Effect of pioglitazone on carotid intima-media thickness and arterial stiffness in type 2 diabetic nephropathy patients

Atherosclerosis is the major cause of morbidity and mortality in patients with type 2 diabetes, and pioglitazone has been reported to have anti-inflammatory and potential antiatherogenic effects. The aim of the present study was to determine whether pioglitazone, glibenclamide, or voglibose affects carotid intima-media thickness (IMT), pulse wave velocity (PWV), and urinary albumin excretion (UAE) in normotensive type 2 diabetic nephropathy patients. Forty-five normotensive type 2 diabetes patients with microalbuminuria were randomized to 12-month treatment with pioglitazone (30 mg/d, n = 15), glibenclamide (5 mg/d, n = 15), or voglibose (0.6 mg/d, n = 15). Pre- and posttreatment UAE, PWV, and IMT values were compared between treatment groups and a group of age-matched healthy control subjects (n = 30). Pretreatment PWV, IMT, and UAE values differed little between the 3 groups, but UAE was greater in the 45 type 2 diabetes patients (132.5 +/- 36.4 microg/min) than in the control subjects (6.2 +/- 1.8 microg/min, P < .001). IMT (0.76 +/- 0.12 mm) was significantly greater in the diabetics than in the controls (0.60 +/- 0.08 mm, P < .01). PWV (1,840 +/- 320 cm/s) was also significantly greater in the diabetics than in the controls (1,350 +/- 225 cm/s, P < .01). After 6 and 12 months, UAE, IMT, and PWV in the pioglitazone treatment group were significantly lower than those in the glibenclamide treatment group and voglibose treatment group (UAE: 6 months, P < .05 and 12 months, P < .01; IMT and PWV: 6 months, P < .05 and 12 months, P < .05). Pioglitazone, but not glibenclamide or voglibose, appears to be effective in reducing UAE, IMT, and PWV in normotensive type 2 diabetes patients with microalbuminuria.     

Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease

BACKGROUND: Advanced glycation end products (AGEs)-receptor (RAGE) axis is implicated in diabetic vascular complication. Since a soluble form of RAGE (sRAGE) could be generated from the cleavage of cell surface RAGE in endothelial cells (ECs), serum sRAGE levels may be elevated in diabetes consequent to EC damage. In this study, we examined whether sRAGE levels were elevated in type 2 diabetic patients compared with non-diabetic healthy subjects. METHODS: Serum sRAGE levels were examined in 75 Japanese type 2 diabetic patients (29 men and 46 women; mean age 66 +/- 11 years) and 75 age- and sex-matched non-diabetic healthy control subjects. We explored the association between sRAGE levels and coronary artery disease (CAD) in diabetic patients. RESULTS: Serum sRAGE levels were significantly higher in diabetic patients than in non-diabetic subjects (965.3 +/- 544.2 vs 415 +/- 150.4 pg/mL, p < 0.001). In the univariate analysis, diastolic blood pressure (inversely), LDL cholesterol, triglycerides, HDL cholesterol, hemoglobin A(1c), and creatinine were significantly associated with sRAGE. After performing multivariate analyses, the presence of diabetes (p < 0.0001) was a sole independent determinant of sRAGE. Furthermore, there was a significant difference in sRAGE levels between diabetic patients with CAD and those without CAD (1680.6 +/- 891.1 vs 855.2 +/- 372.1 pg/mL, p < 0.001). Multiple stepwise regression analysis revealed that sRAGE and creatinine levels were independent determinants of CAD. CONCLUSIONS: The present study demonstrated that serum sRAGE levels were significantly higher in type 2 diabetic patients than in non-diabetic subjects and positively associated with the presence of CAD.     

Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine

CONTEXT: Berberine, a natural plant alkaloid, is usually used as an antibiotic drug. The potential glucose-lowering effect of berberine was noted when it was used for diarrhea in diabetic patients. In vitro and in vivo studies have then showed its effects on hyperglycemia and dyslipidemia. OBJECTIVE: The objective of the study was to evaluate the efficacy and safety of berberine in the treatment of type 2 diabetic patients with dyslipidemia. DESIGN: One hundred sixteen patients with type 2 diabetes and dyslipidemia were randomly allocated to receive berberine (1.0 g daily) and the placebo for 3 months. The primary outcomes were changes in plasma glucose and serum lipid concentrations. Glucose disposal rate (GDR) was measured using a hyperinsulinemic euglycemic clamp to assess insulin sensitivity. RESULTS: In the berberine group, fasting and postload plasma glucose decreased from 7.0 +/- 0.8 to 5.6 +/- 0.9 and from 12.0 +/- 2.7 to 8.9 +/- 2.8 mm/liter, HbA1c from 7.5 +/- 1.0% to 6.6 +/- 0.7%, triglyceride from 2.51 +/- 2.04 to 1.61 +/- 1.10 mm/liter, total cholesterol from 5.31 +/- 0.98 to 4.35 +/- 0.96 mm/liter, and low-density lipoprotein-cholesterol from 3.23 +/- 0.81 to 2.55 +/- 0.77 mm/liter, with all parameters differing from placebo significantly (P < 0.0001, P < 0.0001, P < 0.0001, P = 0.001, P < 0.0001, and P <0.0001, respectively). The glucose disposal rate was increased after berberine treatment (P = 0.037), although no significant change was found between berberine and placebo groups (P = 0.063). Mild to moderate constipation was observed in five participants in the berberine group. CONCLUSIONS: Berberine is effective and safe in the treatment of type 2 diabetes and dyslipidemia.     

The level of 2-h post-challenge glucose is an independent risk factor of carotid intima-media thickness progression in Korean type 2 diabetic patients

OBJECTIVE: To evaluate the relationship between the metabolic abnormalities commonly associated with diabetes and the changes in carotid intima-media thickness (IMT) in Korean type 2 diabetic patients who do not have clinically manifest cardiovascular disease (CVD). DESIGN: In a prospective study, a total of 152 type 2 diabetic patients were recruited from a group of outpatients at the Yonsei University Hospital. MATERIALS AND METHODS: The carotid IMTs of 152 subjects with type 2 diabetes (mean age 63.5+/-7.0 years) were determined at baseline and after a mean follow-up time of 23.7+/-3.7 months. Fasting plasma glucose, serum total cholesterol (TC), serum triglyceride, high-density lipoprotein cholesterol (HDL-C), HbA1c, oral glucose tolerance test (OGTT) results for 2-h post-challenge glucose (2hPG), and blood pressure measurements were collected every 3 months and averaged. RESULTS: The highest quartiles of baseline C-peptide and homeostatic model assessment (HOMA) index showed more IMT progression than the lowest quartiles. The change in the mean IMT correlated with average values of HbA1c (r=.219, P=.007), the 2-h post-challenge glucose (r=.239, P=.003), HDL-C (r=-.228, P=.005), LDL-C (r=.175, P=.033), and non-HDL-C (r=.194, P=.016). Multiple regression analysis demonstrated that the independent risk factor for the mean IMT change in diabetic patients was the average 2hPG level (P=.004). The change in the mean IMT of those in the lowest quartile of average 2hPG (<11.1 mmol/l) was 823+/-176 to 841+/-146 microm (P=.276). In the highest quartile (2hPG >15.3 mmol/l), however, the mean IMT increased from 794+/-127 to 882+/-153 microm (P<.001). CONCLUSION: The 2hPG parameter among the various metabolic parameters exerts the greatest influence upon the prevention of carotid IMT progression in type 2 diabetic subjects. The level of 2hPG is an independent risk factor for the progression of carotid IMT in Korean type 2 diabetic patients.     

Urinary mevalonate excretion rate in type 2 diabetes: role of metabolic control

An increased cholesterogenesis has been described in obese dyslipidemic type 2 diabetic patients and in a small number of patients with poor glucose control. So far, it is not clear if increased cholesterogenesis in type 2 diabetes is related to the degree of glycemic control or depends on the commonly associated dyslipidemia or both. Therefore, the aim of the present study was to investigate the relationships among cholesterogenesis and degree of metabolic control in a group of non-obese normolipidemic type 2 diabetic patients. Fifty four (25 men and 29 postmenopausal women) non-obese type 2 diabetic patients with cholesterol and triglyceride plasma levels, respectively, below 6.40 and 2.85 mmol/l and 20 normal subjects matched for age and sex were studied. Endogenous cholesterol synthesis was evaluated by the determination of 24-h urinary mevalonate excretion (MVA). In the diabetic group the mean glycated hemoglobin was 8.47+/-2.2% (range 4.6-14.6%), the mean total cholesterol, triglycerides, HDL and LDL cholesterol were, respectively, 4.86+/-0.7, 1.64+/-0.5, 1.19+/-0.3 and 2.87+/-0.7 mmol/l. The mean 24-h MVA urine excretion rates were 1.41+/-0.3 micromol/24 h in control subjects and 1.66+/-0.7 micromol/24 h in diabetics (P=0.05). In diabetics, urinary mevalonate excretion was significantly correlated with glycated hemoglobin concentrations (HbA(1c)) (r=0.65; P=0.0001) and body mass index (BMI) (r=0.33; P=0.009). In the multivariate analysis both HbA(1c) and BMI were independent predictors of urinary mevalonate. These data demonstrate that lower the degree of blood glucose control, higher is the whole body cholesterol production even in the absence of overt dyslipidemia. In conclusion, the relationship between mevalonate excretion rate and glycated hemoglobin gives further weight to the importance of intensive blood-glucose control in diabetic disease and adds a new element to the list of potentially atherogenic factors strictly related to hyperglycemia in type 2 diabetic patients.     

Characteristics of type 2 diabetic patients responding to voglibose administration as an adjunct to sulfonylurea

In this study, we characterized type 2 diabetic patients responding well to the alpha-glucosidase inhibitor voglibose administration as an adjunct to sulfonylurea treatment. Thirty-three type 2 diabetic patients were enrolled in an open prospective study. All the patients had been treated for at least 1 year with a sulfonylurea drug, in whom HbA1c level had been stable for at least 12 weeks. The patients were given voglibose at a dose of 0.2 mg t.i.d. for 12 weeks. Voglibose administration significantly decreased the mean HbA1c level in all the patients at 4, 8, and 12 weeks. Twelve (36%) of the study patients were responders, when the responders were defined as patients whose HbA1c level at 12 weeks fell by at least 1.0% from baseline, or those whose HbA1c level at 12 weeks was < or =7.0%, falling by at least 0.5% from baseline. The baseline fasting plasma glucose (FPG) was significantly lower, and the baseline homeostasis model assessment (HOMA) beta-cell function (HOMA-%beta) was significantly higher in the responders than in the non-responders. There were more patients who had FPG <170 mg/dl and/or HOMA-%beta > or =30% in the responders than in the non-responders (P<0.005). None of the patients with both FPG > or =170 mg/dl and HOMA-%beta >30% responded to the adjunct treatment. These results indicate that baseline FPG and HOMA-%beta are useful clinical markers to predict the effectiveness of the adjunct therapy of voglibose in sulfonylurea-treated type 2 diabetic patients.     

Decrease in carotid intima-media thickness in hypothyroid patients after normalization of thyroid function

OBJECTIVE: This case-control study was carried out to assess whether levothyroxine (L-T4) replacement might cause regression of the enhanced atherosclerosis seen in hypothyroid patients. PATIENTS AND METHODS: Intima-media thickness (IMT) in the common carotid artery (CCA) was measured from digitalized still images taken during scanning by high-resolution ultrasonography as an indicator of early atherosclerosis. Thirty-five hypothyroid patients were examined for their CCA IMT before and 1 year after normalization of thyroid function by L-T4 replacement. As control, 35 healthy subjects were enrolled from among the participants in a local health-check programme conducted at the Osaka City University Hospital. RESULTS: Basal CCA IMT was significantly higher in hypothyroid patients [0.635 +/- 0.018 (mean +/- SE) mm] than in control subjects (0.559 +/- 0.021 mm, P < 0.005). After 1 year of euthyroidism, 34 out of 35 patients showed a significant decrease of CCA IMT, to 0.552 +/- 0.015 mm (P < 0.0001), a level comparable to normal controls. CCA IMT change was closely associated with basal levels of total cholesterol (r = -0.472, P= 0.0031), low-density lipoprotein (LDL) cholesterol (r = -0.441, P= 0.0076) and the total/HDL cholesterol ratio (r =-0.435, P= 0.0057), but not with any of the other variables measured except for age (r = -0.353, P= 0.0296). CONCLUSIONS: This study demonstrated that L-T4 treatment might have the potential to reverse the progression of atherosclerosis in hypothyroid patients. Furthermore, it suggests that increased levels of LDL cholesterol and the total/HDL cholesterol ratio have an important role in the increased common carotid intima-media thickness in hypothyroid patients.     

Abnormal foot function in diabetic patients: the altered onset of Windlass mechanism.

AIM: The aim of this study was to examine foot function in the presence of diabetes-induced alterations of the anatomical and biomechanical unit formed by the Achilles tendon, plantar fascia and metatarso-phalangeal joints. More specifically, we focused on the Windlass mechanism, the physiological mechanism which entails stiffening of the foot during propulsion. METHODS: Sixty-one diabetic patients, with or without neuropathy, and 21 healthy volunteers were recruited. The thickness of Achilles tendon and plantar fascia was measured by ultrasound. The main biomechanical parameters of foot-floor interaction during gait were acquired by means of dedicated platforms. The range of motion of the 1st metatarso-phalangeal joint was measured passively. RESULTS: The plantar fascia (PF) and Achilles tendon (AT) were significantly thickened in diabetic patients [control subjects: PF 2.0+/-0.5 mm, AT 4.0+/-0.5 mm; diabetic patients without neuropathy: PF 2.9+/-1.2 mm (P=0.002), AT 4.6+/-1.0 mm (P=0.016); diabetic patients with neuropathy: PF 3.0+/-0.8 mm (P<0.0001), AT 4.9+/-1.7 mm (P=0.026)]. Joint mobility was significantly reduced [control subjects: 100.0+/-10.0 degrees; diabetic patients without neuropathy: 54.0+/-29.4 degrees (P<0.0001); diabetic patients with neuropathy: 54.9+/-17.2 degrees (P<0.0001)]. Loading times and force integrals under the heel and the metatarsals increased [metatarsal loading time (% stance phase): control subjects 88.2+/-4.1%; diabetic patients without neuropathy 90.1+/-4.7% (P=0.146); diabetic patients with neuropathy 91.7+/-6.6% (P=0.048)]. CONCLUSIONS: Increased thickness of Achilles tendon and plantar fascia, more evident in the presence of neuropathy, may contribute to an overall increase of tensile force and to the occurrence of an early Windlass mechanism, maintained throughout the whole gait cycle. This might play a significant role in the overall alteration of the biomechanics of the foot-ankle complex.     

Voglibose administration before the evening meal improves nocturnal hypoglycemia in insulin-dependent diabetic patients with intensive insulin therapy

Nocturnal hypoglycemia is one of the serious complications of intensive insulin therapy in patients with insulin-dependent diabetes mellitus (IDDM; type 1 DM). We assessed the effect of voglibose (alpha-glucosidase inhibitor) administration before the evening meal on nocturnal hypoglycemia in IDDM patients with intensive insulin therapy. Ten IDDM patients received 0.3 mg voglibose just before the evening meal for 5 days. The diet and insulin regimen were not changed throughout the study. Nocturnal plasma glucose levels (10 PM, 3 AM, and 7 AM) were studied in these patients before and during voglibose administration. Blood glucose levels were measured at 3 AM before and during voglibose treatment. The mean plasma glucose level at 3 AM was 3.4+/-0.4 mmol/L before voglibose treatment and 7.3+/-1.0 mmol/L during treatment. Plasma glucose at 3 AM was elevated in 9 of 10 patients with voglibose. The decrease in plasma glucose from 10 PM to 3 AM was 6.5+/-0.8 mmol/L before voglibose administration but 3.2+/-0.9 mmol/L during treatment (P < .01). The hypoglycemia rate was 52% (17 of 33 nights) before voglibose administration but only 9.1% (3 of 33 nights) during treatment. We conclude that voglibose administration before the evening meal improves nocturnal hypoglycemia in IDDM patients with intensive insulin therapy.     

Natural course of kidney function in Type 2 diabetic patients with diabetic nephropathy.

AIMS: To determine the natural course of kidney function and to evaluate the impact of putative progression promoters in Caucasian Type 2 diabetes mellitus (DM) patients with diabetic nephropathy who had never received any antihypertensive treatment. METHODS: A long-term observational study of 13 normotensive to borderline hypertensive Type 2 DM patients with diabetic nephropathy. Glomerular filtration rate (GFR) was measured approximately every year (51Cr-EDTA plasma clearance technique). Albuminuria, blood pressure (BP) and haemoglobin A1c (HbA1c) was determined 2-4 times per year and serum cholesterol every second year. RESULTS: The patients (12 males/one female), age 56+/-9 (mean +/- SD) years, with a known duration of diabetes of 10+/-6 years, were followed for 55 (24-105) (median (range)) months. GFR decreased from 104 (50-126) to 80 (39-112) ml x min(-1) x 1.73 m(-2) (P = 0.002) with a median rate of decline of 4.5 (-0.4 to 12) ml x min(-1) x year(-1). During follow-up, albuminuria rose from 494 (301-1868) to 908 (108-2169) mg/24 h (P = 0.25), while BP, HbA1c and serum cholesterol remained essentially unchanged. In univariate analysis the rate of decline in GFR did not correlate significantly with neither baseline nor mean values during follow-up of BP, albuminuria, HbA1c and serum cholesterol. CONCLUSIONS: Our study suggests that normotensive to borderline hypertensive Type 2 DM patients with diabetic nephropathy have a rather slow decline in kidney function, but we did not unravel the putative progression promoters responsible for the variation in rate of decline in GFR.     

Relative hypoleptinemia in patients with type 1 and type 2 diabetes mellitus

OBJECTIVE: To determine the relation between plasma leptin concentrations and metabolic control in human diabetes mellitus. DESIGN AND SUBJECTS: Cross sectional study consisting of 156 patients with diabetes mellitus type 1 (n=42), type 2 (n=114), and non-diabetic subjects (n=74). RESULTS: Plasma leptin concentrations were lower (P<0.05) in type 1 (8.3+/-1.7 ng/ml) and type 2 diabetic (14.9+/-1.8 ng/ml) than in non-diabetic humans (18.3+/-1.9 ng/ml). Only female type 1 and type 2 diabetic subjects also had decreased leptin/BMI ratios (P<0.05 vs non-diabetic females). The log rank test identified age-adjusted correlation of plasma leptin concentration with sex (P<0.0004) and body mass index (P<0.0218), but not with glycosylated haemoglobin A1c (P>0.5) in all groups. Plasma leptin was correlated with age (P<0.0058) and serum triglycerides (P<0.0199) in type 1 diabetic patients, and with serum cholesterol (P<0.0059) and LDL (P<0.0013) in type 2 diabetic patients. CONCLUSIONS: Defective leptin production and/or secretion might be present independently of metabolic control in female patients with type 1 or type 2 diabetes mellitus.     

Determinants of early carotid atherosclerosis progression in young patients with type 1 diabetes mellitus.

The results of cross-sectional studies addressing early preintrusive atherosclerosis in type 1 diabetic patients are conflicting. In an observational longitudinal study we determined the course of carotid artery intima-media thickness (IMT) over a period of 2.5 years in mean. A total of 102 patients with type 1 diabetes mellitus (age < or = 40 years, diabetes duration > or = 2 years at baseline examination) who were participants of the baseline examination was studied again in a follow-up. HbA1c, albumin excretion rate (AER), lipids, systolic and diastolic blood pressure, retinopathy, and current smoking status were assessed at baseline and follow-up. The IMT of the common carotid artery was measured by high-resolution ultrasound, the maximum IMT was evaluated. The annual progression rate (APR) was calculated from the difference between baseline and follow-up IMT reading and the time between both examinations. The follow-up IMT was significantly higher, compared to the baseline measurement: 0.65 +/- 0.18 vs. 0.57 +/- 0.14 mm (p < 0.001), the mean APR was 0.033 mm/year. The APR was correlated with age (r = 0.337, p < 0.01), diabetes duration (r = 0.252, p < 0.05), hypertension (r = 0.225, p < 0.05), and systolic blood pressure (r = 0.281, p < 0.05) at the baseline examination. Comparing subgroups, defined according to APR tertiles, with no IMT progression (first tertile, mean APR - 0.012 mm/year), mild progression (second tertile, mean APR 0.037 mm/year), and advanced progression (third tertile, mean APR 0.088 mm/year), patients with advanced progression significantly (p < 0.05) more often had hypertension and nephropathy than subjects with mild progression. In a multiple linear regression analysis, the changes of plaque frequency and of the nephropathy status between baseline and follow-up examinations were independent predictors of the APR.     

Relationship between carotid atherosclerosis and erythrocyte membrane cholesterol oxidation products in type 2 diabetic patients

Oxidative stress is well known to play a critical role in atherosclerosis. This study investigated an appropriate marker of in vivo oxidative stress and whether it could predict macroangiopathy in diabetes. The lipid composition of erythrocyte membranes was analyzed in 64 type 2 diabetic patients using gas chromatography-mass spectrometry (GC/MS). After 3,5,7-cholestatriene (a cholesterol oxidation product) was detected, the peak height ratio of 3,5,7-cholestatriene to cholesterol was calculated. Carotid artery intima-media thickness (IMT) was measured to evaluate atherosclerosis. The IMT was independently associated with 3,5,7-cholestatriene (P<0.0001), age (P=0.0001), and HbA1c (P=0.05) by stepwise multiple regression analysis (R2=0.416, P<0.0001). When the subjects were divided into groups with or without carotid atherosclerosis, the 3,5,7-cholestatriene level was significantly higher in 37 subjects with atherosclerosis than in 27 subjects without it (0.41+/-0.22 vs. 0.16+/-0.16%, P<0.0001). Among 38 subjects with no clinical manifestations of macroangiopathy and long-term good glycemic control, the 3,5,7-cholestatriene level was also significantly higher in the patients with carotid atherosclerosis than in those without it (0.40+/-0.20 vs. 0.18+/-0.12%, P=0.0003). These data suggest that the 3,5,7-cholestatriene level in erythrocyte membrane lipids may be a useful predictor of subclinical atherosclerosis.     

Levels of transforming growth factor beta 1 in south Indian type 2 diabetic subjects

BACKGROUND AND AIMS: The prosclerotic cytokine TGFbeta has been implicated as an important downstream mediator in the progression of the renal pathological changes occurring in diabetic patients. This study was undertaken to determine (1) whether serum levels of zTGFbeta1 was elevated in South Indian type 2 diabetic subjects and (2) whether treatment with oral hypoglycaemic agents/insulin and angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) influenced TGFbeta1 levels in diabetic subjects. METHODS: Among the 131 study subjects, 101 were consecutive type 2 diabetic patients and the other 30 subjects were non-diabetic, normoglycaemic (NGT, M : F 15 : 15) healthy subjects who had undergone an Oral Glucose Tolerance Test (OGTT) during medical checkup. TGFbeta1 was determined using solid-phase sandwich enzyme-linked immunosorbent assay. RESULTS: Mean serum TGFbeta1 levels were significantly elevated (p < 0.0001) in the type 2 diabetic subjects (30 +/- 13.1 ng/mL) when compared with the non-diabetic subjects (19 +/- 8.3 ng/mL). Diabetic subjects who were being treated with a combination of OHA and insulin (n = 53;25.6 +/- 11.5 ng/mL) had significantly (p = 0.0009) lower levels of TGFbeta1 when compared with those who were being treated with OHA alone (n = 48;34.1 +/- 13.4 ng/mL). Nearly 36% of the diabetic subjects were being treated with ACEI/ARB, and they had significantly (p = 0.01) lower levels of TGFbeta1 (n = 36;25.4 +/- 12.6 ng/mL) when compared with those who were not being treated with ACEI/ARB (n = 65;32 +/- 12.9 ng/mL). CONCLUSION: The present study demonstrated significantly elevated TGFbeta1 levels in South Indian type 2 diabetic patients when compared with the non-diabetic subjects. Insulin and ACEI/ARB treatment appears to have a protective effect by lowering TGFbeta1 concentrations in these subjects.     

Association of cholesterol levels,hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment,and progression of aortic stenosis in the community

OBJECTIVES: This study was designed to analyze the association among cholesterol levels, lipid-lowering treatment, and progression of aortic stenosis (AS) in the community. BACKGROUND: Aortic stenosis is a progressive disease for which there is no known medical treatment to prevent or slow progression. Despite plausible pathologic mechanisms linking hypercholesterolemia to AS progression, clinical studies have been inconsistent and affected by referral bias, and the role of lipid-lowering therapy is uncertain. METHODS: We determined the association between blood cholesterol levels and progression of native AS (assessed by Doppler echocardiography at baseline and at least six months later; mean interval, 3.7 +/- 2.3 years) in a community-based study of 156 patients (age 77 +/- 12 years; 90 men). Thirty-eight patients received statin treatment during follow-up. RESULTS: In untreated subjects, mean gradient increased from 22 +/- 12 mm Hg to 39 +/- 19 mm Hg, and aortic valve area (AVA) decreased from 1.20 +/- 0.35 cm(2) to 0.91 +/- 0.33 cm(2) (both p < 0.001). The annualized change in AVA was -0.09 +/- 0.17 cm(2)/year (-7% +/- 13%/year). Neither total cholesterol (r = -0.01, p = 0.92) nor low-density lipoprotein cholesterol (r = 0.01; p = 0.88) showed a significant correlation to AS progression. Nevertheless, progression of AS was slower in patients receiving statins compared with untreated patients (decrease in AVA -3 +/- 10% vs. -7 +/- 13% per year, respectively; p = 0.04), even when adjusted for age, gender, cholesterol, and baseline valve area (p = 0.04). The association of statin treatment with slower progression was confirmed when analysis was restricted to patients coming for a systematic follow-up (p=0.02). The odds ratio of AS progression with statin treatment was 0.46 (95% confidence interval, 0.21 to 0.96). CONCLUSIONS: In the community, progression of AS shows no trend of association with cholesterol levels. Statin treatment, however, is associated with slower progression, suggesting that the effects of statin treatment on progression of AS should be pursued with appropriate clinical trials.     

Porphyromonas gingivalis infection is associated with carotid atherosclerosis in non-obese Japanese type 2 diabetic patients

The aim of the present study was to investigate whether non-obese Japanese type 2 diabetic patients with porphyromonas gingivalis infection have atherosclerotic vascular diseases. A total of 134 non-obese Japanese type 2 diabetic patients (96 men and 38 women, aged 36 to 84 years, body mass index [BMI] 20.1 to 26.9 kg/m(2)) were studied. In conjunction with BMI, glycosylated hemoglobin (HbA(1c)), fasting glucose, and serum lipids (triglycerides, total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol) were measured. LDL cholesterol was calculated using the Friedewald formula. Using high-resolution B-mode ultrasound scan, we measured intimal medial thickness (IMT) in plaque-free segments of bilateral common carotid arteries, and the mean of IMT in 2 vessels was used for the analysis. Furthermore, we calculated the degree of stenosis in plaque segments of bilateral common carotid arteries. The degree of carotid atherosclerosis was expressed as a percentage ratio between the area of plaque and that of the lumen using the formula (Lumen Area Residual - Lumen Area)/Lumem Area x 100. Both the areas were automatically measured by the system on a frozen transverse scanning plane at the site of maximal narrowing. When 2 or more plaques were present in the vessel, only that causing the greatest degree of stenosis was considered for analysis. Values represent mean+/-SEM unless otherwise stated. Immunoglobulin G (IgG) titer against porphyromonas gingivalis was 245 +/- 65 (mean +/- 2 SD) in nondiabetic healthy subjects. In contrast, there was a wide variation in IgG titer against porphyromonas gingivalis in type 2 diabetic patients studied (range, 16 to 26,800). Thus, we classified our type 2 diabetic patients into 2 subpopulations according to the value of mean +/- 2 SD (= 310) of nondiabetic healthy subjects: one with high IgG titer against porphyromonas gingivalis (>310) (1,422 +/- 408) and the other with normal IgG titer against porphyromonas gingivalis (<310) (152 +/- 10, P =.002). The populations did not differ with respect to age, sex, BMI, fasting glucose, HbA(1c), serum triglycerides, total, HDL, and LDL cholesterol levels. Although the mean IMT in plaque-free segments was not different between the 2 groups (0.73 +/-0.03 v 0.68 +/- 0.02 mm, P =.098), the degree of stenosis in plaque segments was significantly higher in the high IgG titer group (12.0% +/- 2.2%) than in normal one (5.5% +/- 1.4%, P =.009). From these results, it can be concluded that porphyromonas gingivalis infection, although still a subclinical infection, is associated with atherosclerotic vascular disease in non-obese Japanese type 2 diabetic patients.     

Serum levels of substance P are decreased in patients with type 1 diabetes.

Morphological and immunohistochemical studies in diabetic subjects have shown a depletion of the neuropeptide substance P (SP) in the central and peripheral nervous system. This is the first study investigating serum levels of substance P in type 1 diabetes patients (n=50) and controls (n=75) by means of an enzyme immunoassay. The serum level of SP was significantly decreased in the diabetic group compared to the control group (10.12+/-0.29 vs. 12.25+/-0.38 pg/ml; p<0.0001). In diabetic patients, there was no correlation of substance P levels with age, serum creatinine, albuminuria, total cholesterol, HDL- or LDL-cholesterol, triglycerides, HbA1c, type or duration of diabetes and gender. Furthermore, there was no difference in serum levels of SP in patients with or without retinopathy, but SP was significantly decreased in patients with neuropathy (9.59+/-0.48 vs. 10.78+/-0.83 pg/ml; p=0.04). These data show that SP is decreased in serum of type 1 diabetes patients, especially in those with diabetic neuropathy. Subsequent and already ongoing prospective studies in well validated diabetic patients with neuropathy may characterize the impact of this neurogenic marker in the course of diabetic neuropathy.     

Progression of mitral regurgitation: a prospective Doppler echocardiographic study.

OBJECTIVES: This study was performed to define the rates and determinants of progression of organic mitral regurgitation (MR). BACKGROUND: Severe MR has major clinical consequences, but the rates and determinants of progression of the degree of regurgitation are unknown. Quantitative Doppler echocardiographic methods allow the quantitation of regurgitant volume (RVol), regurgitant fraction (RF) and effective regurgitant orifice (ERO) to define progression of MR. METHODS: In a prospective study of MR progression, 74 patients had two quantitative Doppler echocardiographic examinations of MR (with at least two methods) 561 +/- 423 days apart without an intervening event. RESULTS: Progression of MR was observed, with increase in RVol (77 +/- 46 ml vs. 65 +/- 40 ml, p < 0.0001), RF (47 +/- 16% vs. 43% +/- 15%, p < 0.0001), and ERO (50 +/- 35 mm2 vs. 41 +/- 28 mm2, p < 0.0001). Annual rates (95% confidence interval) were, respectively, 7.4 ml/year (5.1, 9.7), 2.9%/year (1.9, 3.9) and 5.9 mm2/year (3.9, 7.8). However, wide individual variation was observed, and regression and progression of RVol >8 ml was found in 11% and 51%, respectively. In multivariate analysis, independent predictors of progression of RVol were progression of the lesions, particularly a new flail leaflet (p = 0.0003), and progression of mitral annulus diameter (p = 0.0001). Regression of MR was associated with marked changes in afterload, particularly decreased blood pressure (p = 0.008). No significant effect of treatment was detected. CONCLUSIONS: Organic MR tends to progress over time with increase in volume overload (RVol) due to increase in ERO. Progression of MR is variable and determined by progression of lesions or mitral annulus size. These data should help plan follow up of patients with organic MR and future intervention trials.     

Pancreatic scintigraphy with 99mTc-interleukin-2 at diagnosis of type 1 diabetes and after 1 year of nicotinamide therapy

BACKGROUND: To evaluate the clinical utility of pancreatic scintigraphy with 99mTc-interleukin-2 to identify Type 1 diabetic patients with pancreatic inflammation at diagnosis. METHODS: 99mTc-interleukin-2 scintigraphy was performed on 42 newly diagnosed Type 1 diabetic patients, before and after 1 year of treatment with nicotinamide (25 or 50 mg/kg/day) in addition to intensive insulin therapy. Metabolic status was monitored every 3 months for 1 year. Sixteen normal subjects were studied as control. RESULTS: Significant pancreatic accumulation of 99mTc-interleukin-2 was found in 31% of the patients at the time of diagnosis. Patients positive or negative for pancreatic accumulation of interleukin-2 scintigraphy did not show any difference in metabolic or immunologic parameters at diagnosis. Positive patients, however, showed higher C-peptide values at 3 months and lower insulin requirement at 1 year, compared to negative patients (insulin requirement (IR): 0.33+/-0.11 vs 0.67+/-0.24 IU/kg/day, positive vs negative patients; p=0.0001); patients positive to IL2 scintigraphy treated with nicotinamide at 25 mg/kg were the only group showing a significant reduction in IR 1 year after diagnosis (IRt0: 0.53+/-0.30 vs IRt12: 0.28+/-0.07 IU/kg/day; p=0.013). After 1 year, all the positive patients showed a significant decrease in pancreatic uptake of 99mTc-interleukin-2 (P/B: 7.87+/-2.28 at diagnosis vs 5.00+/-1.23 after 1 year; p<0.0001 paired t-test). CONCLUSION: 99mTc-interleukin-2 scintigraphy at diagnosis of Type 1 diabetes may identify patients with pancreatic inflammation. In such patients, treated with nicotinamide at 25 mg/kg, insulin requirement and pancreatic inflammation after 1 year were significantly reduced suggesting that IL2 scintigraphy may be of potential use for assessing the autoimmune phenomena in endocrine pancreas.