Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy. A multicenter prospective 8 years follow up study.

BACKGROUND: Although numerous studies and metanalysis have shown the beneficial effect of statin therapy in CVD secondary prevention, there is still controversy such the use of statins for primary CVD prevention in patients with DM. The purpose of this study was to evaluate the occurrence of total major adverse cardio-vascular events (MACE) in a cohort of patients with type 2 diabetes complicated by nephropathy treated with statins, in order to verify real life effect of statin on CVD primary prevention. METHODS: We conducted an observational prospective multicenter study on 564 patients with type 2 diabetic nephropathy free of cardiovascular disease attending 21 national outpatient diabetes clinics and followed them up for 8 years. 169 of them were treated with statins (group A) while 395 were not on statins (group B). RESULTS: Notably, none of the patients was treated with a high-intensity statin therapy according to last ADA position statement. Total MACE occurred in 32 patients from group A and in 68 patients from group B. Fatal MACE occurred in 13 patients from group A and in 30 from group B; nonfatal MACE occurred in 19 patients from group A and in 38 patients from group B. The analysis of the Kaplan-Meier survival curves showed a not statistically significant difference in the incidence of total (p 0.758), fatal (p 0.474) and nonfatal (p 0.812) MACE between the two groups. HbA1c only showed a significant difference in the incidence of MACE between the two groups (HR 1.201, CI 1.041-1.387, p 0.012). CONCLUSIONS: These findings suggest that, in a real clinical setting, moderate-intensity statin treatment is ineffective in cardiovascular primary prevention for patients with diabetic nephropathy. Trial registration ClinicalTrials.gov Identifier NCT00535925. Date of registration: September 24, 2007, retrospectively registered.

High cardiovascular risk in patients with Type 2 diabetic nephropathy: the predictive role of albuminuria and glomerular filtration rate. The NID-2 Prospective Cohort Study.

BACKGROUND: In Type 2 diabetic patients, clinical diagnosis of diabetic nephropathy (DN) is generally based on the concomitant presence of abnormal albuminuria and severe retinopathy. In this high-risk population, cardiovascular (CV) outcome has never been evaluated. METHODS: A cohort of 742 Type 2 diabetic patients with DN from 17 national centres was selected by the presence of persistent albuminuria ≥ 30 mg/day and severe diabetic retinopathy and was followed prospectively. Time to CV event (CV death, non-fatal myocardial infarction, non-fatal stroke, revascularization, major amputation) was the primary composite end point and it was analysed by multivariable Cox's proportional hazards model. The interaction between albuminuria and glomerular filtration rate (GFR) was specifically investigated. RESULTS: Median follow-up was 4.6 years. Overall 242 events (26% of which fatal) were observed in 202 patients. The proportion of CV events increased from 19 to 40% as GFR declined from the highest (≥ 90 mL/min/1.73 m(2)) to the lowest (<45 mL/min/1.73 m(2)) category and was equal to 25 and 33% in microalbuminuria and macroalbuminuria, respectively. In multivariable analysis, the interaction between albuminuria and GFR was statistically significant (P = 0.012). Albuminuria, indeed, had a remarkable prognostic effect in subjects with high GFR that virtually disappeared as GFR became <30 mL/min/1.73 m(2). Age, smoking habit, previous occurrence of myocardial infarction or stroke and proliferative retinopathy were all found to have a statistically significant prognostic effect on CV outcome. CONCLUSIONS: A clinically based diagnosis of DN in Type 2 diabetes allows the identification of subjects with high CV risk. Albuminuria has a relevant prognostic effect on CV morbidity and mortality; its effect is especially pronounced when GFR is normal or near normal.

The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques: effects of rosiglitazone treatment.

The role of ubiquitin-proteasome system in the accelerated atherosclerotic progression of diabetic patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic diabetic and nondiabetic patients, as well as the effect of rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma activator, in diabetic plaques. Plaques were obtained from 46 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Diabetic patients received 8 mg rosiglitazone (n = 23) or placebo (n = 23) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLA-DR), ubiquitin, proteasome 20S activity, nuclear factor (NF)-kappaB, inhibitor of kappaB (IkappaB)-beta, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Compared with nondiabetic plaques, diabetic plaques had more macrophages, T-cells, and HLA-DR+ cells (P < 0.001); more ubiquitin, proteasome 20S activity (TNF-alpha), and NF-kappaB (P < 0.001); and more markers of oxidative stress (nitrotyrosine and O2(-) production) and MMP-9 (P < 0.01), along with a lesser collagen content and IkappaB-beta levels (P < 0.001). Compared with placebo-treated plaques, rosiglitazone-treated diabetic plaques presented less inflammatory cells (P < 0.01); less ubiquitin, proteasome 20S, TNF-alpha, and NF-kappaB (P < 0.01); less nitrotyrosine and superoxide anion production (P < 0.01); and greater collagen content (P < 0.01), indicating a more stable plaque phenotype. Similar findings were obtained in circulating monocytes obtained from the two groups of diabetic patients and cultured in the presence or absence of rosiglitazone (7.0 micromol/l). Ubiquitin-proteasome over-activity is associated with enhanced inflammatory reaction and NF-kappaB expression in diabetic plaques. The inhibition of ubiquitin-proteasome activity in atherosclerotic lesions of diabetic patients by rosiglitazone is associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by downregulating NF-kappaB-mediated inflammatory pathways.

Cardiovascular risk factors and disease management in type 2 diabetic patients with diabetic nephropathy.

OBJECTIVE: The purpose of this study was to assess the prevalence of cardiorenal risk factors, their management in a routine clinical setting, and the actual achievement of international guideline targets in a large cohort of type 2 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: A multicentric cross-sectional study was performed in the Campania region in Italy to evaluate cardiorenal risk factors and their management in light of international guidelines. Overall, 28,550 diabetic patients were screened in the 21 participating centers; 847 (348 male and 449 female) patients with type 2 diabetes and a clinical diagnosis of diabetic nephropathy were recruited. RESULTS: Of these subjects, 749 had microalbuminuria and 98 had macroalbuminuria. Targets for blood pressure, HbA(1c), LDL cholesterol, HDL cholesterol, and triglycerides were reached in, respectively, 17.5, 32.3, 30.7, 47, and 55.2% of the patients. Chronic renal failure (glomerular filtration rate <60 ml/min) was revealed in 41% and anemia in 23.8% of the patients. CONCLUSIONS: This is the first study to investigate a large cohort of type 2 diabetic patients with early and moderate diabetic nephropathy strictu sensu. Notably, impaired renal function can be often diagnosed in these patients even in the presence of microalbuminuria. Thus, clinical diagnosis of diabetic nephopathy allows us to identify a group of patients at very high cardiorenal risk, for whom care is really difficult. We suggest that a correct diagnosis of diabetic nephropathy should always be made and that sodium intake and anemia should be routinely evaluated in these patients.

Increased vascular endothelial growth factor expression but impaired vascular endothelial growth factor receptor signaling in the myocardium of type 2 diabetic patients with chronic coronary heart disease.

OBJECTIVES: The aim of the present study was to evaluate the expression and the activity of vascular endothelial growth factor (VEGF) in the hearts of diabetic patients with chronic coronary heart disease (CHD). BACKGROUND: Diabetes is characterized by a decreased collateral vessel formation in response to coronary ischemic events, although the role of VEGF in human diabetic macroangiopathy has not been fully investigated. METHODS: Biopsies of left ventricular (LV) myocardium were obtained from 10 patients with type 2 diabetes and 10 non-diabetic patients with chronic CHD, all undergoing surgical coronary revascularization. Right ventricle myocardial samples taken from normal hearts were used as control specimens. Vascular endothelial growth factor and VEGF-receptors (flt-1 and flk-1) were evaluated by Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR. Akt and endothelial nitric oxide synthase (eNOS) protein expression and their phosphorylated forms were also evaluated by Western blot. RESULTS: Vascular endothelial growth factor, flt-1, and flk-1 messenger ribonucleic acid (mRNA) and protein expressions were increased in non-diabetic patients with CHD compared with control subjects. Remarkably, in diabetic patients, VEGF mRNA and protein levels were significantly higher, whereas flt-1, flk-1 mRNA, and protein were lower when compared with non-diabetic patients. Interestingly, phospho-flk-1 was reduced in diabetic patients compared with non-diabetic patients. As a consequence, Akt phosphorylation, eNOS protein and its phosphorylated form were significantly higher in the samples from non-diabetic patients compared with diabetic patients. CONCLUSIONS: Chronic CHD in diabetic patients is characterized by an increased VEGF myocardial expression and a decreased expression of its receptors along with a down-regulation of its signal transduction. The latter could be partially responsible for the reduced neoangiogenesis in diabetic patients with ischemic cardiomyopathy.

Management of cardiovascular risk factors in advanced type 2 diabetic nephropathy: a comparative analysis in nephrology, diabetology and primary care settings.

OBJECTIVES: Advanced diabetic nephropathy (DN) is characterized by a marked development of cardiovascular and renal disease. These patients are frequently managed by different health professionals with the consequence that the quality of care may differ substantially. To compare the management of cardiovascular risk factors in patients with type 2 DN and an estimated glomerular filtration rate (GFR) of 15-60 ml/min per 1.73 m2 followed in nephrology, diabetology and primary care. METHODS: This multicentre cross-sectional study verified the control of blood pressure (BP), total cholesterol, triglycerides, glycosylated haemoglobin A1c (HbA1c) and haemoglobin in patients exclusively followed in either nephrology (n = 266), diabetology (n = 246) or primary care (n = 195) of the same metropolitan area for at least 1 year. RESULTS: Primary care patients were older and had a greater prevalence of previous cardiovascular events. The GFR was lower in nephrology than in diabetology and primary care (33 +/- 13 versus 47 +/- 9 and 40 +/- 12 ml/min per 1.73 m2, P < 0.0001). The prevalence of BP target (< 130/80 mmHg) was similarly low in nephrology, diabetology and primary care (14, 13 and 10%, P = 0.421) probably because of insufficient prescription of diuretics and low-salt diet. Whereas the prevalence of the triglycerides target was similar, that of total cholesterol (< 200 mg/dl) was larger in diabetology (63%) than in nephrology and primary care (59 and 46%, P = 0.003) because of greater statin prescription in hypercholesterolemic individuals (70, 50 and 41%, respectively, P = 0.002). The attainment of HbA1c less than 7% was less frequent in diabetology (32%) than in nephrology and primary care (61 and 46%, P = 0.0003) despite a more frequent prescription of insulin/oral agents in diabetology. The control of anaemia was better in diabetology. Multivariate analysis adjusted for the patient case-mix and physician-level clustering confirmed these differences except for anaemia. CONCLUSION: Patients with advanced DN, despite the worst renal and cardiovascular prognosis, are at high risk of being under-treated independently of the type of clinical setting.

Irbesartan reduces the albumin excretion rate in microalbuminuric type 2 diabetic patients independently of hypertension: a randomized double-blind placebo-controlled crossover study.

OBJECTIVE: ACE inhibitors delay the progression from incipient to overt diabetic nephropathy and reduce albumin excretion rate (AER), independently of blood pressure. Angiotensin II type 1 receptor antagonists produce similar effects on microalbuminuria and mean arterial pressure. The aim of this study was to evaluate the effect of irbesartan on microalbuminuria and blood pressure in hypertensive and normotensive type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Sixty-four microalbuminuric hypertensive (group 1) and 60 microalbuminuric normotensive (group 2) type 2 diabetic male patients, matched for age, BMI, HbA(1c), and diabetes duration, were enrolled. Each group was divided into two subgroups receiving either irbesartan (150 mg b.i.d. orally) or placebo for 60 days. After 15 days of washout, irbesartan was given to the subgroups who had received the placebo, and vice versa, in a randomized double-blind crossover study. RESULTS: In microalbuminuric hypertensive type 2 diabetic subjects, irbesartan reduced 24-h mean systolic and diastolic pressure and AER. In microalbuminuric normotensive type 2 diabetic patients, irbesartan reduced AER. CONCLUSIONS: These results indicate the beneficial effects of irbesartan on AER in type 2 diabetic subjects, independently of its antihypertensive effects.

Lack of effect of aspirin in primary CV prevention in type 2 diabetic patients with nephropathy: results from 8 years follow-up of NID-2 study.

The risk-to-benefit ratio for the use of low dose of aspirin in primary cardiovascular (CV) prevention in patients with diabetes mellitus remains to be clarified. We assessed the effect of aspirin on risk of CV events in type 2 diabetic patients with nephropathy, in order to verify the usefulness of Guidelines in clinical practice. We carried out a prospective multicentric study in 564 patients with type 2 diabetic nephropathy free of CV disease attending outpatient diabetes clinics . A total of 242 patients received antiplatelet treatment with aspirin 100 mg/day (group A), and 322 were not treated with antiplatelet drugs (group B). Primary end point was the occurrence of total major adverse cardio-vascular events (MACE). Secondary end points were the relative occurrence of fatal MACE. The average follow-up was 8 years. Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22 patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. Kaplan-Meier analysis did not show a statistically significant difference of cumulative MACE between the two groups. A not statistically significant difference in the incidence of both fatal (p = 0.225) and nonfatal CV events (p = 0.573) between the two groups was observed. These results were confirmed after adjustment for confounders (HR for MACE 1.11, 95 % CI 0.91-1.35). These findings suggest that low dose of aspirin is ineffective in primary prevention for patients with nephropathy.

Autonomic dysfunction is associated with brief episodes of atrial fibrillation in type 2 diabetes.

BACKGROUND AND AIMS: This study aimed to investigate the relationship between asymptomatic episodes of atrial fibrillation (AF) and abnormalities of the autonomic nervous system in type 2 diabetic patients who did not have evidence of atrial fibrillation at baseline. METHODS AND RESULTS: In a multicentric cross-sectional controlled study, 1992 patients with type 2 diabetes were screened. All underwent ambulatory ECG recording for 48-hour at 3, 6, 9, and 12months. Heart rate variability (HRV) was used as indicator of autonomic activity. One hundred seventy-six diabetics with silent atrial fibrillation episodes (SAFE group) and 288 without silent atrial fibrillation (non-SAFE group) were enrolled. These selected diabetics were matched on clinical and anthropometric data to 120 control subjects without diabetes of the control group. HRV analysis evidenced that LF/HF ratio was significantly higher in the SAFE group than in the non-SAFE group (P<0.05) in the whole period of HM analysis. AF absolute burdens were positively correlated with LF/HF ratio (r=0.31, P<0.001). Multiple regression analysis showed that LF/HF ratio was an independent determinant of AF episodes. CONCLUSIONS: This study originally showed a strong relationship between autonomic dysfunction and silent atrial fibrillation in type 2 diabetes.

Glucose metabolism and coronary heart disease in patients with normal glucose tolerance.

CONTEXT: Several investigations as well as prospective studies have shown a significant correlation between glucose metabolism and atherosclerosis in patients without diabetes, but differences in parameters of glucose metabolism among the various degrees of coronary disease in such patients have not been specifically evaluated. OBJECTIVE: To investigate glucose metabolism in patients with normal glucose tolerance (NGT) and coronary heart disease (CHD). DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of 234 men (mean [SD] age, 56.2 [6.1] years) with NGT and suspected CHD who were admitted from January 1 through June 30, 2001, to an academic medical center in Italy for coronary angiography. MAIN OUTCOME MEASURES: Correlation of glucose metabolic factors and extent of atherosclerosis determined by coronary angiography. Factors included levels of fasting and postload glucose and insulin, glycosylated hemoglobin (HbA1c), and lipids, as well as insulin resistance measured by homeostasis model assessment (HOMA-IR). RESULTS: Patients were divided into 4 groups based on coronary angiography: no significant stenosis (n = 42), 1-vessel disease (n = 72), 2-vessel disease (n = 64), and 3-vessel disease (n = 56). Simple correlation analysis showed that the factors correlated with the extent of atherosclerosis were levels of postload glucose (r = 0.667), HbA1c (r = 0.561), postload insulin (r = 0.221), and fasting insulin (r = 0.297), as well as HOMA-IR (r = 0.278) (P<.001 for all). Multiple stepwise regression analysis suggested that the factors independently associated with the number of stenosed coronary arteries were levels of postload plasma glucose (r = 0.572), HbA1c (r = 0.413), postload insulin (r = 0.267), and fasting insulin (r = 0.174), as well as HOMA-IR (r = 0.250) (P<.001 for all). Similar results were obtained after grouping patients by Duke Myocardial Jeopardy Score. CONCLUSIONS: For patients with NGT and different extents of atherosclerotic disease, postload glycemia and HbA1c level are not equally distributed but are significantly higher in those with more severe disease. This suggests that the glycemic milieu correlates with the cardiovascular risk according to a linear model.

Coronary artery disease is detectable by multi-slice computed tomography in most asymptomatic type 2 diabetic patients at high cardiovascular risk.

OBJECTIVE: Non-invasive testing often does not identify coronary artery disease (CAD) in diabetic subjects. This study was designed in order to examine the prevalence of CAD in a cohort of asymptomatic type 2 diabetic patients at high cardiovascular risk and negative nuclear imaging, using multi-slice computed tomography (MSCT) angiography. METHODS: In total, 770 type 2 diabetic patients were screened from January 2008 through July 2010. Of these, 132 Caucasians with diabetic nephropathy and asymptomatic for angina were eligible for a cross-sectional study. Patients underwent MSCT after ischaemia was excluded by myocardial Single Photon Emission Computed Tomography (SPECT) at rest and after dynamic exercise. When obstructive plaques were found (≥ 50% lumen narrowing), patients were sent to conventional coronary angiography (CCA). RESULTS: Six subjects were not included in the analysis because of motion artefacts. MSCT was positive for CAD in 114 patients (90%). Within patients with positive MSCT, 60 (48% of all) showed one or more obstructive plaques. CCA confirmed significant stenosis (≥ 50%) in 48 of these 60 patients (80%). Some 21 (35%) showed stenosis ≥ 75% and were submitted to the revascularisation procedure. CONCLUSION: MSCT seems to better identify CAD than myocardial SPECT in asymptomatic patients with type 2 diabetes and diabetic nephropathy.

Dipeptidyl peptidase 4 inhibition may facilitate healing of chronic foot ulcers in patients with type 2 diabetes.

The pathophysiology of chronic diabetic ulcers is complex and still incompletely understood, both micro- and macroangiopathy strongly contribute to the development and delayed healing of diabetic wounds, through an impaired tissue feeding and response to ischemia. With adequate treatment, some ulcers may last only weeks; however, many ulcers are difficult to treat and may last months, in certain cases years; 19-35% of ulcers are reported as nonhealing. As no efficient therapy is available, it is a high priority to develop new strategies for treatment of this devastating complication. Because experimental and pathological studies suggest that incretin hormone glucagon-like peptide-1 may improves VEGF generation and promote the upregulation of HIF-1α through a reduction of oxidative stress, the study evaluated the effect of the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase-4, such as vildagliptin, on angiogenesis process and wound healing in diabetic chronic ulcers. Although elucidation of the pathophysiologic importance of these aspects awaits further confirmations, the present study evidences an additional aspect of how DPP-4 inhibition might contribute to improved ulcer outcome.

Tight glycemic control may increase regenerative potential of myocardium during acute infarction.

AIMS: We analyzed the effects of tight glycemic control on regenerative potential of myocardium during acute myocardial infarction. PATIENTS AND METHODS: Seventy-five patients with their first acute myocardial infarction undergoing coronary bypass surgery were studied: 25 patients with glycemia below 140 mg/dl served as the control group; hyperglycemic patients (glucose>140 mg/dl) were randomized to intensive glycemic control (IGC; n=20; glucose goal, 80-140 mg/dl), conventional glycemic control (CGC; n=20; glucose goal, 180-200 mg/dl), or glucose-insulin-potassium (GIK; n=10; glucose goal, 180-200 mg/dl) for almost 3 d before surgery, using insulin infusion followed by sc insulin treatment. During surgery, myocyte precursor cells (MPC) (c-kit/MEFC2/GATA4-positive cells), oxidation of MPC DNA (c-kit/8-hydroxydeoxyguanosine-positive cells), senescent MPC (c-kit/p16INK4a-positive cells), and cycling cardiomyocytes (Ki-67-positive cells) were analyzed in biopsy specimens taken from the peri-infarcted area. RESULTS AND DISCUSSION: Before surgery, plasma glucose reduction was greater in the IGC group than in the CGC and GIK groups (P<0.001 for both). IGC patients had higher MPC (P<0.01) and cycling myocytes (P<0.01), as well as less oxidized (P<0.01) and senescent MPC (P<0.01) in peri-infarcted specimens compared with both CGC and GIK patients. Tight glycemic control, by reducing senescent MPC, may increase regenerative potential of the ischemic myocardium.

Peri-procedural tight glycemic control during early percutaneous coronary intervention is associated with a lower rate of in-stent restenosis in patients with acute ST-elevation myocardial infarction.

OBJECTIVE: We examined the effects of peri-procedural intensive glycemic control (IGC) during early percutaneous coronary intervention (PCI) on restenosis rate in hyperglycemic patients with ST-segment elevation myocardial infarction (STEMI). RESEARCH DESIGN AND METHODS: A total of 165 hyperglycemic patients (glucose ≥ 140 mg/dl) with first STEMI undergoing PCI were studied. Patients were randomized to IGC for almost 24 h after PCI (n = 82; glucose, 80-140 mg/dl) followed by multidose sc insulin during the hospital stay or conventional glycemic control (CGC; n = 83; glucose, 180-200 mg/dl) followed by conventional therapy. Coronary angiography was performed at study entry and at 6-month follow-up. Blood samples for glycemia, hemoglobin A1c, inflammatory markers (C-reactive protein and TNF-α), monocyte chemoattractant-protein-1, and oxidative stress (nitrotyrosine) were collected immediately before and 24 h, 30 and 180 d after PCI. RESULTS: After insulin infusion, mean plasma glucose during the peri-procedural period was greater in the CGC group than in the IGC group (CGC, 191 ± 15 mg/dl; IGC, 145 ± 35 mg/dl; P < 0.001). After the insulin infusion period, the levels of markers of oxidative stress (nitrotyrosine), inflammation (C-reactive protein, TNF-α), and monocyte chemoattractant-protein-1 were significantly higher in CGC patients compared with IGC patients. Moreover, ICG during PCI reduces restenosis by half (48 and 24%) at 6 months. During follow-up, there was no difference in mortality rates, glucose, inflammatory and oxidative stress markers among the groups. In-stent restenosis was positively associated with mean plasma glucose levels as well as oxidative stress and inflammatory markers during the insulin infusion period. CONCLUSIONS: In hyperglycemic patients with STEMI, optimal peri-procedural glycemic control by reducing oxidative stress and inflammation may improve the outcome after PCI.

Kidney in diabetes: from organ damage target to therapeutic target.

Despite the growing of pharmacological options for the treatment of diabetes, epidemiological studies suggest that a substantial proportion of patients does not achieve glycemic goals and so suffers from the risk of chronic complications. This review explores the inhibition of renal glucose reabsorption as a novel approach to treat hyperglycemia. Sodium-glucose cotransporter 2 (SGLT2), a low-affinity high-capacity transporter located in the brush-border membrane of the early segment (S1) of the proximal renal tubule, accounts for about 90% of the reabsorption of glucose from tubular fluid. Competitive inhibitors of SGLT2 that are responsible for renal excretion of glucose provide a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. They act independently of insulin secretion, thereby minimizing the risk of hypoglycemia and weight gain, to control energy balance in a negative direction, a distinctive advantage of this class of drugs over existing oral hypoglycemic agents. Although this group of medications is still under investigation, it appears to be safe and generally well tolerated and it would be expected to improve the treatment of type 2 diabetes as monotherapy or in combination with other oral or parenteral agents. Dapagliflozin is the first agent within this class, which induces clinically meaningful reductions in FPG, PPG, HbA1c, and body weight in type 2 diabetes.

Progress in the oral treatment of type 2 diabetes: update on DPP-IV inhibitors.

Glucagon-like peptide-1 (GLP-1) is a gut hormone that plays an important role in regulating glucose homeostasis by both its pancreatic and extrapancreatic activity. Defects of GLP-1 characterize type 2 diabetes as a primary or perhaps consequent phenomenon, resulting in inappropriately low insulin secretion after oral ingestion of nutrients. The discovery that cleavage by the ubiquitous enzyme dipeptidyl peptidase-IV (DPP-IV) is the primary route of GLP-1 metabolism formed the rationale behind the proposal to prevent degradation of endogenously released GLP-1 by DPP-IV inhibition as a novel approach to the management of type 2 diabetes. Enhanced insulin secretion as well as delayed gastric emptying, reduced glucagon secretion, and inhibited apoptosis of beta cells resulting from blockade of incretin degradation, have been proposed as the major actions of DPP-IV inhibitors as antidiabetic agents. Clinical studies to date indicate that DPP-IV inhibitors effectively ameliorate islet dysfunction and improve glucose control in patients with type 2 diabetes. They appear to have excellent therapeutic effectiveness as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. Their pharmacokinetic and pharmacodynamic profiles support once-daily dosing, with relatively few adverse effects.

Adapting the GLP-1-signaling system to the treatment of type 2 diabetes.

Glucagon-like peptide-1 (GLP-1) may contribute to the decreased incretin effect characterizing type 2 diabetes. Multiple actions other than insulin secretion stimulation give to GLP-1 a highly desirable profile for an antidiabetic agent. To overcome the need for continuous infusion of the native compound, which is rapidly degraded by dimethyl-peptidyl-peptidase-IV (DPP-IV), analogues with low affinity for this protease have been developed. A second major strategy is represented by DPP-IV inhibitors that act to increase endogenous GLP-1. On the basis of the promising results in clinical trials, the incretin-based therapy may offer an useful option for diabetes management.

Increased activity of the ubiquitin-proteasome system in patients with symptomatic carotid disease is associated with enhanced inflammation and may destabilize the atherosclerotic plaque: effects of rosiglitazone treatment.

OBJECTIVES: We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic and symptomatic patients and the effect of rosiglitazone, a peroxisome proliferator-activated receptor-gamma activator, in symptomatic plaques. BACKGROUND: The role of the ubiquitin-proteasome system, the major pathway for non-lysosomal intracellular protein degradation in eucaryotic cells, in the progression of atherosclerotic plaque to instability is unclear. METHODS: Plaques were obtained from 40 symptomatic and 38 asymptomatic patients undergoing carotid endarterectomy. Symptomatic patients received 8 mg rosiglitazone (n = 20) or placebo (n = 20) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-lymphocytes (CD3), inflammatory cells (HLA-DR), ubiquitin-proteasome activity, nuclear factor kappa B (NFkB), inhibitory kappa B (IkB)-beta, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). RESULTS: Compared with asymptomatic plaques, symptomatic plaques had more macrophages, T-lymphocytes, and HLA-DR+ cells (p < 0.001); more ubiquitin-proteasome activity and NFkB (p < 0.001); and more markers of oxidative stress (nitrotyrosine and O2- production) and MMP-9 (p < 0.01) along with a lesser collagen content and IkB-beta levels (p < 0.001). Compared with placebo-treated plaques, rosiglitazone-treated symptomatic plaques presented fewer inflammatory cells (p < 0.01); less ubiquitin, proteasome 20S, and NFkB (p < 0.01); less nitrotyrosine and O2- production (p<0.01); and greater collagen content (p<0.01), indicating a more stable plaque phenotype. CONCLUSIONS: Ubiquitin-proteasome overactivity is associated with enhanced inflammatory reaction in symptomatic plaques. The inhibition of ubiquitin-proteasome activity in lesions of symptomatic patients by rosiglitazone is associated with plaque stabilization, possibly by down-regulating NFkB-mediated inflammatory pathways.

Effects of insulin on left ventricular function during dynamic exercise in overweight and obese subjects.

AIMS: We designed this study in order to determine the effect of insulin on cardiac function in overweight and obese subjects during exercise. METHODS AND RESULTS: The cardiac function of 62 normal glucose tolerant subjects, aged 30-40 and divided into normal weight (group 1, n=22, BMI 20-24.9 kg/m(2)), overweight (group 2, n=20, BMI 25-29.9 kg/m(2)), and obesity (group 3, n=20, BMI 30-35 kg/m(2)) was evaluated at rest and during dynamic exercise through angiocardioscintigraphy, when on hyperinsulinaemic euglycaemic clamp (test A) and when on normal saline infusion (test B). Left ventricular function at rest was statistically greater (P<0.05) in both tests in overweight and obese subjects compared with normal weight controls, with no statistical difference (P=0.057) within groups between insulin and normal saline infusion. During exercise, cardiac function improved in all the subjects in both tests. The increase was lower in overweight and obese patients, even if statistically significant only in obese vs. control subjects in both tests (P<0.05). Insulin sensitivity showed a significant correlation (P< or =0.001) with left ventricular ejection fraction (LVEF) at rest and with change in LVEF during clamp. CONCLUSION: Our findings suggest a metabolic pathogenesis for the impaired LV function in obesity.