Giovanni Sartore

ROSES: role of self-monitoring of blood glucose and intensive education in patients with Type 2 diabetes not receiving insulin. A pilot randomized clinical trial.

Diabet. Med. 28, 789–796 (2011)

Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update

Diabetes is associated with a greatly increased risk of cardiovascular disease (CVD), which cannot be explained only by known risk factors, such as smoking, hypertension, and atherogenic dyslipidemia, so other factors, such as advanced glycation end-products (AGEs) and oxidative stress, may be involved. In this frame, hyperglycemia and an increased oxidative stress (AGE formation, increased polyol and hexosamine pathway flux, and protein kinase C activation) lead to tissue damage, thus contributing to the onset of cardiovascular complications. Several studies have identified in various cell systems, such as monocytes/macrophages and endothelial cells, specific cellular receptors (RAGE) that bind AGE proteins. The binding of AGEs on RAGE induces the production of cytokines and intracellular oxidative stress, thus leading to vascular damage. Soluble RAGE levels have been identified as hypothetical markers of CVD, but, in this regard, there are sparse and conflicting data in the literature. The purpose of this review was to examine all the available information on this issue with a view to clarifying or at least highlighting the points that are still weak, especially from the point of clinical view.

LDL physical properties, lipoprotein and Lp(a) levels in acromegalic patients. Effects of octreotide therapy

High vascular morbidity and mortality is associated with acromegaly. The aim of the present study was to assess the effects of octreotide therapy on several known cardiovascular risk factors and to correlate them with octreotide-induced hormonal changes. Lipid levels, LDL particle size distribution as evaluated by single vertical spin density gradient ultracentrifugation, apolipoproteins AI and B, lipoprotein (a) [Lp(a)] concentrations and apo(a) phenotypes were evaluated in 20 non-diabetic acromegalic patients (6 M, 14 F), with normal thyroid, adrenal and gonadal function, aged 29-66 years. Normal subjects (20), matched for age, sex and BMI served as control for lipid variables. Acromegalic patients were characterized by lower HDL cholesterol (and apoA-I) and by higher Lp(a) concentrations in comparison to controls. Treatment with octreotide (100 microg t.i.d. for 3 months) led to: an increase in HDL cholesterol (median: + 22%), a decrease in LDL cholesterol (-14%) and a decrease of the Lp(a) levels (all phenotypes) (-28%). The expected decreases of IGF-I levels (median: -48%) and 7-h AUC of GH (-50%), insulin (-40%) and glucagon (-20%) were observed. Only Lp(a) modifications showed a correlation with GH modifications. The study of LDL physical properties showed that acromegalic patients had smaller and/or more dense LDL particles, in comparison with normal controls (relative flotation rate, Rf: 0.40 +/- 0.03 versus 0.42 +/- 0.02 P < 0q05), an alteration that might contribute to the high vascular risk of acromegalic patients. However, the LDL subfraction distribution remained unmodified during octreotide therapy (Rf 0.39 +/- 0.03). In conclusion, this study shows that in acromegalic patients octreotide treatment is indeed associated with an amelioration of some lipoprotein parameters, i.e. LDL, HDL, and Lp(a) concentrations. However, this treatment has no effect on the small and/or dense LDL particles present in these patients.

Reduced susceptibility to oxidation of low-density lipoprotein in patients with overproduction of nitric oxide (Bartter's and Gitelman's syndrome)

Background The oxidation of low-density lipoprotein (LDL) might play an important role in the development of atherosclerosis. Objective To establish whether greater than normal production of nitric oxide (NO) in vivo protects LDL from oxidation. Patients and methods We studied nine subjects affected by Bartters and Gitelmans syndrome (both characterized by greater than normal production of NO), and 10 subjects matched for age, sex and lipid levels as controls. LDL particles were isolated from plasma by density gradient ultracentrifugation. Susceptibility of LDL to oxidation was evaluated after incubation with copper sulfate solution, by measuring the formation of conjugated dienes, the thiobarbituric acid-reactive substances, and the volatile peroxidation products of n-3 (propanal) and n-6 (pentanal and hexanal) polyunsaturated fatty acids. Phospholipid fatty acid composition of LDL was determined by gas chromatography. LDL α-tocopherol concentrations were measured. Results Patients with Bartters and Gitelmans syndrome had LDL particles smaller and/or denser than those of controls [Rf = 0.38 ± 0.03 versus 0.42 ± 0.02 (mean ± SD), P < 0.01], which hence were assumed to be more oxidizable. The phospholipid fatty acid composition of LDL and the α-tocopherol concentrations did not significantly differ between patients and controls. The duration of the lag phase, which is the time preceding formation of conjugated dienes, did not differ between groups, but the lag phase times were related to urinary excretion of nitrite/nitrate from patients (r = 0.66, P < 0.05). Moreover, patient LDL had produced less thiobarbituric acid-reactive substances after 5 h (P < 0.04), and less pentanal and hexanal after 5 and 6h (P < 0.04 and P < 0.02, respectively) than had that of controls. Conclusions Greater than normal production of NO in vivo is associated with lower than normal susceptibility of LDL to oxidation in vitro, suggesting that NO plays a protective role in the development of atherosclerosis.

Glucose Variability in Diabetic Pregnancy

BACKGROUND Fetal overgrowth is the most important complication of gestational (GDM) and pregestational diabetes mellitus. METHODS We correlated maternal glucose profiles, as detected by continuous glucose monitoring (CGM), with fetal growth parameters for 80 pregnant women (32 with type 1 diabetes, 31 with GDM, and 17 healthy controls). Glucose profiles were monitored in the first, second, and third trimesters of pregnancy for type 1 diabetes women and in the second and third trimesters for GDM women and controls. To analyze glycemic variability, we considered the mean amplitude of glycemic excursion, mean glycemia, the continuous overlapping net glycemic action (CONGA), the SD, the High Blood Glucose Index (HBGI), the Low Blood Glucose Index, and the interquartile range (IQR). RESULTS Mean age was the same for the three groups. Prepregnancy body mass index was higher for the women with diabetes (GDM and type 1) than for controls. The newborns mean birth weight and ponderal index were higher, although not significantly so, for the women with diabetes than for controls. For the type 1 diabetes patients, ponderal index correlated with the HBGI in the first trimester, CONGA1 and IQR in the second, and mean glycemia and SD in the third. For GDM patients, ponderal index correlated with mean glycemia and the HBGI in the second trimester. CONCLUSIONS Fetal exposure to glycemic variability and hyperglycemia seems to be important in determining fetal overgrowth in pregnant women with diabetes. Optimal glucose control and less glucose variability are needed as early as possible in both type 1 diabetes and GDM patients to ensure normal fetal growth.

Plasma lipoproteins, apoproteins and cardiovascular disease in Type 2 diabetic patients. A nine-year follow-up study

BACKGROUND AND AIM To evaluate the role of lipoprotein abnormalities as risk factors for macroangiopathy in Type 2 diabetes. METHODS AND RESULTS This prospective nine-year follow-up study involved 113 Type 2 diabetic patients (50 men and 63 women, mean age 66.9 +/- 9.9 years), 37 of whom had clinical signs of coronary heart disease (CHD) and cerebrovascular disease (CVD) at baseline. During the follow-up, 32 patients died: 17 of CHD, five of CVD, and 10 of non-vascular causes. The patients who died because of vascular disease were more frequently smokers, and had baseline symptoms of vascular disease; they were also significantly different from the other patients insofar as they were older, and had higher fasting plasma glucose levels, lower fasting C-peptide levels, and lower apoprotein (apo) AII, apo CII, apo CIII and apo E levels. Univariate analysis showed that baseline symptoms of vascular disease, current smoking, age, high fasting plasma glucose levels, low fasting C-peptide levels, and low apo AII, apo CII, apo CIII and apo E levels [but not cholesterol, triglyceride, high-density lipoprotein (HDL)-cholesterol or qualitative low-density lipoprotein or HDL abnormalities] were associated with cardiovascular mortality. Multivariate analysis showed that only age, smoking, glycated hemoglobin (HbA1c) and fasting C-peptide levels were significant independent determinants of macrovascular death. CONCLUSIONS In Type 2 normolipidemic diabetic patients, only age, smoking, HbA1c and fasting C-peptide levels are independent vascular risk factors. The differences in apo concentrations between patients with and without vascular disease may reflect qualitative abnormalities in plasma lipoproteins related to vascular disease.

Correlation Between Baseline Characteristics and Clinical Outcomes in a Large Population of Diabetes Patients Treated with Liraglutide in a Real-World Setting in Italy

PURPOSE Treatment with liraglutide in randomized controlled trials is associated with significant reductions in glycated hemoglobin (HbA1c) and weight loss in type 2 diabetes patients. The aim of this retrospective observational study was to investigate correlations of glycemic control and weight outcomes with baseline characteristics of patients starting liraglutide in outpatient clinics in Italy. METHODS Type 2 diabetes patients were followed from baseline to 4, 8, and 12 months. Changes in glycemic parameters, weight, blood pressure, and lipids were assessed. Subanalyses were performed according to baseline characteristics. Multivariate linear and logistic regressions were used to assess correlations between glycemic efficacy, weight reduction, and liraglutide discontinuation after 12 months and baseline characteristics. FINDINGS Four hundred and eighty-one patients were included. Mean (SD) age at baseline was 57.3 (9.2) years, diabetes duration was 9.5 (6.8) years, weight was 106.7 (20.8) kg, body mass index (BMI; calculated as kg/m(2)) was 37.1 (6.6), HbA1c was 8.7% (1.3%), fasting plasma glucose was 168.5 (45.3) mg/dL; 38.2% were treated previously with insulin and 52.2% were treated with metformin alone. After 12 months, mean (SD) changes were HbA1c -1.2% (1.4%), fasting plasma glucose -28.3 (41.1) mg/dL, weight -3.5 (5.8) kg, BMI -1.3 (2.1), waist circumference -2.6 (6.7) cm (all, P < 0.001). Drop in weight and HbA1c did not differ between baseline BMI classes ≤30 or >30. Weight loss was unchanged among diabetes duration quartiles, and HbA1c reduction was significantly greater in patients with ≤4 years of diabetes duration (P = 0.01). Non-insulin-treated patients reached HbA1c ≤7% significantly more often than treated patients (44.2% vs 21.2%; odds ratio = 2.94; P < 0.001) and had significantly greater weight loss (-4.5 [8.2] kg vs -2.6 [5.4] kg; P = 0.03). Patients on metformin reached HbA1c target more frequently than others (43.1% vs 29.7%; odds ratio = 1.80; 95% CI, 1.05-3.07). Significant positive determinants for HbA1c reduction after 12 months were baseline HbA1c, age, and prior metformin monotherapy, and weight loss at 12 months was positively correlated with baseline weight, and negatively correlated with prior insulin treatment. Overall, 5.0% of patients interrupted liraglutide before the 12th month due to lack of glycemic control; they were less frequently treated with metformin only before liraglutide (29.2% vs 50.2%; P = 0.04). IMPLICATIONS Treatment with liraglutide in a real-world setting is associated with low therapy failure, good glycemic response, weight loss, and improvement in systolic blood pressure and lipid profile. The HbA1c drop did not differ among baseline BMI classes, indicating that efficacy is maintained in patients with lower BMI. The probability of reaching HbA1c ≤7% was significantly higher in patients previously treated with metformin alone and without any previous insulin. This could reinforce the hypothesis that better results with liraglutide could be achieved in patients after early metformin failure.

The effects of psyllium on lipoproteins in type II diabetic patients

We examined the effects of 2 months of psyllium treatment in optimizing metabolic control and lipoprotein profile, and its postprandial effects on lipids in type II diabetes. We recruited 40 type II diabetic patients who were on sulfonylureas and a controlled diet, sequentially assigning them to psyllium treatment (G1) or to a control group (G2) treated with dietary measures alone. After 2 months of treatment, body mass index, waist circumference, HbA1c (hemoglobin A1c) and fasting plasma glucose levels had significantly decreased in both groups. There were no postprandial differences in the lipoprotein profile between the two groups. Triglycerides were significantly lower in G1, but not in G2. Our study contributes toward elucidating the effects of psyllium on serum lipids, and suggests that psyllium treatment may help in reducing triglycerides (a known risk factor for cardiovascular disease) in type II diabetic patients.

Levels and physicochemical properties of lipoprotein subclasses in moderate hypertriglyceridemia

Moderate hypertriglyceridemia is associated with several abnormalities of the plasma lipoprotein particles and it may be a risk factor for atherosclerotic vascular diseases. Plasma lipid, lipoprotein and apolipoprotein levels, as well as lipoprotein composition and physical properties, were examined by ultracentrifugation in a zonal rotor and by gradient gel electrophoresis in 14 patients with moderate hypertriglyceridemia (plasma triglycerides 4.00 +/- 0.32 mmol/l, mean +/- S.D.) and in 14 control subjects. Based on zonal ultracentrifugation hypertriglyceridemic patients have higher levels of cholesterol in all VLDL subclasses (Sf > 200, 100-200, 60-100 and 20-60), in IDL and in small and dense LDL. Both HDL2 and HDL3 cholesterol levels are reduced. The LDL flotation rate is inversely related to plasma triglyceride levels, thus indicating that the higher the plasma triglycerides the smaller and/or denser the LDL are. The triglyceride percent content of LDL2 and HDL3 is increased, while that of esterified cholesterol is reduced in hypertriglyceridemic patients. Gradient gel electrophoresis shows that the LDL peak size is lower (25.2 +/- 0.5 nm, mean +/- S.D.) in hypertriglyceridemic than in control subjects (27.1 +/- 0.4 nm; P < 0.0001). Considering both hypertriglyceridemic and control subjects the LDL peak effluent volume from the zonal rotor (which reflects the LDL flotation rate) is inversely related to the LDL peak size determined by gradient gel electrophoresis (r = -0.71; P = 0.0006) and the plasma triglyceride levels are related to LDL peak effluent volume (r = 0.74; P = 0.0002) and to LDL peak size (r = -0.95; P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Desaturase activities and metabolic control in type 2 diabetes

The aim of this study was to elucidate the effects of a poor glycemic control on fatty acid composition and desaturase activities in type 2 diabetic patients. Plasma phospholipid fatty acid composition and desaturase activities (estimated from fatty acid product to precursor ratios) were measured in 30 type 2 diabetic patients during poor metabolic control and after achieving a good metabolic control. Significant changes were recorded in the percentages of palmitic, stearic, dihomo-gamma-linolenic, docosatetraenoic and docosapentaenoic acid. The delta-5 desaturase activity was significantly higher with poor than with good metabolic control. The changes identified in plasma phospholipid fatty acid composition and the desaturase activity in type 2 diabetic patients go in the opposite direction to those described in similar conditions in type 1 diabetic patients and may be relevant to a better understanding of the role of metabolic control in the progression of chronic complications in type 2 diabetic patients.