Atorvastatin improves metabolic control and endothelial function in type 2 diabetic patients: a placebo-controlled study

Several pieces of evidence support a role of inflammatory processes in the pathogenesis of atherosclerosis; it is also known that endothelial dysfunction is the initial lesion of the atherosclerotic process. Among other markers of endothelial dysfunction, some adhesion molecules seem to play an interesting role. The aim of the present study was to evaluate the effect of atorvastatin vs placebo on some indexes of leukocytes adhesion in a group of Type 2 diabetic patients. Twenty-five Type 2 diabetic patients free from microangiopathic complications and with LDL-cholesterol lower than 180 mg/dl were randomized to receive either atorvastatin (T2DA) or placebo (T2Dp) for twelve months. BMI, fasting plasma glucose, glycated hemoglobin (HbA1c), albumin excretion rate (AER), lipid profile, and serum concentrations of vascular cell adhesion molecule-1 (VCAM1), E-selectin and cadherin-5 were measured at baseline and at the end of the follow-up. At T0 E-selectin was 16 +/- 6 ng/ml in T2DA and 17 +/- 13 in T2Dp; VCAM1 was 413 +/- 112 ng/ml in T2DA and 411 +/- 112 in T2Dp. At T12 VCAM1 and E-selectin did not vary in T2Dp, while a significant reduction was observed in T2DA (VCAM1 275 +/- 104 ng/ml and E-selectin 8 +/- 3 ng/ml; p < 0.001 and p < 0.01, respectively). T2DA also showed a reduction of total and LDL cholesterol and an improved glycemic control respect to T2Dp. Hypolipidemic therapy was the strongest independent predictor of the cytokines variations along the time. These results confirm the role of statins in modulating endothelial function also in Type 2 diabetes, outlining a therapeutic role of these molecules probably independent from the hypolipidemic effect.     

Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.     

Adipocytokines mark insulin sensitivity in euthyroid Hashimoto’s patients

The relationship between inflammation, Hashimoto’s thyroiditis (HT) and insulin resistance is still controversial. In this regard, a pretty complete evaluation of adipocytokines levels in patients with HT has not been performed so far. We assessed retinol binding protein-4 (RBP4), adipocyte-fatty acid binding protein (A-FABP), neutrophil gelatinase–associated lipocalin (NGAL) and tumor necrosis factor-α (TNFα) levels in 93 euthyroid HT patients and 51 healthy controls (CTL), also evaluating the possible correlation between adipocytokines levels and markers of insulin resistance. No significant differences between HT patients and CTL in fasting plasma glucose and insulin levels, and HOMA index were observed. HT patients had significantly higher RBP4, NGAL and A-FABP levels than CTL, while TNFα levels did not differ between the two groups. In HT patients, RBP4 was significantly related with fT3 and fT4 levels, while A-FABP with fT4 only. Moreover, in HT patients, either RBP4 or A-FABP was directly associated with plasma insulin and HOMA index. Circulating levels of these adipocytokines were not influenced by the presence of antithyroid peroxidase or antithyroglobulin autoantibodies or only one of them, neither by autoantibodies titer. In conclusion, euthyroid HT patients are characterized by a peculiar inflammatory response of the adipose tissue, apparently related to an early reduction in insulin sensitivity and to serum thyroid hormone levels, although within the normal range. These results suggest that HT patients with high RBP4 and A-FABP levels might deserve a particular attention, being potentially more exposed to develop insulin resistance and increased cardiovascular risk.     

Diverging association of reduced glomerular filtration rate and albuminuria with coronary and noncoronary events in patients with type 2 diabetes: the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study

OBJECTIVE

Although a reduced estimated glomerular filtration rate (eGFR) was shown to be a powerful independent predictor of cardiovascular disease (CVD), other studies suggested that it confers a much lower risk than albuminuria alone, whereas the combination of the two abnormalities is associated with multiplicative risk. This study aimed at assessing the independent association of previous CVD events, either total or by vascular bed, with eGFR and albuminuria and chronic kidney disease (CKD) phenotypes.

RESEARCH DESIGN AND METHODS

This cross-sectional study evaluated 15,773 patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study in 19 outpatient diabetes clinics in years 2007–2008. Albuminuria was assessed by immunonephelometry or immunoturbidimetry. GFR was estimated by the simplified Modification of Diet in Renal Disease Study and the Chronic Kidney Disease-Epidemiology Collaboration equation. CKD was defined as an eGFR <60 mL/min/1.73 m² or micro- or macroalbuminuria. Major acute CVD events were adjudicated based on hospital discharge records or specialist visits.

RESULTS

CVD risk increased linearly with eGFR decline and albuminuria and became significant for values <78 mL/min/1.73 m² and ≥10.5 mg/24 h, respectively. Beyond traditional CVD risk factors, total CVD showed an independent association with albuminuria alone (odds ratio 1.20 [95% CI 1.08–1.33]), reduced eGFR alone (1.52 [1.34–1.73]), and both abnormalities (1.90 [1.66–2.19]). However, coronary events were associated predominantly with reduced eGFR alone, whereas cerebrovascular and peripheral events showed a stronger correlation with the albuminuric CKD phenotypes.

CONCLUSIONS

These data, although cross-sectional, show that reduced eGFR, irrespective of albuminuria, is associated with significant CVD, particularly in the coronary district.A large body of evidence suggests that individuals with chronic kidney disease (CKD) are more likely to die, particularly from cardiovascular disease (CVD), than to progress to end-stage renal disease (ESRD) (1), although recent findings seem to favor progression (2). In fact, although CVD risk is particularly increased in patients with ESRD, where CVD mortality accounts for the vast majority of deaths (3), even mild-to-moderate renal impairment is associated with CVD, as shown in the general population (4) and in subjects with type 2 diabetes (5).For clinical and epidemiologic purposes, CKD is currently classified into five stages, according to the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI). Classification is based on the presence or absence of kidney damage, as manifested by pathologic abnormalities or by disease markers such as micro- or macroalbuminuria, and glomerular filtration rate (GFR), as calculated by the use of estimating equations from serum creatinine measurements. Although stages 1–2 CKD are identified by evidence of kidney damage, stages 3–5 CKD are defined solely on the basis of estimated GFR (eGFR), irrespective of albuminuria (6). Because staging systems for disease classification should assign people with worse prognoses to more advanced stages, based on that introduced by the NKF KDOQI, subjects with an eGFR <60 mL/min/1.73 m² (i.e., stage ≥3 CKD) without albuminuria would carry the same CVD and renal risk as those with albuminuria but a lower risk than individuals with albuminuria and normal or subnormal eGFR, who are assigned to stages 1–2 CKD.In the Third National Health and Nutrition Examination Survey (NHANES III) cohort, increased albuminuria and reduced eGFR were both associated with increased risk of CVD and all-cause mortality overall and within every eGFR and albuminuria category, respectively (7). A recent meta-analysis confirmed that albuminuria, with no threshold, and an eGFR <60 mL/min/1.73 m² are both independent predictors of death and indicated that these two abnormalities are multiplicatively associated with risk of death without evidence of interaction (8). However, in other samples of the general population, the eGFR cutoff point for optimal discrimination of CVD risk was higher (9,10), whereas more recent reports showed that individuals with reduced eGFR without albuminuria are at much lower CVD risk than subjects with albuminuria without reduced eGFR (11–13). Studies in patients with type 2 diabetes showed that albuminuria and reduced eGFR are associated to the same extent with total CVD events (14,15), whereas albuminuria predicts death from CVD better than reduced eGFR (8,16).Thus, although the independent contribution of albuminuria appears to be relevant, it is unclear whether subnormal eGFR levels (i.e., 60–89 mL/min/1.73 m²) and, particularly, reduced eGFR levels (i.e., <60 mL/min/1.73 m²) in the absence of albuminuria are associated with significant CVD risk. This issue is particularly relevant in patients with type 2 diabetes, because reduced eGFR is more common than previously recognized in these individuals (17), and more importantly, it occurs in the absence of albuminuria in most of them (14,18,19).This study assessed the independent association of previous CVD events, either total or by vascular bed, with eGFR and albuminuria as well as with nonalbuminuric CKD, as defined by an eGFR <60 mL/m/1.73 m² without albuminuria, compared with albuminuric CKD with either reduced (stage ≥3 CKD) or nonreduced (stages 1–2 CKD) eGFR, in a large Italian cohort of patients with type 2 diabetes.     

Bilateral pneumothorax,lung cavitations,and pleural empyema in a cocaine addict

A case of bilateral pneumothorax, lung cavitations, and pleural empyema in a cocaine user is described. The patient was treated by left tube thoracostomy and right lower lobectomy. The postoperative course was uneventful. Six months later, the patient remains asymptomatic. The pathology examination of the specimen revealed infected bronchiectasis, interstitial desquamative pneumonia, diffuse alveolar damage, subsegmental arterial thrombosis, and consequent areas of pulmonary infarction.     

The Dark Side of Extracellular ATP in Kidney Diseases

Intracellular ATP is the most vital source of cellular energy for biologic systems, whereas extracellular ATP is a multifaceted mediator of several cell functions via its interaction, in an autocrine or paracrine manner, with P2 purinergic receptors expressed on the cell surface. These ionotropic and metabotropic P2 purinergic receptors modulate a variety of physiologic events upon the maintenance of a highly sensitive “set point,” the derangement of which may lead to the development of key pathogenic mechanisms during acute and chronic diseases. Growing evidence suggests that extracellular ATP signaling via P2 purinergic receptors may be involved in different renal pathologic conditions. For these reasons, investigators and pharmaceutical companies are actively exploring novel strategies to antagonize or block these receptors with the goal of reducing extracellular ATP production or accelerating extracellular ATP clearance. Targeting extracellular ATP signaling, particularly through the P2X₇ receptor, has considerable translational potential, given that novel P2X₇-receptor inhibitors are already available for clinical use (e.g., CE224,535, AZD9056, and GSK1482160). This review summarizes the current evidence regarding the involvement of extracellular ATP and its P2 purinergic receptor–mediated signaling in physiologic and pathologic processes in the kidney; potential therapeutic options targeting extracellular ATP purinergic receptors are analyzed as well.     

The purinergic 2X7 receptor participates in renal inflammation and injury induced by high‐fat diet: possible role of NLRP3 inflammasome activation

Renal disease associated with type 2 diabetes and the metabolic syndrome is characterized by a distinct inflammatory phenotype. The purinergic 2X₇ receptor (P2X₇R) and the nucleotide‐binding and oligomerization domain‐like receptor containing a pyrin domain 3 (NLRP3) inflammasome have been separately shown to play a role in two models of non‐metabolic chronic kidney disease. Moreover, the NLRP3 inflammasome has been implicated in chronic low‐grade sterile inflammation characterizing metabolic disorders, though the mechanism(s) involved in inflammasome activation under these conditions are still unknown. We investigated the role of P2X₇R (through activation of the NLRP3 inflammasome) in renal inflammation and injury induced by a high‐fat diet, an established model of the metabolic syndrome. On a high‐fat diet, mice lacking P2X₇R developed attenuated renal functional and structural alterations as well as reduced inflammation, fibrosis, and oxidative/carbonyl stress, as compared with wild‐type animals, in the absence of significant differences in metabolic parameters. This was associated with blunted up‐regulation of the NLRP3 inflammasome components NLRP3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), pro‐caspase 1, pro‐interleukin (IL)‐1β, and pro‐IL‐18, as well as reduced inflammasome activation, as evidenced by decreased formation of mature caspase 1, whereas mature IL‐1β and IL‐18 were not detected. Up‐regulated expression of NLRP3 and pro‐caspase 1, post‐translational processing of pro‐caspase‐1, and release of IL‐18 in response to lipopolysaccharide + 2′(3′)‐O‐(4‐benzoylbenzoyl)ATP were attenuated by P2X₇R silencing in cultured mouse podocytes. Protein and mRNA expression of P2X₇R, NLRP3, and ASC were also increased in kidneys from subjects with type 2 diabetes and the metabolic syndrome, showing histologically documented renal disease. These data provide evidence of a major role for the purinergic system, at least in part through activation of the NLRP3 inflammasome, in the process driving ‘metabolic’ renal inflammation and injury and identify P2X₇R and NLRP3 as novel therapeutic targets. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.