A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice - PubMed
pubmed.ncbi.nlm.nih.gov
Ketogenic diets (KDs)-very-low-carbohydrate and very-high-fat diets-have gained popularity as therapeutic against obesity and type 2 diabetes. However, their long-term effects on metabolic health remain understudied. Here, we show that, in male and female mice, a KD protects against weight gain and …

Sci Adv. 2025 Sep 19;11(38):eadx2752. doi: 10.1126/sciadv.adx2752. Epub 2025 Sep 19.

ABSTRACT

Ketogenic diets (KDs)-very-low-carbohydrate and very-high-fat diets-have gained popularity as therapeutic against obesity and type 2 diabetes. However, their long-term effects on metabolic health remain understudied. Here, we show that, in male and female mice, a KD protects against weight gain and induces weight loss but over time leads to the development of hyperlipidemia, hepatic steatosis, and severe glucose intolerance. Unlike mice on conventional high-fat diet, KD-fed mice remain insulin sensitive and display low-insulin levels. Hyperglycemic clamp and ex vivo glucose-stimulated insulin secretion assays revealed systemic and cell-intrinsic impairments in insulin secretion. Transcriptomic profiling of islets from KD-fed mice indicated endoplasmic reticulum (ER)/Golgi stress and disrupted ER-Golgi protein trafficking, which were confirmed by electron microscopy showing a dilated Golgi network consistent with defective insulin granule trafficking and secretion. Together, these results suggest that long-term KD leads to multiple aberrations of metabolic parameters that caution their systematic use as a health-promoting dietary intervention.

PMID:40971428 | PMC:PMC12448075 | DOI:10.1126/sciadv.adx2752

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