Complicações microvasculares e disfunção autonômica cardíaca em pacientes com diabete melito tipo 1

FUNDAMENTO: A presença de neuropatia autonômica cardíaca (NAC) em pacientes com diabete melito (DM) está associada a aumento da mortalidade e a complicações crônicas microvasculares do diabete. OBJETIVO: Investigar uma possível associação entre achados sugestivos de NAC durante a realização do teste ergométrico (TE) e nefropatia e retinopatia em pacientes com DM tipo 1. MÉTODOS: Realizamos um estudo transversal com 84 pacientes com DM tipo 1. Todos os pacientes foram submetidos à avaliação clínica e laboratorial e realizaram TE, sendo que aqueles que apresentaram achados sugestivos de isquemia miocárdica foram excluídos da análise dos dados (n = 3). A avaliação de complicações microvasculares (retinopatia e nefropatia) foi realizada na amostra. RESULTADOS: Os pacientes com nefropatia e aqueles com retinopatia atingiram uma frequência cardíaca (FC) durante o pico de exercício (FC máxima) menor e apresentaram aumento menor da FC em relação ao repouso ( 16;FC pico) quando comparados com aqueles sem estas complicações. Esses pacientes também apresentaram menor redução da FC no segundo e 4º minutos após o final do teste ( 16;FC recuperação dois e 4 minutos). Após realização de análise multivariada com controle para os possíveis fatores de confusão, os 16;FC recuperação em dois e 4 minutos, FC máxima e o 16;FC pico permaneceram significativamente associados à retinopatia; e os 16;FC recuperação no segundo e 4º minutos permaneceram associados à presença de nefropatia. CONCLUSÃO: O TE pode ser considerado um instrumento adicional para a detecção precoce de NAC e para identificar pacientes em maior risco para complicações microvasculares do diabete.

Métodos não-lineares para avaliar mudanças na variabilidade da frequência cardíaca em pacientes com diabetes tipo 2

FUNDAMENTO: A variabilidade da frequência cardíaca (VFC) é um importante indicador da modulação autonômica da função cardiovascular. A diabetes pode alterar a modulação autonômica danificando as entradas aferentes, dessa forma aumentando o risco de doenças cardiovasculares. Foram aplicados métodos analíticos não lineares para identificar os parâmetros associados com VFC indicativos de alterações na modulação autonômica da função cardíaca em pacientes diabéticos. OBJETIVO: Analisamos as diferenças nos padrões da VFC entre pacientes diabéticos e controles saudáveis pareados por idade, utilizando métodos não-lineares. MÉTODOS: Plot de Poincaré Lagged, autocorrelação e análise de flutuação destendenciada foram aplicados para analisar a VFC em registros de eletrocardiograma (ECG). RESULTADOS: A análise do gráfico de Poincaré lagged revelou alterações significativas em alguns parâmetros, sugestivas de diminuição da modulação parassimpática. O expoente de flutuação destendencionada derivado de um ajuste em longo prazo foi maior que o expoente em curto prazo na população diabética, o que também foi consistente com a diminuição do input parassimpático. A função de autocorrelação do desvio dos intervalos inter-batimento exibiu um padrão altamente correlacionado no grupo de diabéticos em comparação com o grupo controle. CONCLUSÃO: O padrão de VFC difere significativamente entre pacientes diabéticos e indivíduos saudáveis. Os três métodos estatísticos utilizados no estudo podem ser úteis para detectar o início e a extensão da neuropatia autonômica em pacientes diabéticos.

Empfänglichkeit hämatopoetischer Zelllinien mesenchymaler CD34 und CD14 Stammzellen des Fettgewebes für eine Infektion mit dem humanen Immunschwächevirus Typ 1 und deren potentieller Nutzen in Prävention und Therapie der HIV-Infektion

Magdeburg, Univ., Med. Fak., Diss., 2013

Kohortenstudie zur Prävalenz von Angiotensin II Typ 1- und Endothelin-1 Typ A-Rezeptor-Autoantikörpern bei (peripherer) arterieller Verschlusskrankheit

Universität Magdeburg, Univ., Dissertation, 2016

Metabolic origin of insulin resistance in obesity with and without type 2 (non-insulin-dependent) diabetes mellitus.

A metabolic hypothesis is presented for insulin resistance in obesity, in the presence or absence of Type 2 (non-insulin-dependent) diabetes mellitus. It is based on physiological mechanisms including a series of negative feed-back mechanisms, with the inhibition of the function of the glycogen cycle in skeletal muscle as a consequence of decreased glucose utilization resulting from increased lipid oxidation in the obese. It considers the inhibition of glycogen synthase activity together with inhibition of glucose storage and impaired glucose tolerance. The prolonged duration of increased lipid oxidation, considered as the initial cause, may lead to Type 2 diabetes. This hypothesis is compatible with others based on the inhibition of insulin receptor kinase and of glucose transporter activities.

Cytomegalovirus infection and new-onset post-transplant diabetes mellitus.

We analyzed data from all consecutive kidney transplant patients at our institution between April 2003 and October 2006. We found 15 cases of late-onset cytomegalovirus (CMV) infection, two of which developed concurrent post-transplant diabetes mellitus (PTDM). In these two cases, PTDM was transient and normal glucose tolerance was achieved after an eight-wk therapeutic course of oral valganciclovir. These findings suggest that CMV infection after organ transplantation may be associated with concurrent PTDM. The distinct causative relationship is yet to be determined.

Potassium channel alterations mediate peripheral nerve hyperexcitability in a mouse model of type 2 diabetes mellitus

Diabetes mellitus (DM) is a major cause of peripheral neuropathy. More than 220 million people worldwide suffer from type 2 DM, which will, in approximately half of them, lead to the development of diabetic peripheral neuropathy. While of significant medical importance, the pathophysiological changes present in DPN are still poorly understood. To get more insight into DPN associated with type 2 DM, we decided to use the rodent model of this form of diabetes, the db/db mice. During the in-vivo conduction velocity studies on these animals, we observed the presence of multiple spiking followed by a single stimulation. This prompted us to evaluate the excitability properties of db/db peripheral nerves. Ex-vivo electrophysiological evaluation revealed a significant increase in the excitability of db/db sciatic nerves. While the shape and kinetics of the compound action potential of db/db nerves were the same as for control nerves, we observed an increase in the after-hyperpolarization phase (AHP) under diabetic conditions. Using pharmacological inhibitors we demonstrated that both the peripheral nerve hyperexcitability (PNH) and the increased AHP were mostly mediated by the decreased activity of Kv1-channels. Importantly, we corroborated these data at the molecular level. We observed a strong reduction of Kv1.2 channel presence in the juxtaparanodal regions of teased fibers in db/db mice as compared to control mice. Quantification of the amount of both Kv1.2 isoforms in DRG neurons and in the endoneurial compartment of peripheral nerve by Western blotting revealed that less mature Kv1.2 was integrated into the axonal membranes at the juxtaparanodes. Our observation that peripheral nerve hyperexcitability present in db/db mice is at least in part a consequence of changes in potassium channel distribution suggests that the same mechanism also mediates PNH in diabetic patients. ∗Current address: Department of Physiology, UCSF, San Francisco, CA, USA.

Regulated expression of GLUT2 in diabetes studied in transplanted pancreatic beta cells.

GLUT2 disappearance is a marker of the beta cell glucose-unresponsiveness associated with diabetes. Understanding the factor(s) leading to this dysfunction may shed light on pathogenesis of diabetes. Since the regulation of GLUT2 expression in diabetes can so far only be studied in in vivo experiments, we developed a novel experimental approach to study the genetic regulation of GLUT2 in diabetes. By encapsulating islets or cell lines in semi-permeable membranes, these cells can be exposed to the diabetic environment of rats or mice and can be retrieved for analysis of GLUT2 expression and for the change in the secretory response to glucose. Immunocytochemical analysis of transporter expression reveals changes in protein expression while transcriptional analysis of GLUT2 gene expression could be performed in cells transfected with promoter-reporter gene constructs. Using this last approach we hope to be able to characterize the promoter regions involved in the beta cell- and diabetes-specific regulation of GLUT2 expression and possibly to determine which factors are responsible for this regulation.

Syndrome métabolique, diabète sucré et vulnérabilité: une approche "syndémique" de la maladie chronique [Metabolic syndrome, diabetes mellitus and vulnerability: a syndemic approach of chronic diseases].

The pandemic metabolic syndrome is generally attributed to our lifestyle. The current therapeutic strategies are centered on the behavioral changes and pharmacotherapy. A deeply analysis reveals the importance of the socio-cultural determinants with a "dose-responses effect according to the socio-economic level. The "syndemic" theory, which puts at the same level the socio-cultural environment, the behaviors and biomedecine, suggests a more holistic approach. This theory suggests introducing other partners of care, such cultural-mediators and welfare workers trained in the care, to have finally an approach centered on the roots of the causes. The healthcare networks centered on the management of the costs of health should not forget the socio-cultural dimension, unless wanting to select the good cases.

Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus on a high-salt diet: a need for higher doses in diabetic patients?

Objective Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.Methods We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks.Results All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero.Conclusion The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system. J Hypertens 29: 2454-2461 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

RasGAP-derived fragment N increases the resistance of beta cells towards apoptosis in NOD mice and delays the progression from mild to overt diabetes.

The caspase-3-generated RasGAP N-terminal fragment (fragment N) inhibits apoptosis in a Ras-PI3K-Akt-dependent manner. Fragment N protects various cell types, including insulin-secreting cells, against different types of stresses. Whether fragment N exerts a protective role during the development of type 1 diabetes is however not known. Non-obese diabetic (NOD) mice represent a well-known model for spontaneous development of type 1 diabetes that shares similarities with the diseases encountered in humans. To assess the role of fragment N in type 1 diabetes development, a transgene encoding fragment N under the control of the rat insulin promoter (RIP) was back-crossed into the NOD background creating the NOD-RIPN strain. Despite a mosaic expression of fragment N in the beta cell population of NOD-RIPN mice, islets isolated from these mice were more resistant to apoptosis than control NOD islets. Islet lymphocytic infiltration and occurrence of a mild increase in glycemia developed with the same kinetics in both strains. However, the period of time separating the mild increase in glycemia and overt diabetes was significantly longer in NOD-RIPN mice compared to the control NOD mice. There was also a significant decrease in the number of apoptotic beta cells in situ at 16 weeks of age in the NOD-RIPN mice. Fragment N exerts therefore a protective effect on beta cells within the pro-diabetogenic NOD background and this prevents a fast progression from mild to overt diabetes.

SOCS-1 protein prevents Janus Kinase/STAT-dependent inhibition of beta cell insulin gene transcription and secretion in response to interferon-gamma.

In the pathogenesis of type I diabetes mellitus, activated leukocytes infiltrate pancreatic islets and induce beta cell dysfunction and destruction. Interferon (IFN)-gamma, tumor necrosis factor-alpha and interleukin (IL)-1 beta play important, although not completely defined, roles in these mechanisms. Here, using the highly differentiated beta Tc-Tet insulin-secreting cell line, we showed that IFN-gamma dose- and time-dependently suppressed insulin synthesis and glucose-stimulated secretion. As described previously IFN-gamma, in combination with IL-1 beta, also induces inducible NO synthase expression and apoptosis (Dupraz, P., Cottet, S., Hamburger, F., Dolci, W., Felley-Bosco, E., and Thorens, B. (2000) J. Biol. Chem. 275, 37672--37678). To assess the role of the Janus kinase/signal transducer and activator of transcription (STAT) pathway in IFN-gamma intracellular signaling, we stably overexpressed SOCS-1 (suppressor of cytokine signaling-1) in the beta cell line. We demonstrated that SOCS-1 suppressed cytokine-induced STAT-1 phosphorylation and increased cellular accumulation. This was accompanied by a suppression of the effect of IFN-gamma on: (i) reduction in insulin promoter-luciferase reporter gene transcription, (ii) decrease in insulin mRNA and peptide content, and (iii) suppression of glucose-stimulated insulin secretion. Furthermore, SOCS-1 also suppressed the cellular effects that require the combined presence of IL-1 beta and IFN-gamma: induction of nitric oxide production and apoptosis. Together our data demonstrate that IFN-gamma is responsible for the cytokine-induced defect in insulin gene expression and secretion and that this effect can be completely blocked by constitutive inhibition of the Janus kinase/STAT pathway.

Causas específicas de mortalidad en una cohorte de pacientes con diabetes mellitus tipo 2

La diabetis mellitus és un trastorn metabòlic a causa del dèficit de secreció d'insulina i a un augment de la seva resistència perifèrica. En el present estudi es van determinar les causes específiques de mortalitat en pacients amb diabetis mellitus. Es va observar que la mortalitat cardiovascular segueix sent la principal causa de mort en pacients amb diabetis metllitus tipus 2, seguida de la mortalitat per neoplàsies. La mortalitat total i específica per patologia cardiovascular o per neoplàsies va ser significativament superior en els pacients homes.