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1.  Mendelian Randomization Studies Do Not Support a Role for Raised Circulating Triglyceride Levels Influencing Type 2 Diabetes, Glucose Levels, or Insulin Resistance 
Diabetes  2011;60(3):1008-1018.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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 log10 triglycerides: 0.61 [95% CI 0.45–0.83]; P = 0.002).
CONCLUSIONS
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.
doi:10.2337/db10-1317
PMCID: PMC3046819  PMID: 21282362
2.  Mendelian Randomization Studies do not Support a Role for Raised Circulating Triglyceride Levels influencing Type 2 Diabetes, Glucose Levels, or Insulin Resistance 
Diabetes  2011;60(3):1008-1018.
Objective
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, raised normal fasting glucose levels, and hepatic insulin resistance.
Research design and methods
We tested 10 common genetic variants robustly associated with circulating triglyceride levels against type 2 diabetes status in 5637 cases, 6860 controls, and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8271 non-diabetic individuals from four studies.
Results
Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (0.59 SD [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 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 non-diabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (0.00 SD per weighted allele [95% CI: −0.01, 0.02]; P = 0.72) or increased fasting glucose levels (0.00 SD per weighted allele [95% CI: −0.01, 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 towards a protective association (OR per 1 SD increase in log10-triglycerides: 0.61 [95% CI: 0.45, 0.83]; P = 0.002).
Conclusion
Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes, or raise fasting glucose or fasting insulin levels in non-diabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.
doi:10.2337/db10-1317
PMCID: PMC3046819  PMID: 21282362

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