Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels
A new article published in Diabetologia (February 2017) by Danish Diabetes Academy Post Doc Yuvaraj Mahendran, suggests that higher branched-chain amino acid (BCAA) levels do not have a causal effect on insulin resistance, while increased insulin resistance drives higher circulating fasting BCAA levels.
MENDELIAN RANDOMISATION STUDY TO DISENTANGLE THE CAUSAL RELATION
In this project, the circulating BCAA levels in blood plasma were measured by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort.
Yuvaraj Mahendran and his group complemented their analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 46,186) and from a GWAS of serum BCAA levels (n = 24,925). They used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels.
INSULIN RESISTANCE INCREASING GRS ASSOCIATE WITH INCREASED BCAA LEVELS
"We showed that the insulin-resistance-increasing GRS was significantly associated with increased BCAA levels in ADDITION-PRO and in GWAS results for serum BCAA levels. And the instrumental variable analyses in ADDITION-PRO indicated that HOMA-IR is causally related to higher circulating fasting BCAA levels", states Yuvaraj Mahendran.
BCAA LEVELS AND INSULIN RESISTANCE
Fasting plasma BCAA levels were associated with higher HOMA-IR in ADDITION-PRO. However, the GRS for circulating BCAA levels was not associated with fasting insulin levels or HOMA-IR in ADDITION-PRO or in GWAS results for HOMA-IR from MAGIC.
INSULIN RESISTANCE DRIVES HIGHER CIRCULATING BCAA LEVELS
"Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance, while increased insulin resistance drives higher circulating fasting BCAA levels", Yuvaraj Mahendran concludes.
AUTHORS AND AFFILIATION
Yuvaraj Mahendran1,2, Anna Jonsson1, Christian Theil Have1, Kristine Højgaard Allin1, Daniel R. Witte 2,3, Marit Eika Jørgensen4, Niels Grarup1, Oluf Pedersen1, Tuomas O. Kilpeläinen1, Torben Hansen1
1Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
2Danish Diabetes Academy, Odense, Denmark
3Institute of Public Health, University of Aarhus, Aarhus, Denmark
4Steno Diabetes Center, Gentofte, Denmark
Source: Diabetologia