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GKA improves glucose tolerance and induces hepatic lipid accumulation in mice with diet-induced obesity

GKA improves glucose tolerance and induces hepatic lipid accumulation in mice with diet-induced obesity
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 , 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 . However, GKAs may disrupt , leading to 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 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 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 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

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