Site-Specific GlcNAcylation of Human Erythrocyte Proteins: Potential Biomarker(s) for Diabetes

OBJECTIVE—O-linked N-acetylglucosamine (O-GlcNAc) is upregulated in diabetic tissues and plays a role in insulin resistance and glucose toxicity. Here, we investigated the extent of GlcNAcylation on human erythrocyte proteins and compared site-specific GlcNAcylation on erythrocyte proteins from diabetic and normal individuals

FICD acts bifunctionally to AMPylate and de-AMPylate the endoplasmic reticulum chaperone BiP

Protein folding homeostasis in the endoplasmic reticulum (ER) is defended by an unfolded protein response that matches ER chaperone capacity to the burden of unfolded proteins. As levels of unfolded proteins decline, a metazoan-specific FIC-domain-containing ER-localized enzyme (FICD) rapidly inactivates the major ER chaperone BiP by AMPylating T518. Here we show that the single catalytic domain of FICD can also release the attached AMP, restoring functionality to BiP. Consistent with a role for endogenous FICD in de-AMPylating BiP, FICD$_{-/-}$ hamster cells are hypersensitive to introduction of a constitutively AMPylating, de-AMPylation-defective mutant FICD. These opposing activities hinge on a regulatory residue, E234, whose default state renders FICD a constitutive de-AMPylase $\textit{in vitro}$. The location of E234 on a conserved regulatory helix and the mutually antagonistic activities of FICD $\textit{in vivo}$, suggest a mechanism whereby fluctuating unfolded protein load actively switches FICD from a de-AMPylase to an AMPylase.Supported by Wellcome Trust Principal Research Fellowship to D.R. (Wellcome 200848/Z/16/Z), a UK Medical Research Council PhD studentship to L.A.P. and a Wellcome Trust Strategic Award to the Cambridge Institute for Medical Research (Wellcome 100140)

Antecedent Hyperglycemia Is Associated With an Increased Risk of Neutropenic Infections During Bone Marrow Transplantation

OBJECTIVE—To use bone marrow transplantation (BMT) as a model for testing the association between hyperglycemia and infection

Metabolic syndrome components and their response to lifestyle and metformin interventions are associated with differences in diabetes risk in persons with impaired glucose tolerance

Aims To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence. Methods We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years. Results In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3–2.3), 1.7 (1.2–2.3) and 2.0 (1.3–3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk. Conclusions MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence

Association of A1C and Fasting Plasma Glucose Levels With Diabetic Retinopathy Prevalence in the U.S. Population: Implications for diabetes diagnostic thresholds

Abstract OBJECTIVE To examine the association of A1C levels and fasting plasma glucose (FPG) with diabetic retinopathy in the U.S. population and to compare the ability of the two glycemic measures to discriminate between people with and without retinopathy. RESEARCH DESIGN AND METHODS This study included 1,066 individuals aged ≥40 years from the 2005–2006 National Health and Nutrition Examination Survey. A1C, FPG, and 45° color digital retinal images were assessed. Retinopathy was defined as a level ≥14 on the Early Treatment Diabetic Retinopathy Study severity scale. We used joinpoint regression to identify linear inflections of prevalence of retinopathy in the association between A1C and FPG. RESULTS The overall prevalence of retinopathy was 11%, which is appreciably lower than the prevalence in people with diagnosed diabetes (36%). There was a sharp increase in retinopathy prevalence in those with A1C ≥5.5% or FPG ≥5.8 mmol/l. After excluding 144 people using hypoglycemic medication, the change points for the greatest increase in retinopathy prevalence were A1C 5.5% and FPG 7.0 mmol/l. The coefficients of variation were 15.6 for A1C and 28.8 for FPG. Based on the areas under the receiver operating characteristic curves, A1C was a stronger discriminator of retinopathy (0.71 [95% CI 0.66–0.76]) than FPG (0.65 [0.60 – 0.70], P for difference = 0.009). CONCLUSIONS The steepest increase in retinopathy prevalence occurs among individuals with A1C ≥5.5% and FPG ≥5.8 mmol/l. A1C discriminates prevalence of retinopathy better than FPG. Tests of glycemia and their thresholds for diabetes diagnosis is an area of long-standing debate. The presence of diabetic retinopathy is arguably the best criterion from which to compare glycemic measures because it is a specific and early clinical complication usually related to diabetes, and it represents a specific and relevant clinical end point for judging an alternative test (1). For these reasons, diabetic retinopathy has served as the basis for diagnostic criteria of type 2 diabetes (2–4) and provides the rationale for the American Diabetes Association's recommendation of a threshold of a fasting plasma glucose (FPG) of 7.0 mmol/l to define the presence of diabetes (4,5). However, an analysis of three recent population-based cross-sectional studies suggested that there may be considerable variation across populations and that the association of FPG with retinopathy prevalence may be more of a continuous relationship than previously thought (5). A1C levels are being considered as an alternative diagnostic tool for diabetes diagnosis (6). Unlike FPG, A1C does not require an overnight fast, is not affected by short-term lifestyle changes, and has less variability within individuals than FPG (7–9). Nevertheless, few studies have examined the prevalence of retinopathy across the spectrum of A1C levels, which could assist in the designation of ideal A1C diagnostic cut points (2,3). The newly released National Health and Nutrition Examination Survey (NHANES) 2005–2006 incorporated a multiple-field retinal photograph examination, presenting an opportunity to reassess the selection of glucose and A1C cut points for diabetes diagnosis. Our objectives were to examine the relation between levels of A1C and FPG and prevalence of retinopathy in the U.S. population and to compare the ability of both measures to differentiate people with and without retinopathy

PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress.

Cell and organelle membranes consist of a complex mixture of phospholipids (PLs) that determine their size, shape, and function. Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes, yet how cells sense and regulate its levels in vivo remains unclear. Here we show that PCYT1A, the rate-limiting enzyme of PC synthesis, is intranuclear and re-locates to the nuclear membrane in response to the need for membrane PL synthesis in yeast, fly, and mammalian cells. By aligning imaging with lipidomic analysis and data-driven modeling, we demonstrate that yeast PCYT1A membrane association correlates with membrane stored curvature elastic stress estimates. Furthermore, this process occurs inside the nucleus, although nuclear localization signal mutants can compensate for the loss of endogenous PCYT1A in yeast and in fly photoreceptors. These data suggest an ancient mechanism by which nucleoplasmic PCYT1A senses surface PL packing defects on the inner nuclear membrane to control PC homeostasis