St-Pierre J, Vohl M C, Brisson D, Perron P, Després J P, Hudson T J, Gaudet D
Dyslipidemia, Diabetes and Atherosclerosis Research Group, Chicoutimi Hospital, Quebec, Canada.
Mol Genet Metab. 2001 Mar;72(3):209-17. doi: 10.1006/mgme.2000.3144.
FAD-dependent glycerol-3-phosphate dehydrogenase (mGPD) enzyme is located in the mitochondrial inner membrane where it catalyzes irreversible oxidation reactions. Type 2 diabetes mellitus (DM) is a multifactorial disorder associated with physiological abnormalities in the glycerol and free fatty acids (FFA) metabolic pathways. In the present study, we have evaluated the association among the mGPD H264R sequence variation and postabsorptive plasma FFA and glycerol concentrations in a sample of French Canadians with and without type 2 DM. A sample of 81 recently diagnosed type 2 DM and 318 nondiabetic, nonobese, normotriglyceridemic French Canadians were screened for the presence of the mGPD H264R genetic variant using a PCR-RFLP-based method. The 318 nondiabetic subjects were free of known type 2 DM covariates (fasting glucose <7.0 mmol/L, body mass index <29 kg/m(2), fasting glycerol <2.0 mmol/L and absence of the N288D sequence variation in the glycerol kinase gene, fasting triglyceride <2.5 mmol/L). The association of mGPD H264R sequence variation with plasma FFA and glycerol concentrations was assessed in different regression models. Among non-DM individuals, the R allele (HR and RR genotypes) was associated with increased plasma FFA and glycerol concentrations (P < 0.05). However, the mean plasma FFA and glycerol concentrations were not affected by the H264R genotype in the type 2 DM sample. Overall, mean plasma FFA concentrations in non-DM RR homozygotes reached values that were similar to those achieved in patients with type 2 diabetes (0.87 +/- 0.63 vs 0.90 +/- 0.48 mmol/L). After controlling for age, gender, body mass index, fasting glucose, and fasting triglyceride concentrations, the relative odds of having fasting plasma FFA levels above the 90th percentile (0.9 mmol/L) in the absence of DM was increased by twofold in H264R heterozygotes (P = 0.04) and fourfold among R264 homozygotes (P = 0.009) compared to noncarriers. In the absence of DM, the mGPD R allele was also associated with higher plasma glycerol concentrations (P < 0.05). Results in non-DM individuals suggest that the mGPD R allele is associated with DM intermediate phenotypes. The absence of a relation between mGPD genotype and DM is in accordance with the view that DM is a complex phenotype in which increased plasma FFA or glycerol concentrations result from metabolic alterations which might obscure the effect of the mGPD polymorphism.
黄素腺嘌呤二核苷酸（FAD）依赖性甘油-3-磷酸脱氢酶（mGPD）位于线粒体内膜，在那里催化不可逆的氧化反应。2型糖尿病（DM）是一种多因素疾病，与甘油和游离脂肪酸（FFA）代谢途径中的生理异常有关。在本研究中，我们评估了法裔加拿大人样本中mGPD H264R序列变异与吸收后血浆FFA和甘油浓度之间的关联，这些样本中有2型糖尿病患者和无2型糖尿病患者。使用基于聚合酶链反应-限制性片段长度多态性（PCR-RFLP）的方法，对81例新诊断的2型糖尿病患者以及318例非糖尿病、非肥胖、正常甘油三酯血症的法裔加拿大人样本进行了mGPD H264R基因变异筛查。318例非糖尿病受试者无已知的2型糖尿病协变量（空腹血糖<7.0 mmol/L、体重指数<29 kg/m²、空腹甘油<2.0 mmol/L以及甘油激酶基因中不存在N288D序列变异、空腹甘油三酯<2.5 mmol/L）。在不同的回归模型中评估了mGPD H264R序列变异与血浆FFA和甘油浓度之间的关联。在非糖尿病个体中，R等位基因（HR和RR基因型）与血浆FFA和甘油浓度升高相关（P<0.05）。然而，2型糖尿病样本中的血浆FFA和甘油平均浓度不受H264R基因型影响。总体而言，非糖尿病RR纯合子的血浆FFA平均浓度达到了与2型糖尿病患者相似的值（0.87±0.63 vs 0.90±0.48 mmol/L）。在控制了年龄、性别、体重指数、空腹血糖和空腹甘油三酯浓度后，与非携带者相比，非糖尿病患者空腹血浆FFA水平高于第90百分位数（0.9 mmol/L）的相对几率在H264R杂合子中增加了两倍（P = 0.04），在R264纯合子中增加了四倍（P = 0.009）。在无糖尿病的情况下，mGPD R等位基因也与较高的血浆甘油浓度相关（P<0.05）。非糖尿病个体的结果表明，mGPD R等位基因与糖尿病中间表型相关。mGPD基因型与糖尿病之间不存在关联，这与以下观点一致，即糖尿病是一种复杂的表型，其中血浆FFA或甘油浓度升高是由代谢改变引起的，这可能掩盖了mGPD多态性的影响。
