The PhD thesis of Lilian Fernandes Silva, MSc, provides new insight into the pathophysiology and genetics of type 2 diabetes and non-alcoholic fatty liver disease.
Metabolic diseases, including obesity, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are increasing worldwide in epidemic proportions. Therefore, understanding the pathophysiology and genetics of these diseases is of great importance. The PhD work focused on the glucokinase regulatory protein gene (GCKR), a risk gene for T2D, and several genetic variants associated with the risk of NAFLD.
A genetic variant GCKR rs780094 has been previously associated with fasting lactate levels associated with glucose metabolism. The researchers investigated the association of GCKR rs780094 with lactate levels in a frequently sampled oral glucose tolerance test in the participants of the Finnish population-based METSIM study to evaluate the effects of increasing GCKR expression on lactate production in liver cells. The C allele of GCKR rs780094 was associated with lower lactate levels in fasting but increased lactate level during hyperglycemia, independently of insulin levels. Increased expression of GKRP induced higher lactate level in HepG2 cells and in human primary hepatocytes upon glucose stimulation by increasing the amount of GCK. The results suggest that the association of rs780094 with lactate levels may involve differential GCKR expression between the carriers of the C and T alleles.
In another study, a metabolomics approach was applied to measure metabolites in the participants of the METSIM study to investigate the associations of rs780094 of GCKR with metabolites. The researchers found novel negative associations of the T allele of GCKR rs780094 with serine and threonine, and positive associations with two metabolites of tryptophan, indolelactate and N-acetyltryptophan. They also found novel significant positive associations of this genetic variant with 12 glycerolipids and 19 glycerophospholipids, and significant negative associations with three glycerophospholipids, and two sphingolipids. The study adds new information about the pleiotropy of GCKR, and shows the associations of the T allele of GCKR rs780094 with lipids. The associations with lipids are especially interesting as they play an important role in liver disease, especially in NAFLD.
In addition, the researchers investigated the association of several genetic variants increasing the risk for NAFDL (PNPLA3, TM6SF2, MBOAT7, GCKR, SAMM50, MnSOD/SOD2, PEMT, LEPR), and two genetic variants associated with decreased risk of NAFLD (PPP1R3B, HSD17B13) with metabolites in the participants of the METSIM study. Multiple statistically significant associations of genetic variants were identified in seven genes (PNPLA3, TM6SF2, GCKR, MBOAT7, SAMM50, PPP1R3B, HDS17B13) with metabolites reflecting different metabolic pathways regulating the liver fat content. The study adds novel information about the pathways and metabolites affected by multiple genetic variants associated with the risk of NAFLD. These findings demonstrate that multiple metabolic pathways are disrupted in NAFLD. Understanding the pathophysiology of NAFLD is important for planning appropriate diagnostic and treatment approaches for this disease. It is concluded that the studies add important knowledge for understanding of the pathophysiology and genetics of T2D and NAFLD.
The doctoral dissertation of Lilian Fernandes Silva, Master of Science, entitled Phenotypic characterization of genetic variants associated with the risk of type 2 diabetes and non-alcoholic fatty liver disease, will be examined at the Faculty of Health Sciences on 14 April 2020. The Opponent in the public examination will be Professor Risto Kaaja of the University of Turku, and the Custos will be Professor Markku Laakso of the University of Eastern Finland.
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