What is the clinical evidence from this study?

Study design: Cross-Sectional. Population: Obesity (n=14). Intervention: GCKR rs1260326 TT genotype vs. GCKR rs1260326 CC genotype. Primary outcome: Fasting fractional hepatic de novo lipogenesis (p=0.036).

June 4, 2015Open Access

Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene

Key Result

The GCKR rs1260326 TT genotype was associated with higher fasting fractional hepatic de novo lipogenesis in obese adolescents compared to the CC genotype (P=0.036).

Study Design

Type

Cross-Sectional (n=14)

Structured PICO

Does the GCKR rs1260326 variant increase hepatic de novo lipogenesis in obese adolescents?

Population

14 obese adolescents, 7 homozygous for the common allele (CC) and 7 homozygous for the risk allele (TT) of the GCKR rs1260326 variant.

Exposure

GCKR rs1260326 risk allele (TT genotype) and carbohydrate drink challenge (75 g glucose and 25 g fructose)

Comparator

GCKR rs1260326 common allele (CC genotype) and carbohydrate drink challenge

Outcome

Hepatic de novo lipogenesis (DNL) during the fasting state and after consumption of a carbohydrate drinksurrogate

The GCKR rs1260326 risk variant is associated with increased hepatic de novo lipogenesis and altered glucose oxidation in obese adolescents, highlighting a genetic link to hypertriglyceridemia.

Main Result

p-value: p=0.036

Abstract

OBJECTIVE: This study's aim was to evaluate whether the GCKR rs1260326 variant increases hepatic de novo lipogenesis (DNL). SETTING AND DESIGN: To test this hypothesis, 14 adolescents, seven homozygous for the common allele (CC) and seven homozygous for the risk allele (TT), underwent measurement of hepatic DNL during the fasting state and after consumption of a carbohydrate (CHO) drink (75 g glucose and 25 g fructose). DNL was assessed through incorporation of deuterium in the palmitate contained in the very low-density lipoprotein. RESULTS: Subjects with TT demonstrated higher fasting fractional DNL (P = .036) and a lower increase in fractional DNL after the CHO challenge (P = .016). With regard to absolute lipogenesis, TT subjects had both higher fasting rates (P = .015) and 44% greater area under the curve of absolute lipogenesis during the study (P = .016), compared to CC subjects. Furthermore, subjects carrying the TT genotype showed higher basal rates of glucose oxidation (P = .0028) and a lower ability than CC subjects to increase the rates of glucose oxidation after the CHO load (P = .054). CONCLUSIONS: This study reports for the first time rates of DNL in obese adolescents and suggests that the GCKR rs1260326 gene variant, which is associated with greater glycolysis, increases hepatic DNL. These data highlight the role of glycolytic carbon flux in liver lipid synthesis and hypertriglyceridemia in these youngsters.