Protein tyrosine kinases play an important role in the regulation of various cellular processes such as growth, differentiation and survival. GTK, a novel SRC-like cytoplasmic tyrosine kinase, was recently cloned from a mouse insulinoma cell line and the present work was conducted in order to find a biological function of GTK in insulin producing and neuronal cells. It was observed that kinase active GTK-mutants, expressed in RINm5F cells, transferred to the cell nucleus and increased the levels of the cell cycle regulatory protein p27KIP1, reduced cell growth and stimulated glucagon mRNA expression. Furthermore, wild type GTK induces neurite outgrowth in the rat adrenal pheochromocytoma PC12 cell line, through activation of the RAP1-pathway, suggesting a role of GTK for cell differentiation. Studies using transgenic mice, expressing GTK under the control of the rat insulin 1 promoter, demonstrated a dual role of GTK for β-cell growth: Whereas GTK increases the β-cell mass and causes enhanced β-cell proliferation in response to partial pancreatectomy it also induced β-cell death in response to proinflammatory cytokines and impaired the glucose tolerance in mice treated with the β-cell toxin streptozotocin suggesting a possible role of GTK for β-cell destruction in Type 1 diabetes. We have also observed that GTK-transgenic islets and GTK-expressing RINm5F cells exhibit a reduced insulininduced activation of the insulin receptor substrate (IRS-1 and IRS-2)-pathways, partly due to an increased basal activity of these. GTK was found to associate with and phosphorylate the SH2 domain adapter protein SHB, which could explain many of the GTK-dependent effects both in vitro and in vivo. In summary, the present work suggests that the novel tyrosine kinase GTK is involved in various signal transduction pathways, regulating different cellular responses, such as proliferation, differentiation and survival.

INTRODUÇÃO: Após a cirurgia pancreática, a função exócrina é determinada pela extensão da ressecção e a quantidade de tecido pancreático remanescente, sendo recomendável a avaliação da insuficiência pancreática exócrina (IPE) em todos os pacientes. A reposição de enzimas pancreáticas é o pilar do tratamento da IPE, pois melhora a absorção de gordura, diminui os sintomas relacionados com a má absorção e melhora a qualidade de vida (QV). OBJETIVO: Sabendo que o ajuste da dose de enzimas pancreáticas é realizado com base nos sinais clínicos relatados pelo paciente, o presente estudo visa aprofundar a avaliação clínica destes e avaliar o atual protocolo de tratamento, mantendo ou melhorando a QV dos pacientes. MÉTODOS: Estudo transversal em que foram avaliados adultos com histórico de ressecção pancreática há 6 meses ou mais. No tempo 1 foi realizada avaliação nutricional antropométrica e recordatório alimentar, avaliação clínica de qualidade de vida (questionário SF-36), investigação hábitos intestinais e exames laboratoriais. No tempo 2 foi realizada nova consulta para discussão dos resultados e orientação nutricional individualizada. Para análise de correlações foi usado o teste de Pearson, para associações o teste de Fisher e para comparação de médias o teste Mann-Whitney. RESULTADOS: Foram avaliados 39 pacientes, 22 (56,4%) do sexo feminino; 33 (84,6%) >=60 anos; tempo pós operatório 14,1± 6,8 anos; exames bioquímicos: em todas as dosagens a maioria dos pacientes apresenta resultados dentro dos valores de referência, mas há alta prevalência de deficiência de vitaminas lipossolúveis; os pacientes têm bom estado nutricional já que grande parte apresenta eutrofia segundo o IMC (46,1%) e segundo a porcentagem de gordura (35,9%); no geral não relatam sintomas gastrointestinais adversos: 61,5% com fezes formadas, 53,8% sem dor abdominal, 84,6% sem esteatorreia; adequação no consumo de macronutrientes: 51,3% consumo adequado de carboidratos e lipídios, e 64,1% de consumo excessivo de proteínas; correlações positivas: a dose de enzimas se correlaciona com a dor (p= 0,004) e o IMC (p= 0,009), ou seja, pacientes que relatam mais dor e que pesam mais são os que recebem as maiores doses de enzimas pancreáticas; correlações negativas: capacidade funcional e parâmetros de avaliação nutricional como IMC (p=0,004), e porcentagem de gordura (p=0,028), e também parâmetros clínicos como a dose de enzimas (p=0,022) e o número de evacuações por dia (p=0,024); associações: a inadequação do consumo de lipídios na dieta está associada com importantes sintomas gastrointestinais como a consistência amolecida das fezes (p=0,005) e flatulência (p=0,012) e ressalta a importância da orientação nutricional aos pacientes em reposição de enzimas pancreáticas. CONCLUSÃO: A maioria dos pacientes apresentou bons resultados de exames bioquímicos, qualidade de vida, consumo de macronutrientes, estado nutricional e sintomas gastrointestinais. Observaram-se importantes correlações e associações que demonstram que o estado nutricional, o consumo alimentar e a dose de enzimas interferem nos sintomas gastrointestinais e na auto-percepção de qualidade de vida dos pacientes. Sendo assim, o atual protocolo é válido, mas deve ser associado a orientação nutricional individualizada / BACKGROUND: After pancreatic surgery, exocrine function is determined by the extent of resection and the amount of remaining pancreatic tissue, and all patients should be evaluated for exocrine pancreatic insufficiency (EPI). Pancreatic enzyme replacement is the mainstay of EPI treatment, since it improves fat absorption, reduces symptoms related to malabsorption and improves quality of life (QoL). OBJECTIVE: Knowing that the adjustment of pancreatic enzymes dose is based on the clinical signs reported by the patient, the present study aims to deepen the clinical evaluation and to evaluate the current protocol of treatment, maintaining or improving patients quality of life. METHODS: A cross-sectional study in which adults were evaluated 6 months or more after pancreatic resection. At time 1, anthropometric evaluation and food recall, clinical evaluation of quality of life (SF-36 questionnaire), intestinal habits and laboratory tests were performed. At time 2 a new consultation was conducted to discuss the results and to provide individualized nutritional guidance. For the correlations analysis the Pearson test was used, for associations the Fisher test and for comparison of means the Mann-Whitney test. RESULTS: 39 patients were evaluated, 22 (56.4%) female; 33 (84.6%) >= 60 years; Time after surgery 14.1 ± 6.8 years; Biochemical tests: at all dosages most patients present results within the reference values, but there is a high prevalence of fat-soluble vitamins deficiency; The patients have good nutritional status since a great part presents eutrophy according to the BMI (46.1%) and according to the percentage of body fat (35.9%); In general they do not report adverse gastrointestinal symptoms: 61.5% with feces formed, 53.8% without abdominal pain, 84.6% without steatorrhea; Adequacy in macronutrient consumption: 51.3% adequate consumption of carbohydrates and lipids, and 64.1% excessive consumption of proteins; Positive correlations: enzyme dose correlates with pain (p = 0.004) and BMI (p = 0.009); that is, patients who report more pain and who weigh more are those who receive the highest doses of pancreatic enzymes; Negative correlations: functional capacity and nutritional assessment parameters such as BMI (p = 0.004), and body fat percentage (p = 0.028), as well as clinical parameters such as enzyme dose (p = 0.022) and number of bowel movements per day p=0.024); Associations: the dietary lipid consumption inadequacy is associated with important gastrointestinal symptoms such as soft stool consistency (p=0.005) and flatulence (p=0.012), and emphasizes the importance of nutritional guidance to patients on pancreatic enzyme replacement therapy. CONCLUSION: Most patients presented good results of biochemical tests, quality of life, macronutrient consumption, nutritional status and gastrointestinal symptoms. Significant correlations and associations have been observed that evidence that nutritional status, food intake and enzyme dose interferes with gastrointestinal symptoms and self-perceived quality of life of patients. Therefore, the current protocol is valid, but should be associated with individualized nutritional guidance

Background: Intestinal inflammation elicited by environmental determinants including dietary proteins and microbes is implicated in type 1 diabetes (T1D) pathogenesis. Also, intrinsic pancreatic abnormalities could precede classic insulitis, contributing to T1D. Materials and Methods: Spontaneous rat T1D models were used for in situ analyses of gut and pancreas to explore novel disease pathways using immunohistochemistry and detailed morphometry, gene expression studies, and molecular screening analyses. Results: In BBdp rats, feeding a cereal diet stimulated T1D under germ-free or specific pathogen-free (SPF) conditions compared with a protective hydrolyzed casein (HC) diet. Cereal-induced T1D was paralleled by increased gut T cell infiltration and TH1-associated pro-inflammatory transcription. HC-fed rats displayed an increased number of anti-inflammatory CD163+ M2 macrophages compared with cereal-fed rats. Cereal-associated promotion of T1D in Lewis diabetes-prone (LEW-DP) rats, a different rat model, similarly featured gut T cell infiltration in conjunction with decreased immunoregulation. The Camp gene was induced in diet-protected HC-fed BBdp rats. Camp encodes the cathelicidin antimicrobial peptide (CAMP), a pleiotropic immunomodulatory host defence factor. Intestinal CAMP was enriched in CD163+ M2 macrophages and could represent a novel marker of these tolerogenic innate immune cells. CAMP expression was also discovered in pancreatic lymph nodes (PLN) and islets, indicating a novel role for this factor in target tissue homeostasis. There was a positive correlation between pancreatic CAMP and total islet number. Also, islet-associated CAMP+ cells were increased in rats with islet inflammation, suggesting upregulation in parallel with insulitis. Exogenous CAMP/LL-37 injections increased the abundance of T1D-protective probiotic bacteria and promoted islet neogenesis in BBdp rats. A prospective partial pancreatectomy (PPx) study was performed to obtain pre-diabetic pancreas biopsies from iii pre-insulitic BBdp rats. The number of endothelium-associated CD68+ macrophages was increased in pre-diabetic pancreata, indicating that perivascular inflammation was an early lesion in the animals. In addition, pre-diabetic pancreata featured enhanced regenerative Reg3a and Reg3b gene expression, indicating abnormal islet expansion preceding insulitis. Conclusions: Small intestinal inflammation paired with deficits in local immunoregulation parallels T1D development. CAMP represents a novel factor in T1D that could have several pleiotropic functions including regulation of commensal microbes, intestinal homeostasis, and pancreatic homeostasis. In addition, target tissue abnormalities precede insulitis and T1D. This research focused on the integrative biology of T1D pathogenesis in spontaneous rat models. This work provides a novel working model that incorporates key roles for gut lumen antigens, intestinal immunity, and the role of islets and altered regenerative capacity in T1D. This research could lead to new therapeutic opportunities for T1D treatment.