Apolipoprotein-CIII O-Glycosylation Is Associated with Micro- and Macrovascular Complications of Type 2 Diabetes

• Published in: International journal of molecular sciences 2024-05, Vol.25 (10), p.5365
• Main Authors: Naber, Annemieke, Demus, Daniel, Slieker, Roderick C, Nicolardi, Simone, Beulens, Joline W J, Elders, Petra J M, Lieverse, Aloysius G, Sijbrands, Eric J G, 't Hart, Leen M, Wuhrer, Manfred, van Hoek, Mandy
• Format: Article
• Language: English
• Subjects: Aged; Antilipemic agents; Apolipoprotein C-III - genetics; Apolipoprotein C-III - metabolism; Apolipoproteins; Cardiovascular disease; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetic Angiopathies - etiology; Diabetic Angiopathies - genetics; Diabetic Angiopathies - metabolism; Diabetic retinopathy; Diabetic Retinopathy - etiology; Diabetic Retinopathy - genetics; Diabetic Retinopathy - metabolism; Female; Glycosylation; Health aspects; Humans; Insulin; Lipids; Lipoproteins; Male; Medical care; Medical care, Cost of; Metabolic disorders; Middle Aged; Polymorphism, Single Nucleotide; Primary care; Quality management; Resveratrol; Risk factors; Sensitivity analysis; Type 2 diabetes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25105365

Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII. We investigated the associations of apo-CIII glycosylation in blood plasma, measured by mass spectrometry of the intact protein, and genetic variants with micro- and macrovascular complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) of type 2 diabetes in a DiaGene study ( = 1571) and the Hoorn DCS cohort ( = 5409). Mono-sialylated apolipoprotein-CIII (apo-CIII ) was associated with a reduced risk of retinopathy (β = -7.215, 95% CI -11.137 to -3.294) whereas disialylated apolipoprotein-CIII (apo-CIII ) was associated with an increased risk (β = 5.309, 95% CI 2.279 to 8.339). A variant of the -gene (rs4846913), previously linked to lower apo-CIII , was associated with a decreased prevalence of retinopathy (OR = 0.739, 95% CI 0.575 to 0.951). Higher apo-CIII levels were associated with neuropathy (β = 7.706, 95% CI 2.317 to 13.095) and lower apo-CIII with macrovascular complications (β = -9.195, 95% CI -15.847 to -2.543). In conclusion, apo-CIII glycosylation was associated with the prevalence of micro- and macrovascular complications of diabetes. Moreover, a variant in the -gene was associated with apo-CIII glycosylation and retinopathy, suggesting a causal effect. The findings facilitate a molecular understanding of the pathophysiology of diabetes complications and warrant consideration of apo-CIII glycosylation as a potential target in the prevention of diabetes complications.