Maternal Moderate Physical Training during Pregnancy Attenuates the Effects of a Low-Protein Diet on the Impaired Secretion of Insulin in Rats: Potential Role for Compensation of Insulin Resistance and Preventing Gestational Diabetes Mellitus

The effects of pregestational and gestational low-to-moderate physical training on insulin secretion in undernourished mothers were evaluated. Virgin female Wistar rats were divided into four groups as follows: control (C, n = 5); trained (T, n = 5); low-protein diet (LP, n = 5); trained with a low-protein diet (T + LP, n = 5). Trained rats ran on a treadmill over a period of 4 weeks before mate (5 days week(-1) and 60 min day(-1), at 65% of VO2max). At pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8% casein diet, and controls were provided with a 17% casein diet. At third day after delivery, mothers and pups were killed and islets were isolated by collagenase digestion of pancreas and incubated for a further 1 h with medium containing 5.6 or 16.7 mM glucose. T mothers showed increased insulin secretion by isolated islets incubated with 16.7 mM glucose, whereas LP group showed reduced secretion of insulin by isolated islets when compared with both C and LP + T groups. Physical training before and during pregnancy attenuated the effects of a low-protein diet on the secretion of insulin, suggesting a potential role for compensation of insulin resistance and preventing gestational diabetes mellitus.

Effect of Type 2 Diabetes Mellitus on the Pharmacokinetics of Metformin in Obese Pregnant Women

Background and Objective The use of metformin throughout gestation by women with polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus (T2DM) significantly reduces the number of first-trimester spontaneous abortions and the rate of occurrence of gestational diabetes and hypertensive syndromes. Metformin is taken up into renal tubular cells by organic cation transport 2 (OCT2) and eliminated unchanged into the urine. The objective of this study was to analyse the influence of T2DM on the pharmacokinetics of metformin in obese pregnant women and in a control group of non-diabetic obese pregnant women with PCOS. Methods Eight non-diabetic obese pregnant women with PCOS and nine obese pregnant women with T2DM taking oral metformin 850 mg every 12 h were evaluated throughout gestation. Serial blood samples were collected over a 12-h period during the third trimester of pregnancy. Steady-state plasma concentrations of metformin were determined by high-performance liquid chromatography with a UV detector. The pharmacokinetic results of the two groups, reported as median and 25th and 75th percentile, were compared statistically using the Mann Whitney test, with the level of significance set at p < 0.05. Results The pharmacokinetic parameters detected for PCOS versus T2DM patients, reported as median, were, respectively: elimination half-life 3.75 versus 4.00 h; time to maximum concentration 2.00 versus 3.00 h; maximum concentration 1.42 versus 1.21 mu g/mL; mean concentration 0.53 versus 0.56 mu g/mL; area under the plasma concentration time curve from time zero to 12 h 6.42 versus 6.73 mu g.h/mL; apparent total oral clearance 105.39 versus 98.38 L/h; apparent volume of distribution after oral administration 550.51 versus 490.98 L; and fluctuation (maximum minimum concentration variation) of 179.56 versus 181.73%. No significant differences in pharmacokinetic parameters were observed between the groups. Conclusion T2DM in the presence of insulin use does not influence the pharmacokinetics of metformin in pregnant patients, demonstrating the absence of a need to increase the dose, and consequently does not influence the OCT2-mediated transport in pregnant women with PCOS.

Analysis of the mRNA expression of the S100 beta protein in adipocytes of patients with diabetes mellitus, type 2

Objective: This study aims to explore the possible relationship between the expression level of S100 beta protein mRNA with diabetes mellitus type 2 in adipocytes from patients with this disease in comparison with normoglycemic individuals. Materials and methods: Samples of adipose tissue of eight patients from the coronary section of the Institute Dante Pazzanese of Cardiology (IDPC), four in Group Diabetes and four of Normoglycemic group, were evaluated by RT-PCR real time. Results: An increase around 15 times values, between the threshold cycle (Delta Ct), of mRNA expression of S100 beta protein in adipocytes of the diabetes group was observed in comparison to the control group (p = 0.015). Conclusion: Our results indicate, for the first time, that there is coexistence of increased expression of the S100 beta and the type 2 diabetes mellitus gene. Arq Bras Endocrinol Metab. 2012;56(7):435-40

Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus

Background Oxidative stress is recognized as a major pathogenic factor of cellular damage caused by hyperglycemia. NOX/NADPH oxidases generate reactive oxygen species and NOX1, NOX2 and NOX4 isoforms are expressed in kidney and require association with subunit p22phox (encoded by the CYBA gene). Increased expression of p22phox was described in animal models of diabetic nephropathy. In the opposite direction, glutathione is one of the main endogenous antioxidants whose plasmatic concentrations were reported to be reduced in diabetes patients. The aim of the present investigation was to test whether functional single nucleotide polymorphisms (SNPs) in genes involved in the generation of NADPH-dependent O2•- (-675 T → A in CYBA, unregistered) and in glutathione metabolism (-129 C → T in GCLC [rs17883901] and -65 T → C in GPX3 [rs8177412]) confer susceptibility to renal disease in type 1 diabetes patients. Methods 401 patients were sorted into two groups according to the presence (n = 104) or absence (n = 196) of overt diabetic nephropathy or according to glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease (MDRD) equation: ≥ 60 mL (n = 265) or < 60 mL/min/1.73 m2 (n = 136) and were genotyped. Results No differences were found in the frequency of genotypes between diabetic and non-diabetic subjects. The frequency of GFR < 60 mL/min was significantly lower in the group of patients carrying CYBA genotypes T/A+A/A (18.7%) than in the group carrying the T/T genotype (35.3%) (P = 0.0143) and the frequency of GFR < 60 mL/min was significantly higher in the group of patients carrying GCLC genotypes C/T+T/T (47.1%) than in the group carrying the C/C genotype (31.1%) (p = 0.0082). Logistic regression analysis identified the presence of at least one A allele of the CYBA SNP as an independent protection factor against decreased GFR (OR = 0.38, CI95% 0.14-0.88, p = 0.0354) and the presence of at least one T allele of the GCLC rs17883901 SNP as an independent risk factor for decreased GFR (OR = 2.40, CI95% 1.27-4.56, p = 0.0068). Conclusions The functional SNPs CYBA -675 T → A and GCLC rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients and require validation in additional cohorts.

Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population

Background Independent of other cardiovascular (CV) risk factors, increased arterial stiffness has been established as a predictor of morbidity and mortality. The main aim of this study was to investigate the impact of diabetes on arterial stiffness in a representative sample of an urban Brazilian population plus Amerindians. Methods A total of 1,415 individuals from the general population were randomly selected plus 588 Amerindians from a native community in Brazil. In addition, a sub-sample of 380 individuals from the general population had 5-year follow-up data. Pulse wave velocity (PWV) was measured with a non-invasive automatic device (Complior, Colson; Garges les Gonesses, France) and increased arterial stiffness was defined as PWV ≥ 12 m/s. Results In the overall group, diabetic individuals had higher frequencies of increased arterial stiffness and hypertension. They also had higher values of PWV, body mass index, total cholesterol, triglycerides, systolic and diastolic blood pressures compared to non-diabetic individuals (p < 0.01). In an analysis stratified by hypertension, PWV values and increased arterial stiffness frequency were higher in diabetic individuals in both groups (hypertensive and non-hypertensive) (p < 0.05). Furthermore, higher risk for increased arterial stiffness was observed in the diabetic individuals from the overall group (OR = 2.27; CI = 1.47-3.52, p < 0.001) and from the hypertensive group (OR = 2.70; CI = 1.58-4.75, p < 0.001), adjusted for covariates. Regarding the ethnic stratification, diabetic individuals from Amerindian, White, and Mulatto (mixed-race) groups had higher PWV values and a greater frequency of increased arterial stiffness compared to non-diabetic individuals. Both diabetic and non-diabetic individuals had higher PWV values after 5 years. There was no significant difference in the 5-year PWV progression in diabetic compared to non-diabetic individuals. Conclusions These results confirm, in a sample of Brazilian population, that the presence of diabetes is associated with increased arterial stiffness and it may contribute in part to increased cardiovascular risk in diabetic patients.

CYBA C242T polymorphism is associated with obesity and diabetes mellitus in Brazilian hypertensive patients

Diabet. Med. 29, e55e61 (2012) Abstract Aims The CYBA C242T polymorphism has been associated with cardiovascular phenotypes such as hypertension and atherosclerosis, but available data are conflicting. This report investigated the impact of this variant on hypertension and metabolic determinants of cardiovascular risk in a large Brazilian sample. Methods We cross-sectionally evaluated 1856 subjects (826 normotensive subjects and 1030 hypertensive patients) by clinical history, anthropometry, laboratory analysis and genotyping of the CYBA C242T polymorphism. Results Genotype frequencies in the whole population were consistent with the HardyWeinberg equilibrium and genotype distributions were not different between hypertensive and normotensive subjects. Hypertensive patients with the CC genotype presented lower fasting plasma glucose levels (5.9 +/- 0.1 vs. 6.2 +/- 0.1 mmol/l, P = 0.020) and waist circumference (94.5 +/- 0.6 vs. 96.3 +/- 0.6 cm, P = 0.028) than CT + TT ones. Similarly, the prevalence of diabetes mellitus and obesity was also lower in hypertensive patients carrying the CC genotype (16% vs. 21%, P = 0.041; 36% vs. 43%, P = 0.029, respectively). In addition, multiple and logistic regression analysis demonstrated that the CYBA C242T polymorphism was associated with glucose levels, waist circumference, obesity and diabetes mellitus in hypertensive patients independently of potential confounders. Conversely, in normotensive subjects, no significant difference in studied variables was detected between the genotype groups. Conclusions These data suggest that the T allele of the CYBA C242T polymorphism may be used as a marker for adverse metabolic features in Brazilian subjects with systemic hypertension.

BDKRB2+9/-9 Polymorphism Is Associated with Higher Risk for Diabetes Mellitus in the Brazilian General Population

Some mechanisms have been proposed to explain the role of bradykinin on glucose homeostasis and some studies reported that the BDKRB2 +9/-9 polymorphism was associated to the transcriptional activity of the receptor. In this scenario, the main aim of this study was to evaluate the association of the BDKRB2 +9/-9 polymorphism with diabetes mellitus risk in the Brazilian general population. This study included 1,032 subjects of the general urban population. Anthropometrical, blood pressure, biochemical, and genotype analyses for the BDKRB2 +9/-9 bp insertion/deletion polymorphism were performed. Individuals carrying +9/+9 or +9/-9 genotypes had higher glucose values (84.5 mg/dL versus 80.6 mg/dL, resp.) and higher frequency of diabetes mellitus (7.6% versus 3.6%, resp.) compared to individuals carrying -9/-9, adjusting for age and gender. In addition, higher diabetes mellitus risk was associated to presence of the +9/+9 or +9/-9 genotypes (OR = 1.91; 95% CI = 1.09-4.19; P = 0.03). Our data suggest that the BDKRB2 +9/-9 polymorphism may act as a genetic modulator of glucose homeostasis. It was previously associated to insulin sensitivity, glucose uptake, and insulin secretion, and, in this study, data suggest that the polymorphism may increase susceptibility to chronic metabolic conditions such as diabetes in the Brazilian population.

Role of glycated hemoglobin in the care of diabetes mellitus

Introduction: Persistently high glycemic levels are extremely harmful to the organism and can lead patients to several complications of diabetes mellitus. Glycated hemoglobin represents the glycemic levels for what patient is chronically exposed. Methods: Two virtual databases were surveyed in two languages: Portuguese and English. 12 articles were selected and reviewed. Results and discussion: The HbA1c is used since 1958 in the assessment of glycemic control in diabetic patients. It is formed by a chemical reaction between hemoglobin A and acarbohydrate. Each percentage point of glycated hemoglobin represents approximately 35mg/dL in patient's averageglycemia. Conclusion: The glycated hemoglobin should be measured at least twice per year in patients with diabetes in general. In case of change of hypoglycemic therapy, this frequency should be doubled.

Minimal change disease associated with type 1 and type 2 diabetes mellitus

A 19-year-old female with type 1 diabetes for four years, and a 73-year-old female with type 2 diabetes for twenty years developed sudden-onset nephrotic syndrome. Examination by light microscopy, immunofluorescence, and electron microscopy (in one case) identified minimal change disease (MCD) in both cases. There was a potential causative drug (meloxicam) for the 73-year-old patient. Both patients were treated with prednisone and responded with complete remission. The patient with type 1 diabetes showed complete remission without relapse, and the patient with type 2 diabetes had two relapses; complete remission was sustained after associated treatment with cyclophosphamide and prednisone. Both patients had two years of follow-up evaluation after remission. We discuss the outcomes of both patients and emphasize the role of kidney biopsy in diabetic patients with an atypical proteinuric clinical course, because patients with MCD clearly respond to corticotherapy alone or in conjunction with other immunosuppressive agents. Arq Bras Endocrinol Metab. 2012;56(5):331-5

Relationship among social support, treatment adherence and metabolic control of diabetes mellitus patients

This cross-sectional and quantitative study aimed to analyze the relationship among social support, adherence to non-pharmacological (diet and physical exercise) and pharmacological treatments (insulin and/or oral anti-diabetic medication) and clinical and metabolic control of 162 type 2 diabetes mellitus patients. Data were collected through instruments validated for Brazil. Social support was directly correlated with treatment adherence. Adherence to non-pharmacological treatment was inversely correlated with body mass index, and medication adherence was inversely correlated with diastolic blood pressure. There were no associations between social support and clinical and metabolic control variables. Findings indicate that social support can be useful to achieve treatment adherence. Studies with other designs should be developed to broaden the analysis of relations between social support and other variables.

The Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial: Clinical and angiographic profile at study entry

Background The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy. Methods A total of 1,900 diabetic participants with MVD were randomized to PCI or CABG worldwide from April 2005 to March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients. Results The randomized cohort was 63.1 +/- 9.1 years old and 29% female, with a median diabetes duration of 10.2 +/- 8.9 years. Most (83%) had 3-vessel disease and on average took 5.5 +/- 1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia, and 26% had a prior myocardial infarction. Mean hemoglobin A1c was 7.8 +/- 1.7 mg/dL, 29% had low-density lipoprotein <70 mg/dL, and mean systolic blood pressure was 134 +/- 20 mm Hg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial participants have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts. Conclusions The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI versus CABG debate in diabetic patients with MVD. (Am Heart J 2012;164:591-9.)

Autoantibodies and High-Risk HLA Susceptibility Markers in First-Degree Relatives of Brazilian Patients with Type 1 Diabetes Mellitus: A Progression to Disease Based Study

The objective of this study was to determine the frequencies of autoantibodies to heterogeneous islet-cell cytoplasmic antigens (ICA), glutamic acid decarboxylase(65) (GAD(65)A), insulinoma-associated antigen-2 (IA-2A) and insulin (IAA)-and human leukocyte antigen (HLA) class II markers (HLA-DR and -DQ) in first degree relatives of heterogeneous Brazilian patients with type I diabetes(T1DM). A major focus of this study was to determine the influence of age, gender, proband characteristics and ancestry on the prevalence of autoantibodies and HLA-DR and -DQ alleles on disease progression and genetic predisposition to T1DM among the first-degree relatives. IAA, ICA, GAD(65)A, IA-2A and HLA- class II alleles were determined in 546 first-degree-relatives, 244 siblings, 55 offspring and 233 parents of 178 Brazilian patients with T1DM. Overall, 8.9% of the relatives were positive for one or more autoantibodies. IAA was the only antibody detected in parents. GAD(65) was the most prevalent antibody in offspring and siblings as compared to parents and it was the sole antibody detected in offspring. Five siblings were positive for the IA-2 antibody. A significant number (62.1%) of siblings had 1 or 2 high risk HLA haplotypes. During a 4-year follow-up study, 5 siblings (expressing HLA-DR3 or -DR4 alleles) and 1 offspring positive for GAD(65)A progressed to diabetes. The data indicated that the GAD(65) and IA-2 antibodies were the strongest predictors of T1DM in our study population. The high risk HLA haplotypes alone were not predictive of progression to overt diabetes.

Metformin, but not glimepiride, improves carotid artery diameter and blood flow in patients with type 2 diabetes mellitus

OBJECTIVE: To compare the effects of glimepiride and metformin on vascular reactivity, hemostatic factors and glucose and lipid profiles in patients with type 2 diabetes. METHODS: A prospective study was performed in 16 uncontrolled patients with diabetes previously treated with dietary intervention. The participants were randomized into metformin or glimepiride therapy groups. After four months, the patients were crossed over with no washout period to the alternative treatment for an additional four-month period on similar dosage schedules. The following variables were assessed before and after four months of each treatment: 1) fasting glycemia, insulin, catecholamines, lipid profiles and HbA(1) levels; 2) t-PA and PAI-1 (antigen and activity), platelet aggregation and fibrinogen and plasminogen levels; and 3) the flow indices of the carotid and brachial arteries. In addition, at the end of each period, a 12-hour metabolic profile was obtained after fasting and every 2 hours thereafter. RESULTS: Both therapies resulted in similar decreases in fasting glucose, triglyceride and norepinephrine levels, and they increased the fibrinolytic factor plasminogen but decreased t-PA activity. Metformin caused lower insulin and pro-insulin levels and higher glucagon levels and increased systolic carotid diameter and blood flow. Neither metformin nor glimepiride affected endothelial-dependent or endothelial-independent vasodilation of the brachial artery. CONCLUSIONS: Glimepiride and metformin were effective in improving glucose and lipid profiles and norepinephrine levels. Metformin afforded more protection against macrovascular diabetes complications, increased systolic carotid artery diameter and total and systolic blood flow, and decreased insulin levels. As both therapies increased plasminogen levels but reduced t-PA activity, a coagulation process was likely still ongoing.

A modified laparoscopic sleeve gastrectomy for the treatment of diabetes mellitus type 2 and metabolic syndrome in obesity

BACKGROUND: Ghrelin is a gastrointestinal peptide hormone (a 28-amino acid peptide) produced primarily by X/A cells in the oxyntic glands of the stomach fundus and cells lining the duodenum cavern. It suppresses insulin secretion and action and commands a significant role in regulating food intake. The aim of the present study was to show that modified laparoscopic sleeve gastrectomy (MLSG), in which a significant part of the gastric fundus and body of the stomach is removed up to 1 inch from the pylorus vein, may contribute to decreasing circulating ghrelin levels. METHODS: A study population consisting of 150 individuals was monitored after undergoing a MLSG, with individuals chosen based on a documented history of diabetes mellitus type 2 and metabolic syndrome, clinical results determining a body mass index (BMI) of 35 to 60 kg/m(2), peptide C level greater than 1, negative anti-glutamic acid decarboxylase, negative anti-insulin, and confirmed stability of drug/insulin treatment and glycosylated hemoglobin greater than 6.5% for at least 24 and 3 months, respectively, before enrollment. RESULTS: Twenty-four months after surgery, 150 patients (86.6%) presented with normal glycemic levels between 77 and 99 mg/dL. All patients improved average serum insulin levels by 9 mU/L and average glycosylated hemoglobin levels by 5.1% (normal range, 4%-6%). All patients tested negative for Helicobacter pylori and stopped using insulin, with 3 patients prescribed twice-daily use of an oral hypoglycemiant. In 14% of cases, patients experienced partial hair loss with low serum zinc levels and were prescribed oral zinc reposition and topical hair stimulants. The average weight loss recorded was 44.6% for patients with a BMI less than 45 kg/m(2) and 58% for patients with a BMI greater than 50 kg/m(2). CONCLUSIONS: The MLSG is a safe procedure with a low morbidity rate (2.7%) (4 cases of fistula and 2 of bleeding) and no surgical mortality in this study. This surgery can promote control of diabetes mellitus type 2 and aid the treatment of exogenous overweight and morbidly obese individuals. The results of this study show that only through resection of the ghrelin-producing gastric area can most obesity cases and diabetes type II conditions be reverted to nonobese and controlled diabetes. (c) 2012 Elsevier Inc. All rights reserved.

Stem cell therapy for type 1 diabetes mellitus: a review of recent clinical trials

Stem cell therapy is one of the most promising treatments for the near future. It is expected that this kind of therapy can ameliorate or even reverse some diseases. With regard to type 1 diabetes, studies analyzing the therapeutic effects of stem cells in humans began in 2003 in the Hospital das Clínicas of the Faculty of Medicine of Ribeirão Preto - SP USP, Brazil, and since then other centers in different countries started to randomize patients in their clinical trials. Herein we summarize recent data about beta cell regeneration, different ways of immune intervention and what is being employed in type 1 diabetic patients with regard to stem cell repertoire to promote regeneration and/or preservation of beta cell mass.