Sigisfredo L. Brenelli

Insulin modulates leptin-induced STAT3 activation in rat hypothalamus

Insulin and leptin have overlapping effects in the control of energy homeostasis, but the molecular basis of this synergism is unknown. Insulin signals through a receptor tyrosine kinase that phosphorylates and activates the docking proteins IRSs (insulin receptor substrates), whereas the leptin receptor and its associated protein tyrosine kinase JAK2 (Janus kinase 2) mediate phosphorylation and activation of the transcription factor STAT3 (signal transducer and activator of transcription). Here, we present evidence for the integration of leptin and insulin signals in the hypothalamus. Insulin induced JAK2 tyrosine phosphorylation, leptin receptor phosphorylation which, in the presence of leptin, augmented the interaction between STAT3 and this receptor. Insulin also increased the leptin‐induced phosphorylation of STAT3 and its activation. These results indicate that insulin modulates the leptin signal transduction pathway, and may provide a molecular basis for the coordinated effects of insulin and leptin in feeding behavior and weight control.

Formação de profissionais de saúde no Brasil: uma análise no período de 1991 a 2008

Estudo conduzido com o objetivo de contribuir para o planejamento e implementacao de politicas de qualificacao profissional no campo da saude. Foram analisados 14 cursos de graduacao da area da saude: biomedicina, ciencias biologicas, educacao fisica, enfermagem, farmacia, fisioterapia, fonoaudiologia, medicina, medicina veterinaria, nutricao, odontologia, psicologia, servico social e terapia ocupacional, no periodo de 1991 a 2008. Dados sobre numero de ingressantes, taxa de ocupacao de vagas, distribuicao de concluintes por habitante, genero e renda familiar foram coletados a partir dos bancos do Ministerio da Educacao. Para o curso de medicina, a relacao foi de 40 candidatos por vaga nas instituicoes publicas contra 10 nas privadas. A maioria dos ingressantes era composta por mulheres. A regiao Sudeste concentrou 57% dos concluintes, corroborando o desequilibrio de distribuicao regional das oportunidades de formacao de profissionais de saude e indicando a necessidade de politicas de incentivo a reducao dessas desigualdades.Study conducted to support the planning and implementation of public policies on human health resources. Fourteen undergraduate health courses were analyzed: biomedicine, biological sciences, physical education, nursing, pharmacy, physical therapy, speech and language therapy, medicine, veterinary medicine, nutrition, dentistry, psychology, social work and occupational therapy between 1991 and 2008. Data on number of students admitted, college admission rates, rates of graduating student by inhabitant, gender, geographic area and family income were collected from the Brazilian Ministry of Education database. For medicine undergraduate programs there were 40 applicants per place at public institutions and 10 at private ones. Most students admitted were females. The Southeast region concentrated 57% of graduating students. The study revealed trends that indicates opportunity inequalities in the regional distribution of health professional education, thus supporting the need for policies aimed at reducing such inequalities.

Defects in insulin signal transduction in liver and muscle of pregnant rats.

Summary Pregnancy is known to induce insulin resistance, but the exact molecular mechanism involved is unknown. In the present study, we have examined the levels and phosphorylation state of the insulin receptor and of insulin receptor substrate 1(IRS-1), as well as the association between IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) in the liver and muscle of pregnant rats (day 20 of gestation) by immunoprecipitation and immunoblotting with anti-insulin receptor, anti-IRS-1, anti-PI 3-kinase and anti-phosphotyrosine antibodies. There were no changes in the insulin receptor concentration in the liver and muscle of pregnant rats. However, insulin stimulation of receptor autophosphorylation, as determined by immunoblotting with antiphosphotyrosine antibody, was reduced by 30 ± 6 % (p < 0.02) in muscle and 36 ± 5 % (p < 0.01) in liver at day 20 of gestation. IRS-1 protein levels decreased by 45 ± 6 % (p < 0.002) in liver and by 56 ± 9 % (p < 0.002) in muscle of pregnant rats. In samples previously immunoprecipitated with anti-IRS-1 antibody and blotted with antiphosphotyrosine antibody, the insulin-stimulated IRS-1 phosphorylation levels in the muscle and liver of pregnant rats decreased by 70 ± 9 % (p < 0.01) and 75 ± 8 % (p < 0.01), respectively. The insulin-stimulated IRS-1 association with PI 3-kinase decreased by 81 ± 6 % in muscle (p < 0.01) and 79 ± 11 % (p < 0.01) in the liver during pregnancy. These data suggest that changes in the early steps of insulin signal transduction may have a role in the insulin resistance observed in pregnancy. [Diabetologia (1997) 40: 179–186]

Effect of chronic growth hormone treatment on insulin signal transduction in rat tissues

Growth hormone (GH) is known to produce insulin resistance, but the exact molecular mechanism remains unclear. We have chronically treated rats with GH and observed that the levels of insulin receptor in the liver or muscle were similar in both the GH-treated and non-treated rats. Insulin-stimulated receptor autophosphorylation was unaltered in the liver, but was reduced in the muscle of rats treated with GH. Insulin receptor substrate-1 (IRS-1) and phosphatidylinositol (PI) 3-kinase protein levels decreased in the liver but not muscle of GH-treated rats. There was no change in hepatic and muscle IRS-2 concentrations. A common finding in liver and muscle was the decrease in IRS-1 and IRS-2 tyrosine phosphorylation associated with a reduction in the interaction between these substrates and PI 3-kinase. These data suggest that changes in the early steps of insulin signal transduction may have a role in the insulin resistance observed in rats exposed to an excess of GH.

Effect of glucagon on insulin receptor substrate-1 (IRS-1) phosphorylation and association with phosphatidylinositol 3-kinase (PI 3-kinase).

In the present study we have examined the levels and phosphorylation state of the insulin receptor and insulin receptor substrate 1 (IRS‐1) as well as the association between IRS‐1 and phosphatidylinositol 3‐kinase (PI 3‐kinase) in the liver and muscle of rats treated with glucagon. There was a decrease in the insulin‐stimulated receptor and IRS‐1 phosphorylation levels which was paralleled by a reduced association between IRS‐1 and PI 3‐kinase in vivo in the liver and muscle of glucagon‐treated rats. These observations suggest that glucagon, probably acting through cAMP, may impair insulin signaling in the three early steps in insulin action after binding.

Tissue-specific regulation of early steps in insulin action in septic rats.

Sepsis is known to induce insulin resistance, but the exact molecular mechanism involved is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and of insulin receptor substrate 1 (IRS-1), as well as the association between IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) in the liver and muscle of septic rats by immunoprecipitation and immunoblotting with anti-insulin receptor, anti-IRS-1, anti-PI 3-kinase and anti-phosphotyrosine antibodies. There were no changes in the insulin receptor concentration and phosphorylation levels in the liver and muscle of septic rats. IRS-1 protein levels were decreased by 40+/-3% (p < 0.01) in muscle but not in liver of septic rats. In samples previously immunoprecipitated with anti-IRS-1 antibody and blotted with antiphosphotyrosine antibody, the insulin-stimulated IRS-1 phosphorylation levels in the muscle of septic rats decreased by 38+/-5% (p < 0.01) and insulin-stimulated IRS-1 association with PI 3-kinase decreased by 44+/-7% in muscle (p < 0.01) but no changes were seen in liver. These data suggest that there is a tissue-specific regulation of early steps of insulin signal transduction in septic rats, and the changes observed in muscle may have a role in the insulin resistance of these animals.

Modulation of early steps in insulin action in the liver and muscle of epinephrine treated rats.

Epinephrine is known to produce insulin resistance, but the exact molecular mechanism involved is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and of insulin receptor substrate 1 (IRS-1), as well as the association between IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) in the liver and muscle of rats treated with epinephrine. The results demonstrate a decrease in insulin-stimulated receptor and IRS-1 phosphorylation levels which was accompanied by a reduction in the association of IRS-1 with PI 3-kinasein vivo in liver and muscle of epinephrine treated rats. These data suggest that molecular post-receptor defects may explain some aspects of the insulin resistance induced by catecholamines.

Tissue-specific regulation of IRS-2/PI 3-kinase association in aged rats

Abstract We have examined the insulin-stimulated IRS-2 association with PI 3-kinase and the phosphorylation of AKT/PKB, which is functionally located downstream of the PI 3-kinase, in aged (obese) rats. The IRS-2 protein levels were similar in 2 and 20 month-old rats in both tissues, liver and muscle. There were reductions in insulin-induced IRS-2 tyrosine phosphorylation in liver and muscle, accompanied by a decrease in IRS-2/PI 3-kinase association and in AKT/PKB phosphorylation only in muscle tissue of aged rats. This regulation may be important in the altered glucose metabolism observed in aged (obese) rats.

Undergraduate programs for health professionals in Brazil: an analysis from 1991 to 2008.

Estudo conduzido com o objetivo de contribuir para o planejamento e implementacao de politicas de qualificacao profissional no campo da saude. Foram analisados 14 cursos de graduacao da area da saude: biomedicina, ciencias biologicas, educacao fisica, enfermagem, farmacia, fisioterapia, fonoaudiologia, medicina, medicina veterinaria, nutricao, odontologia, psicologia, servico social e terapia ocupacional, no periodo de 1991 a 2008. Dados sobre numero de ingressantes, taxa de ocupacao de vagas, distribuicao de concluintes por habitante, genero e renda familiar foram coletados a partir dos bancos do Ministerio da Educacao. Para o curso de medicina, a relacao foi de 40 candidatos por vaga nas instituicoes publicas contra 10 nas privadas. A maioria dos ingressantes era composta por mulheres. A regiao Sudeste concentrou 57% dos concluintes, corroborando o desequilibrio de distribuicao regional das oportunidades de formacao de profissionais de saude e indicando a necessidade de politicas de incentivo a reducao dessas desigualdades.Study conducted to support the planning and implementation of public policies on human health resources. Fourteen undergraduate health courses were analyzed: biomedicine, biological sciences, physical education, nursing, pharmacy, physical therapy, speech and language therapy, medicine, veterinary medicine, nutrition, dentistry, psychology, social work and occupational therapy between 1991 and 2008. Data on number of students admitted, college admission rates, rates of graduating student by inhabitant, gender, geographic area and family income were collected from the Brazilian Ministry of Education database. For medicine undergraduate programs there were 40 applicants per place at public institutions and 10 at private ones. Most students admitted were females. The Southeast region concentrated 57% of graduating students. The study revealed trends that indicates opportunity inequalities in the regional distribution of health professional education, thus supporting the need for policies aimed at reducing such inequalities.

The single health system (SUS) as a school: social responsibility towards the population's healthcare and the education of future health professionals

O sis te ma edu ca ci o nal es te ve por mu i to tem po cen tra do na ati vi da de do pro fes sor, con si de ra do o agen te ati vo do pro ces so en si no-apren di za gem. Nes te con tex to, é ele quem de fi ne e pro gra ma o que o alu no vai apren der, como e quan do. O foco no en si no, em con tra pon to ao foco na apren di za gem, de ter mi na, as sim, a car ga ho rá ria do cur so, opor tu ni da des de apren di za gem, es que ma de au las e ava li a ção, num pro gra ma fe cha do. Mas o apren der não é pas si vo. Não há ape nas uma re a li da de, pois cada um apre en de um fato, uma si tu a ção, de acor do com sua dis po ni bi li da de de per ce ber e a trans for ma se gun do seu re per tó rio de co nhe ci men tos pré vi os, vi vên ci as e mo ti va ção para apren der de ter mi na da ma té ria. Para apren der, há que ela bo rar, trans for mar, in te grar o novo co nhe ci men to a es tru tu ras pré vi as, ou seja, há que ser ati vo. Para dar con se quên cia a este con ce i to, pro põe-se mu dar o en fo que do sis te ma edu ca ci o nal a fim de en fa ti zar o apren di za do do alu no, não mais ape nas o en si no. Pa ra le la men te a essa ne ces si da de de trans for ma ção, vi ven ci a mos mu dan ças na so ci e da de. O en si no na área da sa ú de, tra di ci o nal men te cen tra do nas do en ças e usan do como in su mos para o sa ber os “in di gen tes” dos hos pi ta is pú bli cos e San tas Ca sas, tran si ta para uma nova re a li da de. Nes ta, o in di ví duo ga nha a con di ção de ci da dão, e a re for ma sa ni tá ria cul mi na, por meio de uma “cons ti tu i ção ci da dã”, com a cri a ção do SUS. O pro fes sor não é mais o cen tro do pro ces so pe da gó gi co, seu sa ber não é mais su fi ci en te para as ne ces si da des bi op si cos so ci a is, que re que rem ações e in ter ven ções que con si de rem um con tex to am pli a do. A do en ça como es tru tu ra fun da men tal do pro ces so de apren di za do pas sa a ser subs ti tu í da pela sa ú de. A ge ra ção de co nhe ci men to, res pon sá vel pelo avan ço bi o ló gi co no cam po da sa ú de e que foi a gran de res pon sá vel pela re vo lu ção na ciên cia mé di ca do sé cu lo 20, não é su fi ci en te para re sol ver as de man das da aten ção pri má ria e me lho rar sua re so lu bi li da de. Essa ma triz ge ra da pelo co nhe ci men to car te si a no pre ci sa ser am pli a da, e, as sim, sur ge mais um de sa fio aos pro fes so res da área da sa ú de: va lo ri zar, in cen ti var e aper fe i ço ar a pes qui sa clí ni ca.