Abstract
The prospero homeobox 1 (PROX1) gene may show pleiotropic effects on metabolism. We evaluated postprandial metabolic alterations dependently on the rs340874 genotypes, and 28 non-diabetic men were divided into two groups: high-risk (HR)-genotype (CC-genotype carriers, n = 12, 35.3 ± 9.5 years old) and low-risk (LR)-genotype (allele T carriers, n = 16, 36.3 ± 7.0 years old). Subjects participated in two meal-challenge-tests with high-carbohydrate (HC, carbohydrates 89%) and normo-carbohydrate (NC, carbohydrates 45%) meal intake. Fasting and 30, 60, 120, and 180 min after meal intake plasma samples were fingerprinted by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In HR-genotype men, the area under the curve (AUC) of acetylcarnitine levels was higher after the HC-meal [+92%, variable importance in the projection (VIP) = 2.88] and the NC-meal (+55%, VIP = 2.00) intake. After the NC-meal, the HR-risk genotype carriers presented lower AUCs of oxidized fatty acids (−81–66%, VIP = 1.43–3.16) and higher linoleic acid (+80%, VIP = 2.29), while after the HC-meal, they presented lower AUCs of ornithine (−45%, VIP = 1.83), sphingosine (−48%, VIP = 2.78), linoleamide (−45%, VIP = 1.51), and several lysophospholipids (−40–56%, VIP = 1.72–2.16). Moreover, lower AUC (−59%, VIP = 2.43) of taurocholate after the HC-meal and higher (+70%, VIP = 1.42) glycodeoxycholate levels after the NC-meal were observed. Our results revealed differences in postprandial metabolites from inflammatory and oxidative stress pathways, bile acids signaling, and lipid metabolism in PROX1 HR-genotype men. Further investigations of diet–genes interactions by which PROX1 may promote T2DM development are needed.
Highlights
Type 2 diabetes mellitus (T2DM) is a major public health issue affecting 415 million people worldwide in 2015 [1], and it is expected that it will affect over 439 million people by 2030 [2] and 642 million by 2040 [1]
We hypothesize that one of the pathways involved in the T2DM development in subjects with the prospero homeobox 1 (PROX1) rs340874 CC genotype may be a lipid metabolism path, and its further oxidative stress consequences can be modulated by different diets with varying macronutrients content
The studied genotypes groups were well matched without any between-group differences in age, anthropometric measurements, body mass index (BMI), body fat and fat free mass content, fasting glucose and insulin concentrations, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), HOMA-B, and glycated hemoglobin (HbA1c)
Summary
Type 2 diabetes mellitus (T2DM) is a major public health issue affecting 415 million people worldwide in 2015 [1], and it is expected that it will affect over 439 million people by 2030 [2] and 642 million by 2040 [1]. The T2DM is characterized by impaired β-cell function and insulin resistance, which leads to chronic hyperglycemia [3]. The Genome-Wide Association Studies (GWAS) and other, different scale meta-analyses and studies have indicated that the rs340874 single nucleotide polymorphism (SNP) in the prospero homeobox 1 (PROX1) gene is a strong genetic susceptibility factor for T2DM [4,5,6]. It has been shown that allele C of rs340874 is associated with reduced insulin sensitivity, β-cell function, insulin secretion, and fasting glucose levels [7,8,9]. It has been suggested that reduced expression of PROX1 results in altered β-cell insulin secretion and thereby confers the T2DM susceptibility [5]
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