Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated efficacy for weight loss in obesity; however, up to 40% of weight lost may derive from lean body mass. The ketogenic diet independently improves insulin sensitivity and promotes fat oxidation while preserving lean tissue. This study aimed to describe changes in body composition, insulin sensitivity, and cardiometabolic markers in patients who followed a personalized ketogenic dietary protocol while receiving low-dose semaglutide over a 6-month insulin resistance reversal program. Methods: Seven analyzed adults (six female, one male) with overweight or obesity (baseline BMI 25.6–47.2 kg/m²) participated in a clinician-supervised 6-month program combining a whole-food ketogenic diet with semaglutide (≤1.0 mg/week). Body composition and fasting metabolic markers were assessed at 1, 3, and 6 months. Results: Mean total weight loss was 21.9 kg, of which a mean of 92% was attributable to BIA-estimated fat mass. Skeletal muscle mass was largely preserved as measured by BIA (mean loss 1.2 kg), and one patient gained lean tissue. Fasting insulin declined by a mean of 15.6 µIU/mL. Visceral fat decreased by a mean of 37.0%. Six of seven patients showed reductions in high-sensitivity C-reactive protein. Triglycerides decreased in six of seven patients, and HDL cholesterol increased in all seven. LDL cholesterol responses were heterogeneous. Conclusions: In this small, uncontrolled case series, combining a ketogenic diet with low-dose semaglutide was associated with substantial fat loss, apparent preservation of lean mass as measured by BIA, and improvements in insulin sensitivity and cardiometabolic markers. Because the semaglutide dose and dietary protocol were individualized to each patient’s response, the program illustrates a personalized approach to insulin resistance. These preliminary findings are hypothesis-generating and warrant confirmation in controlled prospective studies.

Background/Objectives: Beta-hydroxybutyrate (BHB) exists as two enantiomers with potentially distinct biological activities. While D-BHB is the physiological form produced during ketogenesis, L-BHB is present in equal amounts in racemic supplements, yet its biological effects remain poorly understood. Additionally, the ketone precursor 1,3-butanediol (BD) is used in some formulations despite limited safety data. Methods: We investigated acute (single gavage, 2-h time course) and short-term (daily gavage for 8 days) hepatic effects of D-BHB, L-BHB, and 1,3-butanediol compared to a vehicle control in male C57BL/6 mice. Acute studies assessed hepatic ATP dynamics and lipid peroxidation (MDA) at multiple timepoints. Eight-day protocols evaluated mitochondrial function (oxygen consumption, Complex II activity, SDH activity), lipid accumulation (triglycerides), and inflammatory markers (IL-1β, TNF-α, CRP). Results: Acute ATP responses differed markedly among treatments. Compared to the baseline and the control, L- and D-BHB elicited significant increases in ATP, while BD caused sustained ATP depletion. Over this same time, oxidative stress markers remained stable in the control and both BHB groups but increased dramatically with BD. After 8 days, the mitochondrial effects of BD were more apparent with a significant reduction in complex II-supported respiration and activity. Both forms of BHB maintained control levels of inflammation and BD showed significant effects on all inflammatory markers. Hepatic triglycerides increased only with BD treatment. Conclusions: This study reveals striking hepatic effects of various ketone supplements. In contrast to the positive or inert effects of BHB enantiomers, 1,3-butanediol induces significant hepatic stress. These findings have implications for ketone supplement formulation and highlight the therapeutic potential of D- and L-BHB.