The G-250A Promoter Polymorphism of the Hepatic Lipase Gene Predicts the Conversion from Impaired Glucose Tolerance to Type 2 Diabetes Mellitus: The Finnish Diabetes Prevention Study

Abstract

In population-based studies, dyslipidemia related to insulin resistance (high triglyceride level and low high-density lipoprotein cholesterol level) is a risk factor for type 2 diabetes. Therefore, variants in genes regulating lipid and lipoprotein metabolism are potential candidate genes for diabetes. We investigated whether the G-250A polymorphism of the hepatic lipase gene (LIPC) predicts the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. This study randomized subjects to either the intervention group (lifestyle modification aimed at weight loss, such as changes in diet and increased physical exercise) or the control group. Genotyping at position -250 of the LIPC gene was performed with PCR amplification, DraI enzyme digestion, and gel electrophoresis in 490 subjects with IGT whose DNA was available. In the entire study population, the conversion rate to type 2 diabetes was 17.8% among subjects with the G-250G genotype and 10.7% among subjects with the -250A allele (P = 0.032). In univariate analysis, the odds ratio for the G-250G genotype to predict the conversion from IGT to type 2 diabetes was 1.80 (95% confidence interval, 1.05-3.10; P = 0.034). In multivariate logistic regression analysis, the G-250G genotype predicted the conversion to diabetes independently of the study group (control or intervention), gender, weight, waist circumference at baseline, and change in weight and waist circumference. In the intervention group, 13.0% of subjects with the G-250G genotype and 1.0% of the subjects with the -250A allele converted to diabetes (P = 0.001). We conclude that the G-250G genotype of the LIPC gene is a risk factor for type 2 diabetes. Therefore, genes regulating lipid and lipoprotein metabolism may be potential candidate genes for type 2 diabetes.

Hepatic Lipase Gene Variant −514C>T Is Associated With Lipoprotein and Insulin Sensitivity Response to Regular Exercise

“…The second European Atherosclerosis Research Study reported that T allele carriers have the lowest glucose tolerance (24). Recently, the LIPC-205GϾA polymorphism, which is in complete linkage disequilibrium with the LIPC Ϫ514CϾT, has been reported to predict the conversion from impaired glucose tolerance to type 2 diabetes in a 3-year follow-up lifestyle intervention (25).…”

The G‐250A substitution in the promoter region of the hepatic lipase gene is associated with the conversion from impaired glucose tolerance to type 2 diabetes: the STOP‐NIDDM trial

“…We have previously shown that the rare -250A allele was protective from diabetes compared with the G-250G genotype in the FDPS [20]. To compare results of the STOP-NIDDM trial with those of the FDPS we analysed the conversion rate to type 2 diabetes in Finnish subjects (n ¼ 150) from the STOP-NIDDM trial.…”

“…Todorova et al [20] reported that the G-250G genotype was associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study (FDPS). Therefore, we investigated whether the G-250A promoter polymorphism of the LIPC gene predicts the conversion from IGT to type 2 diabetes in another diabetes prevention study, the STOP-NIDDM trial, which included subjects from nine different populations [21].…”

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

“…Interestingly, HL deficiency did not change body weight or food intake in the mice (Escola-Gil et al 2013). In humans, genetic studies have linked HL gene polymorphisms to progression of abdominal obesity and T2DM (Todorova et al 2004). Reduced abdominal obesity and weight loss in subjects are associated with reduced HL activity and prevention of T2DM (Bergeron et al 2001, Todorova et al 2004.…”

“…In humans, genetic studies have linked HL gene polymorphisms to progression of abdominal obesity and T2DM (Todorova et al 2004). Reduced abdominal obesity and weight loss in subjects are associated with reduced HL activity and prevention of T2DM (Bergeron et al 2001, Todorova et al 2004. Other studies have shown that HL gene is associated with dyslipidemia characterised by high levels of atherogenic LDL, low HDL and high triglycerides (Teslovich et al 2010).…”