Mario Velussi

Long-term (23 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.

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 Ca2+-channel blockers (amlodipine, Norvasc, Pfizer, Rome, Italy). Of the hypertensive NIDDM patients attending the outpatients 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 μg/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 · 1.73 m−2 (95% CI 0.92–3.17) during cilazapril and 2.01 ± 0.71 ml · min−1 · 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 · 1.73 m−2 (95% CI 0.86–3.89) during cilazapril and 2.33 ± 0.83 ml · min−1 · 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.

Incidence of Coronary Heart Disease in Type 2 Diabetic Men and Women Impact of microvascular complications, treatment, and geographic location

OBJECTIVE—Cardiovascular disease (CVD) is the main cause of morbidity/mortality in diabetes. We set forth to determine incidence and identify predictors (including microvascular complications and treatment) of first coronary heart disease (CHD) event in CVD-free type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A cohort of 6,032 women and 5,612 men, sampled from a nationwide network of hospital-based diabetes clinics, was followed up for 4 years. Baseline assessment included retinopathy, nephropathy, and foot ulcers. First CHD events (myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, and electrocardiogram-proven angina) were analyzed for 29,069 person-years. RESULTS—The age-standardized incidence rate (per 1,000 person-years) of first CHD event (n = 881) was 28.8 (95% CI 5.4–32.2) in men and 23.3 (20.2–26.4) in women. Major CHD (myocardial infarction, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty) was less frequent in women (5.8 [4.3–7.2]) than in men (13.1 [10.9–15.4]; a sex ratio of 0.5 [0.4–0.6]). Incidence rates of all outcomes were higher in patients with microvascular complications (for major CHD, age-adjusted rate ratios were 1.6 [1.2–2.21] in men and 1.5 [1.0–2.2] in women). By multivariate Cox analysis, age and diabetes duration were risk predictors common in both sexes. In men, glycemic control and treated hypertension were additional independent risk factors, but residing in the south was associated with a significant 29% risk reduction. In women, higher triglycerides/lower HDL cholesterol and microvascular complications were independent risk factors. CONCLUSIONS—In CVD-free patients with type 2 diabetes, risk of first CHD event depends on sex, geographic location, and presence of microvascular disease. Hyperglycemia and hypertension, particularly in men, and diabetic dyslipidemia, especially in women, are risk factors amenable to more aggressive treatment.

Recurrence of Cardiovascular Events in Patients With Type 2 Diabetes : Epidemiology and risk factors

OBJECTIVE—The purpose of this study was to assess incidence of and risk factors for recurrent cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS—We estimated the incidence of recurrent cardiovascular events in type 2 diabetic patients, aged 40–97 years, followed by a network of diabetes clinics. The analysis was conducted separately for 2,788 patients with CVD at enrollment (cohort A) and for 844 patients developing the first episode during the observation period (cohort B). RESULTS—During 4 years of follow-up, in cohort A the age-adjusted incidence of a recurrent event (per 1,000 person-years) was 72.7 (95% CI 58.3–87.1) in men and 32.5 (21.2–43.7) in women, whereas in cohort B it was 40.1 (17.4–62.9) in men and 22.4 (12.9–32.0) in women. After controls were included for potential predictors (familial CVD, obesity, smoking, diabetes duration, glycemic control, microvascular complications, geographic area, and antihypertensive and lipid-lowering treatment), male sex, older age, and insulin use were significant independent risk predictors (cohort A) and serum triglyceride levels ≥1.69 mmol/l emerged as the only metabolic (negative) prognostic factor (cohort B). In both cohorts, a prior CVD episode, especially myocardial infarction, was by far the strongest predictor of recurrent CVD. CONCLUSIONS—Approximately 6% of unselected diabetic patients in secondary prevention develop recurrent major CVD every year. Those with long-standing previous CVD show a higher incidence of recurrence. Male sex, age, high triglyceride levels, and insulin use are additional predictors of recurrence.

Kidney Hemodynamics After Ketone Body and Amino Acid Infusion in Normal and IDDM Subjects

Little information is available on the hemodynamic response (renal reserve) of the diabetic kidney during an acute amino acid infusion, which has been shown to increase glomerular filtration rate (GFR) in normal humans. We recently found that the infusion of ketone bodies is able to raise GFR in both normal subjects and insulin-dependent diabetes mellitus (IDDM) patients. The aim of this study was to evaluate the renal reserve in 15 IDDM patients with a duration of diabetes of >9 yr [8 with albumin excretion rate <15 μg/min (group 1) and 7 with albumin excretion rate >100 μg/min (group 2)] and in 8 normal subjects during amino acid infusion (33 μmol · kg−1 · min−1 , Travasol 10% wt/vol solution containing 0.154 mM sodium chloride concentration; Travenol, Savage, MD) and during acetoacetic sodium salt (25 μmol · kg−1 · min−1) infusion. Blood glucose was clamped at euglycemic levels. The infusion of sodium acetoacetate resulted in a 10- to 15-fold increase in circulating concentrations of ketone bodies, which were similar in magnitude in normal subjects and diabetic patients. The GFR peak increase above baseline after sodium acetoacetate infusion was 28% in normal subjects and 27% in group 1 and 19% in group 2 diabetic patients. The infusion of amino acid solution produced a three- to fivefold increase in plasma concentrations of amino acids in both normal subjects and diabetic patients. The GFR peak increase above baseline after amino acid infusion was significantly lower in diabetic patients (IDDM group 1: 5%, P < .01; IDDM group 2: 6%, P < .01) than in normal subjects (38%). During sodium acetoacetate infusion, proximal sodium reabsorption increased as well as distal sodium delivery in normal subjects and group 1 and group 2 IDDM patients. During amino acid infusion, only normal subjects showed a significant increase in proximal sodium reabsorption and distal sodium delivery, whereas no change was found in group 1 and group 2 IDDM patients. Amino acid infusion resulted in a marked increase in the albumin fractional clearance rate in both normal subjects and diabetic patients. On the contrary, ketone body infusion slightly increased the albumin fractional clearance rate in group 2 diabetic patients but not in group 1 diabetic patients and normal subjects. This study demonstrates that long-standing diabetic patients, irrespective of the presence of impaired renal function, show a peculiar defect in the kidney hemodynamic response to amino acid but not to ketone body infusion. These results question the use of an amino acid load to test for glomerular filtration reserve in diabetic patients, because a lack of response may simply be related to an altered response of the kidney to amino acids. A macula densa feedback mechanism could not account for the increase in GFR after both amino acid and ketone body infusion, because these compounds increase the sodium distal delivery. Amino acids increase albumin excretion rate with a mechanism independent of GFR and renal plasma flow changes, in that this effect occurs even in diabetic patients who showed no changes in these variables.

Metabolic Control of Kidney Hemodynamics in Normal and Insulin-Dependent Diabetic Subjects: Effects of Acetoacetic, Lactic, and Acetic Acids

Diabetes mellitus is associated with important changes in renal hemodynamics. The purpose of this study was to determine whether an increase in blood concentration patterns of ketone bodies and lactic acid, organic acids often elevated in poorly controlled insulin-dependent diabetes mellitus (IDDM), could contribute to increase glomerular filtration rate (GFR) and renal plasma flow (RPF) regardless of changes in circulating levels of glucose and insulin. Six IDDM patients and six normal subjects were given a saline infusion (15 μmol · min−1 · kg−1) for 2 h, an acetoacetic acid infusion (15 μmol · min−1 · kg−1) for another 2 h, and then a saline infusion after an overnight fast during euglycemic insulin-glucose clamp. Acetoacetic acid infusion resulted in an increase of blood ketone bodies in the range of 0.7–1.5 mM from a basal value of 0.1–0.3 mM. GFR was 125 ± 16 and 136 ± 17 ml · min−1 · 1.73 m−2 in normal and IDDM subjects, respectively, during baseline saline infusion and 138 ± 21 (P < .01 vs. basal level) and 158 ± 15 ml · min−1 · 1.73 m−2 (P < .001 vs. basal level) during acetoacetic acid infusion. During the last saline infusion, renal hemodynamic patterns decreased again to baseline levels. Another six IDDM patients and six normal subjects were given saline, lactic acid, and saline infusions at the same rates of infusion after an overnight fast during euglycemic insulin-glucose clamp. Lactic acid concentration increased from ∼0.5–0.8 to 1.0–1.5 mM in both groups. GFR was 125 ± 9 and 144 ± 18 ml · min−1 · 1.73 m−2 in normal and IDDM subjects, respectively, during baseline saline infusion and 135 ± 8 and 158 ± 16 ml · min1 · 1.73 m−2 during lactic acid infusion (P < .01 vs. basal level). Acetoacetic acid and lactic acid infusion resulted in a 14.7 and 7.6% increase, respectively, in RPF compared with baseline values in normal subjects and in a 12.6 and 6.9% increase, respectively in IDDM subjects. With the same protocol of the previous organic acid infusion, another five normal and six IDDM patients were given an acetic acid infusion (15 μmol · kg−1 · min−1), resulting in an increase of plasma circulating levels of acetic acid from 0.1–0.2 to 0.3–0.4 mM, which was associated with negligible changes in ketone body and lactic acid concentrations. Neither GFR nor RPF were influenced by acetic acid administration. During acetoacetic acid and lactic acid infusion, both lactic and ketone body acid tubular reabsorption rates were three to five times higher than during saline infusion. In conclusion, lactic acid and acetoacetic acid infusion resulting in circulating patterns of these intermediate metabolites comparable with those often found in poorly controlled IDDM subjects induced a significant increase in GFR and RPF in normal and IDDM subjects. The increased GFR was associated with stimulation of organic acid tubular reabsorption rate and was not related to sodium and liquid overload, because it returned to basal value when saline alone was administered again.

Analysis of midwall shortening reveals high prevalence of left ventricular myocardial dysfunction in patients with diabetes mellitus: the DYDA study

Background: Individuals with diabetes mellitus (DM) have a higher risk to develop heart failure. Clinical guidelines emphasize the importance of early diagnosis of left ventricular dysfunction (LVD) and preventive interventions in these patients. In this study we assessed the prevalence of LVD, systolic or diastolic, in DM patients without known cardiac disease recruited in the ‘left ventricular DYsfunction in DiAbetes (DYDA)’ study. Design and methods: We performed clinical, ECG, laboratory, and echocardiographic exams in 960 patients (61 ± 8 years, 59% hypertensive) recruited in the DYDA study from 37 Italian diabetes referral centres. ECG and echo exams were read in central facilities. Systolic LVD was defined as ejection fraction ≤50% or midwall shortening (MFS) ≤15%. Diastolic LVD was identified when transmitral E/A was out of the range of 0.75–1.5 or deceleration time of mitral E wave ≤140 msec. Results: Echocardiographic data were obtained in 751 patients (78.2%). Isolated systolic LVD was detected in 22.0% of patients, isolated diastolic LVD in 21.5%, and combined systolic and diastolic LVD in 12.7%. All patients with systolic LVD had MFS ≤15%, while only 9% had an ejection fraction ≤50%. Higher LV mass, relative wall thickness, prevalence of concentric geometry, and LV hypertrophy characterized the patients with LVD. Conclusions: LVD is present in more than half of DM patients without clinically detectable cardiac disease and is associated with LV hypertrophy and concentric LV geometry. One-third of patients exhibits systolic LVD detectable at the midwall level.

Predictors of early-stage left ventricular dysfunction in type 2 diabetes: results of DYDA study:

Background: Better knowledge of prevalence and early-stage determinants of subclinical left ventricular dysfunction (LVD) in type 2 diabetes would be useful to design prevention strategies. The objective of the LVD in Diabetes (DYDA) study was to assess these points in patients without established cardiac disease. Method: Baseline clinical, ECG, laboratory and echocardiographic data from 751 patients (61 ± 7 years, 59% hypertensive) recruited by 37 Italian diabetes clinics were analysed. Clinical history, life habits, laboratory data (NT-proBNP, HsCRP, HbA1c, serum glucose, lipids and creatinine, liver enzymes, microalbuminuria, glomerular filtrate) and data on microvascular complications and drug therapy were collected. Results: LVD was present in 59.9% of patients. Age (OR 1.05, 95% CI [1.02–1.07]), HbA1c (OR 1.27, 95% CI [1.09–1.49]), triglycerides (OR 1.003, 95% CI [1.001–1.006]), treatment with metformin (OR 1.62, 95% CI [1.09–2.40]) and doxazosine (OR 2.48, 95% CI [1.10–5.55]) were independent predictors of LVD. Glitazones were associated with reduced risk of diastolic dysfunction (OR 0.44, 95% CI [0.22–0.87]) whereas waist circumference and metformin were adversely associated with systolic dysfunction (OR 1.02, 95% CI [1.01–1.04] and 1.57, 95% CI [1.01–2.43], respectively). Conclusion: In asymptomatic and fairly controlled diabetic patients, age, worse HbA1c, traits of insulin resistance, such as visceral adiposity and triglycerides or treatment with metformin, and use of doxazosin indicate greater risk of LVD. Glitazones, at this stage, seem to be associated with better diastolic performance.

Inappropriately high left ventricular mass in patients with type 2 diabetes mellitus and no overt cardiac disease. The DYDA study.

Background An inappropriately high left ventricular mass (iLVM) may be detected in patients with diabetes mellitus. Several hemodynamic and nonhemodynamic factors stimulating LVM growth may actively operate in these patients. In this study, we assessed prevalence and factors associated with iLVM in patients with diabetes mellitus. Methods We analyzed baseline data from 708 patients (61 ± 7 years, 57% treated for hypertension) with type 2 diabetes mellitus without evidence of cardiac disease enrolled in the left ventricular dysfunction in diabetes study. iLVM was diagnosed by Doppler echocardiography as LVM more than 28% of the expected LVM predicted from height, sex and stroke work. Results iLVM was detected in 166 patients (23%), irrespective of concomitant hypertension. Patients with iLVM were more frequently women, had higher BMI and prevalence of metabolic syndrome, higher serum triglyceride levels and were treated more frequently with metformin and diuretics. In a multivariate model, female sex [odds ratio (OR) 1.502 (95% confidence interval (CI) 1.010–2.231), P = 0.04], higher serum triglyceride levels [OR 1.007 (95% CI 1.003–1.012), P < 0.001] and BMI [OR 1.220 (95% CI 1.116–1.335), P < 0.001] emerged independently related to iLVM. Conclusion iLVM is detectable in about a quarter of patients with type 2 diabetes mellitus without evidence of cardiac disease and is unrelated to blood pressure levels. The association between LVM and some components of metabolic syndrome in these patients may have important practical implications.

Poor metabolic control and predisposition to hypertension, rather than hypertension itself, are risk factors for nephropathy in type 2 diabetes

Sodium-lithium countertransport (Na+/ Li+ CT) activity in erythrocytes has been shown to be high in a subset of patients with essential but not secondary hypertension and in type 1 (insulin-dependent) diabetic patients with nephropathy. More recently it has been shown that the presence of a major gene for Na+/Li+ CT, or another closely linked gene, rather than the actual level of Na+/Li+ CT, increases the risk of hypertension onset. The aim of the present study was to investigate whether Na+/Li+ CT activity is associated with hypertension and nephropathy in type 2 (non-insulin-dependent) diabetes. We studied 18 type 2 diabetic patients with normal blood pressure levels (systolic ≤140 and diastolic ≤85 mmHg) and albumin excretion rate (≤15 μg/min), 19 type 2 diabetic patients with hypertension (systolic ≥145 and diastolic ≥90 mmHg) and a normal albumin excretion rate (≤15 μg/min) and 19 type 2 diabetic patients with an increased albumin excretion rate (≤20 μg/min), irrespective of blood pressure levels. Eighteen normal subjects, matched for sex and age, served as controls. Na+/Li+ CT activity in erythrocytes was higher in type 2 diabetics with a high albumin excretion rate (486±148 μmol/l erythrocytes per hour,P<0.01) and in hypertensive diabetics (410±129,P<0.05), but not in normotensive diabetics (340±141), than in controls (282±96) (mean±SD). Body mass index was higher in diabetics with hypertension and in those with an abnormal albumin excretion rate than in normotensive diabetics and controls. Blood pressure levels were higher in diabetic patients with an increased albumin excretion rate than in normotensive diabetics and controls. Of diabetic patients with a high albumin excretion rate 26% had normal diastolic blood pressure levels. Diabetics with a high albumin excretion rate had higher glycated haemoglobin, cholesterol and triglyceride levels and a longer duration of diabetes than hypertensive diabetics with a normal albumin excretion rate. The association of these clinical features in type 2 diabetes closely resembles that previously reported in type 1 diabetes. A novel finding of the present study is that predisposition to hypertension, as indicated by high Na+/Li+ CT, seems to confer a susceptibility to the development of renal damage in type 2 diabetes, partially independent of blood pressure levels per se, and that diabetic patients with high Na+/Li+ CT and hypertension are, to some extent, protected against the development of nephropathy when the metabolic control is tighter and the duration of the disease shorter.