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

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.

Lipid Peroxidation Is Associated with the Severity of Periodontal Disease and Local Inflammatory Markers in Patients with Type 2 Diabetes

Context: Periodontitis is the most common lytic disease of bone and is recognized as a common complication of diabetes. Lipid peroxidation (LPO) is increased in diabetes and may be related to modulation of the inflammatory response. LPO levels in patients with diabetes and periodontal disease have not been evaluated. Objective: The aim of this study was to evaluate the levels of LPO and its correlation with periodontal status and inflammatory cytokines in type 2 diabetic and nondiabetic patients. Design and Setting: This is a cross-sectional study involving Brazilian patients recruited at the State University of Sao Paulo. Patients: The sample comprised 120 patients divided into four groups based upon diabetic and dyslipidemic status: poorly controlled diabetics with dyslipidemia, well-controlled diabetics with dyslipidemia, normoglycemic individuals with dyslipidemia, and healthy individuals. Main Outcome Measures: Blood analyses were carried out for fasting plasma glucose, glycated hemoglobin, and lipid profile. Periodontal examinations were performed, and gingival crevicular fluid was collected. LPO levels were evaluated by measuring oxidized low-density lipoprotein (ELISA) and malondialdehyde (HPLC). Cytokines were evaluated by the multiplex bead technique. Results: LPO evaluated by malondialdehyde in plasma and gingival crevicular fluid was significantly increased in diabetes groups. Significant correlations between LPO markers and periodontal parameters indicate a direct relationship between these levels and the severity of inflammation and secretion of inflammatory cytokines, particularly in diabetic patients. Conclusion: These findings suggest an important association for LPO with the severity of the local inflammatory response to bacteria and the susceptibility to periodontal disease in diabetic patients. (J Clin Endocrinol Metab 97: E1353-E1362, 2012)

Metabolic Improvements in Obese Type 2 Diabetes Subjects Implanted for 1 Year with an Endoscopically Deployed Duodenal-Jejunal Bypass Liner

Background: The purpose of this study was to evaluate the effect of the duodenal-jejunal bypass liner (DJBL), a 60-cm, impermeable fluoropolymer liner anchored in the duodenum to create a duodenal-jejunal bypass, on metabolic parameters in obese subjects with type 2 diabetes. Methods: Twenty-two subjects (mean age, 46.2 +/- 10.5 years) with type 2 diabetes and a body mass index between 40 and 60 kg/m(2) (mean body mass index, 44.8 +/- 7.4 kg/m(2)) were enrolled in this 52-week, prospective, open-label clinical trial. Endoscopic device implantation was performed with the patient under general anesthesia, and the subjects were examined periodically during the next 52 weeks. Primary end points included changes in fasting blood glucose and insulin levels and changes in hemoglobin A1c (HbA1c). The DJBL was removed endoscopically at the end of the study. Results: Thirteen subjects completed the 52-week study, and the mean duration of the implant period for all subjects was 41.9 +/- 3.2 weeks. Reasons for early removal of the device included device migration (n = 3), gastrointestinal bleeding (n = 1), abdominal pain (n = 2), principal investigator request (n = 2), and discovery of an unrelated malignancy (n = 1). Using last observation carried forward, statistically significant reductions in fasting blood glucose (-30.3 +/- 10.2 mg/dL), fasting insulin (-7.3 +/- 2.6 mu U/mL), and HbA1c (-2.1 +/- 0.3%) were observed. At the end of the study, 16 of the 22 subjects had an HbA1c < 7% compared with only one of 22 at baseline. Upper abdominal pain (n = 11), back pain (n = 5), nausea (n = 7), and vomiting (n = 7) were the most common device-related adverse events. Conclusions: The DJBL improves glycemic status in obese subjects with diabetes and therefore represents a nonsurgical, reversible alternative to bariatric surgery.

Enhancing health care for type 2 diabetes in Northern Brazil: A pilot study of pharmaceutical care in community pharmacy

To evaluate the impact of a medication therapy management (MTM) program on the clinical outcomes and the quality of life (QoL) of a group of elderly patients with type 2 diabetes mellitus (DM). The study was conducted in a community pharmacy in Aracaju, Brazil, from February to November 2009. A quasi-experimental, longitudinal, prospective study was conducted by intervention. The group patients received medication therapy management from a clinical pharmacist. A sample of convenience was obtained for patients of both genders aged from 60 to 75 years. Monthly visits were scheduled over 10 months. At these consultations, sociodemographic, clinical data were obtained. QoL assessment was conducted using a generic instrument-the Medical Outcomes Studies 36-item Short Form Survey (SF-36 (R)). In total, 34 completed the study. The mean age of the patients was 65.9 (4.7) years. In total, 117 DRPs were identified. Patients' baseline and final evaluation measures for glycosylated hemoglobin, capillary blood glucose, blood pressure, and waist circumference were significantly different (p < 0.05). The domains of QoL assessed by the SF-36 (R) also shows significant differences between patients' baseline and final evaluation scores. The co-responsibility and active participation on the part of the elderly may have helped pharmacotherapy achieve its clinical and humanistic aims.

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.

Removal from the plasma of the free and esterified forms of cholesterol and transfer of lipids to HDL in type 2 diabetes mellitus patients

Background: The aim was to investigate new markers for type 2 diabetes (T2DM) dyslipidemia related with LDL and HDL metabolism. Removal from plasma of free and esterified cholesterol transported in LDL and the transfer of lipids to HDL are important aspects of the lipoprotein intravascular metabolism. The plasma kinetics (fractional clearance rate, FCR) and transfers of lipids to HDL were explored in T2DM patients and controls, using as tool a nanoemulsion that mimics LDL lipid structure (LDE). Results: C-14- cholesteryl ester FCR of the nanoemulsion was greater in T2DM than in controls (0.07 +/- 0.02 vs. 0.05 +/- 0.01 h(-1), p = 0.02) indicating that LDE was removed faster, but FCR H-3- cholesterol was equal in both groups. Esterification rates of LDE free-cholesterol were equal. Cholesteryl ester and triglyceride transfer from LDE to HDL was greater in T2DM (4.2 +/- 0.8 vs. 3.5 +/- 0.7%, p = 0.03 and 6.8 +/- 1.6% vs. 5.0 +/- 1.1, p = 0.03, respectively). Phospholipid and free cholesterol transfers were not different. Conclusions: The kinetics of free and esterified cholesterol tended to be independent in T2DM patients and the lipid transfers to HDL were also disturbed. These novel findings may be related with pathophysiological mechanisms of diabetic macrovascular disease.

Algorithm for the treatment of type 2 diabetes: a position statement of Brazilian Diabetes Society

The Brazilian Diabetes Society is starting an innovative project of quantitative assessment of medical arguments of and implementing a new way of elaborating SBD Position Statements. The final aim of this particular project is to propose a new Brazilian algorithm for the treatment of type 2 diabetes, based on the opinions of endocrinologists surveyed from a poll conducted on the Brazilian Diabetes Society website regarding the latest algorithm proposed by American Diabetes Association /European Association for the Study of Diabetes, published in January 2009.

Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: from diagnosis to treatment

Overweight and obesity in youth is a worldwide public health problem. Overweight and obesity in childhood and adolescents have a substantial effect upon many systems, resulting in clinical conditions such as metabolic syndrome, early atherosclerosis, dyslipidemia, hypertension and type 2 diabetes (T2D). Obesity and the type of body fat distribution are still the core aspects of insulin resistance and seem to be the physiopathologic links common to metabolic syndrome, cardiovascular disease and T2D. The earlier the appearance of the clustering of risk factors and the higher the time of exposure, the greater will be the chance of developing coronary disease with a more severe endpoint. The age when the event may occur seems to be related to the presence and aggregation of risk factors throughout life.

Comparison of venous plasma glycemia and capillary glycemia for the screening of type 2 diabetes mellitus in the Japanese-Brazilian community of Mombuca (Guatapará-SP)

Abstract Background To identify the most appropriate cut-off points of fasting glycemia for the screening of diabetes mellitus type 2 (DM2) with the comparison of the properties of capillary glycemia (CG) and venous blood plasma glycemia (PG) in a population of Japanese origin from the community of Mombuca, Guatapará - SP, Brazil. Methods This was a population-based descriptive cross-sectional study conducted on a sample of 131 individuals of both genders aged 20 years or more (66.8% of the target population). CG was measured with a glucometer in a blood sample obtained from the fingertip and PG was determined by an enzymatic method (hexokinase) in venous blood plasma, after a 10-14 hour fast in both cases. Data were analyzed by the receiver operating characteristic (ROC) curve in order to identify the best cut-off point for fasting glycemia (CG and PG) for the diagnosis of DM, using the 2-hour plasma glycemia > 200 mg/dl as gold - standard. Results The ROC curve revealed that the best cut-off point for the screening of DM was 110 mg/dl for CG and 105 mg/dl for PG, values that would optimize the relation between individuals with positive and false-positive results. The area under the ROC curve was 0.814 for CG (p < 0.01) and 0.836 for PG (p < 0.01). Conclusions The cut-off points of 105 mg/dl(5.8 mmol/l) for PG and of 110 mg/dl(6.1 mmol/l) for CG appear to be the most appropriate for the screening of DM2 in the population under study, with emphasis on the fact that the value recommended for CG is 5 mg/dl higher than that for PG, in contrast to WHO recommendations.

Der Einfluss des Angiotensin-II-Typ-2-Agonisten Compound 21 auf den neuronalen Schaden bei der Maus nach traumatischer Hirnläsion mittels Controlled Cortical Impact

Die Beeinflussung des sekundären Hirnschadens nach SHT ist Hauptansatzpunkt der klinischen Therapie. Gleichzeitig sind die zugrunde liegenden Mechanismen zum Großteil unklar und Gegenstand aktueller Forschung. In verschiedenen Studien scheint sich das Renin-Angiotensin-Aldosteron-System als Teil der Pathophysiologie bei der Entstehung des sekundären Hirnschadens und der neuronalen Inflammation nach SHT herauszukristallisieren. Der Fokus richtet sich mitunter auf den AT2- Rezeptor, dessen protektive Wirkung in verschiedensten Ischämiemodellen und Geweben gezeigt werden konnte.rnIn der vorliegenden Promotionsarbeit wurde erstmalig die Wirkung einer AT2- Stimulation auf histologische, inflammatorische und neuromotorische Parameter nach CCI untersucht. Eine neuroprotektive Wirkung der AT2-Stimulation konnte dabei nicht nachgewiesen werden. Es kam weder zu einer Beeinflussung histologischer noch neuromotorischer Parameter, allerdings scheint der AT2-Agonist C21 bei einer Dosierung von 0,03 mg/kg KG zu einer Stimulation der inflammatorischen Reaktion zu führen.

Synthese, Charakterisierung und Testung von Phenylacrylsäure-Derivaten, Benzothiazolen und Diarylthioethern als potentielle Inhibitoren der Dengue-Virus-Typ-2-NS2B-NS3-Protease

Dengue-Fieber ist eine durch Stechmücken der Gattungen Aedes aegypti und Aedes albopticus übertragene, virale Infektionskrankheit des Menschen, welche eine zunehmende Bedrohung für die Weltbevölkerung darstellt; das Infektionsrisiko betrifft vorwiegend Menschen, die in tropischen und subtropischen Gebieten der Erde (Asien, Afrika, Amerika) leben. Bei dem Erreger handelt es sich um ein Flavivirus, bestehend aus einer positiv polarisierten Einzelstrang-RNA, welches in vier verschiedenen Serotypen existiert. Eine Infektion mit Dengue-Viren zeigt sich durch drei mögliche Krankheitsbilder: Klassisches Dengue-Fieber (DF), hämorrhagisches Dengue-Fieber (DHF) oder Dengue-Schock-Syndrom (DSS). Das Dengue-Virus-Genom codiert eine Serin-Protease mit einer klassischen katalytischen Triade, bestehend aus den Aminosäuren His51, Asp75 und Ser135. Die Funktion der Dengue-Virus-Protease besteht in der post-translationalen, proteolytischen Prozessierung des viralen Polyprotein-Vorläufers, womit sie essentiell für die Virus-Replikation ist und damit einen wichtigen therapeutischen Ansatz für die Entwicklung neuer Wirkstoffe gegen Dengue-Fieber darstellt. Die Ziele der vorliegenden Arbeit bestanden darin, neue potentielle Inhibitoren der Dengue-Virus Typ 2 NS2B-NS3 Protease (DEN-2 NS2B-NS3pro) zu synthetisieren, deren Hemmwirkung sowie den Inhibitionstyp mithilfe fluorimetrischer Enzym-Assays zu bestimmen, Struktur-Wirkungs-Beziehungen (u.a. mithilfe von Molecular Docking-Rechnungen) zu analysieren und die erhaltenen Leitstrukturen zu optimieren. In der vorliegenden Arbeit wurden zwei Substanzklassen und damit zwei Teilprojekte behandelt: Phenylacrylsäureamide im ersten Teilprojekt, Benzothiazole und Diarylthioether zusammen im zweiten Teilprojekt. Im ersten Teilprojekt zeigten einige Phenylacrylsäureamide eine schwache Hemmung der DEN-2 NS2B-NS3pro zwischen ca. 50 und 61 % bei einer Inhibitorkonzentration von 50 µM sowie eine nicht-kompetitive Hemmung, welche jedoch durch vielfältige Derivatisierung kaum verändert oder verbessert werden konnte. Darüber hinaus wurden die endogenen Serin-Proteasen alpha-Chymotrypsin und Trypsin durch einige Phenylacrylsäureamide erheblich stärker gehemmt als die DEN-2 NS2B-NS3pro. Das zweite Teilprojekt befasste sich mit der Synthese und Testung von Diarylthioethern mit hydroxy-substituierten Benzothiazol-Bausteinen sowie der Testung einiger methoxy-substituierter Synthese-Vorstufen der Endverbindungen, um die Relevanz und den Einfluss der einzelnen Bausteine auf die Hemmung der DEN-2 NS2B-NS3pro zu untersuchen. Der in der vorliegenden Arbeit synthetisierte, potenteste Inhibitor der DEN-2 NS2B-NS3pro (Hemmung: 90 % [50 µM]; IC50 = 3.6 +/- 0.11 µM) und der DEN-3 NS2B-NS3pro (Hemmung: &amp;gt;99 % [100 µM]; IC50 = 9.1 +/- 1.02 µM), SH65, ein Diarylthioether-Benzothiazol-Derivat, entstand aufgrund der Vorhersage zweier möglicher Bindungsmodi (kompetitiv und nicht-kompetitiv) mithilfe von Molecular Docking-Experimenten an der Röntgen-Kristall-struktur der DEN-3 NS2B-NS3pro (PDB-Code: 3U1I). Nach experimenteller Bestimmung der IC50-Werte bei unterschiedlichen Substratkonzentrationen erwies sich SH65 jedoch als nicht-kompetitiver Inhibitor der DEN-2 NS2B-NS3pro. Trypsin wurde von SH65 vergleichbar stark gehemmt (96% [50 µM]; IC50 = 6.27 +/- 0.68 µM) wie die beiden getesteten Dengue-Virus-Proteasen, nicht jedoch alpha-Chymotrypsin (nur 21% Hemmung bei 50 µM), wodurch diesem Inhibitor zumindest eine relative Selektivität gegenüber Serin-Proteasen zugeschrieben werden kann. SH65 zeigte lediglich Protease-Hemmung in den Enzym-Assays, jedoch keine antivirale Aktivität bei der Testung an Dengue-Virus-infizierten Zellen, was aber wiederum bei der synthetisierten Vorstufe von SH65, welche anstelle der beiden Hydroxy-Gruppen über Methoxy-Gruppen verfügt, der Fall war. Diarylthioether mit mehrfach hydroxy-substituiertem Benzothiazol-Baustein stellen hiermit eine neue, vielversprechende Wirkstoffgruppe zur Hemmung sowohl der Dengue-Virus Typ 2- als auch der Dengue-Virus Typ 3 NS2B-NS3 Protease dar.

Addressing schemes of self-monitoring of blood glucose in type 2 diabetes: a European perspective and expert recommendation

Self-monitoring of blood glucose (SMBG) in type 2 diabetes has increasingly been shown to display beneficial effects on glycemic control. SMBG is not only associated with a reduction of hemoglobin A1c but has also been demonstrated to increase patients' awareness of the disease. SMBG has also the potential to visualize and predict hypoglycemic episodes. International guidelines by the International Diabetes Federation, the European Society of Cardiology, and the European Association for the Study of Diabetes and also the International Society for Pediatric and Adolescent Diabetes emphasize that SMBG is an integral part of self-management. More recently, two European consensus documents have been published to give recommendations for frequency and timing of SMBG also for various clinical scenarios. Recently, a European expert panel was held to further facilitate and enhance standardized approaches to SMBG. The aim was to present simple, clinically meaningful, and standardized SMBG strategies for type 2 diabetes. The panel recommended a less intensive and an intensive scheme for SMBG across the type 2 diabetes continuum. The length and frequency of SMBG performance depend on the clinical circumstances and the quality of glycemic control. The expert panel also recommended further evaluation of various schemes for SMBG in type 2 diabetes in clinical studies.

Metabolomics reveals attenuation of the SLC6A20 kidney transporter in nonhuman primate and mouse models of type 2 diabetes mellitus

To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n = 10) and T2DM (n = 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na(+)-dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.