The researchers demonstrated that glucokinase activation was effective in lowering blood glucose in mice with high-fat diet-induced obesity, while it potentially raised the chance of accelerating hepatic lipid accumulation that triggered the PERK-UPR pathway. Thus, this study provides clinical reference and theoretical basis for the appliance of glucokinase activator (GKA) in treating patients with type 2 diabetes (or combined with non-alcoholic fatty liver disease).

Obesity is a significant risk factor for metabolic disorders including non-alcoholic fatty liver disease and kind 2 diabetes. It has been reported that non-alcoholic fatty liver disease doubles the likelihood of developing type 2 diabetes, independent of obesity and other metabolic risk aspects. Moreover, roughly one-fifth of the worldwide population suffers from non-alcoholic fatty liver disease, and 56% of those individuals have been diagnosed with type 2 diabetes. The variety of patients diagnosed with each conditions is anticipated to rise repeatedly.

Recently, glucokinase activators (GKAs) have emerged as a breakthrough in treating type 2 diabetes. Marketed drugs reminiscent of dorzagliatin have proven effective in lowering blood glucose levels. Nevertheless, GKAs may disrupt lipid metabolism, resulting in fat accumulation within the liver. Consequently, more research is required to determine the security of GKAs in type 2 diabetes patients who even have non-alcoholic fatty liver disease. Moreover, the link between hepatic glucokinase activation and the endoplasmic reticulum stress response stays ambiguous. Further studies are needed to make clear this relationship.

In a study published within the KeAi journal Liver Research, a research team in China found that GKAs improved glucose tolerance and insulin sensitivity. Nevertheless, under high-fat weight loss program feeding, GKAs also induced hepatic lipid accumulation by increasing lipogenic gene expression, which subsequently activated the hepatic PERK-UPR signaling pathway.

We established a mouse model with high-fat diet-induced obesity to check the impact of GKA treatment on glucose and lipid metabolism in obese mice. We then evaluated the effect of GKA treatment on glucose metabolism in mice with diet-induced obesity using glucose and insulin tolerance tests.”

Nan Cai, lead creator

The team’s findings indicated that GKA enhanced glucose tolerance by improving each islet β cell function and insulin signaling. Moreover, GKA exacerbated hepatic lipid accumulation in mice ate up high-fat weight loss program, while not in mice fed with chow weight loss program, as demonstrated by hematoxylin and eosin staining, Oil Red O staining, and transmission electron microscopy. This accumulation induced hepatic pathological changes.

Overall, the study illustrated that while glucokinase activation improves glucose tolerance in mice with diet-induced obesity, it also induces hepatic lipid accumulation that prompts the PERK-UPR pathway. The findings provide a theoretical basis and reference for the appliance of GKAs in personalized treatment of chronic diseases reminiscent of type 2 diabetes and non-alcoholic fatty liver disease.

Source:

Journal reference:

Cai, N., et al. (2023). Glucokinase activator improves glucose tolerance and induces hepatic lipid accumulation in mice with diet-induced obesity. Liver Research. doi.org/10.1016/j.livres.2023.05.003.