The effect of metabolic surgery on type 1 diabetes: meta-analysis

ABSTRACT Objective Metabolic and bariatric surgery has a definite role in the management of obese patients with type 2 diabetes mellitus (T2DM). There is also evidence of such surgery improving the health of type 1 diabetic (T1DM) patients. The aim of this paper is to explore the effect of metabolic and bariatric surgery on T1DM. Materials and methods A comprehensive search of PubMed and Google Scholar was performed to identify relevant papers reporting metabolic and bariatric surgery effects on T1DM. A statistical analysis is applied after data synthesis. A forest plot and Pearson correlation are then calculated. Results Of the 567 papers that were identified, 558 articles did not fulfill the inclusion criteria and were therefore excluded. Nine studies involving 78 patients were selected for this metaanalysis. There was improvement in HBA1c (p value = 0.40), insulin dose (p value = 0.0001) and BMI (p value = 0.00001) after surgery. However, improvement in the HBA1c did not reach statistical significance. There was a weak correlation between postoperative insulin dose and BMI change after surgery (r = -0.177). There was a negligible correlation between HBA1c and BMI change after operations (r = -0.01). Conclusion Current metabolic/bariatric surgery is improving T1DM in obese and morbidly obese patients. This is not exclusively related to excess weight loss (EWL) as previously thought. Therefore, there is a role for other factors, which are potential players to reproduce the same effect in nonobese T1DM patients.

Pancreas transplantation: review / Transplante de pâncreas: revisão

ABSTRACT Vascularized pancreas transplantation is the only treatment that establishes normal glucose levels and normalizes glycosylated hemoglobin levels in type 1 diabetic patients. The first vascularized pancreas transplant was performed by William Kelly and Richard Lillehei, to treat a type 1 diabetes patient, in December 1966. In Brazil, Edison Teixeira performed the first isolated segmental pancreas transplant in 1968. Until the 1980s, pancreas transplants were restricted to a few centers of the United States and Europe. The introduction of tacrolimus and mycophenolate mofetil in 1994, led to a significant outcome improvement and consequently, an increase in pancreas transplants in several countries. According to the International Pancreas Transplant Registry, until December 31st, 2010, more than 35 thousand pancreas transplants had been performed. The one-year survival of patients and pancreatic grafts exceeds 95 and 83%, respectively. The better survival of pancreatic (86%) and renal (93%) grafts in the first year after transplantation is in the simultaneous pancreas-kidney transplant group of patients. Immunological loss in the first year after transplant for simultaneous pancreas-kidney, pancreas after kidney, and pancreas alone are 1.8, 3.7, and 6%, respectively. Pancreas transplant has 10 to 20% surgical complications requiring laparotomy. Besides enhancing quality of life, pancreatic transplant increases survival of uremic diabetic patient as compared to uremic diabetic patients on dialysis or with kidney transplantation alone.

RESUMO O transplante vascularizado de pâncreas é o único tratamento que estabelece normoglicemia e normaliza os níveis séricos de hemoglobina glicosilada em pacientes diabéticos tipo 1. O primeiro transplante de pâncreas vascularizado foi realizado para tratar um paciente diabético tipo 1 em dezembro de 1966, por William Kelly e Richard Lillehei. No Brasil, Edison Teixeira realizou o primeiro transplante de pâncreas segmentar isolado em 1968. Até a década de 1980, os transplantes de pâncreas ficaram restritos a poucos centros dos Estados Unidos e da Europa. A introdução dos imunossupressores tacrolimo e micofenolato mofetila, a partir de 1994, propiciou a melhora significativa dos resultados e a consequente realização de transplantes em escala crescente em vários países. Segundo o Registro Internacional de Transplante de Pâncreas, foram realizados, até 31 de dezembro de 2010, mais de 35 mil transplantes de pâncreas. Sobrevida no primeiro ano dos pacientes e dos enxertos pancreáticos excede, respectivamente, 95 e 83%. A melhor sobrevida dos enxertos pancreático (86%) e renal (93%), no primeiro ano pós-transplante, está na categoria de transplante simultâneo de pâncreas e rim. As perdas imunológicas no primeiro ano pós-transplante para transplante simultâneo de pâncreas e rim, transplante de pâncreas após rim e transplante de pâncreas isolado foram, respectivamente, 1,8, 3,7, e 6%. O transplante de pâncreas apresenta de 10 a 20% de complicações cirúrgicas, necessitando laparotomia. O transplante de pâncreas, além de melhorar a qualidade de vida, proporciona o aumento da sobrevida em diabéticos urêmicos, comparados aos diabéticos em diálise ou transplantados renais.

Reversal of Hypoglycemia Unawareness with a Single-donor, Marginal Dose Allogeneic Islet Transplantation in Korea: A Case Report

Pancreatic islet transplantation is a physiologically advantageous and minimally invasive procedure for the treatment of type 1 diabetes mellitus. Here, we describe the first reported case of successful allogeneic islet transplantation alone, using single-donor, marginal-dose islets in a Korean patient. A 59-yr-old patient with type 1 diabetes mellitus, who suffered from recurrent severe hypoglycemia, received 4,163 islet equivalents/kg from a single brain-death donor. Isolated islets were infused intraportally without any complications. The immunosuppressive regimen was based on the Edmonton protocol, but the maintenance dosage was reduced because of mucositis and leukopenia. Although insulin independence was not achieved, the patient showed stabilized blood glucose concentration, reduced insulin dosage and reversal of hypoglycemic unawareness, even with marginal dose of islets and reduced immunosuppressant. Islet transplantation may successfully improve endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus.

Islet transplantation in rodents. Do encapsulated islets really work? / Transplante de ilhotas de Langerhans em modelos experimentais em roedores. Ilhotas encapsuladas realmente funcionam?

CONTEXT: Diabetes mellitus type I affects around 240 million people in the world and only in the USA 7.8 percent of the population. It has been estimated that the costs of its complications account for 5 percent to 10 percent of the total healthcare spending around the world. According to World Health Organization, 300 million people are expected to develop diabetes mellitus by the year 2025. The pancreatic islet transplantation is expected to be less invasive than a pancreas transplant, which is currently the most commonly used approach. OBJECTIVES: To compare the encapsulated and free islet transplantation in rodents looking at sites of islet implantation, number of injected islets, viability and immunosuppression. METHODS: A literature search was conducted using MEDLINE/PUBMED and SCIELO with terms about islet transplantation in the rodent from 2000 to 2010. We found 2,636 articles but only 56 articles from 2000 to 2010 were selected. RESULTS: In these 56 articles used, 34 percent were encapsulated and 66 percent were nonencapsulated islets. Analyzing both types of islets transplantation, the majority of the encapsulated islets were implanted into the peritoneal cavity and the nonencapsulated islets into the liver, through the portal vein. In addition, the great advantage of the peritoneal cavity as the site of islet transplantation is its blood supply. Both vascular endothelial cells and vascular endothelial growth factor were used to stimulate angiogenesis of the islet grafts, increasing the vascularization rapidly after implantation. It also has been proven that there is influence of the capsules, since the larger the capsule more chances there are of central necrosis. In some articles, the use of immunosuppression demonstrated to increase the life expectancy of the graft. CONCLUSION: While significant progress has been made in the islets transplantation field, many obstacles remain to be overcome. Microencapsulation provides a means to transplant islets without immunosuppressive agents and may enable the performance of xenotransplantation. The use of alternative donor sources, fewer islets per capsule and the appropriate deployment location, such as the peritoneal cavity, may give a future perspective to the application of immunoprotective capsules and viability in clinical practice. A variety of strategies, such as genetic engineering, co-encapsulation, improvement in oxygen supply or the establishment of hypoxia resistance will also improve the islet transplantation performance. It remains to be determined which combination of strategies with encapsulation can fulfill the promise of establishing a simple and safe transplantation as a cure for diabetes.

CONTEXTO: Diabetes mellitus tipo I afeta cerca de 240 milhões de pessoas no mundo e 7,8 por cento só nos EUA. Foi estimado que o custo de suas complicações fosse de 5 por cento-10 por cento dos custos mundiais em saúde. De acordo com a OMS (Organização Mundial de Saúde), espera-se que cerca de 300 milhões de pessoas desenvolvam o diabetes mellitus até o ano de 2025. É esperado que o transplante de ilhotas pancreáticas seja menos invasivo que o transplante pancreático, opção atual de maior uso. OBJETIVOS: Comparar as ilhotas encapsuladas e as ilhotas livres em roedores nos seguintes aspectos: local de implantação das ilhotas, número de ilhotas, viabilidade e imunossupressão. MÉTODOS: A pesquisa bibliográfica foi conduzida com o uso de citações do MEDLINE/PUBMED e SCIELO que apresentassem termos sobre transplante de ilhotas em roedores no período de 2000 a 2010. Foram achados 2.636 artigos, mas somente 56 desse período foram selecionados. RESULTADOS: Nos 56 artigos utilizados, 34 por cento eram encapsulados e 66 por cento eram não-encapsulados. Analisando ambos os tipos de transplante de ilhotas, a maioria delas encapsuladas, foi implantada na cavidade peritonial e as não-encapsuladas, através da veia porta, no fígado. A grande vantagem da cavidade peritonial como local de transplante era a oferta sanguínea. As células endoteliais e o fator de crescimento endotelial foram usados para estimular a angiogênese nas ilhotas, aumentando a vascularização rapidamente após a implantação. Foi também provada a influência das cápsulas, dado que quanto maior a cápsula maior era a chance de necrose central. Em alguns artigos, o uso de imunossupressão demonstrou aumento da expectativa de vida do enxerto. CONCLUSÃO: Enquanto algum progresso significativo não tenha sido obtido no campo de transplante de ilhotas, restam ainda muitos obstáculos a serem vencidos. A microencapsulação viabiliza o transplante de ilhotas sem o uso de imunossupressores, o que pode permitir o xenotransplante. O uso de fontes doadoras alternativas, menor quantidade de ilhotas por cápsula e local de implantação adequado, como a cavidade peritonial, podem dar melhor perspectiva na aplicação de cápsulas imunoprotegidas, aumentando viabilidade na prática clínica. Uma série de estratégias, como engenharia genética, coencapsulamento, melhora da oferta de oxigênio ou o estabelecimento de resistência à hipóxia também podem aprimorar os resultados do transplante de ilhotas. Deve-se determinar ainda qual a combinação de estratégias com relação ao uso de ilhotas encapsuladas que possam cumprir com as promessas de um transplante simples e seguro para a cura do diabetes.

Terapia celular para el tratamiento de la diabetes: Más allá de las células madre / Cell therapy for diabetes mellitus: Beyond stem cells

La diabetes tipo 1 es una enfermedad de etiología autoinmune que se caracteriza por la destrucción de las células ß pancreáticas, produciendo un déficit absoluto de insulina. El tratamiento clínico estándar consiste en la aplicación de insulina. Sin embargo, en un número importante de pacientes y debido a la dificultad en lograr un control metabólico preciso, generalmente se asocia con complicaciones graves a nivel vascular con repercusión renal y ocular entre otras. Por otra parte, un estricto control metabólio, a menudo se asocia con hipoglucemias con riesgo de muerte. Esto motivó la investigación y el desarrollo de alternativas de tratamiento. Una de ellas es el trasplante de células productoras de insulina, las células ß, obtenidas por medio del aislamiento y trasplante de islotes de un páncreas cadavérico. Los mejores resultados con esta modalidad de trasplante se obtuvieron con la inyección sucesiva de islotes pancreáticos de diferentes donantes y terapia inmunosupresora exenta de corticoides. Sin embargo, la escasez de órganos por un lado, y el hecho de que cada implante de islotes de otro páncreas aumenta las posibilidades de rechazo inmunológico, hace que este tratamiento se vea limitado a centros de alta experiencia y pacientes muy seleccionados. Asimismo, las drogas inmunosupresoras que deben administrarse de por vida, pueden producir efectos no deseados en el organismo. La medicina regenerativa abre la posibilidad de utilizar células madre con capacidad de diferenciarse en células productoras de insulina, utilizando de manera conjunta factores tróficos que serían capaces de estimular a las propias células madre de cada parénquima.

Type 1 diabetes is an autoimmune disease of unknown etiology characterized by destruction of pancreatic beta cells, leading to absolute insulin deficiency. Standard therapy includes the use of exogenous insulin. However, due to the difficulty to achieve a tight metabolic control, a number of patients will present severe complications, including vascular, renal and ophthalmologic disease. On the other hand, a more strict metabolic control is often associated with episodes of life threatening hypoglycemia. This motivated the research and development of new alternative treatments, such as the transplantation of insulin producing beta cells, obtained from cadaveric pancreatic islets. Best results with this therapy were observed with consecutive islet injection from more than one donor and immunosuppressive therapy without steroids. However, the scarcity of organs as well as an increased immune reaction derived from the use of pancreas from different donors have limited this therapy to markedly selected patients and highly experienced centers. Furthermore, lifelong administration of immunosuppressive drugs may produce undesired secondary effects. Regenerative medicine opens the possibility of using stem cells capable of differentiating into insulin-producing cells after stimulation by diverse trophic factors that may act over stem cells located within a specific tissue.

Trasplante simultáneo de páncreas y riñon en diabetes mellitus tipo 1: Experiencia de un centro en Chile / Simultaneous kidney and pancreas transplantation (SKPT) in patients with type 1 diabetes and chronic renal failure: Experience in 12 patients in Chile

Background: Simultaneous kidney and páncreas transplantation (SKPT) is the best alternative for end stage renal disease among patients with insulin dependent diabetes mellitus. Aim: To report our experience with SKPT. Material andMethods: Retrospective analysis ofl2 recipients of SKPT transplanted in one center starting in 1994, with a meanfollow-upperiod of6.8years (2-15). Results: Eleven ofl2 recipients were in chronic hemodialysis before SKPT. Mean A, B, DR and HLA mismatch was 4.3. Mean preformed anti HLA antibodies was 3.3 percent. Mean cold ischemia times for páncreas and kidney were 6 and 10 hours, respectively. In the first eight cases, the páncreas was drained to the bladder, and in the last four, an enteric drainage was performed. Eleven recipients were induced with antibodies, and maintenance immunosuppression consisted ofCyclosporine or Tacrolimusplus an antiproliferative agent. Ten year patient survival was 70 percent. Páncreas and kidney survival, defined by insulin and dialysis independence, were 72 and 73 percent respectively. Fifty percent of recipients experienced acute graft rejection (cellular or humoral), with good response to treatment except in one case. Conclusions: This experience shows that SKPT is associated with an excellent patient survival associated to insulin and dialysis independence in 70 percent of patients at 10 years.

Trasplante de páncreas tipos, selección de receptores y donantes / Pancreas trasplantion: the different modalities, donor and recipient selection

En este artículo se describe el estado actual del trasplante de páncreas, los tipos de trasplante más frecuentes -trasplante de páncreas aislado, trasplante de páncreas riñón- sus indicaciones, resultados y las características de receptores y donantes.

This article describes pancreas transplantation, the more frequent modalities such as pancreas transplantation alone and simultaneous pancreas kidney transplantation, their indications and outcomes, as well as the characteristics of suitable recipients and donors.

Transplante de ilhotas pancreáticas humanas: revisão da literatura e implantação de um laboratório de isolamento de ilhotas pancreáticas / Human pancreatic islet transplantation: literature review and establishment of a pancreatic islet isolation laboratory

O diabetes melito tipo 1 (DM1) está associado ao desenvolvimento de complicações crônicas de elevada morbi-mortalidade em indivíduos jovens em idade produtiva. A terapia intensiva com insulina comprovadamente diminui o aparecimento das complicações crônicas da doença. Entretanto, essa terapia ainda está associada ao aumento da incidência de hipoglicemia. Em pacientes com “DM1 lábil”, os quais apresentam hipoglicemias graves sem sintomas de alerta, o transplante de ilhotas pancreáticas humanas é uma das melhores alternativas para restaurar a secreção de insulina e a percepção da hipoglicemia. Cerca de 80% dos pacientes que receberam transplante de ilhotas de mais de um doador, submetidos ao tratamento imunossupressor do protocolo de Edmonton, adquiriram independência de insulina após 1 ano do transplante. Porém, apenas 10% destes pacientes permaneceram livres de insulina após 5 anos. Entretanto, mesmo aqueles pacientes que necessitaram utilizar novamente insulina tiveram a normalização da homeostase glicêmica e da percepção da hipoglicemia, com prevenção da hipoglicemia grave. Sendo assim, o transplante de ilhotas é capaz de diminuir os níveis de glicose plasmática e HbA1c, reduzir a ocorrência de hipoglicemias graves e melhorar a qualidade de vida dos pacientes. O objetivo deste artigo foi fazer uma breve revisão da literatura sobre o isolamento e transplante de ilhotas pancreáticas humanas e relatar a implantação de um laboratório de isolamento de ilhotas humanas no Serviço de Endocrinologia do Hospital de Clínicas de Porto Alegre.

Type 1 diabetes mellitus (DM1) is associated with chronic complications of high morbidity and mortality in young adults in a productive age. Insulin therapy has proved to reduce the chronic complications of diabetes. However, this therapy is still associated to an increased incidence of hypoglycemia. In patients with “brittle DM1”, who have severe hypoglycemia without any symptoms (hypoglycemia unawareness), the pancreatic islet transplantation is one of the best alternatives for restoring insulin secretion and hypoglycemia perception. About 80% of the patients who received islet transplantation from more than one donor, on immunosuppressive treatment with the Edmonton’s protocol, maintained insulin independence 1 year after transplantation. Nevertheless, only 10% of these patients remained free of insulin after 5 years post-transplantation. However, even those patients who returned to insulin treatment had a normalization of the glucose homeostasis and hypoglycemia perception. Therefore, islet transplantation is able to diminish plasmatic glucose and HbA1c levels, to reduce the occurrence of severe hypoglycemia, and to improve the quality of life of the patients. The purpose of this paper is to briefly review islet isolation and transplantation process, and report the establishing of a human islet isolation laboratory in the Endocrine Service at Hospital de Clínicas de Porto Alegre.

Transplante de ilhotas na prática clínica: estado atual e perspectivas / Islet transplantation as a clinical tool: present state and future perspectives

O transplante de ilhotas é um procedimento em desenvolvimento, como alternativa para o tratamento do diabetes tipo 1 que está na fronteira entre o experimental e o clínico. É uma terapia celular na qual as células são implantadas em território diferente do fisiológico em que apenas determinado número incerto conseguirá se adaptar. Aperfeiçoar este processo para obter os mesmos resultados que no transplante de pâncreas, representa um desafio para o qual convergem contribuições da biologia celular, da imunologia e das técnicas de laboratório que se entrelaçam de maneira extremamente complexa. Este trabalho revisa a literatura expondo a evolução do procedimento, a sua metodologia atual e os resultados clínicos obtidos. As perspectivas futuras do transplante diante dos recentes avanços também são discutidas.

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.

Protocolo clínico para seleção de candidatos ao transplante de ilhotas / Clinical protocol for selection of the candidates for islet transplantation

OBJETIVO: Descrever o perfil clínico dos candidatos ao programa de transplante de ilhotas da Pontifícia Universidade Católica do Paraná (PUC-PR), em Curitiba. MÉTODOS: O processo de avaliação clínica foi estruturado em etapas: triagem, pré-avaliação, avaliação e lista de espera. Os critérios de inclusão utilizados foram: ocorrência de hipoglicemia assintomática, complicações crônicas progressivas da doença, idade entre 18 e 65 anos e pelo menos cinco anos de doença. RESULTADOS: De setembro de 2003 a setembro de 2006 foram avaliados 92 candidatos, dos quais 25 preencheram os critérios de triagem, sendo selecionados para pré-avaliação. O principal motivo de não qualificação foi o uso de insulina em dose > 0,7 UI/kg/d. Dos 25 candidatos incluídos na pré-avaliação, sete não concordaram em assinar o termo de consentimento. Quatro candidatos completaram todas as etapas de seleção, porém apenas dois permanecem em lista de espera. CONCLUSÕES: Os candidatos ao transplante de ilhotas devem ser rigorosamente selecionados. Dois pacientes preencheram todos os critérios e encontram-se em lista de espera.

BACKGROUND: Our intention is to describe the clinical profile of the candidates for islet transplantation in Curitiba, Brazil. METHODS: The clinical evaluation was organized in stages: Screening, Initial Evaluation, Evaluation and Waiting List. Candidates’ inclusion criteria were hypoglycemia unawareness, glycemic imbalance, chronic progressive diabetic complications, 18-65 years of age and at least 5 years of type 1 diabetes evolution. RESULTS: From September 2003 through September 2006, 92 candidates were clinically evaluated, and 25 fulfilled the Screening criteria, being selected at this stage. The main reason for exclusion was insulin requirement of more than 0.7 IU/kg/day. At the Initial Evaluation, seven of the 25 patients were excluded as have not agreed to sign the informed consent. Until now, 4 candidates completed the Evaluation stage and two of them are currently enlisted. CONCLUSIONS: Candidates for islet transplantation must be rigorously evaluated. Two patients fulfilled all the selection criteria and are currently enlisted.

Transplante de pâncreas e ilhotas em portadores de diabetes melito: [revisão] / Pancreas and islet transplantation in patients with diabetes mellitus: [review]

O transplante simultâneo de pâncreas/rim tem indicações específicas, riscos e benefícios. O procedimento, cada vez mais realizado, traz vantagens se comparado ao paciente em diálise, em relação à qualidade de vida, anos de vida ganhos e evolução das complicações crônicas. Se o paciente tiver a opção de realizar o transplante de rim com doador vivo, que apresenta sobrevida semelhante do enxerto e do paciente aos dez anos, o procedimento deverá ser considerado. O transplante de pâncreas após rim, quando efetivo, pode melhorar a evolução das complicações cardiovasculares, mas em contrapartida provoca maior mortalidade nos primeiros meses após a cirurgia. O transplante isolado de pâncreas também ocasiona a maior mortalidade pós-operatória, resultado da complexidade do procedimento e da imunossupressão. O transplante de ilhotas tem sua indicação para um seleto grupo de diabéticos com instabilidade glicêmica.

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.

Potencial role of stem cell therapy in type 1 diabetes mellitus: [review]

Type 1 diabetes mellitus is the result of the autoimmune response against pancreatic beta-cell(s). At the time of clinical diagnosis near 70 percent of beta-cell mass is been destroyed as a consequence of the auto-destruction that begins months or even years before the clinical diagnosis. Although marked reduction of chronic complications was seen after development and progression of insulin therapy over the years for type 1 diabetic population, associated risks of chronic end-organ damage and hypoglycemia still remain. Besides tight glucose control, beta-cell mass preservation and/or increase are known to be other important targets in management of type 1 diabetes as long as it reduces chronic microvascular complications in the eyes, kidneys and nerves. Moreover, the larger the beta-cell mass, the lower the incidence of hypoglycemic events. In this article, we discuss some insights about beta-cell regeneration, the importance of regulation of the autoimmune process and what is being employed in human type 1 diabetes in regard to stem cell repertoire to promote regeneration and/or preservation of beta-cell mass.

O diabetes melito tipo 1 (DM1) é o resultado de uma resposta auto-imune contra as células-beta pancreáticas. Por ocasião do diagnóstico clínico do DM1, aproximadamente 70 por cento da massa de células-beta foram destruídas como conseqüência de uma autodestruição que se iniciou há anos ou meses antes dos primeiros sinais da doença. Embora a redução acentuada das complicações crônicas na população com DM1 foi observada após o desenvolvimento e evolução da insulinoterapia, os riscos associados às lesões dos órgãos-alvo e hipoglicemia persistem. Além do controle intensivo da glicemia, a preservação e/ou o aumento da massa de células-beta são reconhecidos como alvos importantes no tratamento do DM1. Isto vem associado à redução das complicações crônicas microvasculares na retina, rins e nervos e a menor incidência de eventos hipoglicêmicos. Neste artigo, discutimos alguns aspectos da regeneração das células-beta pancreáticas, a importância da regulação do processo auto-imune e o que está sendo empregado no DM1 humano com relação ao repertório das células-tronco nesse sentido.

Transplante de pâncreas na síndrome de Mauriac: evolução clínica e laboratorial após um ano de acompanhamento / Pancreas transplantation in Mauriac syndrome: clinical and biochemical parameters after one year follow up

O transplante de pâncreas tem se mostrado método eficaz no tratamento do diabetes mellitus tipo 1 (DM1) em casos selecionados, com redução da necessidade diária de insulina e normalização da glico-hemoglobina (A1c). Não há conhecimento, ainda, sobre o efeito do transplante de pâncreas em pacientes com síndrome de Mauriac (SM). Apresentamos um caso de SM refratário ao tratamento clínico instituído (insulinoterapia intensiva, atividade física programada, acompanhamento psicológico e nutricional), com persistência de níveis de glicemia de jejum e A1c continuamente elevados, dislipidemia e IGF-1 (fator de crescimento insulina símile) reduzido, sendo indicado o transplante pancreático. Após 1 ano do transplante de pâncreas total, o paciente permanecia assintomático, insulino-independente, com glicemia de jejum adequada (<110mg/dl), normalização do perfil lipídico e de IGF-1, com redução importante da A1c (4,6 por cento), melhora da auto-estima e maior qualidade de vida para o paciente. O transplante de pâncreas mostrou-se método eficaz no controle da SM, com reversão importante dos parâmetros clínico-laboratoriais nesse caso. Objetiva-se divulgar o primeiro caso de SM controlado com transplante de pâncreas descrito na literatura médica indexada, como alternativa terapêutica nesse grupo de pacientes.

The first successful simultaneous pancreas-kidney transplant in India.

Insulin-dependent diabetes mellitus is associated with renal failure, diabetic retinopathy, neuropathy and vasculopathy. We report the first successful simultaneous pancreas-kidney transplant in India in a young diabetic with renal failure. The dual transplant has cured his diabetes and renal failure and has had a beneficial effect on his neuropathy, retinopathy and quality of life. Obstacles to dual transplant in India include a lack of suitable recipients and a cadaver donor programme that is still in its infancy.

Caged Pancreatic Islet for IDDM

The goals of this research are to improve the functionality (insulin secretion rate and pattern) and to expand the life-span of immunoprotected pancreatic islets. The low functionality (less than 15% of the insulin release rate of native islets in pancreas) required a large number of islets within the implant, which causes complications in surgery and discomfort for patients. The limited life-span of the islets in a biohybrid artificial pancreas (BAP) may require frequent cell reseeding and cause further supply problems in islet transplantation. Improved islet functionality and prolonged life-span will minimize the volume of the BAP by reducing the number of islets needed for diabetic patients to achieve normoglycaemia and reduce problems associated with islet supply. It is hypothesized in this research that 1) by mimicking facilitated oxygen transport in avascular tissues, the immunoprotected islets release a higher amount of insulin, recover their intrinsic biphasic release pattern, and prolong their life-span, and 2) insulinotropic agents further promote insulin secretion from islets. Based on these hypotheses, a new BAP system will be designed which contains the water-soluble polymeric conjugates of oxygen carriers (or oxygen binding vehicles) and islet stimulants of sulfonylurea compounds and glucagon-like insulinotropic peptide-1 with entrapped islets in the BAP. The research examines their effects on islet viability, the amount of insulin secretion, the insulin release profile, and the life-span of immunoprotected pancreatic islets. Especially, the combined synergy effects of both hypotheses will be emphasized. The successful results in improving functionality and life- span of islets entrapped in an immunoprotected membrane can be applied in the delivery of microencapsulated therapeutic cells and to the miniaturization of a BAP. In addition, the approaches proposed in this research will provide a potential solution to the shortage problem of human cell or tissue sources.

Microencapsulation and tissue engineering as an alternative treatment of diabetes

In the 70's, pancreatic islet transplantation arose as an attractive alternative to restore normoglycemia; however, the scarcity of donors and difficulties with allotransplants, even under immunosuppressive treatment, greatly hampered the use of this alternative. Several materials and devices have been developed to circumvent the problem of islet rejection by the recipient, but, so far, none has proved to be totally effective. A major barrier to transpose is the highly organized islet architecture and its physical and chemical setting in the pancreatic parenchyma. In order to tackle this problem, we assembled a multidisciplinary team that has been working towards setting up the Human Pancreatic Islets Unit at the Chemistry Institute of the University of São Paulo, to collect and process pancreas from human donors, upon consent, in order to produce purified, viable and functional islets to be used in transplants. Collaboration with the private enterprise has allowed access to the latest developed biomaterials for islet encapsulation and immunoisolation. Reasoning that the natural islet microenvironment should be mimicked for optimum viability and function, we set out to isolate extracellular matrix components from human pancreas, not only for analytical purposes, but also to be used as supplementary components of encapsulating materials. A protocol was designed to routinely culture different pancreatic tissues (islets, parenchyma and ducts) in the presence of several pancreatic extracellular matrix components and peptide growth factors to enrich the beta cell population in vitro before transplantation into patients. In addition to representing a therapeutic promise, this initiative is an example of productive partnership between the medical and scientific sectors of the university and private enterprises.

Experiencia inicial con trasplante de páncreas e islotes asociado a trasplante renal en pacientes diabéticos / Clinical experience with pancreas and islet transplantation in diabetes patients treatment

Antecedentes: El trasplante de tejido pancreático es en la actualidad el sistema más fisiológico de aporte de insulina en pacientes diabéticos. Objetivo: Presentar los resultados con el trasplante de páncreas vascularizado e islotes en pacientes diabéticos. Diseño: Retrospectivo y discutido. Material y métodos: En un período de tres años se efectuaron 5 trasplantes de páncreas vascularizado y 3 trasplantes de islotes en pacientes diabéticos tipo I. Se evaluaron variables bioquímicas y clínicas de seguimiento postrasplante. Resultados: No se registró mortalidad postoperatoria. Dos pacientes fallecieron al 4º y 14º mes. El resto están vivos y con función de sus órganos a 22, 10 y 9 meses postrasplante en el caso de trasplante vascularizado. En el caso de islotes trasplantados mejoró notablemente el manejo metabólico, bajando los requerimientos diarios de insulina. Conclusión: El trasplante vascularizado de páncreas sigue siendo la mejor opción terapéutica, para revertir completamente la insuficiencia endocrina. El trasplante de islotes ofrece un menor riesgo y puede ser implementado en una población altamente seleccionada

Trasplante renopancratico. Experiencia inicial en un centro de trasplante en Argentina / Kidney and pancreas tranplantation. Initial experience at a single transplant center in Argentina

Luego de más de 10 000 casos comunicados en todo el mundo hasta 1998, el trasplante simultáneo de páncreas y riñon se ha estabelecido como una práctica clínica segura y probablemente constituya el mejor tratamento existente para la diabetes mellitus con nefropatía terminal. Presentamos nuestros resultados de 12 trasplantes pancreáticos (8 vascularizados y 4 de islotes), realizados en pacientes diabéticos insulino-dependientes. Once de ellos recibieron simultáneamente un riñon. Uno requiró un retrasplante renal. Todos los páncreas vascularizados se implantaron en forma intraperitoneal, con anastomosis a los vasos ilíacos y drenaje exócrino a la vejiga. La sobrevida a un año para paciente, páncreas vascularizado y riñon fue de 86 por ciento, 86 por ciento y 71 por ciento respectivamente. Todo están libres de insulina y diálisis; el receptor de mayor sobrevida lleva 37 meses. Los islotes se obtuvieron de donantes cadavéricos únicos y se transplantaron en el peritoneo, por vía laparoscópica, sin procesos previos de cultivo ni purificación (islotes equivalentes por paciente: 3x10(5), 4x10(5), 1x10(6) y 5x10(5). Ninguno de los receptores de islotes quedó libre de insulina pero redujeron sus requerimentos en aproximadamente 40 por ciento, con mejor control metabólico (promedio HbA1c pretrasplante 9.4 + 1.8 vs 7.9 + 1.6 postrasplante). Un injerto renal se perdió en este grupo por trombosis venosa. El transplante renopancreático ofrece al paciente diabético en insuficiencia renal terminal la doble posibilidad de independizarse de la diálisis y del uso de insulina exógena. Los resultados funcionales con el páncreas entero son mejores que con islotes. Sin embargo, para aquellos pacientes diabéticos que no son aptos para recibir un páncreas vascularizado, el trasplante celular puede mejorar el metabolismo de los carbohidratos exponiendo al paciente a riesgo quirúrgicos mínimos.