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We sought to determine whether early nerve damage may be detected by corneal confocal microscopy (CCM), skin biopsy, and neurophysiological tests in 86 recently diagnosed type 2 diabetic patients compared with 48 control subjects. CCM analysis using novel algorithms to reconstruct nerve fiber images was performed for all fibers and major nerve fibers (MNF) only. Intraepidermal nerve fiber density (IENFD) was assessed in skin specimens. Neurophysiological measures included nerve conduction studies (NCS), quantitative sensory testing (QST), and cardiovascular autonomic function tests (AFTs). Compared with control subjects, diabetic patients exhibited significantly reduced corneal nerve fiber length (CNFL-MNF), fiber density (CNFD-MNF), branch density (CNBD-MNF), connecting points (CNCP), IENFD, NCS, QST, and AFTs. CNFD-MNF and IENFD were reduced below the 2.5th percentile in 21% and 14% of the diabetic patients, respectively. However, the vast majority of patients with abnormal CNFD showed concomitantly normal IENFD and vice versa. In conclusion, CCM and skin biopsy both detect nerve fiber loss in recently diagnosed type 2 diabetes, but largely in different patients, suggesting a patchy manifestation pattern of small fiber neuropathy. Concomitant NCS impairment points to an early parallel involvement of small and large fibers, but the precise temporal sequence should be clarified in prospective studies.

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Aims/hypothesis Cardiac autonomic nervous dysfunction (CAND) raises the risk of mortality, but the glycaemic threshold at which it develops is unclear. We aimed to determine the prevalence of, risk factors for and impact of CAND in glucose intolerance and diabetes. Methods Among 1,332 eligible participants aged 55-74 years in the population-based cross-sectional KORA S4 study, 130 had known diabetes mellitus (k-DM), and the remaining 1,202 underwent an OGTT. Heart rate variability (HRV) and QT variability were computed from supine 5 min ECGs. Results In all, 565 individuals had normal glucose tolerance (NGT), 336 had isolated impaired fasting glucose (i-IFG), 72 had isolated impaired glucose tolerance (i-IGT), 151 had combined IFG-IGT (IFG-IGT) and 78 had newly detected diabetes mellitus (n-DM). Adjusted normal HRV limits were defined in the NGT population (5th and 95th percentiles). Three HRV measures were more frequently abnormal in those with k-DM, n-DM, IFG-IGT and i-IFG than in those with NGT (p<0.05). The rates of CAND (≥2 of 4 HRV indices abnormal) were: NGT, 4.5%; i-IFG, 8.1%; i-IGT, 5.9%; IFG-IGT, 11.4%; n-DM, 11.7%; and k-DM, 17.5% (p<0.05 vs NGT, except for i-IGT). Reduced HRV was associated with cardiovascular risk factors used to construct a simple screening score for CAND. Mortality was higher in participants with reduced HRV (p<0.05 vs normal HRV). Conclusions/interpretation In the general population aged 55-74 years, the prevalence of CAND is increased not only in individuals with diabetes, but also in those with IFG-IGT and, to a lesser degree, in those with i-IFG. It is associated with mortality and modifiable cardiovascular risk factors which may be used to screen for diminished HRV in clinical practice.

Type 1 diabetes is an autoimmune disease in which the patient's immune system destroys the insulin-secreting beta-cells in the pancreatic islets of Langerhans. A majority of cases is thought to occur as a result of gene-environment interactions. The identity of the environmental factors remains unknown mainly because of the difficulty in linking past exposures with later disease development. Overall, the data suggest a model in which individuals develop diabetes by several different pathways, each influenced by numerous genetic and environmental variables. The most investigated environmental factors are diet and viruses. In this review, we examine the evidence that the source of dietary proteins can modify diabetes outcome, describe new approaches to identify candidate diabetes-related dietary agents, examine possible links with gut dysfunction, discuss some of the limitations, and propose a multifactorial model for dietary modification of diabetes. The key to diabetes pathogenesis, its prevention, and the ultimate success of beta-cell replacement therapies lies in understanding how the environment controls disease expression. Dietary proteins could be one of these keys.

Prospective analyses of biomarkers of inflammation and distal sensorimotor polyneuropathy (DSPN) are scarce and limited to innate immunity. We therefore aimed to assess associations between biomarkers reflecting multiple aspects of immune activation and DSPN. The study was based on 127 case subjects with incident DSPN and 386 noncase subjects from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (follow-up 6.5 years). Proximity extension assay technology was used to measure serum levels of biomarkers of inflammation. Of 71 biomarkers assessed, 26 were associated with incident DSPN. After adjustment for multiple testing, higher levels of six biomarkers remained related to incident DSPN. Three of these proteins (MCP-3/CCL7, MIG/CXCL9, IP-10/CXCL10) were chemokines, and the other three (DNER, CD40, TNFRSF9) were soluble forms of transmembrane receptors. The chemokines had neurotoxic effects on neuroblastoma cells in vitro. Addition of all six biomarkers improved the C statistic of a clinical risk model from 0.748 to 0.783 ( = 0.011). Pathway analyses indicated that multiple cell types from innate and adaptive immunity are involved in the development of DSPN. We thus identified novel associations between biomarkers of inflammation and incident DSPN pointing to a complex cross talk between innate and adaptive immunity in the pathogenesis of the disease.

Newly hatched chickens are highly susceptible to infection by opportunistic pathogens during the first 1 or 2 weeks of life. The use of cytokines as therapeutic agents has been studied in animal models as well as in immunosuppressed patients. This approach has become more feasible in livestock animals, in particular poultry, with the recent cloning of cytokine genes and the development of new technologies, such as live delivery vectors. We have recently cloned the gene for chicken interferon-gamma (Ch-IFN-gamma). Poly-HIS-tagged recombinant Ch-IFN-gamma was expressed in Escherichia coli, was purified by Ni chromatography, and was found to be stable at 4 degrees C and an ambient temperature for at least several months and Several weeks, respectively. Ch-IFN-gamma was capable of protecting chick fibroblasts from undergoing virus-mediated lysis, induced nitrite secretion from chicken macrophages in vitro, and enhanced MHC class II expression on macrophages. Administration of recombinant Ch-IFN-gamma to chickens resulted in enhanced weight gain over a 12-day period. Furthermore, the therapeutic potential of Ch-IFN-gamma was assessed using a coccidial challenge model. Birds were treated with Ch-IFN-gamma or a diluent control and then infected with Eimeria acervulina. Infected birds treated with Ch-IFN-gamma showed improved weight gain relative to noninfected birds. The ability of Ch-IFN-gamma to enhance weight gain in the face of coccidial infection makes it an excellent candidate as a therapeutic agent.

OBJECTIVEThe autonomic nervous system (ANS) regulates both the cardiovascular system and energy balance and is disturbed in diabetes and obesity. The effect of different approaches of caloric restriction on ANS function has not been assessed in individuals with diabetes. Thus, we sought to determine whether low-energy diets differing in fiber, red meat, and coffee intake exert differential effects on cardiac autonomic function. RESEARCH DESIGN AND METHODSIn this randomized parallel-group pilot trial, obese patients with type 2 diabetes were randomly allocated to consume either a diet high in cereal fiber, free of red meat, and high in coffee (n = 13) or a diet low in fiber, high in red meat, and coffee free (n = 15) over 8 weeks. Eight measures of heart rate variability (HRV) indicating vagal and/or sympathetic modulation over 3 h and inflammatory markers were determined during a hyperinsulinemic-euglycemic clamp. RESULTSAfter 8 weeks, both dietary interventions resulted in a mean weight loss of 5-6 kg, a mean decline in heart rate of 4-6 bpm, and improvement in vagally mediated HRV. However, the changes in HRV parameters from baseline to 8 weeks did not differ between the groups. In the entire study cohort, incremental HRV from baseline to 8 weeks was associated with enhanced oxidative glucose utilization (P < 0.05), but not with insulin sensitivity and inflammatory markers. CONCLUSIONSIn obese patients with type 2 diabetes, energy restriction per se over 8 weeks contributed to improved cardiac vagal function in relation to improved oxidative glucose utilization. This preliminary finding should be verified in a confirmatory trial. Cardiovascular autonomic neuropathy detected by reduced heart rate variability (HRV) affects ;20% of individuals with diabetes (1). HRV measures the fluctuations in autonomic inputs to the heart (2) and is considered a prognostic marker in various conditions including diabetes (1), metabolic syndrome (3), and cardiovascular disease (2). Spectral analysis of HRV indicates that efferent vagal activity is a major contributor to the high-frequency component, while the low-frequency component