Effects of antihypertensive treatments on incidence of diabetes: a case-control study.

AIMS: Aim of this case-control study is the assessment of the relationship between antihypertensive treatment and incidence of diabetes in an unselected cohort of subjects participating in a screening program for diabetes. METHODS: A case-control study nested within a cohort of nondiabetic subjects with a mean follow-up of 27.7 ± 11.3 months was performed, comparing 40 cases of incident diabetes and 160 controls matched for age, sex, body mass index, fasting plasma glucose, 2-h post-load glycemia, smoking and alcohol abuse. RESULTS: When considering antihypertensive treatment at enrolment, a lower proportion of cases was exposed to ACE-inhibitors/angiotensin receptor blockers (ACE-i/ARB) in comparison with controls. A non-significant trend toward a higher exposure to diuretics, which were mainly represented by thiazide diuretics, was observed in cases. In a multivariate analysis, including both ACE-i/ARB and diuretics, a protective effect of ACEi/ARB, and an increased risk with diuretics were observed. Similar results were obtained in alternative models, after adjusting for systolic and diastolic blood pressure at enrolment, diagnosis of hypertension, concurrent treatment with ß-blockers or calcium-channel blockers, and number of antihypertensive medications. CONCLUSIONS: Diuretics seem to be associated with a higher incidence of diabetes, whereas treatment with ACEi/ARB could have a protective effect.

Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR) e waist body mass index (wBMI): Which is better?

Obesity and overfat are most commonly assessed using the body mass index (BMI), which evaluates "total obesity", without accounting for body fat distribution. Therefore, several indexes of obesity have been proposed, combining BMI with other measures or singular parameters. The aim of the study was to evaluate the accuracy of a new, simple index that takes into account both BMI and Waist Circumference (WC), Waist Body Mass Index (wBMI) in comparison to BMI, WC e Waist-to-Height Ratio (WHtR) for the identification of overfat and obese patients identified by fat mass percentage (FM%). 2400 non diabetic patients were enrolled. From the analysis carried out it emerges that wBMI, BMI, WC and WHtR all have a statistically significant positive correlation (p-Value < 0.001) with FM%. The multivariate analysis showed the positive relationship between these four indexes and the FM. To assess the accuracy of these indices in diagnosing the condition of overfat and obesity we used the statistical analysis Receiver Operating Characteristic (ROC). The Area Under the Curve (AUC) derived from the ROC showed that for the male gender the indicator with the greatest discriminating capacity of the conditions of overfat and obesity was the WHtR and the wBMI for the female gender. The wBMI is therefore configured as an additional tool at the disposal of the healthcare professional aimed at framing the overfat and obese patient and monitoring him during the course of treatment. Moreover wBMI is an indicator able to provide information about the FM% constituting an accurate tool for the evaluation of the overfat and obese patient.

Hypertriglyceridaemic waist phenotype and ß-cell function in subjects with normal and impaired glucose tolerance.

AIM: To determine the association between the hypertriglyceridaemic waist phenotype, a combination of enlarged waist circumference and increased triglyceride levels, and ß-cell function in subjects with normal glucose tolerance and those with impaired glucose tolerance. METHODS: We studied 1344 outpatients clinic without diabetes. Overnight fasting blood samples were obtained to measure plasma glucose, insulin and lipids. An oral glucose tolerance test was performed in all subjects. All patients were divided in four groups, two groups with normal glucose tolerance and two with impaired glucose tolerance, with or without the hypertriglyceridaemic waist phenotype. Insulin resistance and ß-cell function were calculated by homeostatsis model assessment 2 indices. RESULTS: Twenty per cent of subjects showed the hypertriglyceridaemic waist phenotype and 23.8% had impaired glucose tolerance. We found a progressive significant increase (P < 0.001) of insulin resistance from subjects with normal glucose tolerance without the hypertriglyceridaemic waist phenotype with respect to patients with impaired glucose tolerance with the hypertriglyceridaemic waist phenotype. In subjects with normal glucose tolerance, the hypertriglyceridaemic waist phenotype was associated with a mild, but not significant, increase of homeostatsis model assessment 2-ß levels; but, in patients with impaired glucose tolerance, the hypertriglyceridaemic waist phenotype was associated with significantly lower homeostatsis model assessment 2-ß levels [127.0 (103.0-162.7) vs. 123.0 (96.0-147.0); P < 0.05]. The hypertriglyceridaemic waist phenotype displayed a higher (odds ratio 95% CI) ß-cell dysfunction of 1.8 (1.3-2.6) and insulin resistance of 5.0 (2.7-8.5) compared with 1.3 (0.9-1.9) and 2.4 (1.8-3.2), respectively, of waist circumference alone. CONCLUSION: In this study, the hypertriglyceridaemic waist phenotype is associated with increased insulin resistance and an overstimulation of ß-cell function in subjects with normal glucose tolerance, while patients with impaired glucose tolerance with the hypertriglyceridaemic waist phenotype showed a reduction in ß-cell function. These data suggest the importance of the identification of patients with impaired glucose tolerance combined with the hypertriglyceridaemic waist phenotype for an early intervention in relation to the high risk of developing Type 2 diabetes.

Motivational readiness for treatment in weight control programs: the TREatment MOtivation and REadiness (TRE-MORE) test.

BACKGROUND AND AIMS: The degree of motivation before starting the treatment represents a pre-treatment predictor of successful weight management. The aim of this study is to develop and validate a new self-reported questionnaire of motivation and readiness to change before starting a lifestyle modification program (the TREatment MOtivation and REadiness test) (TRE-MORE) for overweight patients. METHODS AND RESULTS: TRE-MORE was evaluated in a consecutive series of 129 obese patients attending our Outpatient Clinic. Validation of the questionnaire was performed through test-retest reliability, internal consistency, psychopathological correlates, and concurrent validity. Subjects have been evaluated by means of a clinical interview, and different self-reported questionnaires, assessing the eating specific and general psychopathology, and quality of life. TRE-MORE total and subscales scores showed good test-retest reliability and internal consistency. We identified 10 items grouped in 3 areas (obstacles and desire to overcome, taking care of themselves, and sharing the problems, current lifestyle). TREMORE scores were significantly correlated with eating specific psychopathology and quality of life measures. Univariate and Receiver Operating Characteristic curve analysis showed that TRE-MORE total and subscales scores represent a good model for predicting a weight loss >5% of the initial weight after 6 months of treatment. CONCLUSION: TRE-MORE represents a validated and easy-to-use questionnaire assessing at the meantime the treatment motivation and readiness with good predictive capacity for weight loss.

Relationship between GLP-1 levels and dipeptidyl peptidase-4 activity in different glucose tolerance conditions.

AIM: The reduced levels of glucagon-like peptide 1 (GLP-1) after an oral glucose load in Type 2 diabetic patients could be dependent either on a reduced synthesis or an increased degradation; but GLP-1 and dipeptidyl peptidase IV (DPP-IV) levels during an oral glucose tolerance test (OGTT) have not been studied together. The aim of the present study was to investigate GLP-1 and DPP-IV levels during an OGTT in patients with different degrees of glucose tolerance. METHODS: Fifty six subjects (34 female, 22 male) matched for sex, age, body mass index (BMI) and waist circumference underwent a 75 g oral glucose tolerance test. Twenty-eight had normal glucose tolerance, 15 had impaired glucose tolerance and 13 had Type 2 diabetes mellitus. GLP-1 assay was performed with an ELISA kit, and DPP-IV assay using a colorimetric method. RESULTS: At 30 min GLP-1 levels were significantly lower in subjects with impaired glucose tolerance and type 2 diabetes mellitus compared to those with normal glucose tolerance. The area under the GLP-1 curve was significantly different among the three groups; there was a significant decrease between subjects with normal and impaired glucose tolerance(P = 0.004) and between those with normal glucose tolerance and type 2 diabetes mellitus. (P < 0.001), while the area under the curve for DPP-IV showed no significant difference between the groups. CONCLUSIONS: These results suggest that an increase of GLP-1 degradation does not play a role in the early stages of diabetes mellitus.

Glucagon-like peptide-1 response to meals and post-prandial hyperglycemia in Type 2 diabetic patients.

BACKGROUND: The impaired response of glucagonlike peptide-1 (GLP-1) to meals in diabetic patients can contribute to the pathogenesis of impaired insulin secretion and post-prandial hyperglycemia. This study is aimed at the assessment of the relationship between meal-induced GLP-1 and post-prandial hyperglycemia in Type 2 diabetic patients. METHODS: Twenty-one drug-naïve Type 2 diabetic patients were studied. Blood glucose and active GLP-1 levels were measured 0, 30, 60, 90, and 120 min after a standard test meal. A continuous glucose monitoring (CGM) system was applied for the following 3 days. Nutrient intake at each meal was calculated on the basis of patients' food records. For each patient, post-prandial 120-min glucose incremental area under the curve (iAUC) was included in linear regression model exploring its relationship with total energy and carbohydrate intake, and the angular coefficient for total energy (EAC) and carbohydrate (CAC) was calculated. RESULTS: GLP-1 levels peaked 30 min after the test meal. Logarithmically transformed 60-min GLP-1 iAUC showed a significant inverse correlation with glycated hemoglobin (HbA1c) (p<0.01). A significant inverse correlation of 60-min GLP-1 iAUC was also observed with EAC and CAC (both p<0.01), meaning that patients with a lower GLP-1 response to the test meal had a higher increment of post-prandial glucose for each additional unit of total energy or carbohydrate intake. CONCLUSIONS: In Type 2 diabetic patients, a lower GLP-1 response to meals is associated with a higher HbA1c, and with a greater degree of meal-induced hyperglycemia, both in a meal test and during CGM in "real-life" conditions.

Exenatide: a review from pharmacology to clinical practice.

BACKGROUND: Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying. METHODS: In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c

Motivational readiness to change in lifestyle modification programs.

Weight management programs still remain a great challenge as drop out rates represent a growing problem. It is essential to try and identify the predictors of success, in order to make a proposal really custom-tailored to the patients. Among the most valuable applications of valid weight loss prediction models is the early identification of individuals with the least estimated probability of success, who should be directed to alternative therapies. Equally important are improvements in the matching between treatments and participants, which are dependent on the measurement of relevant pre-treatment variables. In the treatment of obesity and in many other pathologies and dependencies, the motivation to change has an important role both in the period of the weight loss and in the phase of the maintenance of the result. Therefore, if the patient is considered to be ready to lose weight, weight loss therapy should be initiated, if not, the immediate goal will be to prevent further weight gain and explore barriers to weight reduction. Many papers have been published regarding the measurement of the degree/level of motivation of the patient towards a specific treatment. Unfortunately, most of these questionnaires have been created and then applied to different areas; in particular they have been used before starting specific therapies for addiction. Unfortunately, a validated and easy-to-use questionnaire assessing at the meantime treatment motivation and readiness with adequate predictive capacity for weight loss actually is not available in most languages, so that empiric non-objective methods continue to be used.

National Cholesterol Education Program and International Diabetes Federation definitions of metabolic syndrome in the prediction of diabetes. Results from the FIrenze-Bagno A Ripoli study.

BACKGROUND: The International Diabetes Federation (IDF) proposed to modify the diagnostic criteria for metabolic syndrome (MS) previously issued by the National Cholesterol Education Program (NCEP). Aim of the present investigation is to compare the predictive value for diabetes of NCEP and IDF definitions of MS in a large sample of predominantly Caucasian subjects. METHODS: A prospective observational study was performed on a cohort study (n = 3096) enrolled in a diabetes-screening programme, the FIrenze-Bagno A Ripoli study. All subjects with fasting glucose >126 mg/dl and/or post-load glucose > or =200 mg/dl (5.7%) were excluded from the present analysis. Follow-up of each subject was continued until diagnosis of diabetes, death or until 31 December 2005. Mean follow-up was 27.7 +/- 11.3 months. RESULTS: Among subjects enrolled, 13.7 and 25.2% were affected by MS using NCEP and IDF criteria respectively. During follow-up, 38 new cases of diabetes were diagnosed, with a yearly incidence rate of 0.5%. The relative risk for diabetes in subjects with MS was 10.10 [5.13; 20.00] and 7.87 [3.70; 16.7] using NCEP and IDF definitions respectively. After adjustment for age, sex, fasting glucose and waist circumference, NCEP-defined MS, but not IDF-, was significantly associated with incident diabetes (hazard ratio, 95% CI: 2.41 [1.01; 5.95] and 2.05 [0.80; 5.29] respectively). CONCLUSIONS: Although the reasons for the proposed changes in diagnostic criteria for MS are easily understandable, the newer IDF definition, while increasing estimates of prevalence of the syndrome, reduces the effectiveness of MS in identifying subjects at risk for diabetes. Further research is needed before the previous NCEP criteria are abandoned.

Treatment with insulin secretagogues and cancer-related mortality in type 2 diabetic patients a retrospective cohort study.

BACKGROUND: Recent evidence suggests that some hypoglycemic treatments could affect the incidence of malignancies. This study was aimed at the assessment of cancer-related mortality in type 2 diabetic patients treated with different hypoglycemic drugs. METHODS: A retrospective observational cohort study was performed on a consecutive series of 3002 type 2 diabetic outpatients. Cancer-related death was identified through the City Registry Office. For patients visited for the first time after January 1 (st), 2000, information on incidence of cancer was also available. RESULTS: During a mean follow-up of 4.3+/-2.5 years, 87 cases of cancer-related death were recorded, with a yearly incidence rate of 0.70%. Patients receiving secretagogues showed a significantly higher mortality than the rest of the sample (unadjusted OR [95%CI] 1.76 [1.15-2.69], p=0.009), which was maintained after adjustment for confounders (HR 2.29 [1.21-4.02], p=0.003). Conversely, no significant association of cancer-related mortality was observed with insulin sensitizers or exogenous insulin. In comparison with patients receiving no hypoglycemic treatment, those on secretagogue or insulin monotherapy showed a higher cancer-related mortality (HR 2.25 [1.10-4.78], p=0.034 and HR 2.11 [1.01-4.50], p=0.048, respectively). The effect of treatments on incidence of malignancies was similar to that observed on cancer-related death. CONCLUSIONS: Insulin secretagogues and, to a lesser extent, exogenous insulin, appear to be associated with increased mortality for cancer, even after adjustment for multiple confounders. This issue deserves further investigation through epidemiological studies on larger samples of patients.

Future perspectives on glucagon-like peptide-1, diabetes and cardiovascular risk.

AIMS: Glucagon-like peptide-1 (GLP-1), a gastrointestinal hormone mainly produced in the post-prandial state, reduces blood glucose through the stimulation of insulin secretion and the inhibition of glucagon release. Long-acting GLP-1 receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors which increase GLP-1 levels, are used as hypoglycemic treatments in type 2 diabetes. This paper aims at reviewing the potential benefit of those treatments in the prevention of cardiovascular risk in type 2 diabetic patients. DATA SYNTHESIS: Experimental studies have shown that GLP-1 has several potentially beneficial actions on cardiovascular risk. Some of those, such as protection from myocardial ischemic damage and improvement of cardiac function, have also been demonstrated in humans. However, the equivalence of GLP-1 agonists and DPP-4 inhibitors with GLP-1, with respect to cardiovascular risk profile, cannot be assumed or taken for granted. Drugs of those two classes have been shown to effectively reduce glycated hemoglobin and to have a specific effect on post-prandial glucose; furthermore, they seem to reduce blood pressure and to have some favorable effects on lipid profiles. Additionally, GLP-1 agonists induce weight loss in diabetic patients. CONCLUSION: The profile of action of GLP-1 receptor agonists and DPP-4 inhibitors suggests the possibility of an actual reduction in cardiovascular risk, which needs to be confirmed by large long-term clinical trials.

A comparison of mealtime insulin aspart and human insulin in combination with metformin in type 2 diabetes patients.

This randomized, open-label, cross-over study compares the efficacy of mealtime rapid-acting analog insulin aspart with human insulin, in combination with metformin. A total of 30 patients with type 2 diabetes, inadequately controlled (HbA(1c)>7.5%) with oral hypoglycemic agents (OHAs), were assigned to human insulin 30 min before meals or aspart immediately before meals, both with metformin 500 mg t.i.d. for 90 days. Patients then switched to the alternate insulin. At 90 and 180 days, blood glucose and lipids were measured at baseline and every 30 min after test meals, for 3h. HbA(1c) and hypoglycemic events were also assessed. After 3 months, HbA(1c) was significantly reduced with aspart, but not human insulin (-0.4+/-0.7% versus +0.1+/-0.7%, p<0.05). During meal tests, blood glucose area under the curve (AUC) was significantly lower with aspart than human insulin (1240+/-476 min/mmol/l versus 1588+/-766 min/mmol/l, p<0.01). AUCs for lipids were similar for both treatments. Neither group experienced serious hypoglycemic events. These results encourage treatment with mealtime insulin aspart plus metformin, in type 2 diabetes patients with postprandial hyperglycemia inadequately controlled by OHAs alone.

How many components for the metabolic syndrome? Results of exploratory factor analysis in the FIBAR study.

BACKGROUND AND AIMS: Factor analysis can be used as a basis for the determination of diagnostic criteria for the metabolic syndrome (MS). This approach can be used as a basis for the determination of diagnostic criteria for MS. METHODS AND RESULTS: Exploratory factor analysis of Adult Treatment Panel (ATP)-III and International Diabetes Federation (IDF) criteria for MS, entered as dichotomic variables, was performed on 2945 patients enrolled in a screening programme for diabetes. The ability of calculated factors to identify patients with MS-related conditions (glucose intolerance, hyperuricaemia, and elevation of alanine aminotransferase; ALT) was assessed through Receiver Operator Characteristics (ROC) curve analysis. Alternative sets of criteria based on ATP-III and IDF definitions of MS were also assessed. A two-factor structure was found for both ATP-III and IDF criteria. Factor 1 (associated with fasting hyperglycaemia, hypertension, and elevated waist circumference) was capable of identifying subjects with MS-related conditions to a greater extent than factor 2 (low HDL-cholesterol and hypertriglyceridaemia). When a composite variable (low HDL-cholesterol and/or hypertriglyceridaemia) was used for dislipidaemia, a single factor structure was obtained both for ATP-III and IDF definitions; this factor structure was retained when hyperuricaemia was added as a fifth component of MS. Such a modified definition of MS was not inferior to original ATP-III and IDF criteria in the identification of subjects with glucose intolerance and elevated ALT. CONCLUSIONS: A modification of current ATP-III or IDF criteria is necessary in order to obtain a single-factor structure. Alternative definitions of MS, including additional features, such as hyperuricaemia, can maintain a monofactorial structure, and an association with related conditions not inferior to that of original criteria.

National Cholesterol Educational Program and International Diabetes Federation diagnostic criteria for metabolic syndrome in an Italian cohort: results from the FIBAR Study.

BACKGROUND: The adoption of the International Diabetes Federation (IDF) criteria for metabolic syndrome (MS), in comparison with the National Cholesterol Educational Program (NCEP) criteria, produces different changes in estimates of prevalence in diverse populations. Few data are available in Caucasian non-diabetic subjects. PATIENTS AND METHODS: The prevalence of NCEP- and IDF-defined MS was assessed in a sample of 2,945 individuals, aged 55.2+/-11.5 yr, enrolled in a screening program for diabetes. Association of different definitions of MS with glucose intolerance (120-min glucose 7.8 mmol/l after a 75 g-oral glucose load) and hyperuricemia (>0.38 mmol/l) was also assessed. RESULTS: The prevalence of MS was 16.6% and 29.7% with NCEP and IDF definitions, respectively. The prevalence of NCEP-defined MS was higher than IDF-MS through all age ranges; among those aged >60 yr, the prevalence of IDF-MS reached 52.8% (vs 33.1% for NCEP-MS). Both NCEP- and IDF-MS were associated with glucose intolerance and hyperuricemia. Individuals fulfilling IDF, but not NCEP criteria for MS, showed a prevalence of glucose intolerance (22.7%) significantly (p<0.05) lower than those fulfilling NCEP criteria only (31.6%) or both sets of criteria (31.8%). CONCLUSION: In Caucasian subjects without known diabetes, IDF criteria produce a relevant increase in estimates of prevalence of MS, particularly in older subjects, when compared with NCEP criteria. NCEP-MS seems to be more effective than IDF-MS in the identification of glucose intolerant subjects.

Group versus individual cognitive-behavioral treatment for obesity: results after 36 months.

OBJECTIVE: This study is aimed at the comparison between an individual and a group cognitive-behavioral program for the treatment of obesity. DESIGN: Parallel series, prospective, 3-year study. A group program of 10 weekly sessions focused on lifestyle modification was compared with a similar, individual 10-session program. Fifty-seven patients were assigned to individual treatment, and 84 patients to the group program. SUBJECTS: One hundred- forty-one obese female outpatients without binge eating disorder, aged 42.0+/-11.6 years (m+/-SD), with Body Mass Index (BMI) 37.3+/-5.2 kg/m(2). MEASUREMENTS: BMI and waist circumference were measured at 0, 6, 12 and 36 months. Analysis was performed on an intention-to-treat basis. RESULTS: Mean weight loss was superior with the group program at 6 months (2.0+/-3.9 vs 0.8+/-2.5 kg/m(2); p<0.05), while no difference between the two treatments was observed at 12 and 36 months. Mean waist circumference was significantly different at 6 months (group 97.4+/-2.5 vs individual 102.9+/-2.4, p<0.05), still remaining superior in the patients following individual treatment (100.2+/-5.0 vs 103.7+/-5.9) at 12 months, while no difference between the two treatments was observed at 36 months. The proportion of patients losing more than 5% of initial body weight with the group program (16.6, 15.5, and 38.1% at 6, 12, and 36 months, respectively) was not significantly different from that observed with individual treatment (5.3, 14.0, and 35.0%, respectively). CONCLUSION: A group cognitive-behavioral program for the treatment of obesity is not inferior to a similar program applied in individual setting, and it may enhance weight loss (especially fat mass, according to the waist measurement) in the short term.

Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes.

OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA). DESIGN AND METHODS: This was a cross-sectional study comprising a total of 881 patients, aged < or = 70 years, diagnosed with type 2 diabetes after the age of 40 years, and consecutively recruited in five clinics located in different geographic areas of Italy (Milan, Florence, Rome, Naples and Catania). Their mean disease duration was 8.1 (6.9; s.d.) years. GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta. Anthropometric and clinical data were collected and compared amongst patients with or without autoantibodies. RESULTS: Sixty-three (7.1%) patients had one or more autoantibodies, 58 (6.6%) had GADA, 22 (2.5%) had IA-2A, six (0.7%) had IA-2betaA and 19 (2.15%) had two or more autoantibodies. IA-2A or IA-2betaA, in the absence of GADA, were found in only five patients. Autoantibody-positive patients were more often female (63.5 vs 36.5%; P < 0.009), had higher glycated haemoglobin (Hb A1c) (P < 0.001), lower body mass index (BMI; P < 0.0005) and waist/hip ratio (WHR; P < 0.01); female gender being the main contributor to BMI and WHR. We did not observe any differences in age at diagnosis or duration of disease with respect to the presence or absence of islet autoantibodies. The proportion of patients on insulin therapy was higher in patients with two or more antibodies, compared with those with one antibody only, and no antibodies (P for trend < 0.001), and among patients with GADA, in those with higher antibody titre (73.9% in those with > 10 units vs 42.0% in those with < or = 10 units; P < 0.007). CONCLUSIONS: Patients with adult onset diabetes characterized by autoimmunity to beta-cells showed a clinical phenotype with anthropometric features that differed from those classically observed in patients with type 2 diabetes. The number and titre of autoantibodies, which reflect the severity of autoimmunity and beta-cell impairment, amplified this difference. The usefulness of autoantibody screening in adult-onset diabetes is further emphasized by these findings.

Diabetic microangiopathy: IGFBP control endothelial cell growth by a common mechanism in spite of their species specificity and tissue peculiarity.

Endothelial cells (EC) play a role in many diseases including diabetes mellitus. EC share common functions, such as angiogenesis and vascular remodeling both regulated by proliferation and apoptosis, anti-thrombotic properties, regulation of vascular tone, control in the passage of nutrients and secretion of peptides and growth factors. However, EC are characterized by site-specificity so their characteristics depend on the organs and tissues where they are. The IGF system induces important growth factors that control cell growth in different microvascular EC (mEC). This family includes IGF-I and IGF-II peptides, their receptors and regulatory proteins IGF-binding proteins (IGFBP-1 to IGFBP-6). The IGFBP modulate their interaction with the IGF membrane receptors and might be regulated at a transcriptional and post-transcriptional level, thus determining the biological IGF-dependent effects on target cells. The IGF system is also a mediator of vascular diseases, and its altered balance might contribute to endothelial dysfunction with the development and evolution of diabetic microangiopathy. We reported here the reviewed literature of IGFBP production from various sources of mEC, showing that they predominantly express IGFBP-2 through IGFBP-5 mRNA. The different pattern of IGFBP secretion depends on the anatomical district and on the species of the tissues. Nevertheless, based on our and other experimental observations, we suggested that a common mechanism of IGFBP regulation in mEC could be hypothized. In retinal and glomerular EC the IGFBP4/IGFBP5 ratio controls the response of these cells to IGF-I and high levels of glucose, in terms of cellular growth.

Upregulation of mesangial growth factor and extracellular matrix synthesis by advanced glycation end products via a receptor-mediated mechanism.

Enhanced advanced glycosylation end product (AGE) formation has been shown to participate in the pathogenesis of diabetes-induced glomerular injury by mediating the increased extracellular matrix (ECM) deposition and altered cell growth and turnover leading to mesangial expansion. These effects could be exerted via an AGE-receptor-mediated upregulation of growth factors, such as the IGFs and transforming growth factor-beta (TGF-beta). We tested this hypothesis in human and rat mesangial cells grown on nonglycated or native bovine serum albumin (BSA), glycated BSA with AGE formation (BSA-AGE), or glycated BSA in which AGE formation was prevented by the use of aminoguanidine (BSA-AM), in the presence or absence of an antibody, alpha-p60, directed against the p60/OST protein named AGE-receptor 1 (AGE-R1), or normal control (pre-immune) serum. The mRNA and/or protein levels of IGF-I, IGF-II, IGF receptors, IGF binding proteins (IGFBPs), TGF-beta1 and the ECM components fibronectin, laminin, and collagen IV were measured, together with cell proliferation. Both human and rat mesangial cells grown on BSA-AGE showed increased IGF-I and total and bioactive TGF-beta medium levels and enhanced IGF-I, IGF-II, and TGF-beta1 gene expression, compared with cells grown on BSA, whereas total IGFBP and IGFBP-3 medium content, IGF receptor density and affinity, and IGF-I receptor transcripts were unchanged. Moreover, cells grown on BSA-AGE showed increased ECM protein and mRNA levels versus cells cultured on BSA, whereas cell proliferation was unchanged in human mesangial cells and slightly reduced in rat mesangial cells. Growing cells on BSA-AM did not affect any of the measured parameters. Co-incubation of BSA-AGE with anti-AGE-R1, but not with pre-immune serum, prevented AGE-induced increases in IGF-I, TGF-beta1, and ECM production or gene expression; anti-AGE-R1 also reduced growth factor and matrix synthesis in cells grown on BSA. These results demonstrate that mesangial IGF and TGF-beta1 synthesis is upregulated by AGE-modified proteins through an AGE-receptor-mediated mechanism. The parallelism with increased ECM production raises the speculation that the enhanced synthesis of these growth factors resulting from advanced nonenzymatic glycation participates in the pathogenesis of hyperglycemia-induced mesangial expansion.