Increased Indoleamine 2,3-Dioxygenase and Quinolinic Acid Expression in Microglia and Müller Cells of Diabetic Human and Rodent Retina.

Purpose: We investigated the relationship between inflammation, neuronal loss, and expression of indoleamine 2, 3-dioxygenase (IDO) and quinolinic acid (QUIN) in the retina of subjects with type 1 diabetes (T1D) and type 2 diabetes (T2D) and in the retina of rats with T1D. Methods: Retinas from T1D (n = 7), T2D (n = 13), and 20 age-matched nondiabetic human donors and from T1D (n = 3) and control rats (n = 3) were examined using immunohistochemistry for IDO, QUIN, cluster of differentiation 39 (CD39), ionized calcium-binding adaptor molecule (Iba-1, for macrophages and microglia), Vimentin (VIM; for Müller cells), neuronal nuclei (NeuN; for neurons), and UEA1 lectin (for blood vessels). Results: Based on morphologic criteria, CD39+/ionized calcium binding adaptor molecule 1(Iba-1+) resident microglia and CD39-/Iba-1+ bone marrow-derived macrophages were present at higher density in T1D (13% increase) and T2D (26% increase) human retinas when compared with controls. The density and brightness of IDO+ microglia were increased in both T1D and T2D human retinas. The intensity of QUIN+ expression on CD39+ microglia and VIM+ Müller cells was greatly increased in both human T1D and T2D retinas. T1D retinas showed a 63% loss of NeuN+ neurons and T2D retinas lost approximately 43% when compared with nondiabetic human retinas. Few QUIN+ microglia-like cells were seen in nondiabetic retinas, but the numbers increased 18-fold in T1D and 7-fold in T2D in the central retina. In T1D rat retinas, the density of IDO+ microglia increased 2.8-fold and brightness increased 2.1-fold when compared with controls. Conclusions: Our findings suggest that IDO and QUIN expression in the retinas of diabetic rats and humans could contribute to the neuronal degeneration that is characteristic of diabetic retinopathy.

SIRT1 Polymorphisms and Serum-Induced SIRT1 Protein Expression in Aging and Frailty: The CHAMP Study.

The nutrient sensing protein, SIRT1 influences aging and nutritional interventions such as caloric restriction in animals, however, the role of SIRT1 in human aging remains unclear. Here, the role of SIRT1 single-nucleotide polymorphisms (SNPs) and serum-induced SIRT1 protein expression (a novel assay that detects circulating factors that influence SIRT1 expression in vitro) were studied in the Concord Health and Ageing in Men Project (CHAMP), a prospective cohort of community dwelling men aged 70 years and older. Serum-induced SIRT1 expression was not associated with age or mortality, however participants within the lowest quintile were less likely to be frail (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.17-0.69, N = 1,309). Serum-induced SIRT1 expression was associated with some markers of body composition and nutrition (height, weight, body fat and lean % mass, albumin, and cholesterol) but not disease. SIRT1 SNPs rs2273773, rs3740051, and rs3758391 showed no association with age, frailty, or mortality but were associated with weight, height, body fat and lean, and albumin levels. There were some weak associations between SIRT1 SNPs and arthritis, heart attack, deafness, and cognitive impairment. There was no association between SIRT1 SNPs and the serum-induced SIRT1 assay. SIRT1 SNPs and serum-induced SIRT1 expression in older men may be more closely associated with nutrition and body composition than aging and age-related conditions.

Diabetic Cardiomyopathy: The Case for a Role of Fructose in Disease Etiology.

A link between excess dietary sugar and cardiac disease is clearly evident and has been largely attributed to systemic metabolic dysregulation. Now a new paradigm is emerging, and a compelling case can be made that fructose-associated heart injury may be attributed to the direct actions of fructose on cardiomyocytes. Plasma and cardiac fructose levels are elevated in patients with diabetes, and evidence suggests that some unique properties of fructose (vs. glucose) have specific cardiomyocyte consequences. Investigations to date have demonstrated that cardiomyocytes have the capacity to transport and utilize fructose and express all of the necessary proteins for fructose metabolism. When dietary fructose intake is elevated and myocardial glucose uptake compromised by insulin resistance, increased cardiomyocyte fructose flux represents a hazard involving unregulated glycolysis and oxidative stress. The high reactivity of fructose supports the contention that fructose accelerates subcellular hexose sugar-related protein modifications, such as O-GlcNAcylation and advanced glycation end product formation. Exciting recent discoveries link heart failure to induction of the specific high-affinity fructose-metabolizing enzyme, fructokinase, in an experimental setting. In this Perspective, we review key recent findings to synthesize a novel view of fructose as a cardiopathogenic agent in diabetes and to identify important knowledge gaps for urgent research focus.

Determinants of serum-induced SIRT1 expression in older men: the CHAMP study.

Circulating factors that have an effect on SIRT1 expression are influenced by caloric restriction. To determine the association between frailty and such circulating factors, we measured serum-induced SIRT1 expression from a nested cohort of frail (n = 77) and robust (n = 82) participants from Concord Health and Ageing in Men Project, a population-based study of community-dwelling men older than 70 years. Serum-induced SIRT1 expression was not different between frail and robust men (103.1 ± 17.0 versus 100.4 ± 19.3 µg/L). However, subsequent analyses showed that men with the lowest values (first quartile) were less likely to be frail (odds ratio = 0.5, 95% confidence interval = 0.2-1.0, p = .04) and had higher total body lean mass (p = .001) than the other participants. Serum-induced SIRT1 expression did not correlate with age, diseases, medications, albumin, fasting glucose, or lipids. Overall, there was no association between frailty and serum-induced SIRT1 expression; however, post hoc analysis suggested that there might be a paradoxical association between low serum-induced SIRT1 expression and robustness.