Perspectives of nuclear diagnostic imaging in diabetic cardiomyopathy.

Diabetic cardiomyopathy is a ventricular dysfunction in the absence of coronary artery disease, valvular or hypertensive heart disease. The mechanisms underlying diabetic cardiomyopathy may involve metabolic disturbances, myocardial fibrosis, small vessel disease, microcirculation abnormalities, cardiac autonomic neuropathy and insulin resistance. Diagnostic problems emerge because no specific disease pattern characterizes the disease and because there may be coexistence in diabetes of coronary artery disease and hypertension as independent but compounding causes of biochemical, anatomical and functional alterations impairing cardiac function. In this paper we will review the role of nuclear imaging today, concentrating on the diagnostic capabilities of radionuclide ventriculography, to study the effect of insulin resistance and, more extensively, gated-single photon emission computed tomography with Tc-99m labelled agents. A broad analysis will be dedicated to: 1) positron emission tomography using perfusion agents, with the potential to quantify resting and stress blood flow and coronary flow reserve; 2) radionuclide procedures evaluating aerobic and anaerobic cardiac metabolism; and 3) cardiac neurotransmission imaging, studying the autonomic neuropathy.

Steatohepatitis is associated with diabetes and fibrosis in genotype 1b HCV-related chronic liver disease.

Liver steatosis, diabetes mellitus and hepatitis C virus (HCV) genotype have been implicated in liver fibrosis in HCV-related chronic active hepatitis (CAH). The aim of this study was to evaluate whether steatosis and diabetes were associated with more severe liver fibrosis in patients with genotype 1b HCV-related CAH. One-hundred and eighty patients (98 men, 82 women; age range 17-68 years; median 51) infected with genotype 1b HCV underwent ultrasound examination and liver biopsy because of elevated levels of serum alanine transaminase. Based on liver histology, patients were divided into three steatosis classes: 1 (involving <33% of hepatocytes), 2 (34-66%) and 3 (>66%). Fibrosis was graded with the Ishak score (range: 0-6). Virological and epidemiologic characteristics, biochemical data, body mass index, and apparent duration of disease were recorded. Diabetes was identified according to American Diabetes Association criteria. The median fibrosis grade was 2 (23 patients had liver cirrhosis) in the three steatosis classes, with no significant differences between classes. At multivariate analysis, fibrosis was significantly related to age, alanine transaminase, diabetes, hepatitis B core antibody, steatohepatitis and grading. At binary logistic regression analysis, only diabetes and fibrosis stage were significantly associated with steatohepatitis. Steatosis was not an independent risk factor for liver disease severity in our CAH/genotype 1b HCV-infected patients. Steatohepatitis was associated as well as diabetes and affected the severity of liver fibrosis.

The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis.

AIM: The observation of bright liver echo pattern on ultrasound is commonly considered a sign of hepatic steatosis. However, the interference of liver fibrosis on sensitivity and specificity of bright liver echo pattern has caused many to question its effectiveness as a diagnostic tool. The objective of this study was to evaluate the sensitivity, specificity and predictive values of bright liver echo pattern for liver steatosis. PATIENTS AND METHODS: We studied 235 consecutive patients suspected of having liver disease of various aetiologies. Median age was 52 years (range, 17-72 years), and there was a male/female ratio of 1:18. All patients underwent ultrasound examination before liver biopsy and was performed by two operators. The presence or absence of bright liver echo pattern and posterior attenuation or areas with different patterns of fat infiltration were noted. Histologic evaluation was performed and graded by Ishak score. Steatosis was categorised as absent, 0-2%, 3-29% to 30-49% or >50%. RESULTS: Interobserver concordance was high. Bright liver echo pattern was found in 67% of patients with steatosis of any degree and 89% of patients with steatosis of >or=30%. Only three patients without steatosis, who had a low Ishak score, demonstrated bright liver echo pattern on ultrasonography. The sensitivity, specificity, positive predictive value and negative predictive value of bright liver echo pattern for steatosis were 64%, 97%, 96.0% and 65%, respectively. Among the subgroup of patients who had steatosis of >or=30%, the sensitivity, specificity, positive predictive value and negative predictive value of bright liver echo pattern were 91%, 93%, 89% and 94%, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of posterior attenuation and/or skip areas associated with bright liver echo pattern for steatosis were 89.7%, 100%, 100% and 92.3%, respectively. Univariate analysis showed bright liver echo pattern to be associated only with steatosis and not with fibrosis. CONCLUSION: We concluded that the presence of bright liver echo pattern is a sign of liver steatosis and that liver fibrosis does not interfere with ultrasound measurements. Posterior attenuation and/or skip areas are closely related to steatosis of >or=30%.

Hepatitis C virus carriers with persistently normal ALT levels: biological peculiarities and update of the natural history of liver disease at 10 years.

Some chronic hepatitis C (CHC) patients exhibit persistently normal alanine aminotransferase (ALT) levels (PNAL). Patients with PNAL experience significantly milder disease. In order to understand the differences between CHC patients with elevated ALT levels compared with those with PNAL better, we compared epidemiological, immunological and histological findings, in particular, the value of proliferating hepatocyte activity (PCNA) between the two groups of patients. We studied 40 chronic hepatitis C virus (HCV) carriers with increased ALT who underwent liver biopsy for histological diagnosis and determination of clinical prognosis, and 24 PNAL patients under follow-up for 10 years. Immunological response to different HCV genomic epitopes was tested in both the control group and in PNAL subjects. PCNA values from liver specimens of all patients as well as liver biopsies of PNAL patients at time points 0 and 5 years were calculated according to Hall et al.Age, sex and body mass index (BMI) were not significantly different between the two groups. The median liver histology stage was significantly higher in HCV carriers vs the PNAL group (2.5, range = 2-6 vs 1.5, range = 1-2; P < 0.01). Among PNAL patients, histological stage was not statistically different at the three time points considered. Interferon (IFN)-gamma production was comparable in the two groups. PCNA was significantly higher in the group with elevated ALT levels vs the PNAL group (8%, range = 4-15%vs 5% range = 3-8%; P < 0.05) and no statistically significant differences were found in PNAL patients at time points 0, 5 and 10 years. This study confirms that progression to cirrhosis is slow or absent in PNAL patients after 10 years of follow-up. Accordingly, the hepatic proliferative activity index is low and seems to be stable over time.

Increased vascular endothelial growth factor mRNA expression in the heart of streptozotocin-induced diabetic rats.

The aim of the present study was to evaluate vascular endothelial growth factor (VEGF), fms-like tyrosine kinase 1 (flt-1), and fetal liver kinase (flk-1) expression in the heart of experimental diabetic rats. Ten young adult male Wistar rats (5 streptozotocin [STZ]-induced diabetic rats, without insulin treatment, and 5 controls) were studied. Ninety days after the induction of diabetes, semiquantitative reverse transcription (RT)-polymerase chain reaction (PCR) coamplification of VEGF/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) transcription was performed. RT-PCR was also performed for VEGF receptors flk-1 and flt-1. VEGF mRNA expression, at 234 bp, was detectable in the heart of the rats and was significantly higher in those with diabetes. Densitometric analysis of PCR products showed that VEGF mRNA levels were meanly 4.8-fold higher in STZ-induced diabetic rats than controls (VEGF/GAPDH densitometric ratio, 3.46 +/- 0.20 v 0.74 +/- 0.10, P <.001). No significant difference was found in flt-1 and flk-1 amplification products between STZ-induced diabetic rats and controls (flt-1/GAPDH densitometric ratio, 0.58 +/- 0.01 v 0.64 +/- 0.05, P>.1; flk-1/GAPDH densitometric ratio, 0.66 +/- 0.10 v 0.7 +/- 0.06, P >.2). The increase in VEGF mRNA expression observed in this experimental diabetic model is in contrast with the typical impairment in collateral vessels of diabetic hearts. This apparent discrepancy might be explained by a resistance of cardiac tissue to VEGF. The lack of mRNA flt-1 and flk-1 overexpression in diabetic hearts could be one of the mechanisms for this resistance.

Hepatic uptake of organic anions affects the plasma bilirubin level in subjects with Gilbert's syndrome mutations in UGT1A1.

Although in Gilbert's syndrome (GS), bilirubin glucuronidation is impaired due to an extra TA in the TATA box of the promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 (UGT1A1), many GS homozygotes lack unconjugated hyperbilirubinemia. Accordingly, an additional defect in bilirubin transport might be required for phenotypic expression. Plasma bilirubin and the early fractional hepatic uptake rate (BSP K(1)) of a low dose of tetrabromosulfophthalein (0.59 micromol/kg) were determined in (1) 15 unrelated patients with unconjugated hyperbilirubinemia plus 12 random controls; (2) 4 unrelated GS probands and 15 of their first-degree relatives; (3) 7 unrelated patients with hemolysis due to beta-Thalassemia minor. Subjects were classified by DNA sequencing of the promoter region of both UGT1A1 alleles. In group 1, GS homozygotes showed a highly significant negative linear correlation between plasma bilirubin levels and BSP K(1). BSP K(1) values overlapped considerably between GS and normal subjects, whereas, in group 2, they were clustered within, and sharply segregated among, families. Patients with hemolysis, despite elevated plasma bilirubin levels, had mean BSP K(1) values similar to the normal subjects. Within each GS subgroup with defined UGT1A1 mutations, the plasma bilirubin level is in part determined by the organic anion uptake rate, assessed by early plasma disappearance of low-dose BSP. The lower BSP uptake in GS is not secondary to the hyperbilirubinemia, but probably caused by (an) independent, genetically determined defect(s) in hepatic transport mechanism(s), shared by BSP and bilirubin, that are likely necessary for phenotypic expression of GS.

Effect of treatment with acarbose and insulin in patients with non-insulin-dependent diabetes mellitus associated with non-alcoholic liver cirrhosis.

AIM: Non-insulin-dependent diabetes mellitus (type 2 diabetes) not responding to dietary treatment alone in patients with non-alcoholic liver cirrhosis is characterized by high postprandial hyperglycaemia. The control of postprandial hyperglycaemia in such patients, is generally achieved by the means of progressively higher doses of insulin, with an increasing risk of hypoglycaemia in the late postprandial period. The aim of this study was to evaluate the use of acarbose for the control of postprandial hyperglycaemia in 100 patients with well-compensated liver cirrhosis and type 2 diabetes treated with insulin. METHODS: The study was double blind with randomization of treatments into acarbose (52 patients) vs. placebo (48 patients) with parallel branches over a period of 28 weeks. RESULTS: All patients tolerated the treatments well and no significant variations in liver function tests were observed (< 5% vs. pretreatment). A significant reduction of several parameters was observed only after acarbose treatment: fasting glycaemia (173 +/- 28 vs. 146 +/- 19 mg/dl; p < 0.01), postprandial glycaemia (230 +/- 24 vs. 148 +/- 20 mg/dl; p < 0.01), mean glycaemia (206 +/- 20 vs. 136 +/- 13 mg/dl; p < 0.01), mean variation (180 +/- 14 vs. 51 +/- 10 mg/dl; p < 0.01), HbA1c (8.9 +/- 0.8 vs. 7.2 +/- 0.5; p < 0.05), C-peptide 2 h after a standard meal (4.5 +/- 1.9 vs. 2.8 +/- 1.7 ng/ml; p < 0.05), whereas the parameters did not change significantly after the placebo. After acarbose treatment a significant increase of intestinal voiding/week (+116% vs. +10%; p < 0.01) and a parallel reduction of blood ammonia levels (-52 +/- 9% vs. -9 +/- 5%; P < 0.01) were observed. CONCLUSIONS: The results clearly document the good tolerability and the absence of toxic effects of acarbose on liver, due to the lack of both intestinal absorption and hepatic metabolism of the drug at doses in the therapeutic range. In fact, acarbose increases the peristalsis movements of the gut, stimulates the proliferation of the saccarolytic bacteria and simultaneously reduces the proliferation of proteolytic bacteria, thus resulting active in the reduction of blood ammonia levels. These effects of acarbose may be advantageously exploited in the treatment of type 2 diabetic patients with well-compensated non-alcholic liver cirrhosis.

Alteration of haemostasis in non-metastatic gastric cancer.

BACKGROUND: Cancer is one of the most common acquired causes of venous thromboembolism. AIM: To evaluate haemostasis disorders in patients with non-metastatic gastric cancer. PATIENTS AND METHODS: We studied 11 patients with non-metastatic gastric cancer (9 males and 2 females, median age 54 years) and 20 healthy subjects (15 males and 5 females, median age 48 years) control. We measured prothrombin time, activated partial thromboplastin time, coagulation time, clot lysis time, fibrinogen, clotting factors (II, VII, VIII, IX, X), C protein, S protein, AT III, activated protein C resistance, prothrombin 1+2 fragment, tissue plasminogen activator and D-Dimer in all subjects. RESULTS: Fibrinogen plasma levels were significantly higher in patients with non-metastatic gastric cancer than in control group (505+/-24 mg/dl vs 336+/-30 mg/dl, p<0.001). We also found a significant increase in prothrombin 1+2 fragment plasma concentration compared with controls (3.8+/-0.6 nM vs 0.83+/-0.09 nM, p<0.001). Plasma D-dimer levels were 20-fold higher in patients with non-metastatic gastric cancer compared with controls (9.57+/-0.4 ng/dl vs 0.4+/-0.05 ng/dl, p<0.001). Also tissue plasminogen activator was significantly higher in gastric cancer patients than in controls (20.8+/-2.32 ng/ml vs 9.1+/-1.37 ng/ml, p<0.01). Finally clot lysis time was significantly accelerated in gastric cancer patients compared with control subjects (81+/-37 min vs 233+/-74 min, p<0.01). CONCLUSIONS: Patients with non-metastatic gastric cancer are at risk for thrombotic events due to the combined increase in fibrinogen plasma levels and thrombin formation.

Effects of insulin-glucose infusion on left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin dependent diabetic patients: a radionuclide ventriculographic study.

OBJECTIVES: The aim of this study was to evaluate: 1) the effects of insulin administration on left ventricular ejection fraction (LVEF) during exercise, and 2) the eventual impairment of the cardiovascular response to insulin in noninsulin dependent diabetes mellitus. BACKGROUND: Insulin influences the cardiovascular system, but its effect on left ventricular function has yet to be established. METHODS: The effects of normal saline (test A) and insulin-glucose (insulin = 1.7 mU x kg(-1) x min(-1); glucose = 6 mg x kg(-1)min(-1)) (test B) infusions on systolic and diastolic functions at rest and during dynamic exercise were examined by radionuclide ventriculography. Twenty-two noninsulin-dependent diabetic patients and 22 gender, age and body mass index matched healthy subjects were investigated. RESULTS: Both groups had normal scintigraphic parameters at rest and during dynamic exercise. Rest- and stress-LVEF as well as rest- and stress-peak filling rate were significantly (p < 0.001) lower in diabetic than in healthy subjects, both in test A and B. Rest-LVEF was significantly higher during test B than it was in test A only in diabetic subjects (p < 0.01). Stress-LVEF was significantly higher (p < 0.05) during test B than it was in test A, in both groups. Insulin-glucose infusion did not modify rest- and stress-peak filling rate in either group. No difference in left ventricular end diastolic volume and in mean blood pressure was found between test A and B at rest and during exercise in either group. A significant linear correlation between LVEF and the index of insulin sensitivity was found in diabetic patients. CONCLUSIONS: In both normal and diabetic humans, insulin induces a very important rise in LVEF after submaximal work. However, the rise is significantly lower in diabetic than in nondiabetic subjects. The increase in exercise-LVEF on insulin is likely due to an enhancement of ventricular contractility. Insulin resistance could justify the lower angioscintigraphic indexes in diabetic subjects.

Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels.

BACKGROUND & AIMS: Some patients with serum hepatitis C virus (HCV) have persistently normal aminotransferase (ALT) levels and are affected by cirrhosis. This study prospectively evaluated progression of the disease in a group of anti-HCV-positive patients with persistently normal ALT levels. METHODS: Thirty-seven subjects were studied. Each subject underwent liver biopsy at baseline and after 5 years of follow-up. At baseline, serum samples were tested for genotypes and HCV RNA load. ALT levels and serum HCV RNA were tested every other month and every 6 months, respectively. Patients with increased ALT were discharged from the study and treated with IFN. Five years after the end of IFN therapy, a liver biopsy was performed. RESULTS: Liver biopsy at baseline showed chronic hepatitis in 34 patients and normal histology in 3 patients, 2 of whom were negative for HCV RNA and 1 positive. HCV genotypes were distributed as follows: 2a, 56%; 1b, 41%; and 1a, 3%. At the end of 7-year follow-up, 73% of the patients still had normal ALT values. Liver histology after 5 years was comparable to that observed at entry to study. CONCLUSIONS: Most patients with persistently normal ALT serum levels have very mild chronic hepatitis. However, healthy anti-HCV-positive subjects exist. In patients with HCV-related chronic hepatitis associated with persistently normal ALT levels, the grade of disease activity does not increase over years and progression to cirrhosis is slow or absent.

Comparative efficacy study of atorvastatin vs simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia.

Although there is little information from primary or secondary prevention trials on cholesterol-lowering medication in diabetic patients, the reduction of elevated cholesterol is widely recommended for this group. The American Diabetes Association (ADA) recommends drug therapy in diabetic patients if low density lipoprotein (LDL)-cholesterol remains at > 130 mg/dl, or > 100 mg/dl in patients with macroangiopathy, after dietary intervention. When cholesterollowering medication is indicated, the choice of the drug must take into account the other lipid abnormalities that are often present and the need to maintain optimal glycaemic control. In the present study we compared the efficacy and safety of the novel HMG-CoA reductase inhibitor atorvastatin at the dose of 10 mg/day with simvastatin , lovastatin and pravastatin at doses of 10, 20 and 20 mg/day, respectively, and placebo, in type 2 diabetic patients with moderate elevation of LDL-cholesterol with or without elevation of triglycerides. All the quoted agents are enzyme inhibitors effective in lowering LDL-cholesterol in humans. The efficacy endpoints were the mean per cent changes in plasma LDL-cholesterol (primary), total cholesterol, triglycerides, and high-density lipoprotein (HDL)-cholesterol concentrations from baseline to the end of treatment (24 weeks). Atorvastatin at a dose of 10 mg/day produced: (1) a significant reduction in LDL-cholesterol (-37%) in comparison with equivalent doses of simvastatin (-26%), pravastatin (-23%), lovastatin (-21%), and placebo (-1%); (2) HDL-cholesterol increases (7.4%) comparable to or greater than those obtained with simvastatin (7.1%), pravastatin (3.2%), lovastatin (7.21%), and placebo (-0.5%); (3) a significantly greater reduction in total cholesterol (- 29%) than that obtained with simvastatin (-21%), pravastain (-16%), lovastatin (-18%), and placebo (1%); and (4) a significantly greater reduction in triglycerides than that obtained with all the other drugs and placebo. In all treatment groups no significant variation in fibrinogen concentration was observed. All reductase inhibitors studied had similar levels of tolerance. There were no incidents of persistent elevations of serum aminotransferases or myositis.

Cochlear dysfunction in type 2 diabetes: a complication independent of neuropathy and acute hyperglycemia.

The effects of type 2 diabetes on evoked otoacoustic emissions (e-OAEs) elicited by clicks in subjects with normal hearing and the involvement of the central (CNS) and peripheral nervous system and acute hyperglycemia were investigated. In study 1, 110 type 2 diabetic patients and 106 control subjects matched for age and gender were investigated by e-OAEs. Central and peripheral neuropathy were evaluated respectively by auditory brainstem responses (ABRs) and according to San Antonio Consensus Conference criteria. In study 2, 10 healthy and 10 type 2 diabetic men matched for age, all with normal e-OAEs, underwent a 5-hour hyperglycemic clamp study. e-OAE tests were performed before and during the hyperglycemic clamp. In study 1, e-OAEs were impaired in 51.8% (57 of 110) of the diabetic subjects, in comparison to 4.7% (five of 106) of the control group (P < .0001). Diabetics with impaired e-OAEs (e-OAEs-), in comparison to those with normal e-OAEs (e-OAEs+), were older (51.0+/-5.8 v 45.1+/-6.0 years, P < .001), had diabetes longer (11.5+/-4.4 v 7.0+/-3.9 years, P < .001), achieved poorer metabolic control as judged by hemoglobin A1c ([HbA1c] 6.9%+/-0.4% v 6.5%+/-0.3%, P < .001), and had more peripheral neuropathy (46% v 23%, P < .02). No difference was observed between e-OAEs- and e-OAEs+ subjects for retinopathy or nephropathy. Nevertheless, when the duration of diabetes was corrected by multiple regression analysis, the correlation between sensorineural damage and peripheral neuropathy lost significance (P = .12). Diabetic groups (e-OAEs+ and e-OAEs-) showed greater latency in waves I, III, and V and greater interwave latency for waves I to V than the control group, but there was no significant difference in ABRs between e-OAEs+ and e-OAEs- subjects. In study 2, there were no significant changes in e-OAE intensities compared with basal values during the entire hyperglycemic clamp in either type 2 diabetic or control subjects. No difference was observed between the two groups at each time of the clamp. Thus, type 2 diabetic subjects show a higher rate of compromised e-OAEs than healthy individuals. The e-OAE dysfunction does not associate with either an injury to the auditory nervous pathway or diabetic microvasculopathy. The apparent interference of peripheral neuropathy in e-OAEs loses significance when corrected for the duration of diabetes.

[Non-insulin-dependent diabetes mellitus associated with nonalcoholic liver cirrhosis: an evaluation of treatment with the intestinal alpha-glucosidase inhibitor acarbose]. / Diabete mellito non insulino-dipendente associato a cirrosi epatica non etilica: valutazione del trattamento con un inibitore delle alpha-glucosidasi intestinali, acarbose.

Non-insulin-dependent diabetes mellitus not responding to diet only in patients with non-alcoholic liver cirrhosis is characterized by high post-prandial hyperglycemia. The aim of this study was to evaluate the safety and efficacy of 24 weeks of treatment with 300 mg acarbose per day in 76 consecutive outpatients affected by type 2 diabetes and well-compensated liver cirrhosis. The study design was double-blind cross-over vs placebo. All patients tolerated both treatments well, and no significant variations in liver function tests were observed (< 5% vs pre-treatment). A significant reduction of several parameters was observed only after acarbose: fasting glycemia (19 +/- 6 vs 2 +/- 0.5%; p < 0.01), post-prandial glycemia (41 +/- 9 vs 3 +/- 0.6%; p < 0.01), mean glycemia (30 +/- 8 vs 14 +/- 5%; p < 0.01), daily glycemic variation (52 +/- 8 vs 8 +/- 1%; p < 0.01), HbA1c (16 +/- 1 vs 2 +/- 0.5; p < 0.05), incremental area of C-peptide after a standard meal (80 +/- 19 vs 200 +/- 36 ng/mL/300 min; p < 0.01). After acarbose a significant increase of intestinal voiding/week (98 vs 28%; p < 0.01) and a parallel reduction of blood ammonia levels (52 +/- 9 vs 9 +/- 5%; p < 0.01) were observed. Results clearly document the good tolerability and the absence of toxic effects of acarbose on the liver, due to a theoretic absence of both absorption by the gut and hepatic metabolism of the drug. In fact, acarbose increases peristaltic movement of the gut, stimulates the proliferation of saccharolytic bacteria and simultaneously reduces proteolytic bacterial proliferation, thus actively reducing blood ammonia levels. These unexpected effects of acarbose may be used to advantage for the treatment of type 2 diabetes mellitus in patients with well-compensated liver cirrhosis.

Short- and long-term treatments with iloprost in diabetic patients with peripheral vascular disease: effects on the cardiovascular risk factor plasminogen activator inhibitor type-1.

OBJECTIVES: Iloprost, an analogue of prostacyclin, is often utilised in subjects with diabetes mellitus complicated by macroangiopathy. METHODS: The effects of iloprost infusion on plasminogen activator inhibitor type-1 (PAI-1), glucometabolic control and cardiovascular equilibrium in patients with type-2 diabetes mellitus and peripheral arterial occlusive disease were investigated. Thirteen (7 men/6 women) normal-weight, normotensive and non-smoker type-2 diabetic patients (63.8 +/- 3.4 years, mean +/- SD) with peripheral arterial occlusive disease, stage-II according to Fontaine classification, were enrolled. Eight (four men/four women) patients underwent three study designs, each separated by a 1-week interval: study I, infusion of iloprost (3 ng kg(-1) min(-1) for 5 h) for 1 day alone (short-term treatment); study II, infusion of saline (for 5 h) for 1 day (control treatment); study III, infusion of iloprost (3 ng kg(-1) min(-1) for 5 h) over a period of 28 days (long-term treatment). The remaining five (three men/two women) patients underwent study IV only, infusion of saline over a period of 28 days (placebo treatment). Plasma levels of glucose, plasminogen, PAI-1 activity and fibrinogen, blood pressure and heart rate were determined in all studies, while plasma insulin levels, blood HbA(1c), walking distance and Winsor index only in studies III and IV. RESULTS: Both short- and long-term treatments with iloprost significantly reduced PAI-1 activity (baseline vs end: 17.4 +/- 1.9 AU/ml vs 15.0 +/- 1.6 AU/ml, P < 0.02; 20.5 +/- 7.6 AU/ml vs 7.9 +/- 2.1 AU/ml, P < 0.002, respectively). Long-term treatment with iloprost significantly increased walking distance (baseline vs end: 325 +/- 41 m vs 496 +/- 52 m, P < 0.0001), but not Winsor index. Neither glucometabolic control nor cardiovascular equilibrium were affected by short- and long-term treatments with iloprost. Control and placebo treatments did not cause any significant modifications in the parameters evaluated. CONCLUSION: If confirmed by further investigations, the results of this pilot study suggest that iloprost, infused for both brief and long periods, is able to reduce the cardiovascular risk factor PAI-1, increases free walking capacity and does not affect glucometabolic control and blood pressure in type-2 diabetic patients complicated by macroangiopathy.