Segundo dados de 2012 da Sociedade Brasileira de Diabetes, se estima que cerca de 6% da população brasileira tenha diabetes e cerca de 7 a 8% tenha pré-diabetes. A neuropatia diabética é a complicação mais frequente dessa doença podendo já ocorrer no pré-diabetes. O início da neuropatia diabética é precoce e exibe grande variabilidade de manifestações clínicas, incluindo o comprometimento de diversas fibras nervosas somáticas e autonômicas. O diagnóstico tardio da neuropatia em diabéticos está associado à maior incidência de complicações como, por exemplo, ulcerações e amputações típicas do “pé diabético” e risco cardiovascular aumentado, incluindo a morte súbita. Dados como os citados acima motivaram a presente pesquisa, que se propõe a associar métodos diagnósticos não invasivos, disponíveis em nosso meio, a protocolos de investigação já recomendados pela comunidade científica internacional para neuropatia diabética. Aplicou-se um extenso protocolo de testes com finalidade de rastreamento da neuropatia somática e autonômica em três grupos de indivíduos: grupo DM (com diabetes melitus tipo 2), grupo Pré-DM, pré diabético e grupo C, de controles saudáveis. O teste em estudo foi a Termografia Computadorizada por Infravermelho, método sem contato que capta a emissão da radiação infravermelha pelo corpo humano e que, com auxílio de softwares, possibilita medições de temperatura em graus Celsius. A termografia foi testada na região plantar, utilizando-se de duas variáveis: Índice de Recuperação Térmica e presença ou não de Anisotermia Interdigital. O padrão de referência para a Termografia plantar foram os testes cardíacos de Variabilidade da Frequência Cardíaca. Pesquisas prévias demonstraram uma relação estreita entre a Neuropatia Autonômica Cardíaca (NAC) e neuropatia autonômica sistêmica. Quanto à reprodutibilidade das medidas termográficas, encontrou-se que as medidas relativas de diferenças de temperatura (Δt) são reprodutíveis nos diferentes grupos estudados e são preferíveis às medições de temperatura absoluta, confirmando a literatura. A presença de Anisotermia Interdigital parece ser o teste mais apropriado para identificar neuropatia em suas formas iniciais no grupo com diabetes e pré- diabetes, pela simplicidade de sua aplicação e pela sua boa sensibilidade e especificidade. Com a inclusão da termografia plantar em programas de rastreamento de neuropatia diabética pode-se prever um diagnóstico mais precoce e, assim, um controle mais efetivo de fatores de risco para esta patologia bem como tratamento mais precoce. / According to 2012 data from the Brazilian Society of Diabetes it is estimated that about 6% of the population have diabetes and about 7 to 8% have pre-diabetes. Diabetic neuropathy is the most common complication of this disease and may already occur in the pre-diabetes. The onset of diabetic neuropathy is early and shows great variability of clinical manifestations, including the commitment of various somatic and autonomic nerve fibers. Delayed diagnosis of diabetic neuropathy is associated with higher incidence of complications such as ulcerations and amputations, typical "diabetic foot" and increased of cardiovascular risk, including sudden death. Data such as those mentioned above have motivated this research, which aims to involve non-invasive diagnostic methods available in our area, the research protocols as recommended by the international scientific community for diabetic neuropathy. We applied an extensive testing protocol with the purpose of tracking somatic and autonomic neuropathy in three different groups: DM group, with type 2 diabetes, Pre-DM group, pre diabetic, and C, healthy controls. The test under study was Computerized Infrared Thermography, a no contact method that captures the emission of infrared radiation by the human body and, with the help of software, can make measurements of temperature in degrees Celsius. Thermography was tested in the plantar region, using two variables: Thermal Recovery Index and presence or absence of Interdigital Anisothermal. The reference standard for the plantar thermography tests were cardiac Heart Rate Variability. Previous studies have demonstrated a close relationship between Cardiac Autonomic Neuropathy (CAN) and systemic autonomic neuropathy. The reproducibility of the thermographic measurements was found that the relative measures of temperature differences (Δt) are reproducible in different groups, and are preferable to absolute temperature measurements, confirming the literature. The presence of Interdigital Anisothermal seems to be the most appropriate test to identify neuropathy in their initial forms in the group with diabetes and pre diabetes, because the simplicity of its application and its good sensitivity and specificity. With the addition of plantar thermography in the screening of diabetic neuropathy we may predict an earlier diagnosis and thus a more effective control of risk factors for this disease and earlier treatment.

Segundo dados de 2012 da Sociedade Brasileira de Diabetes, se estima que cerca de 6% da população brasileira tenha diabetes e cerca de 7 a 8% tenha pré-diabetes. A neuropatia diabética é a complicação mais frequente dessa doença podendo já ocorrer no pré-diabetes. O início da neuropatia diabética é precoce e exibe grande variabilidade de manifestações clínicas, incluindo o comprometimento de diversas fibras nervosas somáticas e autonômicas. O diagnóstico tardio da neuropatia em diabéticos está associado à maior incidência de complicações como, por exemplo, ulcerações e amputações típicas do “pé diabético” e risco cardiovascular aumentado, incluindo a morte súbita. Dados como os citados acima motivaram a presente pesquisa, que se propõe a associar métodos diagnósticos não invasivos, disponíveis em nosso meio, a protocolos de investigação já recomendados pela comunidade científica internacional para neuropatia diabética. Aplicou-se um extenso protocolo de testes com finalidade de rastreamento da neuropatia somática e autonômica em três grupos de indivíduos: grupo DM (com diabetes melitus tipo 2), grupo Pré-DM, pré diabético e grupo C, de controles saudáveis. O teste em estudo foi a Termografia Computadorizada por Infravermelho, método sem contato que capta a emissão da radiação infravermelha pelo corpo humano e que, com auxílio de softwares, possibilita medições de temperatura em graus Celsius. A termografia foi testada na região plantar, utilizando-se de duas variáveis: Índice de Recuperação Térmica e presença ou não de Anisotermia Interdigital. O padrão de referência para a Termografia plantar foram os testes cardíacos de Variabilidade da Frequência Cardíaca. Pesquisas prévias demonstraram uma relação estreita entre a Neuropatia Autonômica Cardíaca (NAC) e neuropatia autonômica sistêmica. Quanto à reprodutibilidade das medidas termográficas, encontrou-se que as medidas relativas de diferenças de temperatura (Δt) são reprodutíveis nos diferentes grupos estudados e são preferíveis às medições de temperatura absoluta, confirmando a literatura. A presença de Anisotermia Interdigital parece ser o teste mais apropriado para identificar neuropatia em suas formas iniciais no grupo com diabetes e pré- diabetes, pela simplicidade de sua aplicação e pela sua boa sensibilidade e especificidade. Com a inclusão da termografia plantar em programas de rastreamento de neuropatia diabética pode-se prever um diagnóstico mais precoce e, assim, um controle mais efetivo de fatores de risco para esta patologia bem como tratamento mais precoce. / According to 2012 data from the Brazilian Society of Diabetes it is estimated that about 6% of the population have diabetes and about 7 to 8% have pre-diabetes. Diabetic neuropathy is the most common complication of this disease and may already occur in the pre-diabetes. The onset of diabetic neuropathy is early and shows great variability of clinical manifestations, including the commitment of various somatic and autonomic nerve fibers. Delayed diagnosis of diabetic neuropathy is associated with higher incidence of complications such as ulcerations and amputations, typical "diabetic foot" and increased of cardiovascular risk, including sudden death. Data such as those mentioned above have motivated this research, which aims to involve non-invasive diagnostic methods available in our area, the research protocols as recommended by the international scientific community for diabetic neuropathy. We applied an extensive testing protocol with the purpose of tracking somatic and autonomic neuropathy in three different groups: DM group, with type 2 diabetes, Pre-DM group, pre diabetic, and C, healthy controls. The test under study was Computerized Infrared Thermography, a no contact method that captures the emission of infrared radiation by the human body and, with the help of software, can make measurements of temperature in degrees Celsius. Thermography was tested in the plantar region, using two variables: Thermal Recovery Index and presence or absence of Interdigital Anisothermal. The reference standard for the plantar thermography tests were cardiac Heart Rate Variability. Previous studies have demonstrated a close relationship between Cardiac Autonomic Neuropathy (CAN) and systemic autonomic neuropathy. The reproducibility of the thermographic measurements was found that the relative measures of temperature differences (Δt) are reproducible in different groups, and are preferable to absolute temperature measurements, confirming the literature. The presence of Interdigital Anisothermal seems to be the most appropriate test to identify neuropathy in their initial forms in the group with diabetes and pre diabetes, because the simplicity of its application and its good sensitivity and specificity. With the addition of plantar thermography in the screening of diabetic neuropathy we may predict an earlier diagnosis and thus a more effective control of risk factors for this disease and earlier treatment.

Segundo dados de 2012 da Sociedade Brasileira de Diabetes, se estima que cerca de 6% da população brasileira tenha diabetes e cerca de 7 a 8% tenha pré-diabetes. A neuropatia diabética é a complicação mais frequente dessa doença podendo já ocorrer no pré-diabetes. O início da neuropatia diabética é precoce e exibe grande variabilidade de manifestações clínicas, incluindo o comprometimento de diversas fibras nervosas somáticas e autonômicas. O diagnóstico tardio da neuropatia em diabéticos está associado à maior incidência de complicações como, por exemplo, ulcerações e amputações típicas do “pé diabético” e risco cardiovascular aumentado, incluindo a morte súbita. Dados como os citados acima motivaram a presente pesquisa, que se propõe a associar métodos diagnósticos não invasivos, disponíveis em nosso meio, a protocolos de investigação já recomendados pela comunidade científica internacional para neuropatia diabética. Aplicou-se um extenso protocolo de testes com finalidade de rastreamento da neuropatia somática e autonômica em três grupos de indivíduos: grupo DM (com diabetes melitus tipo 2), grupo Pré-DM, pré diabético e grupo C, de controles saudáveis. O teste em estudo foi a Termografia Computadorizada por Infravermelho, método sem contato que capta a emissão da radiação infravermelha pelo corpo humano e que, com auxílio de softwares, possibilita medições de temperatura em graus Celsius. A termografia foi testada na região plantar, utilizando-se de duas variáveis: Índice de Recuperação Térmica e presença ou não de Anisotermia Interdigital. O padrão de referência para a Termografia plantar foram os testes cardíacos de Variabilidade da Frequência Cardíaca. Pesquisas prévias demonstraram uma relação estreita entre a Neuropatia Autonômica Cardíaca (NAC) e neuropatia autonômica sistêmica. Quanto à reprodutibilidade das medidas termográficas, encontrou-se que as medidas relativas de diferenças de temperatura (Δt) são reprodutíveis nos diferentes grupos estudados e são preferíveis às medições de temperatura absoluta, confirmando a literatura. A presença de Anisotermia Interdigital parece ser o teste mais apropriado para identificar neuropatia em suas formas iniciais no grupo com diabetes e pré- diabetes, pela simplicidade de sua aplicação e pela sua boa sensibilidade e especificidade. Com a inclusão da termografia plantar em programas de rastreamento de neuropatia diabética pode-se prever um diagnóstico mais precoce e, assim, um controle mais efetivo de fatores de risco para esta patologia bem como tratamento mais precoce. / According to 2012 data from the Brazilian Society of Diabetes it is estimated that about 6% of the population have diabetes and about 7 to 8% have pre-diabetes. Diabetic neuropathy is the most common complication of this disease and may already occur in the pre-diabetes. The onset of diabetic neuropathy is early and shows great variability of clinical manifestations, including the commitment of various somatic and autonomic nerve fibers. Delayed diagnosis of diabetic neuropathy is associated with higher incidence of complications such as ulcerations and amputations, typical "diabetic foot" and increased of cardiovascular risk, including sudden death. Data such as those mentioned above have motivated this research, which aims to involve non-invasive diagnostic methods available in our area, the research protocols as recommended by the international scientific community for diabetic neuropathy. We applied an extensive testing protocol with the purpose of tracking somatic and autonomic neuropathy in three different groups: DM group, with type 2 diabetes, Pre-DM group, pre diabetic, and C, healthy controls. The test under study was Computerized Infrared Thermography, a no contact method that captures the emission of infrared radiation by the human body and, with the help of software, can make measurements of temperature in degrees Celsius. Thermography was tested in the plantar region, using two variables: Thermal Recovery Index and presence or absence of Interdigital Anisothermal. The reference standard for the plantar thermography tests were cardiac Heart Rate Variability. Previous studies have demonstrated a close relationship between Cardiac Autonomic Neuropathy (CAN) and systemic autonomic neuropathy. The reproducibility of the thermographic measurements was found that the relative measures of temperature differences (Δt) are reproducible in different groups, and are preferable to absolute temperature measurements, confirming the literature. The presence of Interdigital Anisothermal seems to be the most appropriate test to identify neuropathy in their initial forms in the group with diabetes and pre diabetes, because the simplicity of its application and its good sensitivity and specificity. With the addition of plantar thermography in the screening of diabetic neuropathy we may predict an earlier diagnosis and thus a more effective control of risk factors for this disease and earlier treatment.

The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.

This thesis examined how and why TRPV1 function is being modulated in sensory neuropathy and explored the potential of its rescue in the urinary bladder of STZ-­‐induced diabetic rats. Diabetes induced a rapid decline in TRPV1 function and changes in neurogenically mediated electrically-­‐evoked responses together with a gradual decline in muscarinic function. Diabetic bladder was also deficient in muscarinic and TRPV1 organ bath temperature-­‐induced changes but not in those affecting spontaneous contractile activity. Exposure to a potential neuropathy causative agent, methylglyoxal was studied and its mechanism of action explored through the use of TRPA1 ligands. Methylglyoxal exposure mimicked some of the effects of diabetes on TRPV1, neurogenic electrically evoked responses and muscarinic function. Methylglyoxal effects were seen to be partly through TRPA1 receptor activation but other as yet undefined pathways were also involved. Use of TRPA1 ligands revealed an unexpected complexity of the interaction of the TRPA1 receptor with TRPV1. Finally the potential of reversing the diminished TRPV1 response was examined through the use of three known sensitising agents, bradykinin, NGF and insulin. Bradykinin was the only agent seen to reverse the TRPV1 diminished response back up to to control equivalent levels and through the use of bradykinin selective ligands, it was seen that the dual activation of BK-­‐1 and BK-­‐2 receptor was necessary to rescue the TRPV1 response. The likely mechanism of action of bradykinin was through prostaglandin production as indomethacin blocked TRPV1 rescue. In the acute stage of diabetes, TRPV1 function is downregulated and may be caused by exposure to a neuropathy-­‐causing metabolite such as methylglyoxal. The TRPV1 function still retains plasticity at this acute stage because function could be enhanced back to control levels by bradykinin receptor activation : a potential for early therapeutic intervention.

A investigação de parâmetros biomecânicos no movimento humano tem trazido importantes discussões sobre a função do sistema músculo-esquelético e o controle deste movimento. O andar humano é um dos comportamentos motores mais investigados pela biomecânica e seus aspectos mecânicos contribuem de forma a caracterizar, identificar e intervir em situações patológicas. A investigação de parâmetros dinâmicos, cinemáticos e eletromiográficos na marcha patológica pode beneficiar de forma significativa a compreensão dos mecanismos de controle do andar e as alterações compensatórias geradas, assim como contribuir nas intervenções terapêuticas e preventivas em sujeitos portadores de alguma doença que acometa o sistema músculo-esquelético. No presente estudo, buscou-se descrever e interpretar, sob a perspectiva da biomecânica, o andar em cadência auto-selecionada de sujeitos diabéticos neuropatas em esteira rolante, considerando os parâmetros dinâmicos, temporais, espaciais e eletromiográficos durante a fase de apoio. Investigou-se também aspectos sensoriais plantares e motores a fim de caracterizar os sujeitos neuropatas e controles estudados. Valores da sensibilidade somatossensorial e limiares de tolerância à dor nos sujeitos diabéticos neuropatas apresentaram significativamente maiores em relação ao grupo de sujeitos controle estudado, valores considerados fora do padrão de normalidade esperado. A cadência autoselecionada e a velocidade obtida na esteira rolante foram significativamente menores durante o andar dos neuropatas em relação aos sujeitos controle. Os tempos de apoio simples, duplo, comprimento da passada e do passo durante a marcha nos sujeitos diabéticos neuropatas apresentaram-se significativamente maiores em relação ao grupo controle. Foram observados menores picos de força vertical nos sujeitos neuropatas e menores deflexões da força vertical, conseqüências secundárias da estratégia de redução da velocidade do andar em neuropatas que buscam um padrão mais conservativo e estável do seu andar. As respostas eletromiográficas dos músculos da perna e coxa apresentaram-se com menores magnitudes e com picos de ativação atrasados em relação ao padrão normal de recrutamento, especialmente o m. tibial anterior bilateralmente nos neuropatas. Interpreta-se tal fato como uma provável alteração no mecanismo de controle central e/ou periférico da marcha em sujeitos diabéticos neuropatas decorrente dos déficits sensoriais periféricos e motores conseqüentes da doença investigada. O mecanismo de redução de choques na marcha apresentou-se de forma ineficiente em função das respostas atrasadas eletromiográficas tanto de m. vasto lateral, quanto de m. tibial anterior. Conclui-se que a neuropatia diabética periférica acomete não só respostas somatossensoriais e motoras periféricas mas também mecanismos intrínsecos de controle modificando a eficiência do tornozelo em seu papel na marcha, comprometendo desta forma alguns dos principais requisitos para o andar que são a progressão e o equilíbrio / Biomechanical investigation of the human movement has been bringing important discussions about the musculoskeletal system functions and the control of movement. The human walking is one of the most studied motor behaviors and its mechanical aspects contribute to characterize, identify, and intervene in pathological conditions. Dynamic, kinematic, and electromyographic analyses of pathological gait can significantly help the comprehension of the control mechanism of gait and its compensatory alterations. These analyses can also contribute to therapeutic and preventive interventions in patients whose walking behavior is altered due to some disease that accomplish the neuromotor system. In the present study, we described and interpreted self-cadence walking in a treadmill of neuropathic diabetic subjects under biomechanical considerations, such as dynamic, temporal, spatial, and electromyographic analysis during stance phase. We also studied sensorial and motor aspects in order to characterize the neuropathic and control subjects. The somatossensorial responses and pain tolerance threshold in the neuropathic subjects were significantly higher and considered away from the normal patterns. The self-cadence and the treadmill velocity were significantly lower in neuropathic gait. Single and double stance time, stride and step length were significantly higher during neuropathic gait. The neuropathic subjects showed lower vertical force peaks and lower deflections of vertical force and those findings were secondary consequences of the conservative strategy of lowering the gait velocity adopted by the neuropathic in order to reach a more stable locomotor pattern. The electromyographic responses of the thigh and leg muscles in neuropathic subjects showed lower magnitudes and were delayed comparing to the normal recruitment pattern, specially the anterior tibialis muscle right and left. These findings lead us to conclude that probably central and/or peripheral control mechanisms of the gait of neuropathic diabetic patients are altered due to somatossensorial and motor deficits. The mechanism of load reduction during walking was considered inefficient because of the activation delay of the lateral vastus and anterior tibialis muscles. We conclude that the peripheral diabetic neuropathy damages not only somatossensorial and motor sources but also intrinsic mechanisms of motor control leading to alterations in the ankle efficiency in gait. This resulting distal inefficiency compromises some of the principal requirements to gait, which are progression and balance

A investigação de parâmetros biomecânicos no movimento humano tem trazido importantes discussões sobre a função do sistema músculo-esquelético e o controle deste movimento. O andar humano é um dos comportamentos motores mais investigados pela biomecânica e seus aspectos mecânicos contribuem de forma a caracterizar, identificar e intervir em situações patológicas. A investigação de parâmetros dinâmicos, cinemáticos e eletromiográficos na marcha patológica pode beneficiar de forma significativa a compreensão dos mecanismos de controle do andar e as alterações compensatórias geradas, assim como contribuir nas intervenções terapêuticas e preventivas em sujeitos portadores de alguma doença que acometa o sistema músculo-esquelético. No presente estudo, buscou-se descrever e interpretar, sob a perspectiva da biomecânica, o andar em cadência auto-selecionada de sujeitos diabéticos neuropatas em esteira rolante, considerando os parâmetros dinâmicos, temporais, espaciais e eletromiográficos durante a fase de apoio. Investigou-se também aspectos sensoriais plantares e motores a fim de caracterizar os sujeitos neuropatas e controles estudados. Valores da sensibilidade somatossensorial e limiares de tolerância à dor nos sujeitos diabéticos neuropatas apresentaram significativamente maiores em relação ao grupo de sujeitos controle estudado, valores considerados fora do padrão de normalidade esperado. A cadência autoselecionada e a velocidade obtida na esteira rolante foram significativamente menores durante o andar dos neuropatas em relação aos sujeitos controle. Os tempos de apoio simples, duplo, comprimento da passada e do passo durante a marcha nos sujeitos diabéticos neuropatas apresentaram-se significativamente maiores em relação ao grupo controle. Foram observados menores picos de força vertical nos sujeitos neuropatas e menores deflexões da força vertical, conseqüências secundárias da estratégia de redução da velocidade do andar em neuropatas que buscam um padrão mais conservativo e estável do seu andar. As respostas eletromiográficas dos músculos da perna e coxa apresentaram-se com menores magnitudes e com picos de ativação atrasados em relação ao padrão normal de recrutamento, especialmente o m. tibial anterior bilateralmente nos neuropatas. Interpreta-se tal fato como uma provável alteração no mecanismo de controle central e/ou periférico da marcha em sujeitos diabéticos neuropatas decorrente dos déficits sensoriais periféricos e motores conseqüentes da doença investigada. O mecanismo de redução de choques na marcha apresentou-se de forma ineficiente em função das respostas atrasadas eletromiográficas tanto de m. vasto lateral, quanto de m. tibial anterior. Conclui-se que a neuropatia diabética periférica acomete não só respostas somatossensoriais e motoras periféricas mas também mecanismos intrínsecos de controle modificando a eficiência do tornozelo em seu papel na marcha, comprometendo desta forma alguns dos principais requisitos para o andar que são a progressão e o equilíbrio / Biomechanical investigation of the human movement has been bringing important discussions about the musculoskeletal system functions and the control of movement. The human walking is one of the most studied motor behaviors and its mechanical aspects contribute to characterize, identify, and intervene in pathological conditions. Dynamic, kinematic, and electromyographic analyses of pathological gait can significantly help the comprehension of the control mechanism of gait and its compensatory alterations. These analyses can also contribute to therapeutic and preventive interventions in patients whose walking behavior is altered due to some disease that accomplish the neuromotor system. In the present study, we described and interpreted self-cadence walking in a treadmill of neuropathic diabetic subjects under biomechanical considerations, such as dynamic, temporal, spatial, and electromyographic analysis during stance phase. We also studied sensorial and motor aspects in order to characterize the neuropathic and control subjects. The somatossensorial responses and pain tolerance threshold in the neuropathic subjects were significantly higher and considered away from the normal patterns. The self-cadence and the treadmill velocity were significantly lower in neuropathic gait. Single and double stance time, stride and step length were significantly higher during neuropathic gait. The neuropathic subjects showed lower vertical force peaks and lower deflections of vertical force and those findings were secondary consequences of the conservative strategy of lowering the gait velocity adopted by the neuropathic in order to reach a more stable locomotor pattern. The electromyographic responses of the thigh and leg muscles in neuropathic subjects showed lower magnitudes and were delayed comparing to the normal recruitment pattern, specially the anterior tibialis muscle right and left. These findings lead us to conclude that probably central and/or peripheral control mechanisms of the gait of neuropathic diabetic patients are altered due to somatossensorial and motor deficits. The mechanism of load reduction during walking was considered inefficient because of the activation delay of the lateral vastus and anterior tibialis muscles. We conclude that the peripheral diabetic neuropathy damages not only somatossensorial and motor sources but also intrinsic mechanisms of motor control leading to alterations in the ankle efficiency in gait. This resulting distal inefficiency compromises some of the principal requirements to gait, which are progression and balance

Introduction: Relation of diabetes mellitus (DM) to the diabetic keratopathy and various stages of corneal nerve fiber damage has been well accepted. A possible association between changes in the cornea of diabetic patients and diabetic retinopathy (DR), DM duration, and age at the time of DM diagnosis were evaluated. Neuropathies are among the most common long-term complications of diabetes mellitus. Good glycemic control is essential in prevention of this complication. DM patients with similar mean glucose levels or glycated hemoglobin (HbA1c) levels often exhibit differences in evaluation of diabetic complications. One reason for these differences may be the differences in glucose variability. DM patients with similar mean glucose levels or HbA1c levels often exhibit differences in glucose variability Hypothesis: Diabetes mellitus damages the subbasal nerve fibers of the corneal and affects the density of epithelial, endothelial and stromal cells. Corneal changes in patients with DM are dependent on the degree of diabetic retinopathy (DR), age at diagnosis, duration of DM, and compensation parameters. Purpose: To compare changes in cell density in individual layers of cornea and status of subbasal nerve fibers in patients with type 1 DM (DM 1) and in healthy subjects. To evaluate the dependence...

Diabetic vasculopathy (DV) is the most important consequence of chronic hyperglycemia in patients with diabetes mellitus (DM). This thesis explores the interaction of blood, bone and kidney in the pathogenesis of DV by i) reviewing the current understanding of pathogenesis of macrovascular and microvascular diseases in DM to identify gaps in literature and generate hypotheses relating to various facets of DV ii) undertaking a series of prospective studies to examine these hypotheses iii) analysing the findings and integrating any new information obtained from the clinical studies into the current knowledge base and iv) generating hypotheses upon which future work might be based. The literature search was carried out with the aim of understanding current concepts of pathogenesis of DV and its potential modulators. The original reviews resulting from this process are presented in chapters 2 to 4. A series of pilot studies reported in chapters 7 to 11, were then carried out to interrogate hypotheses originating from this process. The first study was carried out in healthy individuals to define the biological variation of potential modulators of DV, namely erythropoietin (EPO), parathyroid hormone, 25 hydroxyvitamin D and 1, 25-dihydroxyvitamin D to facilitate the design and interpretation of subsequent studies. It revealed a wide biological variation of these modulators in the healthy population thus,emphasizing the need to have a control group in the subsequent study population. To examine whether tubulointerstitial dysfunction occurs before the onset of microalbuminuria, a measurement of the above mentioned parameters was carried out along with markers of tubulointerstitial injury in patients with type 1 and type 2 DM without microalbuminuria and in non-diabetic controls. It was found that tubulointerstitial dysfunction with low levels of EPO and 1, 25-dihydroxyvitamin D and higher excretion of tubular injury markers, occurs before the onset of microalbuminuria. Subsequently, diabetic and nondiabetic chronic kidney disease (CKD) patients with EPO deficiency anaemia were examined to study the effects of EPO therapy on the excretion of tubular injury markers. However, in these patient groups, we were unable to demonstrate an effect of EPO therapy on the markers of tubular injury in spite of a beneficial haematological response. To examine whether vascular calcification (VC) and bone mineral density (BMD) were linked in patients with diabetes mellitus and to explore their relationship to modulators of DV, an assessment of VC and BMD was undertaken in patients with type 2 DM with different degrees of proteinuria and normoalbuminuria. VC was assessed by CT scan and BMD by a DEXA scan. Modulators of DV were measured including serum Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-b-ligand (RANKL). The findings were i) a high prevalence of VC and osteopenia in normoalbuminuric type 2 DM patients with normal serum creatinine ii) a weak inverse relationship between VC and osteopenia iii) proteinuric patients had worse VC but not osteopenia iv) weak relationships between OPG levels and both VC and osteopenia, masked by age in multivariate analysis. The final study examined the relationship between modulators of DV, including OPG and RANKL, and the degree of CKD. It was found that abnormalities of OPG and RANKL occur before the onset of microalbuminuria and progress with deterioration of renal function. Compared to nondiabetics, DM patients have higher OPG levels in the predialysis phase and lower levels in haemodialysis phase, a phenomenon that might indicate endothelial exhaustion in dialysis patients with DM. The derangements associated with DV seem to occur earlier than previously thought. Further work is required to untangle these complexities and to define the contribution of factors such as the adverse blood milieu, the vasculature, abnormal bone and mineral metabolism, and early tubulointerstitial damage. The findings from the studies reported here may help in the formulation of new hypotheses, which might contribute to future work in this area.

Diabetiker entwickeln nach durchschnittlich 10 Jahren Folgeschäden. Die Polyneuropathie mit nachfolgender Osteoarthropathie des Fußes ist eine meist zu spät erkannte und suboptimal versorgte Komplikation. Nicht rechtzeitig erkannte Schäden führen zu Ulcera, sekundären Infektionen, Osteomyelitiden und Amputationen. Fragestellung: Ist eine Ganganalyse incl. Posturographie in der Lage, eine evtl. bestehende Polyneuropathie zu verifizieren, um eine frühzeitige orthopädische Schuhversorgung vornehmen zu können? Material und Methoden: Es wurden Diabetiker (n = 73) mit (mittels Messung der Nervenleitgeschwindigkeit NLG) nachgewiesener Neuropathie und eine gesunde Vergleichsgruppe (n = 38) ohne Neuropathie am Ganganalysesystem GANGAS untersucht. Ergebnisse: Die Allgemeinparameter relative Geschwindigkeit, Schrittlänge und Kadenz, sowie die Belastungsparameter Fersen-, Mittelfuß-, Vorfußbelastung und Belastung beim Auftritt und Abstoß zeigten keine wesentlich signifikanten Unterschiede im Gruppenvergleich. Dagegen zeigte die Posturographie (apparative Untersuchung der Schwankung des Druckschwerpunktes beim Romberg-Test, welche durch die Länge und Geschwindigkeit beschrieben wurde) signifikante Unterschiede zwischen beiden Patientengruppen. So lag z.B. der Median der Weglänge des Druckschwerpunktes beim Test mit geschlossenen Augen bei den Diabetikern bei 21,27 cm und in der Vergleichsgruppe bei 15,4 cm (p = 0,007). Die Bewegungsgeschwindigkeit des Druckschwerpunktes beim Test mit geschlossenen Augen betrug im Median 1,33 cm/sec bei den Diabetikern und 0,96 cm/sec in der gesunden Vergleichsgruppe (p = 0,006). Beim Test mit offenen Augen ergab sich kein signifikanter Unterschied im Gruppenvergleich. Klinische Relevanz: Eine Instabilität des Ganges der Patienten mit diabetischer Neuropathie und entsprechenden Folgeschäden des Fußes läßt sich durch die Ganganalyse mit Standardparametern nach vorliegendem Datenmaterial nicht nachweisen. Die Posturographie ist eine einfache, zeitlich mit geringem Aufwand verbundene Methode, die mit statistischer Signifikanz die subjektiven Kriterien der klinisch-orthopädischen Frühdiagnostik sinnvoll ergänzen und damit die Verdachtsdiagnose eine diabetischen Fußes objektiv nachweisen kann, bevor bleibende Schäden am Fuß entstanden sind. / Every diabetic patient after about ten years develops secondary changes in different tissues. Polyneuropathy with consecutive osteoarthropathy of the foot often is recognized too late and suboptimal treated. Diabetic disorders recognized too late may lead to ulcera, secondery infections and even amputations. Question: Is standard gait analysis including posturography able to verify diabetic neuropathy in order to supply the patient with adapted orthopadic shoeware in time? Materials and methods: A group of diabetics (n=73) with proved neuropathy by measuring nerve conduction velocity and a healthy control group (n=38) without neuropathy were examined by the gait-analysis-system GANGAS. Results: The general parameters: relative speed, length of step and cadence as well as the loading parameters of the heel, middle foot and forefoot during treading and repulsion show no significant differences between both groups. Posturography however (apparative examination of the elongation of focal point of pressure (FPP) according to the Romberg test, described by length and speed) shows significant differences between both groups. For diabetics making the test with closed eyes the mean value of walking length of the FPP was 21,27 cm, for the healthy control persons it was only 15,4 cm (p = 0,007). Asimulary results were found for the speed of movement of FPP during the test with closed eyes: mean value in diabetics 1,33 cm/s and for the healthy control persons 0,96 cm/s (p = 0,006). During this test with open eyes there was no significant difference between both groups. Clinical Relevance: Walking instability of patients with diabetic neuropathy and corresponding sequential damage of the foot could not be proved by the current data with standard parameters. Posturography however is able to give additional information with statistical significance to the subjective criteria of the clinical-orthopedic early diagnosis and verify the diagnosis of a beginning diabetic foot before severe disorders have occured.