Mauro Giordano

Effects of Angiotensin-Converting Enzyme Inhibitors, Ca2+ Channel Antagonists, and α-Adrenergic Blockers on Glucose and Lipid Metabolism in NIDDM Patients With Hypertension

We compared the effects of captopril, nifedipine, and doxazosin on glucose and lipid metabolism in 30 hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients (age = 50 ± 3 years; body mass index = 30 ± 1 kg/m2). Of these patients, 9 were treated with captopril, 11 with nifedipine, and 10 with doxazosin for 12 weeks. Blood pressure, fasting plasma glucose (FPG) concentration, HbA1c, oral glucose tolerance test (OGTT), euglycemic insulin clamp, and plasma lipids were measured before and after a 3-month period. Mean arterial blood pressure (114 ± 2 mmHg) was similar in all groups before initiating antihypertensive therapy and declined to 102 ± 2 (captopril), 103 ± 1 (nifedipine), and 103 ± 2 (doxazosin) mmHg (P < 0.001). Baseline FPG (148 ± 11 mg/dl) and HbA1c (6.3 ± 1%) were similar in all groups and did not change significantly with treatment. Plasma glucose, insulin, and free fatty acid (FFA) concentrations during the OGTT were similar in all groups before antihypertensive treatment and did not change with captopril and nifedipine; after doxazosin, plasma glucose and FFA concentrations during the OGTT decreased (both P < 0.05) without change in plasma insulin response. Insulin-mediated glucose uptake (144 ± 11 mg · m−2 · min−1), glucose oxidation (76 ± 4 mg · m−2 · min−1), and nonoxidative glucose disposal (71 ± 6 mg · m−2 · min−1) were similar in all groups before the start of antihypertensive treatment and did not change in captopril and nifedipine groups. After doxazosin, total glucose uptake (180 ± 25 mg · m−1) increased significantly (P < 0.01); nonoxidative glucose disposal did not change. Plasms lipid levels improved after doxazosin therapy; high-density lipoprotein rose from 40 ± 3 to 44 ± 3 mg/dl (P <0.01 and triglycerides fell from 210 ± 18 to 178 ± 17 (P < 0.05). No changes in plasma lipid levels were observed with captopril or nifedipine. We concluded that in hypertensive NIDDM subjects, 1) captopril, nifedipine, and doxazosin are equally effective in lowering blood pressure; 2) captopril and nifedipine have no adverse effects on glucose tolerance, insulin sensitivity, ot plasma lipid profile; and 3) doxazosin significantly improves insulin sensitivity during the euglycemic insulin clamp, enhances OGTT while decreasing the plasma insulin response, and improves the plasma lipid profile.

Differential Responsiveness of Protein Synthesis and Degradation to Amino Acid Availability in Humans

We investigated the effects of graded hyperaminoacidemia on protein metabolism in eight healthy, young (25 ± 2 years), normal weight (BMI = 25 ± 1 kg/m2), overnight-fasted human subjects. A balanced amino acid solution was infused for 180 min at five different rates: 0.5 (study I), 1.0 (study II), 2.0 (study III), 4.0 (study IV), and 6.0 (study V) mg · kg−1 · min−1 on separate days in random order. Studies were performed with [1-14C]leucine infusion and indirect calorimetry to calculate leucine oxidation (LOX), nonoxidative leucine disposal (NOLD) (an index of protein synthesis), and endogenous leucine flux (ELF) (an index of proteolysis). Basal total plasma amino acid concentrations averaged 1.85 ± 0.1 nunol/1 and increased to 2.27 ± 0.1, 2.70 ± 0.2, 3.84 ± 0.2, 5.87 ± 0.4, and 7.52 ± 0.3 mmol/1 in studies I–V, respectively. ELF decreased from a basal value of 2.27 ± 0.2 to 2.12 ± 0.2, 1.97 ± 0.1, 1.73 ± 0.2, 1.67 ± 0.3, and 1.65 ± 0.1 μmol · kg−1 · min−1 in studies I–V, respectively (P < 0.05 for study I vs. basal, P < 0.01 for studies II–V vs. basal, and NS for studies IV and V vs. study III). LOX increased from a basal value of 0.31 ± 0.04 to 0.38 ± 0.05, 0.41 ± 0.02, 0.64 ± 0.04, 1.11 ± 0.07, and 1.56 ± 0.05 μmol kg−1 · min−1 in studies I–V (all P < 0.01 vs. basal; P < 0.05–0.01 for each study vs. preceding study). Basal NOLD averaged 1.96 ± 0.2 and did not change significantly in studies I and II (2.03 ± 0.2 and 2.10 ± 0.1 μmol · kg−1 · min−1). In contrast, a significant increase in NOLD was observed in studies III, IV, and V (to 2.3 ± 0.15, 2.74 ± 0.2, and 3.25 ± 0.7 (μmol · kg−1 · min−1 , respectively; all P < 0.01 vs. basal; P < 0.05–0.01 for each study vs. preceding study). The net leucine balance (difference between ELF and NOLD) (−0.31 ± 0.06 (μmol · kg−1 · min−1) became less negative in study I (P < 0.01 vs. basal) and positive during studies II–V when the rise in plasma total amino acid levels was ≥50% above basal level (P < 0.01 vs. each preceding study). In conclusion, NOLD, ELF, and LOX exhibit a differential responsiveness to acute changes in substrate availability: 1) small increments (25–50%) in plasma amino acid levels inhibit ELF and stimulate LOX but have no effect on NOLD; 2) stimulation of NOLD is observed only with increments in plasma amino acid levels ≥100% above basal values; and 3) increments in plasma amino acid concentrations >100% above basal values cause a progressive dose-related increase in LOX and NOLD but do not induce any further inhibition of ELF.

Neurotoxicity induced by Cefepime in a very old hemodialysis patient

Neurotoxicity is an unusual complication of cephalosporin therapy. Only few cases of neurotoxicity induced by Cefepime have been described and probably the frequency of Cefepime-induced status epilepticus is underestimated. We report a case of an 82 year-old male, ESRD patient on chronic hemodialysis program affected by pneumonia, who received a treatment with intravenous Cefepime (1 g/day) and developed a seizure 4 days after the starting antibiotic therapy. Cefepime-induced neurotoxicity was suspected and its administration was immediately discontinued. In order to increase Cefepime clearance a hemodialysis session was urgently started and an improvement of his conscious level was observed. On the following day, after a second hemodialysis session his clinical condition and the status of neurotoxicity were completely recovered. The patient was discharged from the hospital in stable clinical condition one week later. At variance with the cases previously reported, the daily dose of Cefepime administrated to our patient was 50% lower and respected drug prescription dosage. Thus, we speculate on the hypothesis that advanced age of our patient and metabolic encephalopathy induced by chronic uremia made him more sensitive to the neurotoxicity induced by the drug. In conclusion, our case suggests that, in very old patients on long-term hemodialysis, it should be considered, to avoid neurotoxicity, to monitor the clinical neurological status, to use Cefepime at lower dosage than that allowed in patients with severe renal impairment (1 g/day) and, when possible, to evaluate Cefepime plasma levels. However, in these patients, other agents of the same class should be considered such as Cefotaxime and Ceftriaxone which are characterized by both an hepatic and renal excretion. In alternative to cephalosporins, antibiotics with the same action spectrum in the absence of neurological toxicity (i.e. Meropenem) should be recommended.

Effect of alpha-adrenergic blockers, ACE inhibitors, and calcium channel antagonists on renal function in hypertensive non-insulin-dependent diabetic patients

In the present study we investigated the effect of a selective alpha 1-adrenergic blocker (doxazosin), an angiotensin-converting enzyme (ACE) inhibitor (captopril), and a calcium channel antagonist (nifedipine) on renal function in hypertensive non-insulin-dependent diabetic patients. 30 NIDD hypertensive patients (age = 50 +/- 3 years; BMI = 30 +/- 1 kg/m2) (mean +/- SEM) were studied before and after a 12-week period of antihypertensive treatment. Ten patients were treated with doxazosin (Cardura) (2-8 mg once daily or 8 mg b.i.d.), 9 with captopril (Capoten) (25-50 mg b.i.d.), and 11 with nifedipine (Procardia-XL) (30-60 mg once daily). Blood pressure, creatinine clearance, 24-hour urinary protein excretion, fasting plasma glucose concentration and glycosylated hemoglobin were measured before and after drug treatment. Fasting plasma glucose and glycosylated hemoglobin (HbA1c) were similar in all three groups prior to the start of antihypertensive therapy and did not change significantly from baseline in any treatment groups. In the doxazosin group creatinine clearance rose from 99 +/- 8 to 122 +/- 8 ml/1.73 m2.min (p < 0.01), while 24-hour urinary protein excretion declined from 2.66 +/- 0.05 to 1.76 +/- 0.02 mg/day/ml/1.73 m2.min (p < 0.01). In diabetics treated with captopril creatinine clearance rose from 93 +/- 6 to 109 +/- 9 ml/1.73 m2.min (p < 0.05), while the 24-hour urinary protein excretion fell from 2.70 +/- 0.05 to 2.03 +/- 0.04 mg/day/ml/1.73 m2.min (p < 0.05). In patients treated with nifedipine creatinine clearance did not change (97 +/- 6 vs. 94 +/- 7 ml/1.73 m2.min), while 24-hour urinary protein excretion decreased from 2.84 +/- 0.04 to 1.95 +/- 0.03 mg/day/ml/1.73 m2.min. Systolic and diastolic blood pressure were similar in doxazosin (150 +/- 3/95 +/- 2 mm Hg), captopril (153 +/- 3/93 +/- 1), and nifedipine (155 +/- 4/93 +/- 1) groups prior to the start of antihypertensive therapy and declined to 143 +/- 3/84 +/- 3 (doxazosin), 139 +/- 3/82 +/- 3 (captopril), and 141 +/- 3/84 +/- 1 (nifedipine) mm Hg (all p < 0.01 vs. pretreatment). In summary, both doxazosin and captopril treatment were associated with significant rises in GFR, while all three antihypertensive agents caused a significant decline in proteinuria. These results indicate that alpha-adrenergic blockers, ACE inhibitors, and calcium channel antagonists can safely and effectively be used in the clinical management of non-insulin-dependent diabetic patients with hypertension.

NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations

The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%–10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely “viral steatosis” and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host’s genetic background predisposes him or her to the development of steatosis. HCV’s impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related “metabolic steatosis” impairs the response rate to interferon-based treatment, whereas it seems that “viral steatosis” may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases.

Na+/Li+ and Na+/H+ countertransport activity in hypertensive non- insulin-dependent diabetic patients: Role of insulin resistance and antihypertensive treatment

We measured erythrocyte Na+/Li+ and Na+/H+ countertransport (CT) activity (millimoles per liter per cell per hour) in 10 healthy control subjects (age, 38 +/- 4 years; body mass index, 25 +/- 1 kg/m2) and in 25 hypertensive patients with non-insulin-dependent diabetes mellitus ([NIDDM] age, 49 +/- 3 years; body mass index, 29 +/- 1 kg/m2; fasting plasma glucose, 157 +/- 12 mg/dL) 4 weeks after discontinuation of previous antihypertensive treatment. Na+/Li+ CT was significantly increased in hypertensive NIDDM patients compared with controls (0.56 +/- 0.04 v 0.30 +/- 0.03, P < .01), whereas Na+/H+ CT was similar to control levels (21 +/- 1 v 20 +/- 2). A positive correlation was found between Na+/Li+ CT and the severity of insulin resistance (r = .69, P < .01), mean arterial pressure ([MAP] r = .64, P < .01), plasma triglyceride concentration (r = .46, P < .05), and plasma total cholesterol (r = .41, P < .05). An inverse correlation was found between Na+/Li+ CT activity and plasma insulin concentration (r = -.47, P < .05). No relationship was observed between Na+/Li+ CT activity and either creatinine clearance or proteinuria. Stepwise multiple regression analysis for all metabolic variables and blood pressure showed that only the severity of insulin resistance was positively correlated with increased Na+/Li+ CT activity. Na+/H+ and Na+/Li+ CT activity were not altered by 3 hours of euglycemic physiologic hyperinsulinemia (84 +/- 3 microU/mL). Hypertensive NIDDM subjects were treated for 3 months with captopril, nifedipine, or doxazosin. After captopril, a reduction of Na+/H+ CT was observed (22 +/- 4 v 13 +/- 2, P < .05); Na+/Li+ CT decreased after doxazosin (0.56 +/- 0.06 v 0.45 +/- 0.05, P < .05) and nifedipine (0.52 +/- 0.06 v 0.42 +/- 0.05, P < .05). In conclusion, in hypertensive NIDDM subjects, (1) Na+/Li+ CT is increased and is correlated with the level of insulin resistance and the MAP; (2) acute physiologic hyperinsulinemia does not affect Na+/Li+ or Na+/H+ CT activity; and (3) Na+/H+ CT activity is reduced by captopril, and Na+/Li+ CT is decreased by doxazosin and nifedipine.

Screening of depressive symptoms in young-old hemodialysis patients: Relationship between beck depression inventory and 15-item geriatric depression scale

Aims: We studied the relationship between the Beck Depression Inventory (BDI) and the 15-item Geriatric Depression Scale (GDS-15) in young–old hemodialysis and hospitalized patients in order to evaluate the possible usefulness of GDS-15 in hemodialysis patients. Methods: Thirty-one hospitalized and 31 young–old hemodialysis patients aged 65–74 (young–old) were enrolled in the study. Comprehensive geriatric assessment (Mini Mental State Examination (MMSE), BDI, GDS-15, Cumulative Illness Rating Scale (CIRS) and Activities of Daily Living (ADL)) was made for all patients. The internal consistency between BDI and GDS-15 was evaluated with Cronbach’s α coefficient. Sensitivity, specificity and receiver operating characteristic (ROC) curves for GDS-15 were determined using BDI as the standard. Results: In the hospitalized group, the prevalence of depressive symptoms, as evaluated by BDI (≧14) and GDS-15 (≧6), were 29 and 32%, respectively. In the hemodialysis group, the prevalence of depressive symptoms, as evaluated by BDI and GDS-15, were 61 and 58%, respectively. A significantly positive correlation between the BDI and GDS-15 was found in hospitalized (r = 0.808; p < 0.001), hemodialysis (r = 0.692; p < 0.001) and both patient groups together (r = 0.777; p < 0.001). The area under the ROC curve was 0.99 in the hospitalized and 0.95 in the hemodialysis groups. The ROC curves indicate a best effectiveness cutoff point (balancing sensitivity and specificity) of ≧6 for GDS-15 compared to BDI. Conclusions: The GDS-15 could be a useful instrument for evaluating depressive symptoms in young–old hemodialysis patients.

Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis

AIM To characterize natural history of cryptogenic cirrhosis (CC) and compare its clinical features and outcomes to those of hepatitis C virus (HCV)-related cirrhosis. METHODS A prospective cohort of 102 consecutive patients at their first diagnosis of CC were enrolled in this study. The clinical data and outcomes were compared to an age- and Child-Pugh class-matched cohort of 110 patients with HCV-related cirrhosis. Diagnosis of cirrhosis was based on compatible clinical and laboratory parameters, ultrasound/endoscopic parameters and, whenever possible, on histological grounds and transient elastography. All cases of cirrhosis without a definite etiology were enrolled in the CC group. The parameters assessed were: (1) severity of liver disease at the time of first diagnosis; (2) liver decompensation during follow-up; (3) hepatocellular carcinoma (HCC); (4) orthotopic liver transplantation; and (5) death. The independent associated factors were evaluated by multiple logistic regression analysis, and survival and its determinants by the Kaplan-Meier model, log-rank test and Cox regression. RESULTS At the first observation, median age was 66 and 65 years and male gender was 36% and 58% for CC and HCV cirrhosis, respectively. CC showed Child-Pugh class A/B/C of 47%/31%/22%, respectively. Compared to HCV cirrhosis, CC exhibited a significantly higher prevalence of metabolic syndrome (12% vs 54%, respectively), overweight/obesity, high BMI, impaired glucose tolerance, high blood pressure, dyslipidemia, hyperuricemia, cardiovascular diseases, extrahepatic cancer, and gallstones. Over a median period of 42 mo of follow-up, liver decompensation, HCC development and death for CC and HCV-related cirrhosis were 60.8%, and 54.4%, 16.7% and 17.2%, 39.2% and 30%, respectively. The median survival was 60 mo for CC. Independent predictors of death were age and Child-Pugh class at diagnosis. CC showed an approximately twofold higher incidence of HCC in Child-Pugh class A. CONCLUSION Undiagnosed nonalcoholic fatty liver disease has an etiologic role in CC that is associated with a poor prognosis, early HCC development, high risk of cardiovascular disease and extrahepatic cancer.

Effects of a 6-days-a-week low protein diet regimen on depressive symptoms in young-old type 2 diabetic patients

OBJECTIVES Late-life depression is one of the main health problems among elderly diabetic subjects. In addition, depression is a common psychopathological condition among renal failure patients and most of these patients follow a low protein diet regimen (LPD). However, the effects of LPD on depressive symptoms are unclear. DESIGN In the present study, the effects of LPD regimen on depressive symptoms in elderly type 2 diabetic subjects with renal failure were investigated. PARTICIPANTS Fifty-two young-old type 2 diabetic patients with renal failure were enrolled in the study. All participants after normal protein diet regimen providing 1.2g/kg per d were instructed to consume either a LPD providing 0.8 g/kg per d, 7 d a wk (LPD 7/7), or a LPD providing 0.8 g/kg per d 6 d a wk (LPD 6/7) randomly. RESULTS Mean 15-item Geriatric Depression Scale (GDS-15) (2.0±0.6) and Beck Depression Inventory (BDI) (4.1±1.0), during normal protein diet regimen, significantly increased to (6.7±1.6) and (12.2±1.4), respectively, after LPD 7/7 (P<0.05 versus normal protein diet). However, after LPD 6/7, mean GDS-15 and BDI significantly decreased to (4.4±1.5) and (6.7±1.6), respectively (P<0.05 versus LPD 7/7). CONCLUSION LPD 6/7 regimen significantly decreased depressive symptoms in young-old type 2 diabetic patients.

Targeting Obesity and Diabetes to Treat Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need that is characterized by the presence of multiple cardiovascular and non-cardiovascular comorbidities. Foremost among these comorbidities are obesity and diabetes, which are not only risk factors for the development of HFpEF, but worsen symptoms and outcome. Coronary microvascular inflammation with endothelial dysfunction is a common denominator among HFpEF, obesity, and diabetes that likely explains at least in part the etiology of HFpEF and its synergistic relationship with obesity and diabetes. Thus, pharmacological strategies to supplement nitric oxide and subsequent cyclic guanosine monophosphate (cGMP)—protein kinase G (PKG) signaling may have therapeutic promise. Other potential approaches include exercise and lifestyle modifications, as well as targeting endothelial cell mineralocorticoid receptors, non-coding RNAs, sodium glucose transporter 2 inhibitors, and enhancers of natriuretic peptide protective NO-independent cGMP-initiated and alternative signaling, such as LCZ696 and phosphodiesterase-9 inhibitors. Additionally, understanding the role of adipokines in HFpEF may lead to new treatments. Identifying novel drug targets based on the shared underlying microvascular disease process may improve the quality of life and lifespan of those afflicted with both HFpEF and obesity or diabetes, or even prevent its occurrence.