by KeAi Communications Co.

GKA treatment improved glucose tolerance in diet-induced obese mice. (A) Cartoon of the experimental design. (B) The body weight of the chow diet (CD) and high-fat diet (HFD) fed mice (n = 10 for each group). (C, D) IPGTT and ITT of mice fed an HFD or CD for 16 weeks (n = 4–5 for each group). (E, F) OGTT analysis of mice with different treatments for 4 weeks, indicated as CD + Vehicle, CD + GKA, HFD + Vehicle, and HFD + GKA. AUC was shown in (F) (n = 5 for each group). (G) ITT and (H) AUC as well as (I) normalized ITT analysis after 30 days of glucokinase activator (GKA, AZD1656) treatment (n = 5 for each group). (J) The fasting plasma insulin and (K) fasting blood glucose levels were analyzed as indicated (n = 5 for each group). (L) HOMA-β and (M) HOMA-IR were calculated accordingly as described in the “materials and methods” section (n = 5 for each group). The heatmaps of (N) glucose metabolism and (O) insulin signaling pathway related genes from indicated groups of mice were demonstrated from transcriptomic analysis (n = 3 for each group). (P, Q) Protein expressions of the insulin signaling pathway were determined by Western blot, with quantification shown in (Q) (n = 3 for each group). Data are presented as the mean ± standard deviation (SD), ^∗P < 0.05, ^∗∗P < 0.01, ^∗∗∗P < 0.001, ^∗∗∗∗P < 0.0001. Abbreviations: Acadl, acyl-CoA dehydrogenase long chain; AUC, area under the curve; GSK3β, glycogen synthase kinase 3beta; HOMA-IR, homeostatic model assessment for insulin resistance; HSP90, heat shock protein 90; Igfbp, insulin-like growth factor binding protein; Igf2r, insulin-like growth factor 2 receptor; IPGTT, intraperitoneal glucose tolerance test; ITT, insulin tolerance test; Mknk2, MAP kinase interacting serine/threonine kinase 2; Mtor, mechanistic target of rapamycin; OGTT, oral glucose tolerance test; Pck1, phosphoenolpyruvate carboxykinase 1; Pfkl, liver-type subunit of phosphofructokinase; Pklr, pyruvate kinase; Pkm, pyruvate kinase M; Prkacb, protein kinase cAMP-activated catalytic subunit beta; Pygl, glycogen phosphorylase L. Credit: Liver Research (2023). DOI: 10.1016/j.livres.2023.05.003

Obesity is a major risk factor for metabolic disorders including non-alcoholic fatty liver disease and type 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 factors.

Furthermore, approximately one-fifth of the global population suffers from non-alcoholic fatty liver disease, and 56% of these individuals have been diagnosed with type 2 diabetes. The number of patients diagnosed with both conditions is expected to rise continuously.

Recently, glucokinase activators (GKAs) have emerged as a breakthrough in treating type 2 diabetes. Marketed drugs such as dorzagliatin have proven effective in lowering blood glucose levels. However, GKAs may disrupt lipid metabolism, leading to fat accumulation in the liver.

Consequently, more research is required to establish the safety of GKAs in type 2 diabetes patients who also have non-alcoholic fatty liver disease. Additionally, the link between hepatic glucokinase activation and the endoplasmic reticulum stress response remains ambiguous. Further studies are needed to clarify this relationship.

In a study published in Liver Research, a research team in China found that GKAs improved glucose tolerance and insulin sensitivity. However, 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 study 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 diet-induced obese mice using glucose and insulin tolerance tests," explained Nan Cai, lead author of the author.

The team's findings indicated that GKA enhanced glucose tolerance by improving both islet β cell function and insulin signaling. Additionally, GKA exacerbated hepatic lipid accumulation in diet-induced obese mice, 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 activates the PERK-UPR pathway. The findings provide a theoretical basis and reference for the application of GKAs in personalized treatment of chronic diseases such as type 2 diabetes and non-alcoholic fatty liver disease.

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

Provided by KeAi Communications Co.