Ketogenic diet administration to mice after a high-fat-diet regimen promotes weight loss, glycemic normalization and induces adaptations of ketogenic pathways in liver and kidney.

OBJECTIVE: The ketogenic diet (KD), characterized by very limited dietary carbohydrate intake and used as nutritional treatment for GLUT1-deficiency syndromes and pharmacologically refractory epilepsy, may promote weight loss and improve metabolic fitness, potentially alleviating the symptoms of osteoarthritis. Here, we have studied the effects of administration of a ketogenic diet in mice previously rendered obese by feeding a high fat diet (HFD) and submitted to surgical destabilization of the medial meniscus to mimic osteoarthritis. METHODS: 6-weeks old mice were fed an HFD for 10 weeks and then switched to a chow diet (CD), KD or maintained on a HFD for 8 weeks. Glycemia, ß-hydroxybutyrate (BHB), body weight and fat mass were compared among groups. In liver and kidney, protein expression and histone post-translational modifications were assessed by Western blot, and gene expression by quantitative Real-Time PCR. RESULTS: After a 10 weeks HDF feeding, administration for 8 weeks of a KD or CD induced a comparable weight loss and decrease in fat mass, with better glycemic normalization in the KD group. Histone ß-hydroxybutyrylation, but not histone acetylation, was increased in the liver and kidney of mice fed the KD and the rate-limiting ketogenic enzyme HMGCS2 was upregulated - at the gene and protein level - in liver and, to an even greater extent, in kidney. KD-induced HMGCS2 overexpression may be dependent on FGF21, whose gene expression was increased by KD in liver. CONCLUSIONS: Over a period of 8 weeks, KD is more effective than a chow diet to induce metabolic normalization. Besides acting as a fuel molecule, BHB may exert its metabolic effects through modulation of the epigenome - via histone ß-hydroxybutyrylation - and extensive transcriptional modulation in liver and kidney.

Time impact on the antidiabetic effects of key bariatric surgeries: a network meta-analysis of randomized controlled trials with meta-regression.

BACKGROUND: Few studies compare the efficacy of the key bariatric procedures in type 2 diabetes management over the long term. None offer a reliable comparison of their respective efficacy loss over time. OBJECTIVES: To analyze and compare the time evolution of the antidiabetic effects of the key bariatric procedures. SETTING: Obesity surgery departments in America, Europe, and Asia. METHODS: All the randomized clinical trials assessing the efficacy of bariatric surgery in type 2 diabetes management with 1-5 years of follow-up were reviewed. A network meta-analysis with meta-regression was performed to compare the effectiveness of each technique and its respective efficacy loss temporal dynamics. RESULTS: Thirty-one trials involving 1906 patients were included. In comparison to Roux-en-Y gastric bypass, the 5-year complete or partial diabetes remission rates were inferior with medical treatment (odds ratio [OR] = .05; 95% credible interval [CrI]: .02-.13) and gastric banding (OR = .38; 95% CrI: .16-.87), equivalent with sleeve gastrectomy (OR = 1.08; 95% CrI: .59-1.97), and superior with 1 anastomosis gastric bypass (OR = 3.00; 95% CrI: 1.12-8.33) and biliopancreatic diversion and its affiliated techniques (OR = 3.71; 95% CrI: 1.16-12.55). However, remission rates and glycemic control progressively decreased whatever the treatment option evaluated. Moreover, this loss of efficacy followed a statistically comparable temporal dynamic to those of Roux-en-Y gastric bypass regardless of the therapeutic strategy implemented. CONCLUSIONS: No therapeutic modality offered stable antidiabetic effects. The gap observed between the techniques after a 5-year follow up concerning remission rates and glycemic control could depend essentially on the magnitude of the effects initially obtained. However, these results need to be confirmed over longer follow-up periods.