Distinct Effects of a Novel GCK-MODY Mutation on Lipid Profiles and Diabetic Complications

Glucokinase (GK) encoded by glucokinase gene (GCK) is the first rate-limiting enzyme in glucose metabolism. The heterozygous inactivating mutations of GCK cause maturity-onset diabetes of the young (GCK-MODY). Unlike other types of diabetes, GCK-MODY is not associated with increased risks of diabetic complications in young patients. However, the long-term effects of mutant GK on lipid profiles and chronic complications in elder patients remain unknown. Herein, we established a knock-in mouse model heterozygeously expressing a novel GCK mutation encoding GK-Q26L that was identified in a Chinese family with early onset diabetes. GK-Q26L mice developed mild early onset diabetes with moderate elevated blood glucose and decreased serum insulin, confirming diabetogenes of GK-Q26L. To determine age- and diet-related diabetic complications and lipid profiles, we have fed the mice with either chow diet or high-fat diet (HFD) for 28, 40, or 60 weeks. We found that, after 28 week of HFD, GK-Q26L alleviated abnormal lipid profiles in plasma and liver, suggesting beneficial effects of GK-Q26L on lipid metabolism. Surprisingly however, those protective effects were disappeared at 40 weeks, and at 60 weeks of HFD, GK-Q26L mice exhibited even more severe abnormal lipid profiles. Consistent with the distinct trends of lipid profiles, HFD-induced kidney injury (increased urinary albumin/creatinine ratio and renal fibrosis) was also alleviated in GK-Q26L mice at 28 weeks of HFD, but aggravated at 60 weeks of HFD. Similar effects on diabetic retinopathy were observed in GK-Q26L mice. These data reveal for the first time that although inactivating GCK mutations have beneficial effects on HFD-induced abnormal lipid metabolism and diabetes related damages of kidney and retina in short-term, it is strongly associated with long-term diabetic nephropathy and retinopathy. This study suggests that more attention should be paid on the long-term chronic complications in elder patients with GCK-MODY. Disclosure Y.Huang: None. Y.Fan: None. X.Li: None. S.Ji: None. S.Chen: None. J.Cui: None. W.Feng: None. H.Shu: None. M.Liu: None. Funding National Natural Science Foundation of China (81830025, 82220108014, 82100865, 81800733, 81900720, 82000796, 82070854); National Key R&D Program of China (2019YFA0802502, 2022YFE0131400); Tianjin Key Medical Discipline Construction Project (TJYXZDXK-030A)