Edited by Helaine E. Resnick, PhD, MPH

Although early detection of diabetic sensorimotor polyneuropathy (DSPN) may facilitate improved treatment outcomes, patients can only benefit from intervention if they receive an early and accurate DSPN diagnosis. Historically, assessment of DSPN–even among highly skilled clinicians–has been inconsistent, and development of objective and reproducible measures has been advocated for some time. In this issue of Diabetes, Ziegler et al. (p. 2454) compared 86 patients recently diagnosed with type 2 diabetes (T2D) with 48 control subjects to determine whether early nerve damage could be detected by corneal confocal microscopy (CCM). This new strategy for quantitative assessment of small nerve fiber damage was related to existing assessments including skin biopsy and neurophysiological tests. Although CCM detected early nerve fiber loss with a slightly greater overall frequency than skin biopsies, there was incomplete overlap across the methods, perhaps due to small fiber pathology developing at different times in different organs. To understand sensitivity among various measures, the researchers identified the proportion of participants whose values fell below the 2.5 percentile limit of normal. Those analyses showed that among six CCM measures such as nerve fiber length, connecting points, and branch density, nerve fiber density was the most sensitive. This measure was below normal limits in 21% of patients with T2D. In contrast, skin biopsies revealed that intraepidermal nerve fiber density was reduced below the 2.5 percentile in only 14% of T2D patients. Taken together, the results indicate that CCM may be a promising tool for early detection of diabetic neuropathy. If further studies confirm the utility of this assessment strategy, new opportunities may be available for early diagnosis and treatment of patients with DSPN. — Laura Gehl, PhD

Ziegler et al. Early detection of nerve fiber loss by corneal confocal microscopy and skin biopsy in recently diagnosed type 2 diabetes. Diabetes 2014;63:2454–2463

New research by Lønborg et al. (p. 2474) sheds light on the question of whether hyperglycemia is the cause or effect of myocardial damage in patients with ST-segment elevation myocardial infarction (STEMI). Elevated glucose is present in about half of all STEMI patients admitted to hospitals, and this hyperglycemia has been thought to increase the chance of reperfusion injury after treatment aimed at minimizing infarct size. Exenatide, which has been shown to have a cardioprotective effect in patients with STEMI, was used in the new study to evaluate the cardioprotective effects of this glucose-lowering treatment in 210 STEMI patients with and without diabetes, as well as the effect of hyperglycemia on area at risk and myocardial salvage index. STEMI patients received either exenatide or saline prior to percutaneous coronary intervention and for 6 h following intervention. Compared with STEMI patients with normal glucose levels, hyperglycemic patients had a larger average area at risk and larger final median infarct size. In contrast, the median myocardial salvage index was equivalent in both groups. Exenatide treatment increased salvage index in both hyper- and normoglycemic patients, suggesting that glucose levels at the time of hospital admission do not affect the cardioprotective impact of this drug. The authors propose that the negative prognosis associated with hyperglycemia at the time of hospital admission results from the larger myocardial area at risk in these patients. Hyperglycemia may therefore be an indicator of greater myocardial damage as well as increased risk of posttreatment injury. — Laura Gehl, PhD

Lønborg et al. Impact of acute hyperglycemia on myocardial infarct size, area at risk, and salvage in patients with STEMI and the association with exenatide treatment: results from a randomized study. Diabetes 2014;63:2474–2485

A report by Ferreira et al. (p. 2538) in this issue of Diabetes provides novel evidence that temporary upregulation of certain antiviral type 1 interferon (IFN)-inducible genes occurs before the appearance of circulating autoantibodies or seroconversion. These prospective data may offer much-needed insight into both potential type 1 diabetes (T1D) risk factors as well as preclinical pathology. Longitudinal samples from 109 genetically predisposed children aged 0.2–9 years (a subset of the BABYDIET cohort) were referenced against a model IFN-β transcriptional signature to determine the timing of the IFN response peak. Twenty-two of the BABYDIET children developed at least one of the four autoantibodies associated with T1D, and of these, nine progressed to T1D. The new report reveals that IFN signatures collected before antibody appearance were significantly augmented in children who later developed autoantibodies, an observation suggesting that elevated IFN signature may be a risk factor for seroconversion. In addition, these data were consistent with differing reports of respiratory infections in the two groups. By contrast, a lower IFN signature was observed in patients with established T1D (n = 64 individuals), suggesting that the IFN response is transient. Results from additional culture studies in T1D patients suggested that the lectin-like receptor SIGLEC-1, which is expressed by monocytes, may be a potential biomarker of elevated IFN expression. The report also highlights a correlation between enhanced IFN response and recent occurrence of respiratory infection, an association that is compatible with the possibility that an antiviral immune response might trigger greater circulation of SIGLEC-1–expressing monocytes. Taken together, these findings support the idea that viral infections are an environmental risk factor for T1D through activation of IFN immune pathways. — Wendy Chou, PhD

Ferreira et al. A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes. Diabetes 2014;63:2538–2550

Results from a study by Clarke-Harris et al. (p. 2528) in this issue of Diabetes support the theory that some epigenetic marks in early childhood persevere for years–even in the face of environmental pressures–and that these marks may be useful in predicting risk of disease later in life. In practice, epigenetic marks only contribute toward the understanding of disease risk if they are both stable and predictive of relevant health outcomes. The newly published investigation suggests that both of these criteria were met. The study focused on variance in DNA methylation in specific CpG loci in the promoter region of peroxisome proliferator–activated receptor γ coactivator 1α (PGC1α). This protein regulates energy homeostasis, including pancreatic β-cell function and adipogenesis, and is therefore relevant to diabetes risk. The investigators sampled blood annually from a birth cohort of 40 children beginning at age 5 years until age 14 years, and they also recorded factors such as body mass and physical activity. Children were stratified by insulin resistance at 14 years and examined in relation to DNA methylation. Results showed that methylation at 5–7 years explained between 77 and 88% of the variation in methylation at 14 years, an observation suggesting that the measure is relatively stable over time. Further, after controlling for sex, age, timing of puberty, and degree of physical activity, methylation of 4 loci was a significant predictor of adiposity up to age 14 years, suggesting that the measures predict a major diabetes risk factor later in life. The researchers caution that these relationships do not imply causality because differential methylation can also be a result of adiposity. Nevertheless, the new data suggest that stable epigenetic marks induced in early life may be a new addition to the array of tools currently employed to predict cardiometabolic disease risk. — Wendy Chou, PhD

Clarke-Harris et al. PGC1α promoter methylation in blood at 5–7 years predicts adiposity from 9 to 14 Years (EarlyBird 50). Diabetes 2014;63:2528–2537

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