Genetics of Complex Traits, Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.
Diabetes. 2011 Mar;60(3):1008-18. doi: 10.2337/db10-1317. Epub 2011 Jan 31.
The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance.
We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies.
Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002).
Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.
循环甘油三酯、胰岛素抵抗与 2 型糖尿病之间关联的因果关系尚不清楚。本研究旨在采用孟德尔随机化方法检验以下假说，即循环甘油三酯水平升高可导致 2 型糖尿病风险增加，并升高正常空腹血糖水平和肝胰岛素抵抗。
我们在 5637 例病例和 6860 例对照以及来自四项研究的 8271 名非糖尿病个体中，针对四项连续结局（反映血糖和肝胰岛素抵抗），检验了 10 种与循环甘油三酯水平显著相关的常见遗传变异与 2 型糖尿病状态之间的关联。
携带较多致甘油三酯升高等位基因的个体，其循环甘油三酯水平升高（20%携带最多等位基因的个体与 20%携带最少等位基因的个体之间差异为 0.59[95%CI 0.52-0.65]）。但携带较多致甘油三酯升高等位基因的个体，其发生 2 型糖尿病的风险并未增加（每增加一个加权等位基因的比值比[OR]为 0.99[95%CI 0.97-1.01]；P = 0.26）。在非糖尿病个体中，携带较多致甘油三酯升高等位基因的个体，空腹胰岛素水平也未见升高（每增加一个加权等位基因增加 0.00[95%CI -0.01 至 0.02]；P = 0.72）或空腹血糖水平升高（0.00[-0.01 至 0.01]；P = 0.88）。工具变量分析证实，循环甘油三酯水平升高与糖尿病风险、空腹血糖或空腹胰岛素水平增加无关，并且提示糖尿病风险降低的趋势（每增加 1-SD 对数（10）甘油三酯水平，OR：0.61[95%CI 0.45-0.83]；P = 0.002）。
遗传上循环甘油三酯水平升高并不会增加 2 型糖尿病或非糖尿病个体的空腹血糖或空腹胰岛素水平。我们结果的一个解释是，循环甘油三酯升高主要继发于糖尿病疾病过程，而非因果关系。
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