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Congenital disorders of glycosylation (CDG) are metabolic hereditary diseases caused by defects in the synthesis of glycoconjugates. CDG have been described in sugar-nucleotide biosynthesis and transporter, glycosyltransferases, vesicular transport, as well as in lipid biosynthesis and glycosylphosphatidylinositol anchors. PMM2-CDG is caused by mutations in the phosphomannomutase-2 (PMM2) gene and shows autosomal recessive inheritance. It affects all organs and tissues, ranging from severe psychomotor retardation to moderate intellectual disability. Alterations in the primary haemostatic system have been reported in these patients and they can lead to severe bleeding or excessive thrombosis with subsequent vascular insufficiency. Despite of being the most common CDG, platelet glycosylation and sialylation defects in PMM2-CDG patients remain incompletely characterized. In this study, we applied a lectin-based flow cytometry approach to report the first characterization of the highly glycosylated platelet membrane glycan profile in a PMM2-CDG patient. In the PMM2-CDG patient's platelet samples, a decreased binding of SNA lectin, indicative of reduced terminal α-2-6 sialic acid content, and an increased binding of PNA lectin, suggesting desialylation of β-1-Nacetylgalactosamine residues, were observed. Reduced expression of terminal sialic acids in platelet membrane glycoproteins may contribute to the increased risk of hemorrhage reported in these patients by promoting platelet clearance and thrombocytopenia.

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The study was designed to assess the possible augmented antidiabetic effects of combining quercetin and liraglutide in a type 1 diabetes model, with emphasis on the contribution of hepatic thioredoxin interacting protein (TXNIP)/insulin receptor substrate 1 (IRS‐1)/phosphatidyl inositol‐3 kinase (PI3K) pathway. The wound‐healing effects were also examined. Diabetes was induced by a single i.p STZ injection (55 mg/kg). Diabetic rats were treated with either quercetin (100 mg/kg/day, orally) or liraglutide (0.3 mg/kg/twice daily, S.C.) or their combination. Drugs were also applied topically on the wound. Blood glucose levels, serum albumin, total protein, total cholesterol and triglycerides were measured. Histopathological examination of the liver, pancreas and skin tissues was performed using haematoxylin and eosin staining. The hepatic malondialdehyde level was measured spectrophotometrically. Hepatic TXNIP and PI3K levels were measured by enzyme‐linked immunsorbent assay (ELISA). Tissue expression of IRS‐1 and phospho‐IRS‐1 (Ser 616) was assessed by immunohistochemistry. Quercetin, liraglutide and their combination effectively decreased blood glucose levels, improved lipid profile, upregulated albumin and total protein serum levels and reduced hepatic oxidative stress with the combination being most effective. Moreover, the combination group showed enhanced wound‐healing effects and almost normalized hepatic and pancreatic histopathology. Quercetin and/or liraglutide significantly decreased TXNIP levels and serine phosphorylation of IRS‐1 and increased PI3K levels compared to the diabetic untreated group. Interestingly, only the combination therapy normalized hepatic IRS‐1 expression. The combination of quercetin and liraglutide showed enhanced antidiabetic effects, possibly through lowering hepatic TXNIP levels, with the resultant up‐regulation of the IRS‐1/PI3K pathway.