The Clinical Significance of Glycoprotein Phospholipase D Levels in Distinguishing Early Stage Latent Autoimmune Diabetes in Adults and Type 2 Diabetes

Abstract

Autoantibodies have been widely used as markers of latent autoimmune diabetes in adults (LADA); however, the specificity and sensitivity of autoantibodies as markers of LADA are weak compared with those found in type 1 diabetes (T1DM). In this study, we aimed to identify other plasma proteins as potential candidates that can be used effectively to determine early stage LADA and type 2 diabetes (T2DM) to facilitate early diagnosis and treatment. These issues were addressed by studying new-onset ‘classic’ T1DM (n = 156), LADA (n = 174), T2DM (n = 195) and healthy cohorts (n = 166). Plasma samples were obtained from the four cohorts. We employed isobaric tag for relative and absolute quantitation (iTRAQ) together with liquid chromatography tandem mass spectrometry (LC-MS) to identify plasma proteins with significant changes in LADA. The changes were validated by Western blot and ELISA analyses. Among the four cohorts, 311 unique proteins were identified in three iTRAQ runs, with 157 present across the three data sets. Among them, 49/311 (16.0%) proteins had significant changes in LADA compared with normal controls, including glycoprotein phospholipase D (GPLD1), which was upregulated in LADA. Western blot and ELISA analyses showed that GPLD1 levels were higher in both LADA and T1DM cohorts than in both T2DM and healthy cohorts, while there were no significant differences in the plasma concentrations of GPLD1 between the LADA and T1DM cohorts. GPLD1 is implicated as a potential candidate plasma protein for determining early stage LADA and T2DM.

Structure-function relationships of HDL in diabetes and coronary heart disease

“…On the other hand, the KO of Phld in mice ameliorated glucose intolerance and hepatic steatosis under high-fat and high-sucrose diet (53). Cross-sectional studies found increased plasma levels of GPLD1 in subjects with prediabetes compared with normoglycemic subjects (54) and in patients with diabetes mellitus type 1 compared with both normoglycemic subjects and T2DM patients (55). To solve these controversies, it will be important to unravel the mode of action of GPLD1 in HDL, notably to identify the GPI-anchored proteins that are shed by GPLD1 and modulate apoptosis, as well as mitochondrial potential and respiration.…”

The Biomedical Uses of Inositols: A Nutraceutical Approach to Metabolic Dysfunction in Aging and Neurodegenerative Diseases

“…Current studies appoint the relevance of GPI-PLD in insulin resistance. Significantly increased levels of GPI-PLD have been identified as a novel biomarker of early prediabetes in humans [ 86 ] and early stages of latent autoimmune diabetes in adults and those with type 2 diabetes [ 87 ]. It has been observed that both insulin and glucose stimulate the secretion of GPI-PLD in rat pancreatic islets [ 88 ].…”

Interaction of Full-Length Glycosylphosphatidylinositol-Anchored Proteins with Serum Proteins and Their Translocation to Cells In Vitro Depend on the (Pre-)Diabetic State in Rats and Humans

“…Soon after identification of GPLD1 in rodent and human serum and liver, the regulation of its amount and activity by various metabolism-related factors has attracted much interest. Typically, upregulation of GPLD1 hepatic protein expression and serum level in the diabetic state was found, such as for spontaneously type I diabetic mice [ 75 ], NOD and low-dose Streptozotocin-induced diabetic CD-1 mice [ 54 ], db/db mice [ 76 ], Streptozotocin-induced diabetic mice [ 76 ] and rats [ 77 , 78 ], and mice fed with high-fat and high-sucrose diet [ 76 ]; and for patients with non-alcoholic steatohepatitis [ 79 ], latent autoimmune diabetes in adults [ 80 ], type 1 diabetes [ 80 ], insulin-resistance [ 81 ], and type 2 diabetes [ 82 ]. Downregulation of GPLD1 hepatic expression was reported for obese nondiabetic women on a low-fat diet with re-gain in insulin sensitivity [ 83 ].…”