Publications by authors named "Freddy Goldberg Eliaschewitz"

18 Publications

  • Page 1 of 1

Glycemic Control and Prevention of Diabetic Complications in Low- and Middle-Income Countries: An Expert Opinion.

Diabetes Ther 2021 May 10;12(5):1491-1501. Epub 2021 Apr 10.

Diabetes Research Centre, University of Leicester, Leicester, UK.

Introduction: Trends on glycemic control and diabetes complications are known for high-income countries, but comprehensive data from low- and middle-income countries (LMIC) are lacking.

Methods: This is an expert opinion based on two retrospective studies. Here we examine the recent subset analysis of relevant data from the IDMPS Wave 7 (International Diabetes Management-Practices Study, 2015-2016) and the GOAL study conducted in multiple LMICs.

Results: Wave 7 sub-analysis was performed in 6113 people with type 2 diabetes from 24 LMIC. Poorly controlled diabetes (hemogloblin A1c [HbA1c] ≥ 7%) was found in 58.6, 73.0 and 78.3% of participants with diabetes duration of < 5, 5-12 and > 12 years, respectively (in association with a high prevalence of macro- and microvascular complications). Moreover, 37.7% of participants with diabetes duration of 5-12 years were treated only with oral antihyperglycemic drugs. The GOAL study investigated the efficacy of insulin in 2704 poorly controlled participants (mean HbA1c 9.7%; diabetes duration 10.1 ± 6.7 years; 10 LMIC). A significant 2% reduction in mean HbA1c levels was observed after 12 months of treatment. Only 7.2% of participants experienced a symptomatic episode of hypoglycemia (nocturnal or severe hypoglycemia events were infrequent).

Conclusion: The rate of well-controlled participants (HbA1c < 7.0%) in the Wave 7 sub-analysis was lower than that observed in the USA (NHANES survey) or in European countries (GUIDANCE study), and the incidence of microvascular complications was higher. The GOAL study showed that insulin treatment improves glycemic control and reduces this gap. The Expert Panel recommends intensifying diabetes treatment as soon as possible, as well as patients' education and other preventive measures, initiatives which require modest costs compared to hospitalization and treatment of diabetes complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13300-021-00997-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099945PMC
May 2021

Efficacy and safety of evogliptin in the treatment of type 2 diabetes mellitus in a Brazilian population: a randomized bridging study.

Diabetol Metab Syndr 2019 19;11:107. Epub 2019 Dec 19.

Centro de Estudos em Diabetes e Hipertensão (CEDH), 2434 Dr Jose Lourenço st., Fortaleza, CE 60115-282 Brazil.

Background: Evogliptin (EVO) is a potent and selective dipeptidyl peptidase-4 inhibitor (DPP4i) developed for the treatment of type 2 diabetes mellitus (T2DM). DPP4is are known to exhibit a better glucose-lowering effect in Asians compared to other ethnic groups. Once EVO's clinical development program was conducted in Asian patients, this bridging study was designed to validate for the Brazilian population the efficacy and safety of the approved dose regimen (once-daily 5.0 mg).

Methods: In this randomized, double-blind, double-dummy, parallel trial, 146 patients with T2DM with inadequate glycemic control on diet and exercise (7.5% ≤ HbA1c ≤ 10.5%) were randomly assigned to a 12-week once-daily treatment with EVO 2.5 mg (N = 35), EVO 5 mg (N = 36), EVO 10 mg (N = 36), or sitagliptin (SITA) 100 mg (N = 39). Absolute changes (Week 12-baseline) in HbA1c, fasting plasma glucose (FPG) and body weight (BW) were obtained. One-sided one sample t test was used to determine if mean HbA1c reduction in each group was < - 0.5% (beneficial metabolic response). An analysis of covariance estimated the change in HbA1c and FPG adjusted by baseline HbA1c, FPG, body mass index (BMI) and study site. Response rates to treatment were also established. No between-group statistical comparisons were planned.

Results: HbA1c mean reductions were - 1.26% (90% CI - 1.7%, - 0.8%), - 1.12% (90% CI - 1.4%, - 0.8%), - 1.29% (90% CI - 1.6%, - 1.0%), and - 1.15% (90% CI - 1.5%, - 0.8%) in groups EVO 2.5 mg, EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. FPG levels showed a mean increase of 10.89 mg/dL in group EVO 2.5 mg, with significant mean reductions of - 18.94 mg/dL, - 21.17 mg/dL, and - 39.90 mg/dL in those treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. BW showed significant reductions of approximately 1 kg in patients treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg. Mean adjusted reductions of HbA1c and FPG levels confirmed the significant clinical benefit of all study treatments. The clinical benefit of EVO's "target" dose (5 mg) was confirmed. No safety concerns were identified.

Conclusions: These results validate for the Brazilian population the approved dose regimen of EVO (once-daily 5 mg). ClinicalTrials.gov Identifier: NCT02689362 (first posted on 02/23/2016).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13098-019-0505-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923891PMC
December 2019

Dyslipidemia: The untreated metabolic dysfunction in people with type 2 diabetes in Latin America. ARETAEUS study outcomes.

J Clin Transl Endocrinol 2019 Mar 25;15:76-80. Epub 2019 Jan 25.

Merck & Co., Inc., Kenilworth, NJ, USA.

Objective: To assess oral antihyperglycemic agents (OAHA) and/or statin treatment initiation in patients with type 2 diabetes (T2D) and time from diagnosis to both types of treatment initiation and intensification.

Research Design And Methods: We reviewed 662 retrospective medical records of patients with T2D diagnosed by 31 general practitioner or specialist sites across Mexico, Argentina, and Brazil. Demographic and clinical information was abstracted from patients' medical records and summarized using descriptive statistics. Between-group differences were assessed with Student's -test for continuous variables and Fisher's exact test for categorical variables. The starting time of each therapy (OAHA and statins, separately) was assessed using Kaplan-Meier estimates.

Results: At diagnosis, patients' mean age was 53 years; 44% had hypertension, 42% were obese, and 23% had dyslipidemia. During the 2-year follow-up, 95% of patients received OAHAs but only 29% of those eligible for statins received this prescription. Mean ± SD and median (Q1, Q3) time to first OAHA was 59 ± 141 days and 1 (1, 31) day, respectively, and 230 ± 232 days and 132 (30, 406) days, respectively, for a statin. During follow-up, 51-53% of patients with HbA1c/FPG values above target did not intensify hyperglycemia treatment.

Conclusion: Dyslipidemia treatment in patients with T2D was delayed despite its known deleterious effect on atherosclerosis development and β-cell mass/function. Anti-hyperglycemic treatment was not intensified when targets were not attained. This prescriptive inertia needs to be corrected because attainment of HbA1c treatment goals becomes more difficult, favoring the development of diabetes complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcte.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369257PMC
March 2019

A safety and tolerability profile comparison between dipeptidyl peptidase-4 inhibitors and sulfonylureas in diabetic patients: A systematic review and meta-analysis.

Diabetes Res Clin Pract 2019 Mar 30;149:47-63. Epub 2019 Jan 30.

Women's Health Technology Assessment Center, Federal University of Sao Paulo (Universidade Federal de São Paulo), Sao Paulo, Brazil; AxiaBio Life Sciences, Sao Paulo, Brazil. Electronic address:

Background: The first treatment approach for type 2 diabetes mellitus is lifestyle change and metformin, but it is usually not sufficient. For some time, the anti-hyperglycemic classes of sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors were considered second-line of treatment, since they show similar efficacy effect. However, the recent ADA-EASD consensus gives the preference to DPP-4 inhibitors compared to sulfonylureas, except if cost is a major problem. We performed a meta-analysis for safety and tolerability profile to comprehend which treatment has less adverse events.

Methods: PUBMED and EMBASE databases were searched from inception until July 2017 to retrieve RCT studies comparing DPP-4 inhibitors and sulfonylureas treatments in adult type 2 diabetes patients. There was no language restriction. We extracted and combined data from studies comparison that reported safety profile and weight change. A random effect, meta-analytic model was applied to all calculations. Cochrane collaboration tool was used to assess quality and bias of the included studies. Trial registered with PROSPERO (CRD42017075823).

Findings: Out of 1472 articles identified in our search and screened for eligibility, 36 studies comparing DPP-4 inhibitors and sulfonylureas were identified. DPP-4 inhibitors in combination with metformin had less overall adverse events (RR: 0·90; 95% CI, 0·86-0·94; p < 0·0001; I = 83%; 17 studies), cardiovascular events (RR: 0·54; 95% CI, 0·37-0·79; p = 0·002; I = 0%; 6 studies), hypoglycemia (RR: 0·17; 95% CI, 0·13-0·22; p < 0·00001; I = 76%; 17 studies) and severe hypoglycemic events (RR: 0·10; 95% CI, 0·05-0·19; p < 0·00001; I = 0%; 12 studies). The mean difference of the weight change was 1·92 kg in favor of DPP-4 inhibitors in combination with metformin in relation to sulfonylureas in combination with metformin. Monotherapy with DPP-4 inhibitors also had less rates of hypoglycemia (RR: 0·31; 95% CI, 0·24-0·41; p < 0·00001; I = 0%; 8 studies) and severe hypoglycemic events (RR: 0·26; 95% CI, 0·10-0·66; p = 0·004; I = 0%; 8 studies) and patients did not gain 1·19 kg.

Interpretation: These results suggest better safety profile for DPP-4 inhibitors than sulfonylureas for both comparisons, and it is more notable when the treatment regimen includes metformin.

Funding: This study was funded by Takeda Pharmaceuticals, Brazil.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diabres.2019.01.025DOI Listing
March 2019

Impact of regulatory assessment on clinical studies in Brazil.

Rev Assoc Med Bras (1992) 2016 Sep-Oct;62(5):447-53

MD - Director of Instituto Vis Research. Member of the Board, Sociedade Brasileira de Medicina Farmacêutica. Representative of Associação Médica Brasileira, São Paulo, SP, Brazil.

Introduction: Despite the recent expansion of clinical studies allocated to Brazil, the delay of local regulatory deadlines directly impacts their completion.

Objective: This article examines the allocation process of clinical studies to Brazil in comparison with other countries, as well as the financial impact of studies not completed due to interruption caused by the delay in the regulatory process.

Method: The allocation processes of studies were compared in nine countries with similar stages of economic development and countries in Latin America using the websites http://data.worldbank.org/data-catalog/GDP-rankings-table and http://worldpopulationreview.com and clinicaltrials.gov, comprising 185 countries. The 46 studies sponsored by the pharmaceutical industry underwent an analysis of the regulatory review process.

Results: 46 studies sponsored by the industry and submitted in the country between June 2007 and June 2013 were analyzed; 18 (39%) were discontinued due to the delay in obtaining the necessary approvals. For the approved studies, patient recruitment began an average of 11 months after the other countries. It is estimated that 530 Brazilians patients did not have the opportunity to participate in these studies. Financial losses were to the order of 14.6 million dollars for the country, including patient, medication and supplies costs, and expenses.

Conclusion: Brazil has enormous potential for the realization of clinical studies. Researchers, associations of disabled people and patients with chronic diseases, sponsors and the authorities must work together to develop an approval process that is efficient, predictable and, most of all, transparent. The current regulatory environment must and can be improved and optimized in order to result in tangible benefits for patients, society and the country's scientific development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/1806-9282.62.05.447DOI Listing
April 2017

Concepts and clinical use of ultra-long basal insulin.

Diabetol Metab Syndr 2016 6;8. Epub 2016 Jan 6.

Sanofi´s Medical Division, América Business Park-5200, Major Sylvio de Magalhães Padilha Av., Jd. Morumbi, São Paulo, SP 05693-000 Brazil.

Diabetes mellitus (DM) is a public health issue, affecting around 382 million people worldwide. In order to achieve glycemic goals, insulin therapy is the frontline therapy for type 1 DM patients; for patients with type 2 DM, use of insulin therapy is an option as initial or add-on therapy for those not achieving glycemic control. Despite insulin therapy developments seen in the last decades, several barriers remain for insulin initiation and optimal maintenance in clinical practice. Fear of hypoglycemia, weight gain, pain associated with blood testing and injection-related pain are the most cited reasons for not starting insulin therapy. However, new generation of basal insulin formulations, with longer length of action, have shown the capability of providing adequate glycemic control with lower risk of hypoglycemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13098-015-0117-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702396PMC
January 2016

Degludec: the new ultra-long insulin analogue.

Diabetol Metab Syndr 2015 26;7:57. Epub 2015 Jun 26.

Hospital Israelita Albert Einstein - São Paulo Brazil, and CPClin Clinical Research Center, Rua Goias 91, São Paulo, CEP01244-030 Brazil.

The development of extended-action insulin analogues was motivated by the unfavorable pharmacokinetic (PK) profile of the conventional long-acting insulin formulations, generally associated with marked inter and intra patient variability and site- and dose-dependent effect variation. The new ultra-long insulin analogue degludec (IDeg) has the same amino acid sequence as human insulin except for the removal of threonine in the position 30 of the B chain (Des-B30, "De") and the attachment, via a glutamic acid linker ("glu"), of a 16-carbon fatty diacid (hexadecanoic diacid, "dec") to lysine in the position 29 of the B chain. These modifications allow that, after changing from the pharmaceutical formulation to the subcutaneous environment, IDeg precipitates in the subcutaneous tissue, forming a depot that undergoes a highly predictable gradual dissociation. Thus, once-daily dosing of IDeg results in a low peak: trough ratio, with consequent low intra-individual variability and plasmatic concentrations less critically dependent upon the time of injections. The clinical development program of IDeg (BEGIN) was comprised of 9 therapeutic confirmatory trials of longer duration (26-52 weeks) and showed that the efficacy of IDeg is comparable to insulin glargine in type 1 (T1D) and type 2 (T2D) diabetes patients across different age, body mass index and ethnic groups. This new ultra-long insulin analogue presents as advantages flexibility in dose timing and lower risk of hypoglycemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13098-015-0037-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486707PMC
July 2015

Type 2 diabetes in Brazil: epidemiology and management.

Diabetes Metab Syndr Obes 2015 5;8:17-28. Epub 2015 Jan 5.

CPClin Clinical Research Center, São Paulo, Brazil ; Albert Einstein Hospital, São Paulo, Brazil.

Type 2 diabetes mellitus (T2DM) is one of the most important epidemic diseases in the world this century, and accounts for 90% of cases of diabetes globally. Brazil is one of the most important examples of the alarming picture of T2DM in emergent societies, being the country with the fourth largest number of people with diabetes. The aim of this paper is to review the literature on diabetes in Brazil, specifically looking at the epidemiology and management of T2DM. A literature search was conducted using PubMed and LILACS to identify articles containing information on diabetes in Brazil. Official documents from the Brazilian government, World Health Organization, and International Diabetes Federation were also reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/DMSO.S72542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298341PMC
January 2015

Influence of gastric emptying on the control of postprandial glycemia: physiology and therapeutic implications.

Einstein (Sao Paulo) 2014 Apr;12(2):251-3

Centro de Pesquisas Clínicas, São Paulo, SP, Brazil.

The maintenance of glucose homeostasis is complex and involves, besides the secretion and action of insulin and glucagon, a hormonal and neural mechanism, regulating the rate of gastric emptying. This mechanism depends on extrinsic and intrinsic factors. Glucagon-like peptide-1 secretion regulates the speed of gastric emptying, contributing to the control of postprandial glycemia. The pharmacodynamic characteristics of various agents of this class can explain the effects more relevant in fasting or postprandial glucose, and can thus guide the individualized treatment, according to the clinical and pathophysiological features of each patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/s1679-45082014rb2862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891173PMC
April 2014

Can we prevent beta cell apoptosis in type 2 diabetes?

Diabetes Metab Res Rev 2012 Dec 5. Epub 2012 Dec 5.

Freddy Goldberg Eliaschewitz, Hospital Albert Einstein, São Paulo, Brazil; CPClin Clinical Research Center, São Paulo, Brazil, CEP-01244-030.

Since the publication of the United Kingdom Prospective Diabetes Study (UKPDS), the progressive nature of type 2 (DM2) diabetes has been identified as the main cause of failure to maintain a long term glycemic control.[1] The need to adjust treatment as the disease progressed was recognized and algorithms for treatments in line with this concept were developed.[2] The UKPDS showed that the progressive character of the disease results from a steady reduction, of approximately 5% per year, in the ability of beta cells to secrete insulin, a process estimated to begin 10 to 12 years before diagnosis, which triggers the onset of diabetes when approximately 50% of beta cell function has been lost. [1] Copyright © 2012 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dmrr.2381DOI Listing
December 2012

Glucose control in acute myocardial infarction: a pilot randomized study controlled by continuous glucose monitoring system comparing the use of insulin glargine with standard of care.

Diabetes Technol Ther 2012 Feb 19;14(2):117-24. Epub 2011 Dec 19.

SEPACO Hospital, São Paulo, Brazil.

Background: This pilot study aimed to verify if glycemic control can be achieved in type 2 diabetes patients after acute myocardial infarction (AMI), using insulin glargine (iGlar) associated with regular insulin (iReg), compared with the standard intensive care unit protocol, which uses continuous insulin intravenous delivery followed by NPH insulin and iReg (St. Care).

Patients And Methods: Patients (n=20) within 24 h of AMI were randomized to iGlar or St. Care. Therapy was guided exclusively by capillary blood glucose (CBG), but glucometric parameters were also analyzed by blinded continuous glucose monitoring system (CGMS).

Results: Mean glycemia was 141±39 mg/dL for St. Care and 132±42 mg/dL for iGlar by CBG or 138±35 mg/dL for St. Care and 129±34 mg/dL for iGlar by CGMS. Percentage of time in range (80-180 mg/dL) by CGMS was 73±18% for iGlar and 77±11% for St. Care. No severe hypoglycemia (≤40 mg/dL) was detected by CBG, but CGMS indicated 11 (St. Care) and seven (iGlar) excursions in four subjects from each group, mostly in sulfonylurea users (six of eight patients).

Conclusions: This pilot study suggests that equivalent glycemic control without increase in severe hyperglycemia may be achieved using iGlar with background iReg. Data outputs were controlled by both CBG and CGMS measurements in a real-life setting to ensure reliability. Based on CGMS measurements, there were significant numbers of glycemic excursions outside of the target range. However, this was not detected by CBG. In addition, the data indicate that previous use of sulfonylurea may be a potential major risk factor for severe hypoglycemia irrespective of the type of insulin treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/dia.2011.0157DOI Listing
February 2012

[Does brittle diabetes exist as a clinical entity?].

Arq Bras Endocrinol Metabol 2009 Jun;53(4):466-9

Núcleo de Terapia Celular e Molecular, Universidade de São Paulo, São Paulo, SP, Brasil.

The best comprehension about the instability of the glycemia levels in type 1 diabetes mellitus (T1DM) patients and the availability of new alternatives to successfully control it, like insulin pump therapy and the insulin analogues, underlined the questions about the brittle diabetes existence as a clinical entity as well as the necessity of define it. The aim of this article was to describe the concept of brittle diabetes in the light of the latest advances in the treatment of type 1 diabetes and propose objective criteria to evaluate the level of glucose liability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/s0004-27302009000400013DOI Listing
June 2009

[Islet transplantation as a clinical tool: present state and future perspectives].

Arq Bras Endocrinol Metabol 2009 Feb;53(1):15-23

Núcleo de Terapia Celular e Molecular, Universidade de São Paulo.

Islet transplant is an innovative treatment for type 1 diabetic patients, which still lies between experimental and approved transplant therapy. Islet cells are seeded in a non-physiological territory where an uncertain fraction will be able to adapt and survive. Thus, the challenge lies in improving the whole procedure, employing the tools of cell biology, immunology and laboratory techniques, in order to reach the results obtained with whole organ transplant. This review describes the procedure, its progress to the present methodology and clinical results obtained. Future perspectives of islet transplantation in the light of recent biotechnological advances are also focused.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/s0004-27302009000100004DOI Listing
February 2009

Leptin and the immune response: an active player or an innocent bystander?

Ann N Y Acad Sci 2009 Feb;1153:184-92

Cell and Molecular Therapy Center, University of São Paulo, São Paulo, Brazil.

Leptin is involved in the control of energy storage by the body. Low serum leptin levels, as seen in starvation, are associated with impaired inflammatory T cell responses that can be reversed by exogenous leptin. Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Several defects in T cell function have also been described, and allergy, autoimmune disease, and lymphomas or other malignancies can be present. Previous studies in Brazilian CVID patients have shown that, in contrast with mononuclear cells from healthy controls, CVID cells cultured with phytohemagglutinin and added leptin increased the proliferative response and decreased activation-induced apoptosis. Interleukin (IL)-2 and especially IL-4 production also increased significantly, although the effects of exposure to leptin were not observed uniformly in CVID patients. The majority, however, responded in some degree, and some exhibited completely restored values of the four parameters.These remarkable results indicate leptin could be used to improve immune function in these patients. On the other hand, we found no specific correlation between serum leptin levels and the number of infectious events over a 24-month period, presence of autoimmunity, allergies, or cancer in these patients. The results suggest that the absolute value of serum leptin does not determine the clinical behavior of patients or responses to leptin in vitro. Of note is the divergence between serum leptin, response to leptin in vitro, and the presence of autoimmunity, indicating the need to identify the cellular and molecular players involved in the regulation of the immune response by leptin in CVID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1749-6632.2008.03971.xDOI Listing
February 2009

[Pancreas and islet transplantation in patients with diabetes mellitus].

Arq Bras Endocrinol Metabol 2008 Mar;52(2):355-66

Departamento de Cirurgia, Departamento de Medicina, Universidade Federal de São Paulo, SP, Brasil.

Pancreas and kidney transplants have specific indications, benefits and risks. The procedure has become more common and more often as long-term success has improved and risks have decreased. Compared with a patient being on dialysis, simultaneous pancreas-kidney transplant offers a distinct advantage when it comes to mortality, quality of life and diabetic complications. Since there can be a living-donor kidney transplant,, a possibly similar patient and graft survival by 10 years follow-up, this procedure should be considered. Pancreas after kidney transplants, when successful, can improve microvascular complications compared with kidney transplant alone, but immediate mortality may be higher. Solitary pancreas transplantation can improve the quality of life in selected patients, but it may also increase the immediate risk of mortality due to the complexity of the surgery and the risks of immunosupression. The results of Islet transplantation differ from the higher metabolic performance achieved by whole pancreas allotransplantation and its applicability is limited to selected adult diabetic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/s0004-27302008000200024DOI Listing
March 2008

Exogenous leptin restores in vitro T cell proliferation and cytokine synthesis in patients with common variable immunodeficiency syndrome.

Clin Immunol 2005 Feb;114(2):147-53

Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, SP, Brazil.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia. Leptin has been implicated as an antiapoptotic compound as well as a stimulant of the immune response. Leptin administration is capable of reversing the immune deficiency that occurs upon starvation. We investigated a possible role for leptin in CVID; a condition associated with lowered plasma leptin levels. Thirty-eight patients were studied. Addition of leptin to the tissue culture media of PBMC from CVID patients increased the proliferative response of lymphocytes to mitogens and decreased activation-induced apoptosis of these cells. IL-2 and specially IL-4 production also increased significantly upon addition of leptin to the PBMC cultures. Our results suggest that leptin may be involved in some of the cellular defects observed in CVID and indicate a novel therapeutic strategy to improve immune function in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2004.09.002DOI Listing
February 2005

Co-localization of nestin and insulin and expression of islet cell markers in long-term human pancreatic nestin-positive cell cultures.

J Endocrinol 2004 Dec;183(3):455-67

Instituto de Química, Universidade de São Paulo, Departamento de Bioquímica CP26077, São Paulo 05513-970 SP, Brazil.

Strategies to differentiate progenitor cells into beta cells in vitro have been considered as an alternative to increase beta cell availability prior to transplantation. It has recently been suggested that nestin-positive cells could be multipotential stem cells capable of expressing endocrine markers upon specific stimulation; however, this issue still remains controversial. Here, we characterized short- and long-term islet cell cultures derived from three different human islet preparations, with respect to expression of nestin and islet cell markers, using confocal microscopy and semi-quantitative RT-PCR. The number of nestin-positive cells was found to be strikingly high in long-term cultures. In addition, a large proportion (49.7%) of these nestin-positive cells, present in long-term culture, are shown to be proliferative, as judged by BrdU incorporation. The proportion of insulin-positive cells was found to be high in short-term (up to 28 days) cultures and declined thereafter, when cells were maintained in the presence of 10% serum, concomitantly with the decrease in insulin and PDX-1 expression. Interestingly, insulin and nestin co-expression was observed as a rare event in a small proportion of cells present in freshly isolated human islets as well as in purified islet cells cultured in vitro for long periods of time. In addition, upon long-term subculturing of nestin-positive cells in 10% serum, we observed reappearance of insulin expression at the mRNA level; when these cultures were shifted to 1% serum for a month, expression of insulin, glucagon and somatostatin was also detected, indicating that manipulating the culture conditions can be used to modulate the nestin-positive cell's fate. Attempts to induce cell differentiation by plating nestin-positive cells onto Matrigel revealed that these cells tend to aggregate to form islet-like clusters, but this is not sufficient to increase insulin expression upon short-term culture. Our data corroborate previous findings indicating that, at least in vitro, nestin-positive cells may undergo the early stages of differentiation to an islet cell phenotype and that long-term cultures of nestin-positive human islet cells may be considered as a potential source of precursor cells to generate fully differentiated/ functional beta cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1677/joe.1.05703DOI Listing
December 2004

Mitogenic effects of Brazilian arthropod venom on isolated islet beta cells: in vitro morphologic ultrastructural and functional studies.

J Investig Med 2003 Mar;51(2):79-85

Department of Internal Medicine, University of Perugia, Italy.

Background: One of the major pitfalls associated with use of isolated adult islets of Langerhans' cells is their minimal mitotic capacity. Consequently, maintenance of a steady viable islet cell mass is very difficult. To explore how to enhance beta-cell mitogenesis, we have examined the effects of venom fractions extracted from a Brazilian scorpion on morphologic and functional beta-cell patterns. The venom was previously known to induce nesidioblastosis-like effects with chronic hypoglycemia and pancreatitis in animal models.

Methods: Venom fractions purified from Tityus bahiensis were incubated with batches of isolated rat islets, while a morphologic examination, glucose-stimulated insulin release, insulin content, and insulin messenger ribonucleic acid (mRNA) were carried out early during incubation. On fixation and double fluorescence immunolabeling (rhodamine for anti-insulin monoclonal antibodies; fluorescein for anti-5-bromodeoxyuridine), the preparations were imaged by confocal laser microscopy (CLM) for morphometric quantification of the mitoses. Insulin recovery and mRNA were also assessed at 21 days of culture.

Results: Under CLM examination, the beta-cell mitotic rate significantly rose from 1 to 12.8% for the venom-exposed islets. At day 7, insulin release and content were significantly lower for the venom-exposed than the control islets. However, at day 21 of culture, insulin release in response to static incubation with glucose and insulin mRNA from the venom-exposed islets was higher than controls (p < .05).

Conclusions: Incubation with the scorpion venom induced a rapid and significant increase in the beta-cell proliferation not associated with a short-term increase in insulin secretion. The latter fully resumed and overcame controls later in culture, possibly after completion of the beta-cell expansion process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jim-51-02-09DOI Listing
March 2003
-->