Background: Diabetic kidney disease (DKD) is a common microvascular complication of diabetes. Despite intensive diabetes care, the prevalence of DKD remains high, and the current clinical management of DKD stabilizes but does not improve kidney function, indicating an urgent need for innovative treatment strategies to prevent DKD. In this regard, the ketogenic diet (KD), a high-fat, very low-carbohydrate diet with adequate protein, has generated tremendous global excitement because of the multidimensional roles of ketone bodies in attenuating inflammation and oxidative stress. Thus, this study aimed to test whether a KD could reduce the incidence of DKD and slow its progression in diabetic mice.
METHODS AND RESULTS:
Methods: 7-week-old male C57BL/6J mice were fed a high-fat diet (HFD) for 16 weeks and received 1 or 2 streptozotocin injections to induce type 2 diabetes (T2D). Only mice with fasting blood glucose >16 mM were considered T2D diabetic, and herein were referred to as diabetic mice. 16 weeks-post diet, diabetic mice either continued HFD feeding, switched to KD, or were treated with endogenous ketone precursor (1,3-butanediol, 2 g/kg; daily/orally) while remaining on the HFD for 6 weeks. Throughout the study design, we also fed mice a low-fat diet (LFD) for 20 weeks to serve as lean control mice.
Results: Diabetic mice switched to KD exhibited marked elevation in circulating β-hydroxybutyrate (β-OHB) levels, the most abundant ketone body, and significant reductions in body weight and blood glucose concentrations compared to their control diabetic mice. Furthermore, these reductions were associated with improvement in glucose homeostasis (glucose and insulin tolerance test), systolic blood pressure, and albuminuria (albumin to creatinine ratio) to levels that matched those lean mice fed an LFD. Consistent with the albuminuria findings, switching to KD reversed glomerular hypertrophy, mesangial expansion, and glomerular basement membrane (GBM) thickening compared to diabetic control mice. Interestingly, despite the elevation of circulating β-OHB levels in the ketone precursor group to similar levels observed in the KD group, diabetic mice treated with 1,3-butanediol showed no changes in metabolic parameters and albuminuria but displayed modest improvement in glomerular hypertrophy, mesangial expansion and GBM thickening relative to diabetic control mice.
Conclusion:
Conclusion: Our findings suggest that KD is a more effective treatment strategy than ketone precursor to improve, treat and reverse DKD. Nevertheless, it remains to be tested whether KD-induced renoprotection is mediated via attenuating inflammatory and oxidative stress responses or simply attributed to reductions in body weight and hyperglycemia.