Women show worse control of type 2 diabetes and cardiovascular disease risk factors than men: results from the MIND.IT Study Group of the Italian Society of Diabetology.

BACKGROUND AND AIMS: The study explores the degree of control of hyperglycaemia and cardiovascular (CV) disease risk factors in men and women with type 2 diabetes and the impact thereon of obesity, central adiposity, age and use of medications. METHODS AND RESULTS: A cross-sectional survey was conducted at 10 hospital-based outpatients diabetes clinics. 1297 men and 1168 women with no previous CV events were studied. Women were slightly (only one year) older and more obese than men: average BMI was respectively 30.7 ± 5.7 vs 28.6 ± 4.1 kg/m(2) (p < 0.001), and prevalence of abdominal obesity was 86% vs 44% (p < 0.001). Women smoked less, but had higher HbA1c, LDL cholesterol, non-HDL cholesterol, systolic blood pressure and serum fibrinogen than men. Accordingly optimal targets for HbA1c (<7%), LDL cholesterol (<100 mg/dL), HDL cholesterol (>40 for men, >50 for women, mg/dL), and systolic blood pressure (<130 mmHg) were less frequently achieved by women than men (respectively 33.8% vs 40.2%; 14.6% vs 19.2%; 34.1% vs 44.5%; 68.8% vs 72%; p < 0.05 for all). Findings were confirmed after stratification for waist circumference (< or ≥ 88 cm for women; < or ≥ 102 cm for men), BMI (< or ≥ 25 kg/m(2)) or age (< or ≥ 65 years). As for treatment, women were more likely than men to take insulin, alone or in combination with oral hypoglycaemic drugs, to be under anti-hypertensive treatment, whereas the use of lipid lowering drugs was similar in men and women. CONCLUSIONS: Control of hyperglycaemia and major CVD risk factors is less satisfactory in women than men. The gender disparities are not fully explained by the higher prevalence of total and central obesity in women; or by a less intensive medical management in women.

Platelet dysfunction in central obesity.

Central obesity is a relevant risk factor for major cardiovascular events due to the atherosclerotic involvement of coronary, cerebral and lower limb arterial vessels. A major role in the increased cardiovascular risk is played by platelets, which show an increased activation and a reduced sensitivity to the physiological and pharmacological antiaggregating agents. This review focuses on platelet dysfunction in central obesity. The mechanisms involved are related to: i) the reduced sensitivity to insulin and other substances acting via intracellular cyclic nucleotides, such as nitrates and prostacyclin; ii) the altered intracellular ionic milieu with elevated cytosolic Ca(2+); and iii) the increased oxidative stress, which elicits isoprostane production from arachidonic acid. Therapeutic guidelines recommend a multifactorial prevention of cardiovascular disease including antiplatelet drugs in high risk patients, even though, at present, the protective effect of antiplatelet therapy in obese, insulin resistant subjects has not been evaluated by specific trials. Some reports, however, suggest a decreased sensitivity to the antiaggregating effects of both acetylsalicylic acid (aspirin) and thienopyridines in human obesity. Platelet defects may play a pivotal role in the reduced efficacy of antiplatelet therapy in obese subjects in the setting of cardiovascular prevention and acute coronary syndrome treatment. Thus, a specifically tailored antiaggregating therapy is likely necessary in obese, insulin resistant subjects, especially in the presence of type 2 diabetes mellitus.

Lower fasting blood glucose, glucose variability and nocturnal hypoglycaemia with glargine vs NPH basal insulin in subjects with Type 1 diabetes.

BACKGROUND AND AIMS: To compare switching from NPH insulin (NPH) to insulin glargine (glargine) with continuing NPH for changes in fasting blood glucose (FBG) in patients with Type 1 diabetes on basal-bolus therapy with insulin lispro as bolus insulin. Secondary objectives included self-monitoring blood glucose, mean daily blood glucose (MDBG) and mean amplitude glucose excursion (MAGE) values alongside changes in HbA(1c) and safety profiles. METHODS AND RESULTS: This was a 30-week, parallel, open-label, multicentre study. Seven-point profiles were used to calculate MDBG and MAGE. Hypoglycaemia and adverse events were recorded by participants. FBG improved significantly with both glargine (baseline-endpoint change: -28.0 mg/dL; 95% CI: -37.3, -18.7 mg/dL; p<0.001) and NPH (-9.8 mg/dL; 95% CI: -19.1, -0.5 mg/dL; p=0.0374). The improvement was significantly greater with glargine than NPH (mean difference: -18.2 mg/dL; 95% CI: -31.3, -5.2 mg/dL; p=0.0064). MDBG (-10.1 mg/dL; 95% CI: -18.1, -2.1 mg/dL; p=0.0126) and MAGE (-20.0 mg/dL; 95% CI: -34.5, -5.9 mg/dL; p=0.0056) decreased significantly with glargine, but not NPH although endpoint values were no different with the two insulins. Baseline to endpoint change in HbA(1c) was similar (-0.56 vs -0.56%) with no differences at endpoint. Overall hypoglycaemia was no different, but glargine reduced nocturnal hypoglycaemia ("serious episodes" with BG < 42 mg/dl, p=0.006) whereas NPH did not (p=0.123), although endpoint values were no different. CONCLUSION: Switching from NPH to glargine is well tolerated and results into lower FBG, and lower glucose variability while reducing nocturnal hypoglycaemia. These data provide a rationale for more aggressive titration to target with glargine in Type 1 diabetes.

The clinical reality of guidelines for primary prevention of cardiovascular disease in type 2 diabetes in Italy.

INTRODUCTION AND AIM: Guidelines for cardiovascular prevention in diabetes have been issued by the national and international scientific societies. No audit as ever been performed to evaluate the implementation of these documents in clinical practice in Italy. The study evaluates the prevalence, treatment, and control of major cardiovascular risk factors in type 2 diabetic patients, to assess the clinical practice of primary cardiovascular prevention in type 2 diabetes. PATIENTS AND METHODS: Two thousand four hundred and sixty-five men and women with type 2 diabetes, aged 50-75 and free of cardiovascular events were recruited on a consecutive basis at 10 hospital based outpatients diabetes clinics. Clinical variables were measured by standard protocol. Biochemical parameters were evaluated at each centre. The laboratories were monitored by an external quality control assessment in order to reach and maintain a standard of quality and traceability among the participating centres. RESULTS: A minority of patients (5%) met the recommended targets for LDL cholesterol, blood pressure, glycated haemoglobin and smoking habits, whereas the vast majority (66%) had unsatisfactory control of three or more of the above. Achievement of desirable control of risk factors differed according to gender and known diabetes duration. Lipid lowering and, to a lesser extent, antihypertensive medications were under-used and their titration insufficiently target-driven. Prophylactic use of antiplatelet agents was scarce, only one out of five patients was treated independent of absolute cardiovascular risk. CONCLUSION: In clinical practice there is poor adherence to national and international guidelines for primary cardiovascular prevention in type 2 diabetes in Italy. The study underlines the great potential for prevention, particularly in women and in high-risk patients.

Resistance to the nitric oxide/cyclic guanosine 5'-monophosphate/protein kinase G pathway in vascular smooth muscle cells from the obese Zucker rat, a classical animal model of insulin resistance: role of oxidative stress.

Some in vivo and ex vivo studies demonstrated a resistance to the vasodilating effects of nitric oxide (NO) in insulin-resistant states and, in particular, obese Zucker rats (OZR). To evaluate the biochemical basis of this phenomenon, we aimed to identify defects of the NO/cGMP/cGMP-dependent protein kinase (PKG) pathway in cultured vascular smooth muscle cells (VSMCs) from OZR and lean Zucker rats (LZR) by measuring: 1) NO donor ability to increase cGMP in the absence and presence of inhibitors of soluble guanylate cyclase (sGC) and phosphodiesterases (PDEs); 2) NO and cGMP ability to induce, via PKG, vasodilator-stimulated phosphoprotein (VASP) phosphorylation at serine 239 and PDE5 activity; 3) protein expression of sGC, PKG, total VASP, and PDE5; 4) superoxide anion concentrations and ability of antioxidants (superoxide dismutase+catalase and amifostine) to influence the NO/cGMP/PKG pathway activation; and 5) hydrogen peroxide influence on PDE5 activity and VASP phosphorylation. VSMCs from OZR vs. LZR showed: 1) baseline cGMP concentrations higher, at least in part owing to reduced catabolism by PDEs; 2) impairment of NO donor ability to increase cGMP, even in the presence of PDE inhibitors, suggesting a defect in the NO-induced sGC activation; 3) reduction of NO and cGMP ability to activate PKG, indicated by the impaired ability to phosphorylate VASP at serine 239 and to increase PDE5 activity via PKG; 4) similar baseline protein expression of sGC, PKG, total VASP, and PDE5; and 5) higher levels of superoxide anion. Antioxidants partially prevented the defects of the NO/cGMP/PKG pathway observed in VSMCs from OZR, which were reproduced by hydrogen peroxide in VSMCs from LZR, suggesting the pivotal role of oxidative stress.

Dietary habits in type II diabetes mellitus: how is adherence to dietary recommendations?

OBJECTIVE: To clarify adherence of type II diabetic patients to dietary recommendations. SUBJECTS AND METHODS: The dietary habits of a group of 540 patients, with type II diabetes (male 322/female 218, mean age 61+/-5 years, body mass index (BMI) 29.7+/-5.2 kg/m(2); mean+/-s.d.) referring to six Italian diabetes centres were evaluated by means of a 3-day diet record (2 workdays, 1 holiday). Diet records were analysed according to Italian food composition tables and compared with the dietary recommendations of the Diabetes and Nutrition Study Group of the European Association for the study of Diabetes. RESULTS: Calorie intake was 1725+/-497 kcal (1800 for men, 1610 for women). Mean intake for each nutrient was close to the recommended amount, except for fibre (12/1000 vs 20 g/1000 kcal). Calculating the percentage of patients who complied with each recommendation, the intakes of saturated fat and fibre least reflected the dietary target: in 43% of patients saturated fat was >10% of total calories, in only 6% was fibre intake > or =20 g/1000 kcal (considered ideal), and in 25% it was > or =15 g/1000 kcal (acceptable). CONCLUSIONS: These results indicate that compliance to dietary recommendations is not completely satisfactory, even in Italy. Calorie intake is a bit elevated, given the high BMI of our diabetic population. As to dietary composition, there are two crucial issues: the high intake of saturated fat and--most importantly--the low intake of fibre. All strategies aiming to a proper implementation of guidelines should take these results into due account.

Insulin activates hypoxia-inducible factor-1alpha in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling.

AIMS/HYPOTHESIS: We previously demonstrated that insulin stimulates vascular endothelial growth factor (VEGF) synthesis and secretion via phosphatidylinositol-3 kinase (PI3-K) and mitogen-activated protein kinase (MAPK) pathways in vascular smooth muscle cells (VSMC) from humans and from insulin-sensitive lean Zucker fa/+ rats. We also showed that this effect is attenuated in VSMC from insulin-resistant obese Zucker fa/fa rats. As it is not known whether the effects of insulin on VEGF involve activation of hypoxia-inducible factor-1 (HIF-1), we aimed to evaluate: (1) whether insulin modulates HIF-1alpha protein synthesis and activity; (2) the insulin signalling pathways involved; and (3) the role of insulin resistance. METHODS: Using aortic VSMC taken from humans and Zucker rats and cultured in normoxia, the following were evaluated: (1) dose-dependent (0.5, 1, 2 nmol/l) and time-dependent (2, 4, 6 h) effects exerted by insulin on HIF-1alpha content in both nucleus and cytosol, measured by Western blots; (2) insulin effects on HIF-1 DNA-binding activity on the VEGF gene, measured by electrophoretic mobility shift assay; and (3) involvement of the insulin signalling molecules in these insulin actions, by using the following inhibitors: LY294002 (PI3-K), PD98059 (extracellular signal regulated kinase [ERK]), SP600125 (Jun N terminal kinase [JNK]), SB203580 (p38 mitogen-activated protein kinase) and rapamycin (mammalian target of rapamycin), and by detecting the insulin signalling molecules by Western blots. RESULTS: In aortic VSMC from humans and Zucker fa/+ rats cultured in normoxia insulin increases the HIF-1alpha content in cytosol and nucleus via dose- and time-dependent mechanisms, and HIF-1 DNA-binding activity on the VEGF gene. The insulin-induced increase of HIF-1alpha is blunted by the translation inhibitor cycloheximide, LY294002, PD98059, SP600125 and rapamycin, but not by SB203580. It is also reduced in Zucker fa/fa rats, which present an impaired ability of insulin to induce Akt, ERK-1/2 and JNK-1/2 phosphorylation. CONCLUSIONS/INTERPRETATION: These results provide a biological mechanism for the impaired collateral vessel formation in obesity.

Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study.

OBJECTIVE: The influence of postprandial blood glucose on diabetes complications is intensively debated. We aimed to evaluate the predictive role of both fasting and postprandial blood glucose on cardiovascular events in type 2 diabetes and the influence of gender. METHODS: In a population of 529 (284 men and 245 women) consecutive type 2 diabetic patients attending our diabetes clinic, we evaluated the relationships, corrected for cardiovascular risk factors and type of treatment, between cardiovascular events in a 5-yr follow-up and baseline values of hemoglobin A1c (HbA1c) and blood glucose measured: 1) after an overnight fast, 2) after breakfast, 3) after lunch, and 4) before dinner. Continuous variables were categorized into tertiles. RESULTS: We recorded cardiovascular events in 77 subjects: 54 of 284 men (19%) and 23 of 245 women (9.4%). Univariate analysis indicated that cardiovascular events were associated with increasing age, longer diabetes duration, and higher HbA1c and fibrinogen in men, and higher systolic blood pressure, albumin excretion rate, HbA1c, and all blood glucose values in women. Smoking was more frequent in subjects with events. When all blood glucose values and HbA1c were introduced simultaneously in the models, only blood glucose after lunch predicted cardiovascular events, with hazard ratio of the third tertile vs. the first and the second tertiles greater in women (5.54; confidence interval, 1.45-21.20) than in men (2.12; confidence interval, 1.04-4.32; P < 0.01). CONCLUSIONS: Postprandial, but not fasting, blood glucose is an independent risk factor for cardiovascular events in type 2 diabetes, with a stronger predictive power in women than in men, suggesting that more attention should be paid to postprandial hyperglycemia, particularly in women.

Prescription of statins to dyslipidemic patients affected by liver diseases: a subtle balance between risks and benefits.

AIM: Statins reduce cardiovascular morbidity and mortality in the general population with an excellent risk-benefit profile. The most frequent adverse events are myopathy and increase in hepatic aminotransferases. In this review, we consider the role of liver in metabolism of statins, their potential hepatic toxicity and the guidelines for their prescription in patients affected by different liver diseases. DATA SYNTHESIS: Statin-induced hepatic toxicity: i) occurs in 1-3% of patients; ii) is characterized by increased aminotransferase levels; iii) is dose-related; iv) is frequently asymptomatic; v) usually reverts after dosage reduction or treatment withdrawal. Finally, after recovery, a rechallenge with the same or other statins may not result in increased aminotranferases. CONCLUSIONS: Caution is needed when prescribing statins to patients with liver disease, and liver toxicity should always be monitored during statin treatment. In particular, i) the potential hepatic toxicity requires frequent control of biochemical parameters related to hepatic cytolysis and cholestasis in all patients on statins; ii) administration of statins is counterindicated in patients with advanced or end-stage parenchymal liver disease due to the relevant impairment of their metabolism; iii) cholestatic disorders with secondary dyslipidemia do not require statin treatment even if relevant alterations of the lipid pattern are detected; iv) patients with acute liver disease of viral or alcoholic etiology should not receive statins until normalization of cytolysis enzymes; v) chronic hepatitis patients may be treated by statins if their cardiovascular risk is elevated and provided that careful follow-up is carried out to rapidly recognize the onset of further liver damage; vi) liver transplantation recipients affected by dyslipidemia induced by immunosuppressive therapy can be treated with statins under careful clinical control; vii) the benefits of statins should likely overcome the risks in the large majority of dyslipidemic patients affected by non-alcoholic hepatosteatosis, a disease frequently diagnosed in insulin-resistant subjects.

Insulin activates vascular endothelial growth factor in vascular smooth muscle cells: influence of nitric oxide and of insulin resistance.

BACKGROUND: We aimed to evaluate whether insulin influences vascular endothelial growth factor (VEGF) synthesis and secretion in cultured vascular smooth muscle cells (VSMCs) via nitric oxide (NO) and whether these putative effects are lost in insulin-resistant states. MATERIALS AND METHODS: In VSMC derived from human arterioles and from aortas of insulin-sensitive Zucker fa/+rats and insulin-resistant Zucker fa/fa rats incubated with different concentrations of human regular insulin with or without inhibitors of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3-K), mitogen-activated protein kinase (MAPK), nitric oxide synthase (NOS) and guanosine 3',5'cyclic monophosphate(cGMP)-dependent protein kinase (PKG), we measured protein expression (Western blot) and secretion (ELISA) of VEGF. RESULTS: We found that in VSMCs from humans and from insulin-sensitive Zucker fa/+rats, insulin increases VEGF protein expression and secretion, with mechanisms blunted by wortmannin and LY294002 (PI3-K inhibitors), PD98059 (MAPK inhibitor), L-NMMA (NOS inhibitor) and Rp-8pCT-cGMPs (PKG inhibitor). Also the NO donor sodium nitroprusside (SNP) and the cGMP analogue 8-Bromo-cGMP increase VEGF protein expression and secretion, with mechanisms inhibited by wortmannin and PD98059. The insulin effects on VEGF are impaired in VSMCs from Zucker fa/fa rats, which also present a reduced insulin ability to increase NO. CONCLUSIONS: In VSMCs from humans and insulin-sensitive Zucker fa/+rats: (i) insulin increases VEGF protein expression and secretion via both PI3-K and MAPK; (ii) the insulin effects on VEGF are mediated by nitric oxide. The insulin action on both nitric oxide and VEGF is impaired in VSMCs from Zucker fa/fa rats, an animal model of metabolic and vascular insulin-resistance.

Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: possible role in platelet hyperactivation in obesity.

BACKGROUND: Subjects with central obesity exhibit platelet hyperactivity, which is involved in the atherosclerotic process and therefore can account for the increased risk of cardiovascular morbidity and mortality. The aim of the study was to evaluate whether alterations of platelet function in obesity involve synthesis and/or action of the two antiaggregating cyclic nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). MATERIALS AND METHODS: In platelets from 16 obese and 15 control subjects we investigated the influence on platelet responses to the Adenosine-5-diphosphate sodium salt (ADP) exerted by (i) prostacyclin analogue Iloprost (0.31-5 nmol L(-1)) and the cAMP analogue 8-bromo-cAMP (10-500 micro mol L(-1)); and by (ii) nitric oxide (NO) donor sodium nitroprusside (SNP) (5-100 micro mol L(-1)) and the cGMP analogue 8-bromo-cGMP (10-500 micro mol L(-1)). IC(50) (minimal concentration of each inhibitor necessary to reduce platelet response to ADP by half) was determined. Iloprost and SNP ability to increase cyclic nucleotides was also measured. RESULTS: Significantly greater IC(50) were observed in obese subjects than in healthy controls (1.59 +/- 0.16 vs. 0.80 +/- 0.08 nmol L(-1), P = 0.0001 for Iloprost, and 27.6 +/- 6.5 vs. 7.0 +/- 1.7 micro mol L(-1), P = 0.006, for SNP); when data from control and obese subjects were pooled together, IC(50) of Iloprost and SNP correlated with the homeostasis model assessment (HOMA IR), which is a parameter used to measure the insulin resistance (r = 0.588, P = 0.029 and r = 0.640, P = 0.006, respectively). Also the antiaggregating effect of 8-Br-cAMP and 8-Br-cGMP was smaller in the obese subjects. Finally, the ability of Iloprost to increase platelet cAMP and the ability of SNP to increase both cGMP and cAMP were reduced in obese subjects. CONCLUSIONS: Platelet resistance to the antiaggregating effects of prostacyclin and NO in obesity is attributable to impairment of cyclic nucleotide synthesis and action. As cyclic nucleotides are the main effectors of platelet antiaggregation, the resistance to them can account for platelet hyperactivity in obesity.

Insulin stimulates glucose transport via nitric oxide/cyclic GMP pathway in human vascular smooth muscle cells.

OBJECTIVE: In cultured human vascular smooth muscle cells, insulin increases cyclic GMP production by inducing nitric oxide (NO) synthesis. The aim of the present study was to determine whether in these cells the insulin-stimulated NO/cyclic GMP pathway plays a role in the regulation of glucose uptake. METHODS AND RESULTS: Glucose transport in human vascular smooth muscle cells was measured as uptake of 2-deoxy-d-[3H]glucose, cyclic GMP synthesis was checked by radioimmunoassay, and GLUT4 recruitment into the plasma membrane was determined by immunofluorescence. Insulin-stimulated glucose transport and GLUT4 recruitment were blocked by an inhibitor of NO synthesis and mimicked by NO-releasing drugs. Insulin- and NO-elicited glucose uptake were blocked by inhibitors of soluble guanylate cyclase and cyclic GMP-dependent protein kinase; furthermore, glucose transport was stimulated by an analog of cyclic GMP. CONCLUSIONS: Our results suggest that insulin-elicited glucose transport (and the corresponding GLUT4 recruitment into the plasma membrane) in human vascular smooth muscle cells is mediated by an increased synthesis of NO, which stimulates the production of cyclic GMP and the subsequent activation of a cyclic GMP-dependent protein kinase.

Diabetic muscle infarction associated with multiple autoimmune disorders, IgA deficiency and a catastrophically poor glycaemic control: a case report.

We report a case of diabetic muscle infarction in a 22-yr-old woman, with an 11-yr history of poorly controlled Type 1 diabetes complicated by laser-treated pre-proliferative retinopathy, macroalbuminuria and severe autonomic neuropathy, also affected by IgA deficiency, autoimmune hypothyroidism, coeliac disease and polygenic familiar hypercolesterolaemia. She was admitted to our Hospital for pain to the left thigh hindering her from walking. The pain had appeared without trauma about 2 months before admission, and worsened progressively in spite of anti-inflammatory drugs. Clinical picture (localised tender mass without skin signs of inflammation in an afebrile patient) and laboratory data (erythrocyte sedimentation rate 113 mm in 1 hr, fibrinogen 635 mg/dl) suggested the diagnosis of diabetic muscle infarction. Magnetic resonance imaging (MRI) confirmed this hypothesis showing a hyperintense area in T2-weighted sequences at adductor muscle group with enhancement after intravenous contrast. Symptoms subsided over the following 4 weeks after bed rest, analgesics, aspirin and a good glycaemic control. The 3-month follow-up MRI showed total recovery. At hospital admission, the patient presented a very poor glycaemic control (HbA1c 15.5%). After discharge, she started--in order to avoid the weight gain associated with intensive insulin therapy--a daily intense isometric training, undergoing frequent hypoglycaemic episodes. In a few months, in spite of repeated laser treatment, retinopathy progressed to the proliferative stage with bilateral vitreous haemorrhages and visual acuity decreased dramatically notwithstanding vitrectomy. This case confirms the association of diabetic muscle infarction with poorly controlled long-standing diabetes with microvascular complications, suggests the possible role of autoimmunity, and underlines the risk of repeated hypoglycaemic episodes and isometric exercise in the progression of pre-proliferative retinopathy.

Blood glucose pre-prandial baseline decreases from morning to evening in type 2 diabetes: role of fasting blood glucose and influence on post-prandial excursions.

BACKGROUND: To know the relationships between pre- and postprandial blood glucose (BG), i.e. BG profile shape, is a requisite for an appropriate therapy for type 2 diabetic patients. In non diabetic subjects, pre-breakfast, pre-lunch and pre-dinner BG are similar, so that BG postprandial excursions are superimposed on a stable BG preprandial baseline. We aimed to clarify: (a) whether BG preprandial baseline is stable also in type 2 diabetes and (b) whether fasting BG (FBG) influences the slope of BG preprandial baseline and the relationships between pre- and postprandial BG. DESIGN: We evaluated self-measured BG profiles of 237 type 2 diabetic patients on diet alone (M/F, 152/85; age 58.6 +/- 0.7 years; years from diagnosis 4.8 +/- 0.6; BMI 28.0 +/- 0.3 kg m-2): 536 profiles containing preprandial BG (corresponding HbA1c 6.8 +/- 0.06%) and 208 profiles containing both pre- and postprandial BG (corresponding HbA1c 6.8 +/- 0.09%). The profiles, measured by nurses, of 866 type 2 diabetic patients on diet alone were also considered (corresponding HbA1c 6.7 +/- 0.04%). RESULTS: In self-measured profiles containing only preprandial BG: (i) FBG (6.77 +/- 0.07 mmol L(-1)) is higher than pre-lunch BG (6.09 +/- 0.07 mmol L(-1)), P = 0.0001) and pre-dinner BG (5.84 +/- 0.06 mmol L(-1)), P =0.0001); (ii) the delta value between FBG and pre-dinner BG is correlated with FBG (r = 0.57, P = 0.0001), the highest FBG, the steepest the fall of BG preprandial baseline throughout the day. This trend is confirmed in profiles measured by nurses. In profiles containing both pre- and postprandial BG: (i) there is a trend to preprandial BG fall (P = 0.0001) and to postprandial BG increase (P = 0.0001) from morning to evening; (ii) postprandial excursions are influenced and sometimes masked by the slope of BG preprandial baseline, thus, in profiles with FBG < or = 6.7 mmol L(-1), all postprandial values are higher than FBG (P = 0.0001), whereas in profiles with FBG > 7.8 mmol L(-1), postprandial values are not significantly higher than FBG. CONCLUSION: In type 2 diabetes, the shape of BG profiles changes in relation to FBG, because it deeply influences the slope of BG preprandial baseline on which postprandial excursions are superimposed. Thus, before planning treatment policies, not only the extent of fasting and postprandial hyperglycaemia, but also the shape of profiles should be considered, to safely correct hyperglycaemia without inducing hypoglycaemia.

N-acetyl-L-cysteine exerts direct anti-aggregating effect on human platelets.

BACKGROUND: N-acetyl-L-cysteine, a thiol compound, has been shown to potentiate the inhibition of platelet aggregation exerted by organic nitrates and to increase the anti-aggregating effect of L-arginine, which promotes endogenous synthesis of nitric oxide (NO) acting as substrate of platelet constitutive nitric oxide synthase (NOS). It is not known whether this thiol can exert direct effects on platelet aggregability. MATERIALS AND METHODS: 14 healthy male volunteers provided platelet samples to investigate whether N-acetyl-L-cysteine directly influences platelet function and intraplatelet levels of 3',5' cyclic guanosine monophosphate (cGMP), which represents the second messenger involved in NO-induced antiaggregation. Some experiments were repeated in the presence of NOS inhibitor NG-monomethyl-L-arginine (L-NMMA), of nitric oxide-sensitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), of the selective cGMP phosphodiesterase inhibitor zaprinast and of calcium ionophores (A23187, ionomycin). RESULTS: N-acetyl-L-cysteine at 3000-6000 micromol L-1 decreases the responses of human platelets both in platelet-rich plasma (aggregation induced by adenosine 5-diphosphate) and in whole blood (aggregation induced by collagen). The anti-aggregating effect was prevented by preincubation with L-NMMA and guanylyl cyclase inhibitor ODQ. In resting platelets, N-acetyl-L-cysteine increased the levels of cGMP starting from a concentration of 3000 micromol L-1. Permeabilized platelets exhibited an increased sensitivity to the anti-aggregating effect of N-acetyl-L-cysteine. Also, cGMP phosphodiesterase inhibition or the increase in calcium availability, enhanced N-acetyl-L-cysteine effects on platelets. CONCLUSION: N-acetyl-L-cysteine exerts direct anti-aggregating effects through an increased bioavailability of platelet nitric oxide.

Studies on inhibition of human platelet function by sodium nitroprusside. Kinetic evaluation of the effect on aggregation and cyclic nucleotide content.

In this study, we explored the ability of sodium nitroprusside to inhibit the aggregation of human platelets in platelet-rich plasma (PRP) and whole blood and its effects on intracellular levels of guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). The experiments investigated dose-dependent effects of nitroprusside starting from concentrations in the range of circulating levels achievable in vivo during drug administration in humans. Furthermore, we investigated the time-course of both antiaggregating action and the influence on cyclic nucleotide synthesis. Results showed that sodium nitroprusside inhibited the aggregation induced by adenosine 5-diphosphate (ADP) and collagen starting from concentration as low as 2 micromol/l. The IC(50) value for ADP-induced aggregation in PRP was 18.7+/-2.4 micromol/l. The inhibition of platelet aggregation showed a time-dependent behaviour and was not reversible within 90 min. The accumulation of intraplatelet cGMP in the presence of sodium nitroprusside exhibited a comparable time-course characterized by an early increase, a steady state and a late further increase. The time-course of cAMP synthesis was very similar to that of cGMP. Our data evidenced a long-lasting inhibition of platelet responses by sodium nitroprusside and excluded a desensitization of platelet guanylyl cyclase after 3-h exposure to nitric oxide (NO). Furthermore, they indicated a role of cAMP accumulation in the antiaggregating effects of nitroso donor: the simultaneous increase of intracellular content of cAMP and cGMP can synergize in the reduction of the platelet responses.