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Biomedical subjects

Per M Humpert

Publications and source records attributed to Per M Humpert.

18 recordsLinked to original sources
PubMed2006

Evidence of left ventricular contractile asynchrony by echocardiographic phase imaging in patients with type 2 diabetes mellitus and without clinically evident heart disease.

Left ventricular electromechanical asynchrony has been shown to predict cardiac events in patients with heart failure. This study investigated whether left ventricular asynchrony is present in patients with type 2 diabetes mellitus (DM) with no clinically evident heart disease and normal QRS durations. Asynchrony was evaluated in 24 patients with DM, 15 nondiabetic control subjects, and 20 patients with left bundle branch block (LBBB) due to cardiomyopathy serving as positive controls by conventional tissue Doppler imaging and by a novel method, echocardiographic phase imaging. Asynchrony was significantly higher in patients with DM than in controls and significantly lower than in patients with LBBB. This was shown by tissue Doppler imaging: the SD of time to peak myocardial velocity was 13 +/- 10 ms in controls, compared with 30 +/- 19 ms in patients with DM (p <0.01) and 68 +/- 28 ms in those with LBBB (p <0.001). Similar data were obtained using echocardiographic phase imaging: the SD of phase degrees was 25 degrees +/- 8 degrees in controls, compared with 44 degrees +/- 21 degrees in patients with DM (p = 0.02) and 76 degrees +/- 25 degrees in those with LBBB (p <0.001). Tissue Doppler imaging correlated with echocardiographic phase imaging (r = 0.79, p <0.0001) but was more time consuming (15.5 +/- 4.5 vs 4.5 +/- 2.2 min/patient, p <0.05) and showed higher intraobserver variability (5.6% vs 3.2%, p <0.05). In conclusion, this is the first study showing increased left ventricular asynchrony in patients with DM and no clinical evidence of heart disease.

Bundle-Branch Block↗
PubMed2006

Linking stress to inflammation.

There is ample evidence for the influence of central nervous system modulation through inflammatory cellular reactions under psychosocial stress. These inflammatory reflexes might be of major influence not only for metabolic and vascular disease but also for many autoimmune diseases for which stress has been reported as a risk factor. In prospective trials on the influence of risk factors for the occurrence of cardiovascular events, both psychosocial stress and autonomic nervous control of the cardiovascular system were shown to have a major impact on event rates. The underlying cause of these findings seems to be explained in part by the direct influences of autonomic reflexes, potentially induced by psychosocial tasks, on the progression of atherosclerosis. Hence, future prospective studies that aim at deciphering the influence of chronic psychosocial stress and autonomic function on the pathogenesis of inflammatory and metabolic disease will need to include neurophysiologic, molecular, and clinical parameters. Because the neuroimmunologic axis can be seen as a system connecting mental states with inflammatory reactions, pro-inflammatory mediators and anti-inflammatory strategies should be studied as such in experimental settings.

Humans↗
PubMed2006

Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of diabetic neuropathy in patients with type 1 diabetes.

OBJECTIVE: We studied the association between polymorphisms in the UCP genes and diabetes complications in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We analyzed 227 patients with type 1 diabetes using PCR and subsequent cleavage by restriction endonucleases for the promoter variants A-3826G in the UCP1 gene, G-866A in the UCP2 gene, and C-55T in the UCP3 gene. RESULTS: No effect of the A-3826G polymorphism in the UCP1 gene on diabetes complications was found. Patients who were heterozygous or homozygous for the G-866A polymorphism in the UCP2 gene or the C-55T polymorphism in the UCP3 gene had a significantly reduced prevalence of diabetic neuropathy (UCP2: odds ratio 0.44 [95% CI 0.24-0.79], P = 0.007; UCP3: 0.48 [0.25-0.92], P = 0.031), whereas there was no association with other diabetes complications. This effect was stronger when G-866A and C-55T occurred in a cosegregatory manner (UCP2 and UCP3: 0.28 [0.12-0.65], P = 0.002). Furthermore, a multiple logistic regression model showed an age- and diabetes duration-independent effect of the cosegregated polymorphisms on the prevalence of diabetic neuropathy (P = 0.013). CONCLUSIONS: Our data indicate that both the G-866A polymorphism in the UCP2 gene and the C-55T polymorphism in the UCP3 gene are associated with a reduced risk of diabetic neuropathy in type 1 diabetes. Thus, the results presented here support the hypothesis that higher expression of uncoupling protein might prevent mitochondria-mediated neuronal injury and, ultimately, diabetic neuropathy.

Adult↗
PubMed2006

Posttranslationally modified proteins as mediators of sustained intestinal inflammation.

Oxidative and carbonyl stress leads to generation of N(epsilon)-carboxymethyllysine-modified proteins (CML-mps), which are known to bind the receptor for advanced glycation end products (RAGE) and induce nuclear factor (NF)-kappaB-dependent proinflammatory gene expression. To determine the impact of CML-mps in vivo, RAGE-dependent sustained NF-kappaB activation was studied in resection gut specimens from patients with inflammatory bowel disease. Inflamed gut biopsy tissue demonstrated a significant up-regulation of RAGE and increased NF-kappaB activation. Protein extracts from the inflamed zones, but not from noninflamed resection borders, caused perpetuated NF-kappaB activation in cultured endothelial cells, which was mediated by CML-mps including CML-modified S100 proteins. The resulting NF-kappaB activation, lasting 5 days, was primarily inhibited by either depletion of CML-mps or by the addition of sRAGE, p44/42 and p38 MAPKinase-specific inhibitors. Consistently, CML-mps isolated from inflamed gut areas and rectally applied into mice caused NF-kappaB activation, increased proinflammatory gene expression, and histologically detectable inflammation in wild-type mice, but not in RAGE-/- mice. A comparable up-regulation of NF-kappaB and inflammation on rectal application of CML-mps was observed in IL-10-/- mice. Thus, CML-mps generated in inflammatory lesions have the capacity to elicit a RAGE-dependent intestinal inflammatory response.

Adult↗
PubMed2005

Understanding RAGE, the receptor for advanced glycation end products.

Advanced glycation end products (AGEs), S100/calgranulins, HMGB1-proteins, amyloid-beta peptides, and the family of beta-sheet fibrils have been shown to contribute to a number of chronic diseases such as diabetes, amyloidoses, inflammatory conditions, and tumors by promoting cellular dysfunction via binding to cellular surface receptors. The receptor for AGEs (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules acting as counter-receptor for these diverse molecules. Engagement of RAGE converts a brief pulse of cellular activation to sustained cellular dysfunction and tissue destruction. The involvement of RAGE in pathophysiologic processes has been demonstrated in murine models of chronic disease using either a receptor decoy such as soluble RAGE (sRAGE), RAGE neutralizing antibodies, or a dominant-negative form of the receptor. Studies with RAGE-/- mice confirmed that RAGE contributes, at least in part, to the development of late diabetic complications, such as neuropathy and nephropathy, macrovascular disease, and chronic inflammation. Furthermore, deletion of RAGE provided protection from the lethal effects of septic shock caused by cecal ligation and puncture (CLP). In contrast, deletion of RAGE had no effect on the host response in delayed-type hypersensitivity (DTH). Despite the lack of effect seen in adaptive immunity by the deletion of RAGE, administration of the receptor decoy, sRAGE, still afforded a protective effect in RAGE-/- mice. Thus, sRAGE is likely to sequester ligands, thereby preventing their interaction with other receptors in addition to RAGE. These data suggest that, just as RAGE is a multiligand receptor, its ligands are also likely to recognize several receptors in mediating their biologic effects.

Animals↗
PubMed2005

Advanced glycation end product receptor-mediated cellular dysfunction.

Advanced glycation end products (AGEs), S100/calgranulins, and HMGB1 proteins supposedly play a pivotal role in diabetes mellitus and other chronic inflammatory diseases by promoting cellular dysfunction via binding to cellular surface receptors. Particularly, engagement of the receptor for AGEs (RAGE) has gained major attention because it converts short-lasting cellular activation in sustained cellular dysfunction. Consistently, blockade of ligand-RAGE interaction with soluble RAGE (sRAGE) suppresses chronic cellular activation and dysfunction in animal models of chronic diseases. RAGE-/- mice, however, demonstrate that the protection conferred by RAGE deficiency is lower than that mediated by sRAGE. Furthermore, RAGE-/- mice can be protected by sRAGE in certain settings of the adaptive immune response. This finding implies that abounding RAGE ligands overworking the RAGE pathway might also activate other receptors.

Animals↗
PubMed2005

Tissue factor as a link between wounding and tissue repair.

The initial phase of wound repair involves inflammation, induction of tissue factor (TF), formation of a fibrin matrix, and growth of new smooth muscle actin (alpha-SMA)-positive vessels. In diabetes, TF induction in response to cutaneous wounding, which ordinarily precedes increased expression of vascular endothelial growth factor (VEGF) and alpha-SMA transcription, is diminished, though not to a degree causing excessive local bleeding. Enhanced TF expression in wounds of diabetic mice caused by somatic TF gene transfer increased VEGF transcription and translation and, subsequently, enhanced formation of new blood vessels and elevated blood flow. Furthermore, increased levels of TF in wounds of diabetic mice enhanced wound healing; the time to achieve 50% wound closure was reduced from 5.5 days in untreated diabetic mice to 4.1 days in animals undergoing TF gene transfer (this was not statistically different from wound closure in nondiabetic mice). Thus, cutaneous wounds in diabetic mice display a relative deficiency of TF compared with nondiabetic controls, and this contributes to delayed wound repair. These data establish TF expression as an important link between the early inflammatory response to cutaneous wounding and reparative processes.

Animals↗
PubMed2004

[AGE-RAGE: a hypothesis or a mechanism?].

Acausal relation between hyperglycemia and accelerated atherosclerosis has been recently suggested. The AGE-RAGE interaction is a potential mechanism underlying the accelerated atherosclerosis. Hyperglycemia causes via nonenzymatic glycation the formation of AGEs (advanced glycation endproducts). AGEs as well as other ligands like S100/Calgranulin and Amphoterin mediate receptor-independent and -dependent (via the interaction with RAGE) effects. The ligand-RAGE-interaction results in an activation of NF-kappaB, increased expression of cytokines, chemokines, and adhesion molecules and induces oxidative stress. A relevant role of the ligand-RAGE-interaction has been demonstrated in in vivo studies, both for the accelerated atherosclerosis and increased neointima formation in diabetes mellitus. Recent data analysing atherosclerotic lesions of diabetic patients provide further evidence for the pathogenetic role of the RAGE-ligand-interaction. In addition, new experimental data established that AGEs interact with other receptors than RAGE, while RAGE interacts with a diverse group of ligands. Thus, further studies are needed for the characterization of the ligand-RAGE-interaction. These studies will provide a rationale for the development of new therapeutic approaches for accelerated atherosclerosis in diabetes mellitus.

Animals↗
PubMed2004

Lack of association between polymorphisms of the toll-like receptor 4 gene and cerebral ischemia.

Toll-like receptor-4 (TLR4), an important mediator of the innate immune response, is expressed in atherosclerotic lesions. The common single nucleotide exchange (Asp299Gly) of the TLR4 gene has been previously reported to impair TLR4 function and to be associated with a decreased risk of carotid atherosclerosis. Therefore, we aimed to detect the potential impact of TLR4 genotypes on the risk of cerebral ischemia. We studied the prevalence of two common polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) in 3 independent study populations: (1.) in a cross-sectional study including 769 patients either with type 1 or type 2 diabetes mellitus, of whom 56 (7.2%) had a history of cerebral ischemia (study 1), (2.) a case-control study (study 2) including 128 consecutive patients with cerebral ischemia, mean age 60 +/- 10.9 years and 139 control subjects, and (3.) a case-control study (study 3) including 171 young adults aged < 50 years with cerebral ischemia and 204 control individuals. In all subjects, Asp299Gly and Thr399Ile were detected by restriction length analysis. The prevalence of the TLR4 genotypes was essentially the same between patients with cerebral ischemia and control subjects in all 3 study populations. Furthermore, there was also no association with the subgroup of atherosclerotic stroke in both case-control studies populations. Although TLR4 polymorphisms are associated with a decreased risk of carotid atherosclerotic lesions, our findings indicate that they do not influence the prevalence of cerebral ischemia. This implies that the Asp299Gly TLR4-allele might have a protective role in carotid atherosclerosis, but not in cerebral ischemia.

Adult↗
PubMed2004

Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily.

Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.

Animals↗
PubMed2004

Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with type 2 diabetes.

OBJECTIVE: To establish whether single nucleotide polymorphisms (Asp299Gly and Thr399Ile) of the toll-like receptor 4 have an association with late diabetic complications. RESEARCH DESIGN AND METHODS: The study was conducted in 246 type 1 and 530 type 2 diabetic patients. The alleles of both polymorphisms were detected using PCR and subsequent cleavage by NcoI and HinfI restriction endonucleases. RESULTS: No difference was found between type 1 and type 2 diabetic patients in the prevalence of alleles of the Asp299Gly and Thr399Ile polymorphisms. In most cases, the alleles Gly299 and Ile399 occurred in a co-segregatory manner. The prevalence of the Gly299/Ile399 haplotype was 10.6 and 12.1% in type 1 and type 2 diabetic patients, respectively (P = 0.63). No association with diabetic nephropathy or diabetic neuropathy was found in type 1 diabetic patients. In type 2 diabetic patients, however, heterozygote carriers of the Asp299Gly and Thr399Ile genotypes had a significantly reduced prevalence of diabetic neuropathy (odds ratio 0.35 [95% CI 0.19-0.61]; P = 0.0002); no association with diabetic nephropathy was found. CONCLUSIONS: Our data indicate that Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with reduced prevalence of diabetic neuropathy in type 2, but not in type 1, diabetes. Thus different mechanisms may be involved in the pathophysiology of diabetic neuropathy in type 1 and type 2 diabetes.

Amino Acid Substitution↗
PubMed2004

Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance.

OBJECTIVE: Adiponectin is a plasma protein expressed in adipose tissue. Hypoadiponectinemia is associated with low HDL cholesterol and high plasma triglycerides, which also characterize lipoprotein lipase (LPL) deficiency syndromes. Recently, dramatically increased LPL activity was reported in mice overexpressing adiponectin. We therefore speculated that adiponectin may directly affect LPL in humans. RESEARCH DESIGN AND METHODS: We measured plasma adiponectin and postheparin LPL in 206 nondiabetic men and in a second group of 110 patients with type 2 diabetes. Parameters were correlated with markers of systemic inflammation (C-reactive protein [CRP]) and insulin resistance (homeostatis model assessment of insulin resistance [HOMA-IR]). RESULTS: Nondiabetic subjects with decreased plasma adiponectin had lower LPL activity (r=0.42, P <0.0001). This association of plasma adiponectin with LPL activity was confirmed in the second group of patients with type 2 diabetes (r=0.37, P <0.0001). Multivariate analysis revealed that adiponectin was the strongest factor influencing LPL activity, accounting for 23% of the variation in LPL activity in nondiabetic subjects and for 26% of the variation in LPL activity in type 2 diabetic patients. These associations were independent of plasma CRP and HOMA-IR. CONCLUSIONS: These results demonstrate an association of decreased postheparin LPL activity with low plasma adiponectin that is independent of systemic inflammation and insulin resistance. Therefore, LPL may represent a link between low adiponectin levels and dyslipidemia in both nondiabetic individuals and patients with type 2 diabetes.

Adiponectin↗
PubMed2003

A mechanism converting psychosocial stress into mononuclear cell activation.

Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.

Adrenocorticotropic Hormone↗
PubMed2003

New treatments for diabetic neuropathy: pathogenetically oriented treatment.

Although there is clear evidence from experimental diabetic neuropathy (DN) models that the multiple pathways involved in neuronal degeneration cause overproduction of reactive oxygen species, oxidative stress, and cellular dysfunction, therapeutic approaches addressing these mechanisms have not yet provided a basis for a successful treatment of patients with DN. This review discusses the current knowledge on the pathomechanisms of unchecked reactive oxygen species accumulation, implications for specific treatment, and the need for carefully designed experimental studies and clinical trials closing the gap between promising results in experimental DN and its implementation into a pathogenetically oriented treatment.

Diabetic Neuropathies↗