Thyrotoxic, hypokalemic periodic paralysis (THPP) in adolescents.

INTRODUCTION: Periodic paralysis associated with hyperthyroidism and hypokalemia is an uncommon disorder reported primarily in Asian males and rarely in children. We report three Hispanic adolescent males who were seen with Graves' disease (GD) and THPP. METHODS: The method used was chart review. RESULTS: Two of these boys presented with episodes of paralysis and were diagnosed with GD. The third was initially seen with hyperthyroidism and developed weakness and paralysis when his disease progressed because of therapeutic noncompliance. Hypokalemia was documented in two of the three patients with the third not seen during paralysis. Intravenous K⁺ was required in only one case. All three boys were treated with antithyroid medications and ß blockers, and the musculoskeletal symptoms resolved in all three when hyperthyroidism was controlled after 2 weeks of treatment. The duration for each episode of weakness and paralysis varied in each case and resolved within 15 min to 2 h in case 1, 1-5 h in case 2, and 24 h in case 3. CONCLUSIONS: THPP is considered uncommon except in Asian males and rare in childhood and adolescence. Its occurrence in these three Hispanic boys suggests that it may occur more frequently in the young and in the USA than has been suspected, especially with the changing national demographics. We believe that our experience should raise the awareness of THPP among pediatric care providers.

c-Myc controls proliferation versus differentiation in human pancreatic endocrine cells.

Using immortalized human pancreatic endocrine cell lines, we have shown previously that differentiation into hormone-expressing cells requires cell-cell contact acting in synergy with the homeodomain transcription factor pancreatic duodenal homeobox-1 (PDX-1). Although differentiation is associated with a decrease in cell proliferation, the mechanisms behind this relationship are not known. Using TRM-6, a delta cell line, and betalox5, a beta-cell line, we show here that cell-cell contact and subsequent endocrine differentiation lead to a down-regulation of the c-myc protooncogene. Overexpression of c-Myc obtained with an inducible c-Myc-estrogen receptor fusion protein results in an increase in cell proliferation and the ablation of hormone expression. Moreover, we show that although c-Myc is expressed in a subset of cells from the human fetal and adult pancreas, it is absent in differentiated endocrine cells. The mechanism by which c-Myc interferes with hormone expression may be through effects on the homeodomain transcription factor PDX-1, as immunostaining for PDX-1 in cells with activated c-Myc revealed a redistribution of PDX-1 from the nucleus to the cytoplasm. These results suggest that c-Myc plays a central role in a cell-cell contact-mediated switch mechanism by which cell division vs. differentiation in endocrine cells is determined.

Cell-based therapies for diabetes: progress towards a transplantable human beta cell line.

Achieving normoglycemia is the goal of diabetes therapy. Potentially, there are many ways to achieve this goal, including transplantation of cells exhibiting glucose-responsive insulin secretion. However, to be applicable to the large number of people who might benefit from beta cell replacement, an unlimited supply of beta cells must be found. To address this problem, we have been developing cell lines from the human endocrine pancreas. In one case, a cell line, betalox5, has been developed from human islets that can be induced under some circumstances to differentiate into functional beta cells exhibiting appropriate glucose-responsive insulin secretion. Inducing differentiation is complex, requiring the activation of multiple signaling pathways, including those downstream of those involved in cell-cell contact and the glucagon-like peptide-1 receptor. In addition, transfer of the PDX-1 gene is also necessary to render the cells competent for differentiation. However, it is clear that many other genes are involved in maintaining the commitment of betalox5 cells towards the beta cell lineage. Understanding the complement of genes required to establish and maintain a beta cell lineage commitment would be enormously helpful in efforts to develop a cell line that can be used for beta cell replacement therapies. Here, we provide further information on the characteristics of cell lines that we have developed from the human pancreas that are relevant to the development of a beta cell replacement therapy for diabetes.

Islet specific Wnt activation in human type II diabetes.

The Wnt pathway effector gene TCF7L2 has been linked to type II diabetes, making it important to study the role of Wnt signaling in diabetes pathogenesis. We examined the expression of multiple Wnt pathway components in pancreases from normal individuals and type II diabetic individuals. Multiple members of the Wnt signaling pathway, including TCF7L2, Wnt2b, beta-catenin, pGSK3beta, TCF3, cyclinD1, and c-myc, were undetectable or expressed at low levels in islets from nondiabetic individuals, but were also upregulated specifically in islets of type II diabetic patients. Culture of pancreatic tissue and islet isolation led to Wnt activation that was reversed by the Wnt antagonist sFRP, demonstrating that Wnt activation in that setting was due to soluble Wnt factors. These data support a model in which the Wnt pathway plays a dynamic role in the pathogenesis of type II diabetes and suggest manipulation of Wnt signaling as a new approach to beta-cell-directed diabetes therapy.

Terapia gênica para o diabetes / Gene Therapy for the Diabetes

A administraçäo de insulina exógena tem sido a única forma de tratamento disponível para milhöes de indivíduos portadores de diabetes mellitus do tipo 1 (insulino-dependente). Embora o transplante de pâncreas tenha sido empregado com sucesso para um número limitado de pacientes, ele ainda é considerado um procedimento invasivo com alto risco de complicaçöes. Por outro lado, estudos preliminares onde o transplante de ilhotas pancreáticas foi realizado sem o emprego de glucocorticóides no esquema de imunossupressäo demonstraram resultados Extremamente promissores. Entretanto, o emprego de ilhotas pancreáticas, assim como o transplante de pâncreas, enfrenta o problema da escassez de órgäos disponíveis para transplante. Assim, um dos grandes objetivos da terapia gênica para diabetes é a geraçäo de fontes limitadas de células que apresemtem secreçäo normal de insulina em resposta ao estímulo da glicose, capazes de serem transplantadas sem a necesidade de imunossupressäo sistêmica. Este artigo tem como finalidade revisar como a terapia gênica pode ser empregada na obtençäo desta fonte de células, assim como discutir os últimos avanços no campo da biologia celular e molecular em relaçäo ao crescimento e diferenciaçäo da célula Beta.

Transplante de célulkas como terapia para o diabetes mellitus: desenvolvimento de uma fonte ilimitada de células beta como soluçäo para escassez de tecido pancreático disponível / Cell transplantation therapies for diabetes mellitus: developing unlimited quantites of beta cells how solution of shortage of pancreatic tissue available

Um dos maiores obstáculos ao sucesso do transplante celular como opção terapêutica para o diabetes mellitus refere-se 'a escassez de células R funcionais disponíveis. A expansão in vitro de células O humanas ou de seus precursores, permitirá a obtenção de grandes quantidades de células com a capacidade de secretar insulina em resposta a glicose. Estas células potencialmente poderão ser utilizadas para o transplante em pacientes portadores de diabetes. A expanção de células b humanas e de seus precursores in vitro pode ser alcançada com a utilização de dois métodos distintos. O primeiro refere-se a cultura de células primárias na presença de matrizes extracelulares e fatores de crescimento. Como precursores da células b, as células pancreáticas endócrinas fetais representam uma fonte potencial de células para transplante. O estudo dos fatores que influenciam o crescimento e a diferenciação destas células poderá contribuir para a identificação das condições mais apropriadas para sua cultura in vitro. Neste estudo nós demonstramos que a ativina A, membro da família dos transforming growth factos b induz a diferenciação endócrina, enquanto que a betacelulina, membro da família dos epidermal growth factors, possui um efeito mitogênico nas células humanas pancreáticas epiteliais indiferenciadas. O segundo método para o desenvolvimento de quantidades ilimitadas de células bhumanas baseia-se na expressão de oncogenes dominantes nas células, a qual promove a expansão celular ín vítro independentemente do uso de matrizes extracelulares ou de fatores de crescimento. As linhagens celulares apresentam uma maior capacidade de replicação quando comparadas 'as células primárias, sendo que a posterior indução da atividade da telomerase nestas células resulta em sua total imortalização. Embora os oncogenes confiram 'as células a propriedade de se mutiplicarem indefinidamente, estes exercem efeitos negativos na sua capacidade de diferenciação. Entretanto, neste estudo demonstramos que a imagem celular TRM-6, derivada de ilhotas pancreáticas fetais humanas, é capaz de ser diferenciadas das células d, dependendo da expressão do fator de transição PDX-1 e da promoção do contato intercelular. Da mesma forma, demonstramos que blox5, uma linhagem celular derivada de células b humanas purificadas, pode ser induzida à exibir secreção de insulina em resposta ao estímulo com glicose in vitro e in vivo. Este é o primeiro relato de uma...