chronic treatment with oral sCT significantly reduced both fasting and postprandial glucose and insulin levels by approximately 1.5 mM and 65%, respectively, compared with vehicle. Oral sCT concomitantly improved insulin sensitivity (homeostatic model assessment, HOMA). In contrast, injectable sCT resembling higher systemic exposure did not improve glycaemic control, either acutely or during chronic treatment. Furthermore, both oral and injectable sCT reduced body weight by 15% compared with vehicle (p < 0.05). Conclusion: A novel oral form of sCT showed antidiabetic effects in DIO rats by improving glycaemic control, glucose homeostasis, insulin sensitivity and body weight.     

格列美脲和格列苯脲治疗初诊2型糖尿患者时对心血管危险因素影响的对比研究

目的比较格列美脲和格列苯脲对初诊2型糖尿病患者糖、脂代谢及纤溶酶原活性等心血管危险因素的影响。方法比较格列美脲（n=333）和格列苯脲（n=232）治疗初诊2型糖尿病患者12周前后血糖、糖化血红蛋白、胰岛素抵抗改善情况．同时比较两组血脂及组织型纤溶酶原激活剂（tissue—type plasminogen activator,TPA）和纤溶酶原激活剂抑制物1（plasminogen activator inhibitor-1,PAI—1）的浓度。结果与治疗前相比,格列美脲和格列苯脲治疗后患者血糖均达到良好控制,格列美脲组治疗后低血糖发生率低于格列苯脲组,差异有统计学意义（0．3％vs.1．7％,P〈0．05）。格列美脲组治疗12周后,Homa-胰岛素抵抗比治疗前减少,差异有统计学意义（2．42％±0．91％vs.4．11％±0．85％,P〈0．01）;而在格列苯脲组,治疗前后Homa-胰岛素抵抗比较差异无统计学意义（P〉0．05）。格列美脲组治疗12周后,血清总胆固醇、三酰甘油、低密度脂蛋白胆固醇浓度比治疗前显著下降,而血清高密度脂蛋白胆固醇浓度升高,差异有统计学意义（P〈0．05）;而格列苯脲组治疗前后血脂浓度比较．差异无统计学意义（P〉0．05）。格列美脲治疗12周较治疗前明显升高t-PA,降低PAI-1,差异有统计学意义（P〈0．05）;而格列苯脲治疗前后t—PA、PAI-1比较,差异无统计学意义（P〉0．05）。结论对初诊2型糖尿病患者．格列美脲具有快速稳定控制血糖、改善脂质代谢和显著减轻胰岛素抵抗、改善纤溶活性的作用。     

Effect of highly purified eicosapentaenoic acid ethyl ester on insulin resistance and hypertension in Dahl salt-sensitive rats.

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid derived from fish oil, in comparison to lard on the development of hypertension and insulin resistance in Dahl salt-sensitive (Dahl-S) rats fed a high-sucrose diet (HSD), a model of salt-sensitive hypertension. After 16 weeks of treatment, the glucose infusion rate (GIR) during the euglycemic insulin-glucose clamp test significantly increased in the HSD-EPA-E group compared with the HSD-water or -lard control group. The GIR was approximately three times higher in the HSD-EPA-E group versus the HSD-water or -lard control group, and it was about 70% of the rate in the calorically deprived control group fed a low-fat-high-fiber diet (LF-HFD). In addition, EPA-E significantly suppressed the elevation of plasma glucose and insulin levels after oral glucose loading. These results indicate that EPA-E prevents the development of insulin resistance in Dahl-S rats fed a HSD. Fatty acid analysis of phospholipids in skeletal muscle showed a significant increase in C18:2, C20:5, and C22:5 components in the HSD-EPA-E group and, conversely, a significant decrease in C16:0, C20:4, and C22:6. The present results indicate that the beneficial effect of EPA-E on insulin resistance in Dahl-S rats fed a HSD is likely dependent on the modification of phospholipid components in the skeletal muscle membrane. These findings suggest that EPA-E might prevent the development of insulin resistance in dietary obesity. In addition, the HSD-EPA-E group showed a significant increase in the level of uncoupling protein (UCP) in brown adipose tissue as compared with the HSD-water or -lard control group. However, EPA-E had no effect on the development of hypertension and obesity in Dahl-S rats fed the HSD.     

Acute hyperglycemia alters von Willebrand factor but not the fibrinolytic system in elderly subjects with normal or impaired glucose tolerance.

To assess whether acute hyperglycemia affects fibrinolytic balance in elderly subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT), 40 non-obese elderly subjects (20 NGT, age 68 +/- 8 years; and 20 IGT, age 69 +/- 11 years) were studied. On two experimental days, randomly allocated and spaced 1 week apart, plasma concentrations of glucose, insulin, fibrinogen, tissue plasminogen activator, plasminogen activator inhibitor type 1 and von Willebrand factor (vWF) were measured in each subject at baseline (0) and 30, 60, 90, 120 min after the ingestion of 75 g glucose or a similarly sweet dose of aspartame (250 mg) (control test). In both NGT and IGT elderly subjects, tissue plasminogen activator, plasminogen activator inhibitor type 1 and fibrinogen plasma levels did not significantly change after both oral aspartame and glucose load. In IGT subjects, vWF plasmatic levels decreased after glucose (not aspartame) oral load, reaching the minimum level at 90 min after load (82.7 +/- 7.8 versus 93.7 +/- 10.2, P <0.01). These results demonstrate that acute hyperglycemia does not modify plasma fibrinolysis in elderly subjects. The decrease of plasma concentration of vWF in IGT elderly subjects requires cautious interpretation and further extensive investigations.     

全蝎纯化液对实验性动脉血栓形成t-PA、PAI-1的影响

目的观察全蝎纯化液对新西兰白兔颈总动脉血栓形成组织型纤溶酶原激活物(t-PA)、纤溶酶原活化物抑制剂(PAI-1)、血小板计数(Pt)的变化。方法将50只健康新西兰白兔随机分成5组:空白组、模型组、全蝎纯化液大剂量组(20mg/kg)、全蝎纯化液中剂量组(10mg/kg)和全蝎纯化液小剂量组(5mg/kg)。耳缘静脉注射药物(空白组、模型组注射同等体积的生理盐水)后,采用H2O2损伤新西兰白兔颈总动脉制备血栓模型,造模2h后,采血并取血栓,酶联免疫吸附法(ELISA法)检测血浆t-PA、PAI-1的含量。结果与空白组比较,模型组t-PA明显降低,PAI-1明显升高,差异有统计学意义(P<0.01);与模型组相比,全蝎纯化液各剂量组能明显抑制PAI-1活性,增加t-PA活性,差异均有统计学意义(P<0.01),而各组的血小板计数差异无统计学意义(P>0.05)。结论全蝎纯化液各剂量组可明显促进血浆t-PA的分泌,抑制血浆PAI-1活性,提示全蝎纯化液抗血栓作用机制可能与其促纤溶作用有关。     

Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.     

Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes

Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 micro g/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 micro g/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.     

Type 2 diabetes: assessment of endothelial lesion and fibrinolytic system markers.

This study aimed to investigate whether endothelial cells are damaged and to evaluate fibrinolytic system function in patients with type 2 diabetes. For this proposal, plasma levels of von Willebrand factor (an endothelial marker of injury), homocysteine (an inductor of endothelial injury), D-dimer (a marker of coagulation cascade activation) and plasminogen activator inhibitor-1 (a fibrinolysis marker) were measured in individuals with both type 2 diabetes and high blood pressure, with type 2 diabetes, with high blood pressure and in healthy control individuals. No significant differences among groups were observed for von Willebrand factor and homocysteine plasma levels. The type 2 diabetes and high blood pressure group presented a significant difference to the other groups for D-dimer and also presented high values for plasminogen activator inhibitor-1. The high blood pressure group and type 2 diabetes group presented separately higher values of plasminogen activator inhibitor-1 compared with the control group. High levels of D-dimer and plasminogen activator inhibitor-1 in patients with type 2 diabetes and high blood pressure with normoalbuminuria therefore indicate a state of hypercoagulability and hypofibrinolysis, despite no evident microvascular injury supported by normal levels of von Willebrand factor and homocysteine.     

Infantile obesity: a situation of atherothrombotic risk?

Obesity is a major risk factor for cardiovascular disease frequently associated with hypertension, dyslipidemia, and diabetes. In recent years, alterations in the hemostatic system have been added to these dysfunctions. We analyzed some of these alterations in coagulation and fibrinolysis in obese children (6 to 9 years old) of both sexes. We studied 61 obese children (mean body mass index [BMI], 22.35 kg/m2; 95% confidence interval [CI], 21.82 to 22.87) and 70 non-obese children (mean BMI, 16.58 kg/m2; 95% CI, 16.24 to 16.93) as a control group. The obese subjects presented significantly elevated values for insulin (P < .001), tissue-plasminogen activator ([t-PA] P < .001), plasminogen activator inhibitor-1 ([PAI-1] P < .001), and fibrinogen (P < .001) with respect to the control group. We found no significant differences in the concentration of glucose and fragment 1 + 2 of prothrombin (F1 + 2). In the obese subjects, insulin, PAI-1, and F1 + 2 were positively correlated with the BMI. On the other hand, t-PA was correlated with insulin and PAI-1 but not with the BMI. Therefore, in the obese children, there was an increment of the risk factors for cardiovascular disease.     

Altered islet Beta-cell function before the onset of Type 1 (insulin-dependent) diabetes mellitus

Summary To define the glucose to insulin dose-response relationship before the onset of diabetes, we studied 22 nondiabetic co-twins of patients with Type 1 (insulin-dependent) diabetes mellitus and nine control subjects. All had intravenous glucose tests at 0.02, 0.1 and 0.5 g/kg and were followedup prospectively for at least 6 years. Seven twins developed diabetes a mean of 7 months later; the remaining 15 are now unlikely to develop diabetes. The seven pre-diabetic twins had higher fasting insulin levels than control subjects (4.2±2.0 vs 1.8±1.8 nmol/l; p<0.05); but lower glucose clearance (1.0±0.5 vs 1.9±0.7 %/min; p<0.05), first phase insulin response at 0.5 g/kg (21.1±23.2 vs 143±50 nmol/l; p<0.0001), and total insulin responses at 0.1 g/kg (p<0.05) and 0.5 g/kg (p<0.00005). Using a curve-fitting programme, the normal glucose to insulin relationship was lost in prediabetic twins who had lower coefficient of determination (R²) than control subjects (p<0.01). In contrast, 15 low-risk twins and their nine control subjects had similar fasting glucose and insulin levels, glucose clearance, R² and insulin secretory responses to different glucose loads. The positive predictive values of subnormal R² and subnormal first phase insulin response were 67 % and 58 % respectively. These observations demonstrate an altered glucose to insulin dose-response relationship and loss of maximum insulin secretory response to glucose before the onset of Type 1 diabetes.     

Acute nateglinide administration in subjects with type 2 diabetes: effects on postprandial metabolism, coagulation, and fibrinolysis

BACKGROUND AND AIM: Postprandial glycaemia and lipaemia are known risk factors for atherosclerosis in type 2 diabetes. Coagulation activation in the postprandial state also contributes to acceleration of atherosclerosis. Nateglinide is effective in reducing postprandial glycaemia. Its effect on glycaemia may also be beneficial in postprandial lipaemia and coagulation. The aim of this study was to examine the potential effect of a single dose of nateglinide on postprandial triglyceridaemia, coagulation, and fibrinolysis in patients with type 2 diabetes. METHODS AND RESULTS: Ten subjects with type 2 diabetes, treated with diet alone were recruited in a crossover randomized study. In the morning, after a 12- to 14-h fast, each subject received a standard mixed meal (total energy 783 kcal), preceded by one tablet of 120 mg nateglinide or placebo. Venous blood samples were drawn prior to meal consumption and 6h afterwards for the measurement of plasma glucose, insulin, and C-peptide, lipids, coagulation, and fibrinolysis factors. As expected, there was a significant reduction in postprandial glycaemia after nateglinide administration compared to placebo (P<0.001). Plasma insulin levels were significantly higher after nateglinide than after placebo (P=0.002). Nateglinide administration resulted in a lower overall postprandial reduction of tissue-plasminogen activator than placebo (-2.9+/-1.3 vs. -8.3+/-3.7 ng/ml h, P=0.003). In addition, a significant reduction of postprandial plasminogen activator inhibitor-1 was observed in comparison with the baseline values after nateglinide (P=0.001), although the overall response was not significantly different after nateglinide and placebo (P=0.31). Plasma concentrations of C-peptide, lipids and the remaining coagulation parameters studied were not different between nateglinide and placebo. CONCLUSIONS: Acute nateglinide administration improves postprandial glycaemia and fibrinolytic activity in patients with type 2 diabetes. This combined effect, if confirmed by a long-treatment study, might reduce cardiovascular risk in type 2 diabetes.     

The effect of PGI2 analogue on vascular endothelial function and platelet aggregation in patients with NIDDM

The effect of the short-term administration of beraprost sodium, an analogue of prostaglandin I₂ (PGI₂), on the function of vascular endothelial cells and platelet in non-insulin-dependent diabetes mellitus (NIDDM) patients was investigated. Seven nonobese NIDDM patients with microalbuminuria were recruited for this study. They received a dose of 20 μg of beraprost sodium three times daily for 1 month. Before and after this treatment, various factors concerning functions of vascular endothelial cells and platelet were measured. Treatment with PGI₂ analogue caused a decrease in basal levels of plasma lipoprotein (a) from 16.8 ± 5.3 to 13.2 ± 4.4 mg/dL (p < 0.05), immunoreactive-(i-)endothelin from 2.4 ± 0.3 to 1.6 ± 0.2 pg/mL, and i-thrombomudulin from 9.3 ± 3.7 to 7.9 ± 3.0 FU/L, respectively, and caused a significant increase in basal plasma i-tissue type plasminogen activator (tPA) from 5.3 ± 0.7 to 8.3 ± 1.5 ng/mL (p < 0.01). This treatment also increased maximum response of i-tPA induced by desmopressin infusion. Platelet aggregation due to ADP was inhibited in five of six patients after this treatment. In conclusion, treatment with PGI₂ analogue caused a decrease in the presumed promoting factors of angiopathy such as lipoprotein (a) and endothelin and an increase in the protecting endothelial factor of angiopathy, tissue type plasminogen activator in patients with NIDDM. And immunoreactive thrombomodulin levels which reflect the vascular endothelial cell injury tended to decrease with the treatment. Therefore, it is suggested that this treatment preserves the vascular endothelial function in diabetes.