Thesis (M.S.)--University of Michigan, 1994.

Dados prévios ja demostram que o controle intensivo da glicemia diminui o risco de eventos microvasculares em pacientes com diabetes mellitus. No entanto, seu efeito cardiovascular é incerto. Nós sumarizamos os dados de estudos das principais bases de dados. 2 revisores extraíram dados de estudos randomizados de pacientes com diabetes tipo 2, que visavam 2 níveis de intensidade da glicemia. Investigou-se as retinopatia, neuropatias, nefropatias, mortalidade cardiocascular e total, infarto do miocárdio (IAM), acidente vascular cerebral, amputação de membros e episódios de hipoglicemia. Realizamos a meta-análise para obter o risco relativo (RR). Foram incluídos 7 estudos com 27.814 pacientes. O controle intensivo reduziu o RR de IAM e amputação, além progressão da retinopatia, incidência de neuropatia periférica, incidência e progressão de nefropatia e microalbuminúria. Entretanto, dobrou o risco de episódios de hipoglicemia. Não houve diferenças quanto à mortalidade e outros resultados. Conclui-se que controle intensivo reduziu o risco de alguns eventos, sem reduzir a mortalidade, porém as custas do dobro da incidência de de hipoglicemia. / Previous data already show that intensive glucose control reduces the risk of microvascular events in patients with diabetes mellitus. However, its cardiovascular effect is uncertain. We summarize data from studies of the major databases. 2 reviewers extracted data from randomized studies of patients with type 2 diabetes, aimed at two intensity levels of blood glucose. We investigated the retinopathy, neuropathy, nephropathy, and total mortality cardiocascular, myocardial infarction (IAM), stroke, limb amputation and episodes of hypoglycemia. We conducted a meta-analysis to obtain the relative risk (RR). We included seven studies with 27.814 patients. The intensive control reduced the RR of IAM, and amputation, and progression of retinopathy, incidence of peripheral neuropathy, incidence and progression of nephropathy and microalbuminuria. However, it doubled the risk of hypoglycemia. There were no differences in mortality and other outcomes. We conclude that intensive control reduced the risk of some events without reducing mortality, but the expense of twice the incidence of hypoglycemia.

O diabete melito é uma doença metabólica com alta prevalência na população e quando no estado descompensado pode causar diversas complicações metabólicas e clínicas, entre elas a osteoporose. Entretanto, ainda não foram completamente esclarecidos os mecanismos pelos quais o diabete diminui a densidade mineral óssea e aumenta o risco a fraturas. Recentemente foram descritos alguns genes que estão envolvidos no turnover ósseo: OPG, RANK e RANKL. Além disso, o uso de hipoglicemiantes orais como as tiazolidinedionas (TZD), pode influenciar negativamente o metabolismo ósseo. Com a finalidade de identificar marcadores sensíveis de alteração do metabolismo ósseo foram investigadas as relações entre a expressão dos genes OPG, RANK e RANKL em células do sangue periférico e a resposta a TZDs em pacientes com DM2. Foram selecionados 52 indivíduos (36 diabéticos e 16 normoglicêmicos), no Instituto Dante Pazzanese de Cardiologia. Os indivíduos diabéticos foram tratados com pioglitazona (15, 30 e 45 mg/ dia/ via oral) por 16 semanas. Foram colhidas amostras de sangue, antes e após o tratamento para determinação de exames laboratoriais e extração de RNA total. A expressão de mRNA dos genes OPG, RANK e RANKL foi quantificada e avaliada por RT-PCR em tempo real, empregando-se o GAPD como controle endógeno. Observou-se que nos pacientes DM2 após o tratamento com pioglitazona, houve diminuição da glicemia de jejum, glicemia pós-prandial, insulina, Hb1Ac, índices HOMA-IR e HOMA-β e aumento nas concentrações séricas de HDL, demonstrando a eficácia do tratamento. Ao comparar a expressão dos genes entre o grupo DM2 (sem tratamento) e o grupo normoglicêmico (NG), foi evidenciado um aumento da expressão de OPG no grupo NG em relação ao grupo DM2, e ao analisar a expressão entre as mulheres, constatou-se aumento da expressão de RANK no grupo DM2 em relação ao grupo NG. Além disso, ao correlacionar a expressão dos genes com as dosagens dos parâmetros bioquímicos, constatou-se que o aumento da expressão de RANK e RANKL está relacionado com o aumento das concentrações de cálcio ionizado e diminuição da expressão de OPG. Esses dados sugerem que a atividade osteoclástica está aumentada nos pacientes DM2 e com o tratamento o quadro osteoporótico pode ser agravado. / The diabetes mellitus is a metabolic disease with high prevalence in the population and can cause various metabolic and clinic complications, including osteoporosis, when it is decompensated. However, the mechanisms by which diabetes decreases bone mineral density and increases the risk of fractures are not completely clarified. Recently some genes which are involved in bone turnover were described: OPG, RANK and RANKL. Moreover, the treatment using oral hypoglycemic drugs such as thiazolidinediones (TZD), may negatively affect the bone metabolism. In order to identify sensitive markers related to the bone metabolism, were investigated the relationship between the expression of genes OPG, RANK and RANKL in peripheral blood leukocytes and the response to TZDs treatment in patients with DM2. Fifty-two individuals were selected (36 diabetics and 16 normoglycemics) at Dante Pazzanese Institute of Cardiology. Diabetic patients were treated with pioglitazone (15, 30 and 45 mg I day I oral) during 16 weeks. Blood samples were collected for biochemical analyses and total RNA extraction, before and after treatment. Gene expression of the genes OPG, RANK and RANKL in peripheral blood mononuclear cells was evaluated by Real Time PCR, using the GAPD housekeeping gene as the endogenous reference. In DM2 patients after treatment with pioglitazone there was reduction in their fasting glycemia, postprandial glycemia, insulin, Hb1Ac, HOMA-IR and HOMA-β indices, and their serum concentrations of HDL increased, which demonstrates the effectiveness of the treatment. The bone profile markers have not altered after treatment, suggesting an anabolic action of the insulin in bone metabolism of these patients. Normoglycemics (NG) group gene expression, when compared with DM2 group (with no treatment), had increased OPG expression. Besides, RANK expression in group DM2 was higher than NG group when it was analyzed among women. Furthermore, having correlated the expression of the genes with the biochemical parameters data, the increase on RANK and RANKL gene expression is related to increased concentrations of ionized calcium and to decreased expression of OPG gene. These results are suggestive that osteoclastic activity is higher in DM2 patients, the treatment can exacerbate osteoporosis severity and the bone markers does not have enough sensibility to differentiate changes in individuals with type 2 diabetes mellitus.

Intermittent fasting (IF) is a recently popularized meal timing strategy whereby individuals abstain continuously from any energy intake for 16 to 20 hours each day, subsequently condensing energy intake into a short period spanning 4 to 8 hours. We aimed to test the effects of intermittent fasting in 10 individuals with Type 2 Diabetes Mellitus in conjunction with recommendations to consume a high protein diet in a 6 to 8 week withdrawal study. This study consisted of three phases: baseline, intervention, and follow-up. During the 2-week baseline and intervention phases participants consumed meals at regular times. Biochemical, anthropometric, and physical activity measurements were taken at the end of each phase. Participants reported morning, afternoon and evening self-monitored blood glucose and fasting duration on a daily basis, in addition to completing a remote food photography diary three times within each study phase. Despite the short duration of the intervention phase, intermittent fasting led to significant decreases in weight, BMI, morning SMBG, and overall reductions in waist circumference, C-reactive protein, energy intake, carbohydrate intake, and fat intake. There were significant variations between participants in response to intermittent fasting in respect to changes in lipids and insulin sensitivity, which could not be explained by baseline biochemical or anthropometric measures, fasting duration, energy intake, or physical activity. Upon cessation of intermittent fasting, biochemical changes regressed towards baseline values during the follow-up period. Intermittent fasting was well tolerated by most participants, and no severe adverse events were noted. Morning nausea was the most common complaint, which abruptly ceased when medication timing was changed.

Diss. (sammanfattning) Linköping : Univ. / Härtill 6 uppsatser.

O diabete melito é uma doença metabólica com alta prevalência na população e quando no estado descompensado pode causar diversas complicações metabólicas e clínicas, entre elas a osteoporose. Entretanto, ainda não foram completamente esclarecidos os mecanismos pelos quais o diabete diminui a densidade mineral óssea e aumenta o risco a fraturas. Recentemente foram descritos alguns genes que estão envolvidos no turnover ósseo: OPG, RANK e RANKL. Além disso, o uso de hipoglicemiantes orais como as tiazolidinedionas (TZD), pode influenciar negativamente o metabolismo ósseo. Com a finalidade de identificar marcadores sensíveis de alteração do metabolismo ósseo foram investigadas as relações entre a expressão dos genes OPG, RANK e RANKL em células do sangue periférico e a resposta a TZDs em pacientes com DM2. Foram selecionados 52 indivíduos (36 diabéticos e 16 normoglicêmicos), no Instituto Dante Pazzanese de Cardiologia. Os indivíduos diabéticos foram tratados com pioglitazona (15, 30 e 45 mg/ dia/ via oral) por 16 semanas. Foram colhidas amostras de sangue, antes e após o tratamento para determinação de exames laboratoriais e extração de RNA total. A expressão de mRNA dos genes OPG, RANK e RANKL foi quantificada e avaliada por RT-PCR em tempo real, empregando-se o GAPD como controle endógeno. Observou-se que nos pacientes DM2 após o tratamento com pioglitazona, houve diminuição da glicemia de jejum, glicemia pós-prandial, insulina, Hb1Ac, índices HOMA-IR e HOMA-β e aumento nas concentrações séricas de HDL, demonstrando a eficácia do tratamento. Ao comparar a expressão dos genes entre o grupo DM2 (sem tratamento) e o grupo normoglicêmico (NG), foi evidenciado um aumento da expressão de OPG no grupo NG em relação ao grupo DM2, e ao analisar a expressão entre as mulheres, constatou-se aumento da expressão de RANK no grupo DM2 em relação ao grupo NG. Além disso, ao correlacionar a expressão dos genes com as dosagens dos parâmetros bioquímicos, constatou-se que o aumento da expressão de RANK e RANKL está relacionado com o aumento das concentrações de cálcio ionizado e diminuição da expressão de OPG. Esses dados sugerem que a atividade osteoclástica está aumentada nos pacientes DM2 e com o tratamento o quadro osteoporótico pode ser agravado. / The diabetes mellitus is a metabolic disease with high prevalence in the population and can cause various metabolic and clinic complications, including osteoporosis, when it is decompensated. However, the mechanisms by which diabetes decreases bone mineral density and increases the risk of fractures are not completely clarified. Recently some genes which are involved in bone turnover were described: OPG, RANK and RANKL. Moreover, the treatment using oral hypoglycemic drugs such as thiazolidinediones (TZD), may negatively affect the bone metabolism. In order to identify sensitive markers related to the bone metabolism, were investigated the relationship between the expression of genes OPG, RANK and RANKL in peripheral blood leukocytes and the response to TZDs treatment in patients with DM2. Fifty-two individuals were selected (36 diabetics and 16 normoglycemics) at Dante Pazzanese Institute of Cardiology. Diabetic patients were treated with pioglitazone (15, 30 and 45 mg I day I oral) during 16 weeks. Blood samples were collected for biochemical analyses and total RNA extraction, before and after treatment. Gene expression of the genes OPG, RANK and RANKL in peripheral blood mononuclear cells was evaluated by Real Time PCR, using the GAPD housekeeping gene as the endogenous reference. In DM2 patients after treatment with pioglitazone there was reduction in their fasting glycemia, postprandial glycemia, insulin, Hb1Ac, HOMA-IR and HOMA-β indices, and their serum concentrations of HDL increased, which demonstrates the effectiveness of the treatment. The bone profile markers have not altered after treatment, suggesting an anabolic action of the insulin in bone metabolism of these patients. Normoglycemics (NG) group gene expression, when compared with DM2 group (with no treatment), had increased OPG expression. Besides, RANK expression in group DM2 was higher than NG group when it was analyzed among women. Furthermore, having correlated the expression of the genes with the biochemical parameters data, the increase on RANK and RANKL gene expression is related to increased concentrations of ionized calcium and to decreased expression of OPG gene. These results are suggestive that osteoclastic activity is higher in DM2 patients, the treatment can exacerbate osteoporosis severity and the bone markers does not have enough sensibility to differentiate changes in individuals with type 2 diabetes mellitus.

Τα τελικά προϊόντα προχωρημένης γλυκοζυλίωσης (AGEs: Advanced Glycation Endproducts) παίζουν σημαντικό ρόλο στην παθογένεια των διαβητικών αγγειακών επιπλοκών. Το καλύτερα χαρακτηριζόμενο είναι η N-καρβοξυμεθυλ-λυσίνη (CML). Τα AGEs προκαλούν σημαντικές επιδράσεις στα αγγεία με την πρόσδεσή τους σε ειδικούς υποδοχείς της κυτταρικής επιφάνειας, όπως τον RAGE (Receptor for Advanced Glycation Endproducts). Διαλυτές μορφές του RAGE (sRAGE) εμφανίζονται στο ανθρώπινο αίμα και δρουν ως παγίδα αιχμαλωτίζοντας τους φλεγμονώδεις προσδέτες του RAGE εξωκυττάρια, προστατεύοντας με αυτό τον τρόπο τα κύτταρα από τη βλάβη που προάγεται από τα AGEs. Σκοπός αυτής της εργασίας ήταν να μελετηθούν τα επίπεδα του sRAGE, η πρωτεϊνική έκφραση του RAGE, καθώς και τα επίπεδα CML σε σχέση με διάφορες κλινικές και βιοχημικές παραμέτρους σε παιδιά, εφήβους και νεαρούς ενήλικες με ΣΔ1. Τα επίπεδα sRAGE και CML προσδιορίστηκαν με ELISA και η πρωτεϊνική έκφραση του RAGE στα μονοπύρηνα του περιφερικού αίματος με ανοσοαποτύπωση κατά Western σε 74 παιδιά, εφήβους και νεαρούς ενήλικες με ΣΔ1 (13± 4 χρονών) και 43 μάρτυρες αντίστοιχης ηλικίας, φύλου και σταδίου Tanner. Σ’ αυτή την εργασία τα αυξημένα επίπεδα sRAGE στα παιδιά με ΣΔ1 και πιο ειδικά, σ’ αυτά ηλικίας κάτω από 13 ετών και με διάρκεια διαβήτη κάτω από 5 έτη, μπορεί να είναι ένα προσωρινό προστατευτικό μέτρο ενάντια στην κυτταρική βλάβη και πιθανόν να είναι επαρκές για να εξουδετερώσει επαρκώς τα κυκλοφορούντα CML, εμποδίζοντας έτσι τις διαβητικές αγγειακές επιπλοκές. Επίσης, μια ήπια αύξηση της LDL θα μπορούσε να είναι ένα ερέθισμα για την αύξηση του sRAGE, οδηγώντας στη δέσμευση του CML και τελικά τη μείωση των επιπέδων CML στην κυκλοφορία. Τα μειωμένα επίπεδα της πρωτεϊνικής έκφρασης του RAGE 55 kd (υποδοχέα πλήρους μήκους) μπορεί να αντανακλούν την αυξημένη έκφραση του sRAGE στους ασθενείς με ΣΔ1 συνολικά λόγω της αποκοπής του RAGE με μεταλλοπρωτεϊνάσες. Με την παρουσία κάποιου παράγοντα κινδύνου, όπως αύξηση ηλικίας, περιμέτρου κοιλίας, BMI, συστολικής ή διαστολικής αρτηριακής πίεσης ή επιδείνωση λιπιδαιμικού προφίλ αυξάνεται η πρωτεϊνική έκφραση της ισομορφής αυτής, ενώ φαίνεται αντίστοιχα να μειώνονται τα επίπεδα του sRAGE. Φαίνεται τελικά ότι συνολικά στα παιδιά, τους εφήβους και τους νεαρούς ενήλικες με ΣΔ1 υπάρχει μια υποκλινική διαταραχή του άξονα sRAGE-RAGE-CML, η οποία δύναται να μετατραπεί σε κλινικά εμφανείς αγγειακές βλάβες, αν προστεθούν περαιτέρω επιβαρυντικοί παράγοντες. / The binding of Advanced Glycation Endproducts (AGEs) to their receptor (RAGE) plays a major role in the development of diabetic vascular complications. This work is based on the relation between circulating soluble RAGE (sRAGE) levels in children, adolescents and young adults with IDDM and RAGE protein expression in association with N-(carboxymethyl)lysine (CML), a major antigenic AGEs component. Circulating sRAGE and CML levels were determined by ELISA and RAGE protein expression was evaluated in peripheral blood mononuclear cells by western immunoblotting in 74 children, adolescents and young adults with IDDM (134 years old) and 43 age, sex and Tanner stage-matched controls. Serum sRAGE levels were significantly higher in IDDM than in controls, inversely correlated to diabetes duration and directly correlated to LDL levels. Furthermore, circulating CML levels were not significantly different between IDDM and controls. Also, the protein expression of the RAGE isoforms 55 kd (full-length), 64 kd and 100 kd, measured by western immunoblotting, was significantly lower in IDDM than in controls, whereas RAGE 37 kd levels were not significantly different between IDDM and controls. Finally, when there was a risk factor, such as increased age, poor lipid profile, increased BMI or waist circumference or increased systolic or diastolic pressure, then it seemed that isoforms RAGE 55, 64 and 100 kd were increased. Isoform RAGE 64 kd could be RAGE-v5, a splice variant which resulted in a change of amino acid sequence in the extracellular ligand-binding domain of RAGE. Isoform RAGE 37 kd seemed to be Δ8-RAGE, a soluble splice variant with probably protective function, which had been found increased in patients with increased HDL. Finally, isoform RAGE 100 kd seemed to be some other splice variant in peripheral mononuclear cells. In conclusion, increased serum levels of sRAGE seen in IDDM children may be a temporary protective measure against cell damage and may be sufficient to efficiently eliminate excessive circulating CML. Moreover, the lower protein expression of the full-length RAGE in IDDM may also reflect the increased sRAGE expression in patients due to RAGE cleavage by metalloproteases. Consequently, in IDDM children, adolescents and young adults there may be a subclinical perturbation of the sRAGE-RAGE-CML axis, which could lead to future clinical vascular damage if additional risk factors are added over time.