Calpain-10 interacts with plasma saturated fatty acid concentrations to influence insulin resistance in individuals with the metabolic syndrome

Background: Calpain-10 protein (intracellular Ca2+-dependent cysteine protease) may play a role in glucose metabolism, pancreatic β cell function, and regulation of thermogenesis. Several CAPN10 polymorphic sites have been studied for their potential use as risk markers for type 2 diabetes and the metabolic syndrome (MetS). Fatty acids are key metabolic regulators that may interact with genetic factors and influence glucose metabolism. Objective: The objective was to examine whether the genetic variability at the CAPN10 gene locus is associated with the degree of insulin resistance and plasma fatty acid concentrations in subjects with MetS. Design: The insulin sensitivity index, glucose effectiveness, insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)], insulin secretion (disposition index, acute insulin response, and HOMA of β cell function), plasma fatty acid composition, and 5 CAPN10 single nucleotide polymorphisms (SNPs) were determined in a cross-sectional analysis of 452 subjects with MetS participating in the LIPGENE dietary intervention cohort. Results: The rs2953171 SNP interacted with plasma total saturated fatty acid (SFA) concentrations, which were significantly associated with insulin sensitivity (P < 0.031 for fasting insulin, P < 0.028 for HOMA-IR, and P < 0.012 for glucose effectiveness). The G/G genotype was associated with lower fasting insulin concentrations, lower HOMA-IR, and higher glucose effectiveness in subjects with low SFA concentrations (below the median) than in subjects with the minor A allele (G/A and A/A). In contrast, subjects with the G/G allele with the highest SFA concentrations (above the median) had higher fasting insulin and HOMA-IR values and lower glucose effectiveness than did subjects with the A allele. Conclusion: The rs2953171 polymorphism at the CAPN10 gene locus may influence insulin sensitivity by interacting with the plasma fatty acid composition in subjects with MetS. This trial was registered at clinicaltrials.gov as NCT00429195.

A gene variation (rs12691) in the CCAT/enhancer building α modulates glucose metabolism in metabolic syndrome

Background and aims CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor involved in adipogenesis and energy homeostasis. Caloric restriction reduces CEBPA protein expression in patients with metabolic syndrome (MetS). A previous report linked rs12691 SNP in CEBPA to altered concentration of fasting triglycerides. Our objective was to assess the effects of rs12691 in glucose metabolism in Metabolic Syndrome (MetS) patients. Methods and results Glucose metabolism was assessed by static (glucose, insulin, adiponectin, leptin and resistin plasma concentrations) and dynamic (disposition index, insulin sensitivity index, HOMA-IR and acute insulin response to glucose) indices, performed at baseline and after 12 weeks of 4 dietary interventions (high saturated fatty acid (SFA), high monounsaturated fatty acid (MUFA), low-fat and low-fat-high-n3 polyunsaturated fatty acid (PUFA)) in 486 subjects with MetS. Carriers of the minor A allele of rs12691 had altered disposition index (p = 0.0003), lower acute insulin response (p = 0.005) and a lower insulin sensitivity index (p = 0.025) indicating a lower insulin sensitivity and a lower insulin secretion, at baseline and at the end of the diets. Furthermore, A allele carriers displayed lower HDL concentration. Conclusion The presence of the A allele of rs12691 influences glucose metabolism of MetS patients. Clinical Trials Registry number NCT00429195.

Plasma free fatty acids do not provide the link between obesity and insulin resistance or β-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study

Aims To investigate the relationship between adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and β-cell function. Methods An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made between insulin sensitivity index, acute insulin response to glucose and disposition index and both adiposity measures (BMI, waist circumference and body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. Results After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: β = −0.357; waist circumference: β = −0.380; body fat mass: β = −0.375) and disposition index (BMI: β = −0.215; waist circumference: β = −0.248; body fat mass: β = −0.221) and positively associated with acute insulin response to glucose [BMI: β = 0.200; waist circumference: β = 0.195; body fat mass β = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, but total plasma free fatty acid level was inversely associated with insulin sensitivity index (β = −0.133), acute insulin response to glucose (β = −0.148) and disposition index [β = −0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. Conclusions Plasma free fatty acid levels have a modest negative association with insulin sensitivity, β-cell secretion and disposition index but no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or β-cell dysfunction.

A Constructive Heuristic Algorithm for Distribution System Planning

A constructive heuristic algorithm (CHA) to solve distribution system planning (DSP) problem is presented. The DSP is a very complex mixed binary nonlinear programming problem. A CHA is aimed at obtaining an excellent quality solution for the DSP problem. However, a local improvement phase and a branching technique were implemented in the CHA to improve its solution. In each step of the CHA, a sensitivity index is used to add a circuit or a substation to the distribution system. This sensitivity index is obtained by solving the DSP problem considering the numbers of circuits and substations to be added as continuous variables (relaxed problem). The relaxed problem is a large and complex nonlinear programming and was solved through an efficient nonlinear optimization solver. Results of two tests systems and one real distribution system are presented in this paper in order to show the ability of the proposed algorithm.

Modelagem e desenvolvimento de um banco de dados geográficos : aplicação à elaboração de mapas de sensibilidade ambiental ao derramamento de óleo na área costeira entre galinhos e São Bento do Norte-RN

The area between Galinhos and São Bento do Norte beaches, located in the northern coast of the Rio Grande do Norte State is submitted to intense and constant processes of littoral and aeolian transport, causing erosion, alterations in the sediments balance and modifications in the shoreline. Beyond these natural factors, the human interference is huge in the surroundings due to the Guamaré Petroliferous Pole nearby, the greater terrestrial oil producing in Brazil. Before all these characteristics had been organized MAMBMARE and MARPETRO projects with the main objective to execute the geo-environmental monitoring of coastal areas on the northern portion of RN. There is a bulky amount of database from the study area such as geologic and geophysical multitemporal data, hydrodynamic measurements, remote sensing multitemporal images, thematic maps, among others; it is of extreme importance to elaborate a Geographic Database (GD), one of the main components of a Geographic Information System (GIS), to store this amount of information, allowing the access to researchers and users. The first part of this work consisted to elaborate a GD to store the data of the area between Galinhos and São Bento do Norte cities. The main goal was to use the potentiality of the GIS as a tool to support decisions in the environmental monitoring of this region, a valuable target for oil exploration, salt companies and shrimp farms. The collected data was stored as a virtual library to assist men decisions from the results presented as digital thematic maps, tables and reports, useful as source of data in the preventive planning and as guidelines to the future research themes both on regional and local context. The second stage of this work consisted on elaborate the Oil-Spill Environmental Sensitivity Maps. These maps based on the Environmental Sensitivity Index Maps to Oil Spill developed by the Ministry of Environment are cartographic products that supply full information to the decision making, contingency planning and assessment in case of an oil spilling incident in any area. They represent the sensitivity of the areas related to oil spilling, through basic data such as geology, geomorphology, oceanographic, social-economic and biology. Some parameters, as hydrodynamic data, sampling data, coastal type, declivity of the beach face, types of resources in risk (biologic, economic, human or cultural) and the land use of the area are some of the essential information used on the environmental sensitivity maps elaboration. Thus using the available data were possible to develop sensitivity maps of the study area on different dates (June/2000 and December/2000) and to perceive that there was a difference on the sensitivity index generated. The area on December presented more sensible to the oil than the June one because hydrodynamic data (wave and tide energy) allowed a faster natural cleaning on June. The use of the GIS on sensitivity maps showed to be a powerful tool, since it was possible to manipulate geographic data with correctness and to elaborate more accurate maps with a higher level of detail to the study area. This presented an medium index (3 to 4) to the long shore and a high index (10) to the mangrove areas highly vulnerable to oil spill

Análise multitemporal dos elementos geoambientais da região da Ponta do Tubarão, área de influência dos campos petrolíferos de Macau e Serra, município de Macau/RN

The study area is inserted in Ponta do Tubarão region, Macau City, setentrional littoral of Rio Grande do Norte State, composed of Tertiary and Quatemary sedimentary rocks and sediments. This region is characterized for the intense action of the coastal processes, causing the morphologic instability in part of the area, beyond the interference of human activities, as the Petroliferous Industrial Polo, salt companies and shrimp farms. This justifies the integration of multidisciplinary and multitemporal detailed scientific studies dealing with the evaluation of the changing behavior of this coastal environment by geoenvironments elements characterization, identifying protected and recuperation areas, mainly those under socioeconomic intervention. The main objective was the coastal monitoring using geoprocessing techniques to prepare thematic maps useful for oil spilling environment risk areas survey. The methodology was based on multitemporal interpretation of remote sensing images and field checking, integrated in a Geographical Information System (GIS). The Geologic, Geomorphologic, Vegetation, Soil and Land Use maps were prepared, and later on they allowed the generation of the Natural Vulnerability and Environmental Vulnerability maps. These maps had been classified in accordance with vulnerability degrees: very low, low, medi um, high and very high. Beyond these maps the GIS allowed the analysis of the shoreline evolution for 10 distinct dates, using Landsat 5 TM and 7 ETM+ and SPOT-HRVIR images. This analysis made possible the attendance of the coastal morphodynamic evolution, where the results had been represented by areasof erosion and accretion (or deposition) of sediments, pointing critical areas under erosive process to the petroliferous industry (Macau and Serra fields). The GIS also provided to prepare the Environmental Sensitivity Maps of Oil Spill (SAO Maps) in operational scale (1: 10.000), according to the norms ofthe Ministério do Meio Ambiente (MMA 2002). The SAO Map in operational scale was based on IKONOS images mosaic where the ESI (Environmental Sensitivity Index) was represented according with two tides phases of theregion. Therewere recognizedfiveESI (3, 4,7,9, 1O) for the low tide; to the high tide the ESI number increased to seven (3, 4, 5, 7, 8, 9, 10). All these information are necessary to the decisions making about oi! spill and its derivatives containment. These techniques application makes possible the optimization and implantation ofnew socioeconomics activities of low environmental impact, indicates areas for better productivity and security exploration, and benefits local communities with fauna and flora preservation. The development of these activities is inserted in the scope of Monitoramento Ambiental de Áreas de Risco a Derrames de Petróleo e Seus Derivados Cooperation Project (Rede 05/01 - PETRORISCO, FINEP/CTPETRO/PETROBRAS) of multidisciplinary and interinstitucional characteristics dealing with subjects involving the environmental monitoring and the petroliferous activity

Demographic and metabolic characteristics of individuals with progressive glucose tolerance

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Disturbances in beta-cell function in impaired fasting glycemia

In a cross-sectional study, we assessed beta-cell function and insulin sensitivity index (ISI) with hyperglycemic clamps (10 mmol/l) in 24 subjects with impaired fasting glycemia (IFG, fasting plasma glucose [FPG] between 6.1 and 7.0 mmol/l), 15 type 2 diabetic subjects (FPG >7.0 mmol/l), and 280 subjects with normal fasting glycemia (NFG, FPG <6.1 mmol/l). First-phase insulin release (0-10 min) was lower in IFG (geometric mean 541 pmol/l (.) 10 min; 95% confidence interval [CI] 416-702 pmol/l (.) 10 min) and in type 2 diabetes (geometric mean 376 pmol/l (.) 10 min; 95% CI 247-572 pmol/l (.) 10 min) than NFG (geometric mean 814 pmol/l (.) 10 min; 95% CI 759-873 pmol/l (.) 10 min) (P < 0.001). Second-phase insulin secretion (140-180 min) was also lower in IFG (geometric mean 251 pmol/l; 95% CI 198-318 pmol/l; P = 0.026) and type 2 diabetes (geometric mean 157 pmol/l; 95% CI 105-235 pmol/l; P < 0.001) than NFG (geometric mean 295 pmol/l; 95% CI 276-315 pmol/l): IFG and type 2 diabetic subjects had a lower ISI (0.15 +/- 0.02 and 0.16 +/- 0.02 mumol/kg fat-free mass [FFM]/min/ pmol/l, respectively) than NFG (0.24 +/- 0.01 mumol/kg FFM/min/pmol/l, P < 0.05). We found a stepwise decline in first-phase (and second-phase) secretion in NFG subjects with progressive decline in oral glucose tolerance (P < 0.05). IFG subjects with impaired glucose tolerance (IGT) had lower first-phase secretion than NFG subjects with IGT (P < 0.02), with comparable second-phase secretion and ISI. NFG and IFG subjects with a diabetic glucose tolerance (2-h glucose >11.1 mmol/l) had a lower ISI than their respective IGT counterparts (P < 0.05). We conclude that the early stages of glucose intolerance are associated with disturbances in beta-cell function, while insulin resistance is seen more markedly in later stages.

Constructive heuristic algorithm in branch-and-bound structure applied to transmission network expansion planning

A constructive heuristic algorithm to solve the transmission system expansion planning problem is proposed with the aim of circumventing some critical problems of classical heuristic algorithms that employ relaxed mathematical models to calculate a sensitivity index that guides the circuit additions. The proposed heuristic algorithm is in a branch-and-bound algorithm structure, which can be used with any planning model, such as Transportation model, DC model, AC model or Hybrid models. Tests of the proposed algorithm are presented on real Brazilian systems.

Subclinical abnormalities of glucose metabolism in Brazilian women with a history of gestational diabetes mellitus

Background. To evaluate insulin release and insulin sensitivity in women with prior gestational diabetes mellitus (GDM) to gain a better understanding of type 2 diabetes pathogenesis.Methods. GDM women were individually matched for age, body mass index, and waist/hip ratio with those who were normal glucose tolerant in a previous pregnancy (NGT). All women presented with normal glucose tolerance. Twenty pairs were submitted to the oral glucose tolerance test (OGTT) with plasma glucose, insulin, and C-peptide determinations. of the 20 pairs, 18 participated in hyperglycemic (10.0 mmol/l) clamp experiments with frequent plasma glucose and insulin determinations, allowing us to calculate first- and second-phase insulin release and the insulin sensitivity index. GDM and NGT women were compared using Student's t-test, the Mann-Whitney U-test, Friedman's non-parametric test, and the two proportion test for independent groups.Results. GDM women showed higher glycosylated hemoglobin values; at OGTT, they showed late insulin peak with increased plasma insulin levels only during the second hour, and a similar plasma C-peptide response despite a higher plasma glucose curve; during hyperglycemic clamp procedures, they showed similar biphasic insulin release and insulin sensitivity index. Considering that a woman with previous GDM had a defect in insulin release and/or insulin sensitivity, if its magnitude was at least 25% lower than that of the matched NGT woman, 43.8% showed impairment of first-phase insulin release and 55.6% insulin resistance.Conclusions. GDM women showed some degree of glucose intolerance. It is therefore necessary to follow them for a longer time.

Transmission-expansion planning using the DC model and nonlinear-programming technique

The paper presents a constructive heuristic algorithm (CHA) for solving directly the long-term transmission-network-expansion-planning (LTTNEP) problem using the DC model. The LTTNEP is a very complex mixed-integer nonlinear-programming problem and presents a combinatorial growth in the search space. The CHA is used to find a solution for the LTTNEP problem of good quality. A sensitivity index is used in each step of the CHA to add circuits to the system. This sensitivity index is obtained by solving the relaxed problem of LTTNEP, i.e. considering the number of circuits to be added as a continuous variable. The relaxed problem is a large and complex nonlinear-programming problem and was solved through the interior-point method (IPM). Tests were performed using Garver's system, the modified IEEE 24-Bus system and the Southern Brazilian reduced system. The results presented show the good performance of IPM inside the CHA.

HIPERTENSAO ARTERIAL EM PACIENTES OBESOS COM HIPERTROFIA CARDIACA. EFEITOS DO CAPTOPRIL SOBRE A SENSIBILIDADE A INSULINA E HORMONIO DE CRESCIMENTO

Purpose. To evaluate the effects of captopril (Cpt) on carbohydrate metabolism and growth hormone (GH) in adults hypertensive obese patients with normal (NGT) or impaired (IGT) glucose tolerance and left ventricular hypertrophy. Methods. Ten patients (53 ± 8 years), 8 women and 2 men, white, body mass index (BMI) ≥ 26 kg/m2, left ventricular mass index (LVMI) > 135 g/m2 in man and > 110 g/m2 in woman, with diastolic blood pressure (DBP) 95-115 mmHg after 3 weeks of placebo, were identified by oral glucose tolerance test (OGTT-75 g) as either with NGT or IGT, and treated with Cpt 25 mg t.i.d. for 8 weeks. At the 8 weeks, dosage was increased to 50 mg b.i.d. if DBP > 90 mmHg or the decrease of the DBP < 10%, during the next 8 weeks. OGTT and clonidine tests (0,04 mg/kg) with determinations, every 30 minutes of glucose, insulin, and GH during 2 hours, were performed. Results. Cpt lowered SBP and DBP in the NGT group and IGT group. The LVMI and the left ventricular mass (LVM) decreased in the IGT group with no significant change in the NGT group. Cpt promoted in the IGT group decrease in the area under the curve (AUC) of glucose, and AUC of insulin, with increase of the AUC of the percent of the β cell function, AUC of HC, and insulin sensitivity index with no significantly change in the NGT group. Conclusion. Adults hypertensive obese patients with IGT had decreased significantly in mean fasting level of GH concentrations compared to age, race, and BMI matched hypertensive patients with NGT. Treatment with Cpt induced a significant increased of the GH, with improvement of the metabolism in patients with IGT.

Pancreatic β-cell defects in women at risk of type 2 diabetes

We evaluated insulin release and insulin sensitivity in women with basal and/or postprandial hyperglycemia but normal oral glucose tolerance test (OGTT) in previous pregnancy (GHG). These women were individually matched with females without previous hyperglycemia (NGT). Both groups consisted of normal glucose-tolerant women at the time of this study. They underwent OGTT (75g; n= 32 pairs) and hyperglycemic clamp experiments (10mmoll-1; n=27 pairs) with plasma glucose, insulin, and C-peptide measurements and calculation of insulinogenic index, first- and second-phase insulin release, and insulin sensitivity index (ISI). The GHG group showed higher glycosylated hemoglobin levels (6.2±0.6% versus 5.8±0.8%; P<0.05); lower insulinogenic index at 30min (134.03±62.69pmolmmol-1 versus 181.59±70.26pmolmmoll-1; P<0.05) and diminished C-peptide response in relation to glucose (4.05±0.36nmolmmol-1 versus 4.23±0.36nmolmmol-1; P<0.05) at OGTT. Both groups did not show difference in insulin secretion and ISI by hyperglycemic clamp technique. We concluded that in up to 12 years from index pregnancy, women with previous GHG, presenting normal glucose tolerance and well-matched with their controls, showed β-cell dysfunction without change in ISI. As women with previous GHG are at risk of type 2 diabetes, β-cell dysfunction may be its primary defect. © 2003 Elsevier B.V. All rights reserved.

A constructive heuristic algorithm to Short Term Transmission Network Expansion Planning

In this paper a method for solving the Short Term Transmission Network Expansion Planning (STTNEP) problem is presented. The STTNEP is a very complex mixed integer nonlinear programming problem that presents a combinatorial explosion in the search space. In this work we present a constructive heuristic algorithm to find a solution of the STTNEP of excellent quality. In each step of the algorithm a sensitivity index is used to add a circuit (transmission line or transformer) to the system. This sensitivity index is obtained solving the STTNEP problem considering as a continuous variable the number of circuits to be added (relaxed problem). The relaxed problem is a large and complex nonlinear programming and was solved through an interior points method that uses a combination of the multiple predictor corrector and multiple centrality corrections methods, both belonging to the family of higher order interior points method (HOIPM). Tests were carried out using a modified Carver system and the results presented show the good performance of both the constructive heuristic algorithm to solve the STTNEP problem and the HOIPM used in each step.

Heuristic algorithm to solve the short term transmission network expansion planning

In this paper, a method for solving the short term transmission network expansion planning problem is presented. This is a very complex mixed integer nonlinear programming problem that presents a combinatorial explosion in the search space. In order to And a solution of excellent quality for this problem, a constructive heuristic algorithm is presented in this paper. In each step of the algorithm, a sensitivity index is used to add a circuit (transmission line or transformer) or a capacitor bank (fixed or variable) to the system. This sensitivity index is obtained solving the problem considering the numbers of circuits and capacitors banks to be added (relaxed problem), as continuous variables. The relaxed problem is a large and complex nonlinear programming and was solved through a higher order interior point method. The paper shows results of several tests that were performed using three well-known electric energy systems in order to show the possibility and the advantages of using the AC model. ©2007 IEEE.