Simvastatin maintains steady patterns of GFR and improves AER and expression of slit diaphragm proteins in type II diabetes.

The factors determining the course of glomerular filtration rate (GFR) and albumin excretion rate (AER) and the expression of mRNA of slit diaphragm (SD) and podocyte proteins in microalbuminuric, hypertensive type II diabetic patients are not fully understood. GFR, AER, and SD protein mRNA were studied in 86 microalbuminuric, hypertensive, type II diabetics at baseline and after 4-year random double-blind treatment either with 40 mg simvastatin (Group 1) or with 30 g cholestyramine (Group 2) per day. Both groups had at baseline a GFR decay per year in the previous 2-4 years of 3 ml/min/1.73 m(2). Both Groups 1 and 2 showed a significant decrease of low-density lipoprotein cholesterol levels after simvastatin and cholestyramine treatment (P<0.01). No change from base line values was observed as for hs-C-reactive protein and interleukin-6. A significant decrease of 8-hydroxydeoxyguanosine urinary excretion was observed after simvastatin treatment. GFR did not change from baseline with simvstatin, whereas a decrease was observed with cholestyramine treatment (simvastatin vs cholestyramine: -0.21 vs -2.75 ml/min/1.73 m(2), P<0.01). AER decreased in Group 1 (P<0.01), but not in Group 2 patients. Real-time polymerase chain reaction measurement of mRNA SD proteins (CD2AP, FAT, Actn 4, NPHS1, and NPHS2) significantly increased in kidney biopsy specimens after simvastatin, but not cholestyramine treatment. Simvastatin, but not cholestyramine, 4-year treatment maintains steady patterns of GFR, and improves AER and expression of SD proteins in type II diabetes, despite similar hypocholesterolemic effects in circulation.

Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent.

BACKGROUND AND AIMS: In patients with non-insulin dependent diabetes mellitus (T2DM) and associated chronic liver disease, plasma levels of glucose, insulin and triglycerides are high, lipid peroxidation is increased and natural antioxidant reserves are reduced. Thus, we hypothesised that the re-balancing of cell redox levels and amelioration of liver function could result in a better glucose and lipid metabolism. To study this, we assessed the effect of a new oral formulation of an antioxidant agent - silybin-beta-cyclodextrin (named IBI/S) - in patients with chronic alcoholic liver disease and concomitant T2DM. METHODS: Sixty outpatients were enrolled in a three-centre, double blind, randomised, IBI/S vs placebo study. Forty-two (21 in the group IBI/S - 135 mg/d silybin per os - and 21 in the placebo group) concluded the 6-month treatment period. The efficacy parameters included fasting and mean daily plasma glucose levels, glycosylated hemoglobin (HbA1c), basal, stimulated C-peptide and insulin levels, total-, HDL-cholesterol and triglycerides levels in addition to conventional liver function tests. Insulin sensitivity was estimated by HOMA-IR. Malondialdehyde (MDA) was also measured before and after treatment as an index of oxidative stress. RESULTS: Fasting blood glucose levels, which were similar at baseline in IBI/S group and in the placebo group (173.9 mg/dl and 177.1 mg/dl, respectively), decreased to 148.4 mg/dl (-14.7% vs baseline; p = 0.03) in the IBI/S group while they were virtually unchanged in the placebo group. The comparison between the groups at mo 6 (T6) also showed a significant reduction of glucose levels in the IBI/S group (p = 0.03). The same trend was observed in mean daily blood glucose levels, HbA1c and HOMA-IR, although differences were not significant. Basal and stimulated C-peptide values showed that only a few changes had occured in both groups. Such results indicate that insulin secretion was virtually unaffected, as confirmed also by the insulinemia data. Plasma triglycerides concentrations dropped from a baseline value of 186 mg/dl to 111 mg/dl (T6) in the IBI/S group, with significant differences at all instances with respect to baseline values. By contrast, triglycerides increased from 159 mg/dl at entry to 185 mg/dl (T6) in the placebo group. The difference between the groups at T6 was highly significant (p < 0.01). Total and HDL cholesterol as well as liver function tests did not change significantly during the study in both groups. MDA decreased significantly only in the group receiving IBI/S. No clinically relevant side effects were observed in either group. CONCLUSIONS: Oral administration silybin-beta-cyclodextrin in patients with T2DM and compensated chronic alcoholic liver disease causes a significant decrease in both glucose and triglyceride plasma levels. These effects may be due to the recovery of energy substrates, consistent with a reduced lipid peroxidation and an improved insulin activity.

Long-term (18-month) efficacy of atorvastatin therapy in type 2 diabetics at cardiovascular risk.

BACKGROUND AND AIM: Dyslipidemia (increased triglyceride and low high-density lipoprotein [HDL] levels, with normal or slightly increased total cholesterol levels) is a common characteristic of type 2 diabetics and a major risk factor for cardiovascular diseases. The aim of this study was to evaluate the long-term efficacy of atorvastatin in a cohort of type 2 diabetics. METHODS AND RESULTS: Participants were divided into 3 groups on the basis of whether they had evidence of myocardial infarction or coronary lesions (group A), a family history of hypercholesterolemia (and/or cardiovascular diseases) and total cholesterol levels constantly above 270 mg/dL in blood samples taken at regular 4-month intervals and previously never at target level (group B), or clinical and/or instrumental (electrocardiogram) evidence of cardiovascular risk (group C). Their mean age was 64 +/- 7 years, known disease duration 0.5 +/- 3 years, body mass index (BMI) 27.7 +/- 1.3 Kg/m2, and haemoglobin A1c 8 +/- 0.6%. Total cholesterol was 256 +/- 24 mg/dL in group A, 298 +/- 25 mg/dL in group B and 244 +/- 31 mg/dL in group C (p < 0.05: group B vs groups A and C). HDL-cholesterol (HDL-C) was 45 +/- 7 mg/dL, triglycerides 225 +/- 20 mg/dL, systolic and diastolic blood pressure (DBP) respectively 144 +/- 7 and 85 +/- 8 mmHg, fibrinogen 330 +/- 23 mg/dL and microalbuminuria 58 +/- 9 mg/L. Eighteen months' atorvastatin treatment (10 mg/day in 106 subjects, 20 mg in 14 subjects, 30 mg in 5 subjects, and 40 mg in 30 subjects) led to a significant decrease in total and low-density lipoprotein (LDL)-cholesterol and triglyceride levels (p < 0.01), with about 86% of the patients achieving target levels, and a significant (p < 0.05) increase in HDL-C. There was a significant decrease in fibrinogen, microalbuminuria and DBP (p < 0.01), without any change in diet, BMI, physical activity or antihypertensive treatment. No new cardiovascular events or hospital admissions due to cardiovascular diseases were recorded during the 18 months of the study. CONCLUSIONS: These long-term treatment findings confirm and validate previous medium-term results, and suggest that atorvastatin therapy is effective and safe in the primary and secondary prevention of cardiovascular complications in type 2 diabetes.

Lispro insulin treatment in comparison with regular human insulin in type 2 diabetic patients living in nursing homes.

Lispro insulin has been demonstrated to be effective in reducing post-prandial blood glucose levels. Thirty Type 2 diabetic subjects (18 women and 12 men) living in nursing homes, aged 77 +/- 3 yr, mean systolic pressure 147 +/- 6 and diastolic 82 +/- 4 mmHg, body mass index 27.5 +/- 2 kg/m2, known diabetes duration 10.1+/- 0.7 yr, mean HbA1c 8.5 +/- 0.8%, fasting C-peptide 1.3 +/- 0.5 ng/ml, treated with intensive (4 insulin injections per day) therapy, mean insulin need 45 +/- 7 IU per day, with 2.0 +/- 0.6 hypoglycaemic (blood glucose level below 60 mg/dl) and 13 +/- 4 hyperglycaemic episodes (blood glucose level over 250 mg/dl) per wk, were studied. Their own informed consent or that provided by a family member was obtained before these patients took part in a therapy protocol divided into 3 four-mo periods; in the 1st and 3rd period regular insulin (75% of the total dose) was administered 30 min before each meal, in the second lispro insulin was administered immediately at the end of each meal, according to the carbohydrate quantity ingested with the meal. During the lispro treatment period there was a significant decrease of the mean daily blood glucose 166 +/- 12 regular vs 143 +/- 9 lispro; p<0.01, HbA1c 8.5 +/- 0.6 regular vs 7.6 +/- 0.5 % lispro; p<0.01, triglycerides 261 +/- 40 regular vs 218 +/- 20 mg/dl lispro; p<0.01, hypoglycaemic 2.1 +/- 0.2 regular vs 1.6 +/- 0.3 lispro; p<0.01 and hyperglicaemic 12 +/- 1 regular vs 8 +/- 0.3 lispro; p<0.01 episodes per wk. No statistical difference was recorded between the 1st and the 3rd treatment period. The lispro treatment produced a better metabolic control (mean blood glucose, HbA1c, triglycerides), better lifestyle (less hypo- and hyperglycaemic episodes), better nurse management (no waiting time before, but a more accurate calculation of the right dose administered immediately at the end of each meal). Lispro insulin seems to be a good therapeutic choice not only in Type 1, but also in the large population of elderly Type 2 diabetic patients.

MCC-555 (Mitsubishi-Tokyo Pharmaceuticals).

Mitsubishi-Tokyo (formerly Mitsubishi Chemical) is developing MCC-555, a thiazolidinedione peroxisome proliferation activated receptor (PPAR)-gamma agonist, as a potential treatment for type 2 diabetes [204644]. Johnson and Johnson is developing the compound outside of Japan [304271,322655]. As of March 2000, MCC-555 was in phase II trials as an insulin sensitizer, both in Japan and abroad [371091]. Phase I trials have been completed by Mitsubishi-Tokyo in the UK and Japan [304271]. Johnson and Johnson trials have shown that the drug is 3-fold more potent than rosiglitazone in the diabetic mouse model, KK-Ay. MCC-555 activates the PPARgamma target gene, aP2, with greater maximal efficacy than other agonists of this target [322655]. MCC-555 binds PPARgamma transcriptional activity which is highly context-specific, such that it can function as a full or partial agonist, or an antagonist, depending on the cell type or DNA binding site. These transcriptional properties are partially explained by unique partial agonism of coactivator recruitment to PPARgamma. This context-specific activity may contribute to its enhanced hypoglycemic potency in vivo despite reduced affinity for PPARgamma [335218]. In February 1999, ING Barings reported that Mitsubishi Chemical expected peak potential sales of yen100 billion for MCC-555, although analysts regarded this prediction as being excessively high at the time [405416].

Evidence of a threshold value of glycated hemoglobin to improve the course of renal function in type 2 diabetes with typical diabetic glomerulopathy.

We recently observed that the course of glomerular filtration rate (GFR) rapidly declines in a subgroup of Type 2 diabetic patients (D) with abnormalities of albumin excretion rate (AER) and typical diabetic nephropathy, despite tight blood pressure control. The aim of this study was to evaluate whether amelioration of blood glucose control, using insulin, improves the course of GFR. GFR decay was measured by spline modeling analysis of the plasma clearance rate of 51CR-EDTA, assessed every 6 months. We identified two groups of D using morphometric analysis of renal biopsy, who had values of glomerular basement membrane (GBM) and fractional mesangial volume (Vv mes/glom) respectively below (Group A: 38) or above (Group B: 50) the mean+2SD of values found in 27 kidney donors (GBM: 389 nm; Vv mes/glom: 0.25), as previously described in detail. Median AER was similar at base line in the 2 groups (109 microg/min, 29-1950, in Group A, 113 microg/min, 37-1845, in Group B; n.s.). Conventional metabolic therapy (sulphonylureas and/or biguanides) was used both in Group A and B during a 3 year follow-up period (Period 1). Group B was further divided in two subgroups with body mass index below (Group B, a) and above (Group B, b) the value of 30 kg/m2. Mean +/- SD HbA1c was 8.2 +/- 1.6% in Group A, 8.3 +/- 1.7% in Group B (a) (n.s.) and 9.1 +/- 1.7% in Group B (b) (n.s.). Tight blood pressure control was achieved and maintained using angiotensin converting enzyme inhibitors and/or beta blockers and/or calcium antagonists and/or thiazides. The mean arterial blood pressure (MAP) was 92 +/- 3 mmHg in Group A and 91 +/- 4 mmHg in Group B (n.s.). GFR decay was significantly greater in Group B than in Group A (Group A vs B: +1.21 +/- 0.71 vs -5.86 +/- 1.61 ml/min/1.73 m2/year). Median AER significantly rose in Group B (177 microg/min, p<0.05 vs base line) but not in Group A (134 microg/min, n.s.) during the third year of follow-up. Groups A and B were then followed over 4.1 years (range 3.1-4.4) (Period 2) maintaining the above described antihypertensive regimen, resulting in MAP values similar to those described during Period 1. Group A patients were treated with the same conventional glycemic control during Period 2. Group B (a) was conversely treated with intensive insulin therapy to achieve a HbA1c value below 7.5% (3 daily injections of regular and 1 or 2 daily injections of intermediate acting insulin associated with metformin 500 mg twice daily in 64% of the patients). Group B (b) patients were only treated by metformin (850 mg thrice daily) to achieve a HbA1c value below 7.5%. HbA1c decreased below the 7.5% target value in Group B (a) (7.0 +/- 1.6%, p<0.01 vs Period 1), but not in Group B (b) (8.0 +/- 1.6%, p<0.05 vs Period 1) and in Group A (8.3 +/- 1.7%, n.s. vs Period 1). The GFR decay of Group B, a during Period 2 was lower than that during Period 1 (Period 1 vs Period 2: -5.9 +/- 1.8 vs -1.8 +/- 0.7 ml/min/1.73 m2/year, p<0.01). GFR decay during Period 2 was similar to that observed during Period 1 in Group A (Period 1 vs Period 2: +1.21 +/- 0.71 vs +0.7 +/- 0.6 ml/min/1.73 ml/year, n.s.) and in Group B (b) (Period 1 vs Period 2: -4.4 +/- 0.71 vs -4.2 +/- 0.6 ml/min/1.73 m2/year, n.s.). Median AER did not significantly change in the fourth year of Period 2 , either in Group A or B (Group A vs B: 141 vs 152 microg/min, n.s.). In conclusion, our findings seem to suggest that amelioration of blood glucose control is attained both by insulin and metformin intensive treatment, but only insulin decreases and maintains HbA1c levels below 7.5%. These pattens of HbA1c appear to be a threshold value in order to significantly blunt GFR decay in a subgroup of Type 2 diabetic patients with typical diabetic glomerular lesions, who are less responsive to tight blood pressure control alone. Conversely, the cohort of patients with less severe diabetic glomerulopathy steadily show constant GFR patterns, despite similar abnormalities of albumin excretion rate, and HbA1c average values above 7.5%.

Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate.

Heterogeneity in renal structure has been described in type 2 diabetic patients with both microalbuminuria and proteinuria; in fact, only a subset of type 2 diabetic patients have the typical diabetic glomerulopathy. However, it is currently unknown whether abnormalities in albumin excretion rate (AER) have a different renal prognostic value depending on the underlying renal structure. Aims of this study were: 1) to study the course of renal function in type 2 diabetic patients with altered AER; 2) to evaluate the relationship between the course of glomerular filtration rate (GFR) and renal structure; and 3) to evaluate the relationship between the course of GFR and baseline AER levels, metabolic control, and blood pressure levels during a follow-up period of 4 years. A total of 108 type 2 diabetic patients, 74 with microalbuminuria (MA) and 34 with proteinuria (P), were recruited into a prospective study that encompassed: 1) a baseline kidney biopsy with morphometric measurements of glomerular parameters; 2) intensified antihypertensive treatment for an average 4-year period (blood pressure target <140/90 mmHg); and 3) determinations of GFR at baseline and every 6 months. Mean (+/- SD) GFR significantly decreased from baseline in both MA (-1.3+/-9.4 [95% CI -3.51 to +0.86], P < 0.05) and P (-3.0+/-13.0 ml x min(-1) x 1.73 m(-2) per year [-7.71 to +1.61], P < 0.01). However, the changes in GFR were quite heterogeneous. Thus, on the basis of percent GFR change per year from baseline (delta%GFR), both MA and P patients were defined as progressors or nonprogressors when they were below or above the median, respectively. Baseline parameters of glomerular structure had a strong influence on the course of GFR. Indeed, the odds ratios of being progressors significantly increased across the quartiles of baseline glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(mes/glom)], being 2.71 and 2.85 higher, respectively, in the fourth quartile than in the first quartile (P < 0.01 for both). Conversely, nonprogressors outnumbered progressors in the first quartile of GBM width (odds ratio: 2.14, P < 0.05) and in the first quartile of Vv(mes/glom) (odds ratio: 2.28, P < 0.01). Baseline albumin excretion rate (AER) did not influence delta%GFR; in fact, the number of progressors did not increase across quartiles of baseline AER among either MA or P. Similarly, mean blood pressure levels during follow-up (and intensified antihypertensive therapy) did not affect the course of GFR: the number of progressors and nonprogressors did not change across quartiles of mean blood pressure. In contrast, HbA1c during follow-up had an impact on delta%GFR: the odds ratio for being a progressor increased across quartiles of HbA1c, particularly for the highest quartile (HbA1c >9.0%). In conclusion, the course of renal function is heterogeneous in type 2 diabetic patients with microalbuminuria or proteinuria. In fact, a subset of patients has a rapid decline in GFR over a 4-year follow-up period; these patients have more advanced diabetic glomerulopathy and worse metabolic control than the remaining patients, whose GFR remains stable. These two cohorts are otherwise undistinguishable as regards the degree of AER at baseline and tight blood pressure control. Kidney biopsy has an important prognostic role in these patients. Thus, tight blood pressure control, when not associated with satisfactory glycemic control, is unable to prevent rapid GFR decline in type 2 diabetic patients with typical diabetic glomerulopathy.

Poorly controlled elderly Type 2 diabetic patients: the effects of increasing sulphonylurea dosages or adding metformin.

AIMS: To assess the effects and safety of increasing sulphonylurea dosages or adding metformin in poorly controlled elderly Type 2 diabetic patients. METHODS: A 18-month multicentre clinical study was performed on sulphonylurea-treated diabetic patients over 70 years of age with well-preserved renal function, steady fasting blood glucose > or = 200 mg/dl and HbA1c > or = 9%. Patients were randomly assigned to sulphonylurea increased up to its maximum dosage (1st group) or to addition of metformin (2nd group). Glycaemic control, lipid pattern, haemostatic status and safety were monitored during run-in, at baseline and at scheduled intervals for 18 months. Results refer to 85 patients in the 1st group and 89 patients in the 2nd with complete data. RESULTS: Similar improvements in glycaemic levels were observed with both treatments within the first month and a similar decrease in HbA1c within the third month. No further changes occurred in glycaemic control. In the 1st group, fasting glucose (mmol/l, mean +/- SE) decreased from 14.21 +/- 0.49 to 9.88 +/- 0.21, average day-long glucose from 14.87 +/- 0.27 to 10.69 +/- 0.19 and HbAt1c(%) from 10.32 +/- 0.13 to 8.66 +/- 0.13. In the 2nd treatment group fasting glucose decreased from 14.59 +/- 0.61 to 9.05 +/- 37.28, average day-long glucose from 15.09 +/- 0.29 to 10.32 +/- 0.21 and HbA1c from 10.33 +/- 0.13 to 8.77+/-0.12 (for all P<0.0005). In this 2nd group, a decrease in LDL-cholesterol (P < 0.05) and an increase in HDL-cholesterol levels (P < 0.02) were also observed. In the 1st group, anthrombin III activity increased significantly (P<0.01). In the 2nd group, significant reductions in markers of platelet function (FP4 and betaTG, P < 0.01), thrombin generation (FPA, F1 + 2 and D-D, P<0.01), and fibrinolysis inhibition (PAI-1 activity, PAI-1 antigen, P< 0.001) were observed. Increases in some fibrinolytic activation markers (t-PA activity, and AT-III activity, P<0.01) occurred. Fasting lactate concentrations were unchanged in the metformin-treated group. No serious adverse effects were observed in either group. CONCLUSIONS: These results suggest that either high sulphonylurea dosages or a therapy combining lower sulphonylurea dosages with metformin are effective and safe in an aged but healthy population. Metformin provides additional benefits counteracting several cardiovascular risk factors but must be administered with caution, bearing in mind the general contra-indications for the drug but not age alone.

Atorvastatin for the management of Type 2 diabetic patients with dyslipidaemia. A mid-term (9 months) treatment experience.

Dyslipidaemia, particularly increased triglycerides (TG) and low HDL-cholesterol (HDL-C), represents an important risk factor for Type 2 diabetes (T2DM) macrovascular complications. Our aim was to evaluate the effects of atorvastatin in a population of T2DM patients according to their cardiovascular risk: evidence of myocardial or coronary lesions (group A); evidence of familiar hypercholesterolaemia (group B); evidence of stable cardiovascular risk (group C). The mean age was 64+/-7 yr, mean disease duration 9.5+/-3 yr, the mean body mass index (BMI) 27.7+/-1.3 kg/m2, mean HbA1c 8+/-0.6%; total cholesterol 256+/-24 mg/dl in group A, 298+/-30 and 244+/-31 in groups B and C, respectively (p<0.05 B vs. A and C). Moreover, mean HDL-C values were about 45+/-7 mg/dl, TG 225+/-20 mg/dl, systolic and diastolic blood pressure 144+/-7 mm Hg and 84+/-8 mm Hg, respectively; fibrinogen values 330+/-23 mg/dl and microalbuminuria 58+/-9 mg/l. Lipid profile improved significantly during the treatment with personalised doses of atorvastatin (generally 10 mg/day) designed to achieve the therapeutic goals: the reduction of total cholesterol, TG (p<0.01), LDL-cholesterol (LDL-C) (p<0.01) and an increase of HDL-C were measured. The treatment with atorvastatin induced significant reduction of microalbuminuria and fibrinogen levels (p<0.01). Moreover, in the subgroup of patients with hypertension, diastolic blood pressure values were reduced without modification of antihypertensive treatment. This preliminary study suggests that the management of hypercholesterolaemia with atorvastatin in T2DM patients may be useful both for the primary and secondary prevention of chronic complications of T2DM.

Clustering of albumin excretion rate abnormalities in Caucasian patients with NIDDM. The Italian NIDDM Nephropathy Study Group.

Proteinuria and nephropathy have been found to cluster in families of non-insulin-dependent diabetic (NIDDM) Pima Indian, and in Caucasian insulin-dependent diabetic (IDDM) patients. No information is at present available for Caucasian NIDDM patients. The aim of the present study was to determine whether micro-macroalbuminuria (AER+) is associated with albumin excretion rate abnormalities in diabetic and non-diabetic siblings of probands with NIDDM and AER+. We identified 169 Caucasian families with one NIDDM proband (the patient with longest known NIDDM duration) (101 families with only NIDDM siblings, 33 families with both NIDDM and non-NIDDM siblings and 35 families with only non-NIDDM siblings). Of the probands 56 had AER+ [Prob-NIDDM-(AER+)], 78 had AER-[Prob-NIDDM-(AER-)], 74 siblings of Prob-NIDDM-(AER+), and 113 siblings of Prob-NIDDM-(AER-) also had NIDDM. Data on albuminuria and retinopathy from multiple sibling pairs when the size of the sibship was more than two was adjusted according to a weighting factor. The odds ratio for AER+, in siblings of Prob-NIDDM-(AER+) adjusted for age, hypertension, glycated haemoglobin A1c and other confounding variables was 3.94 (95% confidence intervals: 1.93-9.01) as compared to siblings of Prob-NIDDM-(AER-). The 74 siblings of Prob-NIDDM-(AER+) had higher prevalence of proliferative retinopathy than siblings of Prob-NIDDM-(AER-) (14 vs 2%; p < 0.01). We also identified 66 non-diabetic siblings of 41 NIDDM probands with AER+ and 36 non-diabetic siblings of 27 NIDDM probands with AER-. Albumin excretion was two times higher, although still within the normal range, in the non-diabetic siblings of Prob-NIDDM-(AER+) than in siblings of Prob-NIDDM-(AER-) [median = 13.5 (range 0.5-148) vs 6.6 (range 1-17) micrograms/min (p < 0.05)]. In conclusion higher rates of albumin excretion aggregate in Caucasian families with NIDDM. Proliferative retinopathy is more frequently observed in families showing a clustering of AER+ and NIDDM. These findings suggest that familial factors play a role in the pathogenesis of renal and retinal complications in NIDDM.

Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients.

BACKGROUND/AIMS: Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis. METHODS: A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels. RESULTS: There was a significant decrease (p<0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p<0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p<0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p<0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p<0.01) in malondialdehyde/levels observed in the treated group. CONCLUSIONS: These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.

Renal structure and function in non-insulin dependent diabetic patients with microalbuminuria.

We have recently described heterogeneity in renal structure in non-insulin-dependent diabetic patients (NIDDM) with microalbuminuria (MA; defined as albumin excretion rate from 20 to 200 micrograms/min). Thus, at variance with IDDM patients, "typical" diabetic glomerulopathy by light microscopy is observed only in a third of NIDDM with MA (Category II, CII). Further, despite persistent MA, 30% of NIDDM have normal or near normal renal structure (Category I, CI). Another one-third shows "atypical" patterns of renal injury with absent or mild diabetic glomerular changes, associated with disproportionately severe tubulointerstitial lesions and/or arteriolar hyalinosis and global glomerular sclerosis (Category III, CIII). The aims of this study were to evaluate whether similar patterns of renal lesions could be confirmed in a larger group of NIDDM with MA and to investigate tubular function in order to understand the mechanisms underlying MA in NIDDM patients. Renal biopsies were performed in 53 NIDDM with MA. Categories I, II and III were found in 41%, 26% and 33% of NIDDM with MA, respectively. All 8 patients with proliferative diabetic retinopathy were in CII. We also studied the urinary daily excretion rate of alpha 1-microglobulin (alpha 1 m), a low molecular weight protein, which is a useful indicator of tubular function. alpha 1 m was markedly increased only in CII patients (CI vs. CII vs. CIII: 6.2 +/- 1.2 vs. 13.7 +/- 2.1 vs. 7.3 +/- 0.9 mg/day, ANOVA, P < 0.01). In conclusion, we confirm that there is heterogeneity in renal structure in NIDDM patients with MA. This heterogeneity is not due to renal diseases other than diabetes. Increased alpha 1 m and proliferative retinopathy are useful indicators of the subgroup of MA NIDDM patients with typical diabetic glomerulopathy. It is suggested that diabetic microangiopathy explains the simultaneous occurrence of typical diabetic glomerulopathy, proliferative retinopathy and tubular dysfunction in a subgroup of NIDDM patients with MA.

Patterns of renal injury in NIDDM patients with microalbuminuria.

Microalbuminuria predicts overt nephropathy in non-insulin-dependent diabetic (NIDDM) patients; however, the structural basis for this functional abnormality is unknown. In this study we evaluated renal structure and function in a cohort of 34 unselected microalbuminuric NIDDM patients (26 male/8 female, age: 58 +/- 7 years, known diabetes duration: 11 +/- 6 years, HbA1c: 8.5 +/- 1.6%). Systemic hypertension was present in all but 3. Glomerular filtration rate (GFR) was 101 +/- 27 ml.min-1.1.73 m-2 and albumin excretion rate (AER) 44 (20-199) micrograms/ min. Light microscopic slides were categorized as: C I) normal or near normal renal structure; C II) changes "typical" of diabetic nephropathology in insulin-dependent diabetes (IDDM) (glomerular, tubulo-interstitial and arteriolar changes occurring in parallel); C III) "atypical" patterns of injury, with absent or only mild diabetic glomerular changes associated with disproportionately severe renal structural changes including: important tubulo-interstitial with or without arteriolar hyalinosis with or without global glomerular sclerosis. Ten patients (29.4%) were classified as C I, 10 as C II (29.4%) and 14 as C III (41.2%); none of these patients had any definable non-diabetic renal disease. GFR, AER and blood pressure were similar in the three groups, while HbA1c was higher in C II and C III than in C I patients. Diabetic retinopathy was present in all C II patients (background in 50% and proliferative in 50%). None of the patients in C I and C III had proliferative retinopathy, while background retinopathy was observed in 50% of C I and 57% of C III patients. In summary, microalbuminuric NIDDM patients are structurally heterogeneous with less than one third having "typical" diabetic nephropathology. The presence of both "typical" and "atypical" patterns of renal pathology was associated with worse metabolic control, suggesting that hyperglycaemia may cause different patterns of renal injury in older NIDDM compared to younger IDDM patients.

Therapeutic effect of benfluorex in type II diabetic patients on diet regimen alone.

A randomized double-blind study of benfluorex (150 mg x 3 daily) versus placebo was conducted over 3 months in 32 type II diabetic patients (24 men and 8 women, aged 52 +/- 8.4 years) with mild stable obesity [body-mass index (BMI) 27 +/- 1.6 kg/ m2], moderate fasting hyperglycemia (fasting blood glucose 9 +/- 0.5 mmol/L, HbA1c 6.7 +/- 0.9%) and moderate hyperinsulinemia (18.6 +/- 3.0 microU/mL) when on treatment with diet alone. After a 1-month placebo run-in period, subjects were randomized to benfluorex or placebo three tablets daily. Inclusion parameters and end-of-study measures were body weight, BMI, fasting blood glucose, glycemic profile, HbA1c, fasting insulinemia, basal and stimulated C-peptide, and an insulin tolerance test (0.1 U/kg). The groups were homogeneous at baseline, except for glycemic profile (higher postprandial glycemia in the group randomized to benfluorex). At the end of the study, the groups did not differ in body weight or BMI; however, HbA1c decreased more with benfluorex (6.0 +/- 1.0% versus 6.8 +/- 0.9%, p = 0.024), as did the mean glycemic profile (7.8 +/- 1.4 versus 8.5 +/- 1.7 mmol/L, p < 0.001), including a particular decrease in postprandial glycemia. The decreases in fasting blood glucose and insulinemia appeared larger with benfluorex (7.7 +/- 1.3 versus 8.4 +/- 1.6 mmol/L and 13.5 +/- 4.5 versus 16.1 +/- 5.1 microU/mL, respectively), but were not statistically significant. The increase in the insulin sensitivity index (Kitt) was greater with benfluorex (+0.54 +/- 1.4 versus +0.25 +/- 1.3%/mn), but the difference was not statistically significant. The same was observed for the stimulated C-peptide. In type II diabetics with mild obesity and hyperglycemia previously managed with diet alone, benfluorex has significant long-term effect on HbA1c and mean daily blood glucose, and tends to lower insulinemia.

Effects of cilazapril and amlodipine on kidney function in hypertensive NIDDM patients.

Contrasting information has been reported concerning the course of renal function in NIDDM with hypertension alone or in association with renal damage. The aim of the present study was to elucidate the course of the glomerular filtration rate (GFR) in hypertensive NIDDM patients during antihypertensive therapy. Furthermore, we compared the effects of ACE inhibitors (cilazapril, Inibace, Roche, Milan, Italy) and Ca(2+)-channel blockers (amlodipine, Norvasc, Pfizer, Rome, Italy). Of the hypertensive NIDDM patients attending the outpatient's clinic of the internal medicine departments of the University of Padova and Sassari, 44 participated in the present study. Of these patients, 26 were normoalbuminuric and 18 microalbuminuric. They were randomly treated with either cilazapril or amlodipine. The target of antihypertensive treatment was a value < 140 mmHg for systolic and 85 mmHg for diastolic blood pressure (BP). Microalbuminuria was defined as an albumin excretion rate (AER) between 20 and 200 micrograms/min. GFR was measured by plasma clearance of 51Cr-labeled EDTA at baseline and every 6-12 months during a 3-year follow-up interval. A significant decrease was observed in the values of GFR, AER, and systolic and diastolic BP in normoalbuminuric and microalbuminuric patients during antihypertensive therapy. The GFR fall in the overall population of NIDDM patients was significantly and inversely related to the decrease of mean BP (diastolic + 1/3 pulse pressure) (r = -0.80, P < 0.0001) but not to that of HbA1c, triglycerides, and BMI. The GFR decline (mean +/- SE) per year in the normoalbuminuric patient was 2.03 +/- 0.66 ml.min-1 x 1.73 m-2 (95% CI 0.92-3.17) during cilazapril and 2.01 +/- 0.71 ml.min-1 x 1.73 m-2 (95% CI 0.82-3.11) during amlodipine therapy. The GFR decline per year in the microalbuminuric patient was 2.15 +/- 0.69 ml.min-1 x 1.73 m-2 (95% CI 0.86-3.89) during cilazapril and 2.33 +/- 0.83 ml.min-1 x 1.73 m-2 per year (95% CI 1.03-3.67) during amlodipine therapy. Cilazapril and amlodipine lowered AER to a similar extent in normoalbuminuric and microalbuminuric patients. No significant changes were observed concerning other clinical and biochemical features between the two antihypertensive therapies and particularly HbA1c, BMI, triglycerides, and cholesterol plasma values. These results support the tenet that arterial hypertension plays a pivotal role in contributing to renal damage in NIDDM, even when AER is normal. However, the degree of BP control, with both cilazapril and amlodipine, can successfully delay the slope of GFR decline in hypertensive NIDDM patients with or without incipient nephropathy.

Peripheral, rather than hepatic, insulin resistance and atherogenic lipoprotein phenotype predict cardiovascular complications in NIDDM.

Microalbuminuria, hypertension and hyperinsulinaemia are three independent risk factors for cardiac disease in non insulin-dependent diabetes (NIDDM). However, it is unknown to what extent hyperinsulinaemia reflects resistance to insulin action at hepatic, extrahepatic or at both sites. A cross-sectional study from our Department showed that peripheral insulin resistance, hypertension, microalbuminuria and lipid abnormalities are associated in NIDDM. Non diabetic individuals with the so-called 'atherogenic lipoprotein phenotype', characterized by small dense low density lipoproteins (LDL subclass pattern B) have up to 3-fold higher risk of myocardial infarction. The aim of the present study was to investigate whether impaired peripheral insulin sensitivity, during euglycaemic-hyperinsulinaemic clamp, as well as abnormalities in lipid concentrations and LDL size, predict abnormalities in albumin excretion rate, blood pressure and cardiac function in 73 consecutive normotensive (< 85 mmHg diastolic level) and normoalbuminuric (< 15 micrograms min-1 daily albumin excretion rate) NIDDM patients. These patients showed a bimodal distribution of whole body glucose utilization rate, a parameter of peripheral insulin sensitivity. The cut-off point between the two modes of distribution was located close to the mean value minus one standard deviation in a population of 24 control subjects. Therefore, this latter value was used to identify two subgroups inside the overall population of NIDDM patients, i.e. 28 patients (group 1), with whole body glucose utilization rate, above, and 45 patients (group 2), below, the mean value minus 1 SD in the 24 controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired insulin-induced glucose uptake by extrahepatic tissue is hallmark of NIDDM patients who have or will develop hypertension and microalbuminuria.

Insulin resistance may be a mechanism linking non-insulin-dependent diabetes mellitus (NIDDM) to hypertension and cardiovascular mortality. Microalbuminuria also is an independent risk factor of cardiovascular mortality and of hypertension. Little information is available in the literature on the relationship between microalbuminuria and insulin action. This study investigated the relationships between blood pressure (BP) levels, microalbuminuria, and insulin resistance in NIDDM patients. Seventy-five NIDDM patients attending the outpatient clinic of the Department of Internal Medicine of the University Hospital in Padua, Italy participated in the cross-sectional part of our study. These subjects were divided into four groups on the basis of BP levels and albumin excretion rate (AER): 28 normotensive normoalbuminuric (NIDDM1), 19 hypertensive normoalbuminuric (NIDDM2), 15 normotensive microalbuminuric (NIDDM3), and 13 hypertensive microalbuminuric patients (NIDDM4). We defined microalbuminuria as an AER > 20 micrograms/min. Patients with BP levels > 145/90 mmHg were considered hypertensive. A group of 20 normal subjects served as control subjects. The results from the cross-sectional study indicate that the mean of insulin-induced whole-body glucose utilization, primarily an index of extrahepatic insulin action, was lower at all insulin infusion steps in the group of hypertensive and/or microalbuminuric patients than in the group of normotensive normoalbuminuric patients and control subjects. Hepatic glucose output, an index of insulin action in the liver, was on average less efficiently inhibited in all of the patients than in the control subjects, regardless of the BP levels or the AER.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of hyperglycemia and insulin resistance in determining sodium retention in non-insulin-dependent diabetes.

Sodium retention has been advocated to give rise to hypertension in humans. Increases in blood glucose and insulin concentrations ensue in the stimulation of sodium reabsorption by the kidney. Although the combined occurrence of hyperglycemia and hyperinsulinemia, frequently secondary to insulin resistance with regard to carbohydrate metabolism, is a hallmark of non-insulin dependent diabetes (NIDDM), the role of these abnormalities in determining an impaired natriuresis in NIDDM is not yet fully understood. We studied sodium homeostasis in 14 control subjects and 59 NIDDM normotensive, normoalbuminuric patients who were divided into two groups with markedly impaired (Group 2 NIDDM: 30) and less severely impaired (Group 1 NIDDM: 29) insulin sensitivity during euglycemic-hyperinsulinemic (80 to 90 microU/ml plasma insulin) clamp. A hyperglycemic (9 mmol/liter plasma glucose)--nearly euinsulinemic (20 to 40 microU/ml plasma insulin) clamp was also performed in the same 14 controls and in two cohorts of 22 Group 2 and 17 Group 1 NIDDM patients. The two groups of patients had similar overnight fasting glucose levels (Group 1 NIDDM vs. Group 2 NIDDM: 176 +/- 13 vs. 185 +/- 15 mg/dl, mean +/- SE). Conversely, overnight fasting plasma insulin was significantly higher in Group 2 NIDDM than in Group 1 NIDDM patients (Group 1 NIDDM vs. Group 2 NIDDM: 12 +/- 3 vs. 18 +/- 3 microU/ml, P < 0.05). Both NIDDM Groups had higher plasma glucose and insulin than controls (75 +/- 4 mg/dl and 6 +/- 3 microU/ml). Blood pressure levels and albumin excretion rates were slightly but significantly higher in Group 2 NIDDM, but not in Group 1 NIDDM patients, than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

[Median-term (4 months) treatment with glibenclamide + metformin substituting for glibenclamide + fenformin lowers the lacticemia levels in type-2 diabetics (NIDDM)]. / Il trattamento a medio termine (4 mesi) con glibenclamide + metformina in sostituzione al trattamento con glibenclamide + fenformina abbatte i livelli di lattacidemia in soggetti diabetici tipo II (NIDDM).

60 NIDDM patients, mean age (68 +/- 3 years), BMI (25 +/- 5.1 kg/m2), fasting blood glucose (FG) (170 +/- 10 mg/dl), mean daily blood glucose (MDBG) (180 +/- 10 mg/dl), daily glycosuria (GLU) (15.6 +/- 9 g/24 hours), HbA1c (7.9 +/- 0.6%), basal (1.2 +/- 0.2 ng/ml) and stimulated (3.89 +/- 1.3 mg/ml) C peptide (CP) treated by ASS (7.5 +/- 75 mg), after a strict 4 months follow-up period, were assigned to G + M treatment (7.5 +/- 1.500 mg) during a 4 months period. During G+M treatment FG (171 +/- 13 at t0 to 165 +/- 11 mg/dl: p < 0.01 at t4) varied significantly. MDBG (180 +/- 10 at t0 to 175 +/- 12 mg/dl at t4:p < 0.05), GLU (16 +/- 9 at t0 to 11 + 6 g/24 hours at t4; p < 0.01), HbA1c (8.1 +/- 0.4 at t0 to 7.6 +/- 0.3% at t4; p < 0.01). Basal CP remained unchanged in G+M period and varied significantly during ASS period (1.3 +/- 0.3 ng/ml at t4; p < 0.01) and stimulated CP (unchanged during ASS) was reduced during G+M (4.19 +/- 0.4 to 4.04; p < 0.05). Highly significant variations were observed for LAC (28.4 +/- 2.1 at t0 to 14.9 +/- 0.6 mg/dl: p < 0.01 during G+M treatment). G+M therapy was found to be more effective and safer than ASS therapy in regard to glucose metabolism and lactate production in a selected group of NIDDM patients.