Impact Of High Fat Meal Research Articles

Impact of a High-Fat Meal on the Pharmacokinetics of Sotorasib, a KRAS G12C Inhibitor.

Sotorasib is a small molecule drug that specifically and irreversibly inhibits the KRAS p.G12C mutant protein. This analysis investigated the impact of a high-calorie high-fat meal on the pharmacokinetics, safety, and tolerability of sotorasib in both healthy volunteers and patients with KRAS G12C advanced solid tumors. Each subject received a single oral dose of 360 or 960mg of sotorasib under fasted conditions or with a high-fat meal (fed conditions). The geometric least squares means (GLSM) ratios (fed/fasted) for 360mg of sotorasib Cmax and AUCinf were 1.03 and 1.38, respectively, in healthy volunteers (N=14). The GLSM ratios (fed/fasted) for Cmax and AUC0-24h were 1.38 and 1.75, respectively, with 360mg of sotorasib in cancer patients (N=2). The GLSM ratios (fed/fasted) for Cmax and AUC0-24h were 0.660 and 1.25, respectively, with 960mg of sotorasib in cancer patients (N=8). Sotorasib was well tolerated in fast and fed conditions. The impact of a high-fat meal on sotorasib exposure is less than a 2-fold increase or decrease in Cmax and AUCs.

The impact of a single high-fat meal on indices of cerebrovascular function & health

High-fat diets contribute to elevated risk for cardiovascular, cerebrovascular, metabolic, and neurocognitive diseases with reduced vascular health being a contributing factor. It is well documented that a single high-fat meal (HFM) reduces peripheral vascular function. Despite the elevated risk for/prevalence of cerebrovascular and neurocognitive disease with a high-fat diet, the impact of a single HFM on cerebrovascular function/health is less known. Cerebrovascular pulsatility index (PI) (measure of cerebral vascular stiffness) and cerebral autoregulation (ability of the cerebral vasculature to maintain constant blood flow during changes in arterial blood pressure) are indices of cerebral vascular function/health that are impaired in populations with elevated disease risk. To our knowledge, the impact of a HFM on these indices have not been studied. Accordingly, this study tested the hypothesis that a single HFM will blunt cerebrovascular function/health as indexed by increased PI and transfer function gain. Methods: Fifteen individuals (13 male; age: 28±11yr; BMI: 24±4 kg/m²) participated. Measures were made before and 2hr post-consumption of a HFM (990 kcal, 55g fat, 89g CHO, 35 g protein, 2120 mg sodium) which was purchased from McDonald’s. The HFM consisted of the following: 1 Sausage Biscuit, 1 Egg McMuffn, 2 hash browns, and 1 bottle of water. Continuous measures of beat-to-beat blood pressure and middle cerebral artery blood velocity (MCAV) were obtained during a minimum of 6-min quiet supine rest. Pulsatility index (measure of cerebrovascular stiffness) was calculated as MCAVsystolic − MCAVdiastolic / MCAVmean. Cerebral autoregulation was calculated as transfer function gain between spontaneous beat-to-beat changes in mean blood pressure and MCAVmean. Results: Cerebrovascular stiffness (PI) was increased following the HFM (pre: 0.81±0.12, post: 0.92±0.15; p<0.001). Cerebrovascular autoregulation indexed as transfer function gain was elevated following the HFM in the very low, low, and high frequency ranges ( p=0.01 for all). Pulsatility index and transfer function gain were correlated in the low frequency range before (R=0.77, p<0.01) and after (R=0.64, p=0.02) the HFM. Conclusion: These preliminary data indicate that a single HFM reduces indices of cerebral vascular function/health. Lastly, there is a positive relationship between PI and transfer function gain. Future work will continue to build upon these findings in a larger data set and will consider the impact of long-term exposure to a traditional HFM diet. Funding: The University of Texas at Arlington College of Nursing and Health Innovation and Institutional Start up Funds to Dr. Brothers. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

162-LB: Impact of High-Fat Meal on Circulating microRNA in Youth with T1DM

MicroRNA (miRNA) are small non-coding RNAs that impact translation via degrading or repressing mRNA. From animal models, circulation abundance of miRNA is impacted by feeding. The goal of this project was to compare levels of specific circulating miRNAs between youth with T1DM and controls and the impact of a high fat meal on miRNA abundance. Fourteen youth (6 females, 8 males) with T1DM and 29 normal weight control youth (14 females, 15 males) ingested a milkshake with 830 kcal; 36% carbohydrate, 54% fat (31 grams of saturated fat), and 10% protein. Circulating miRNAs (miR-122, 126, and 130b) at baseline and 150 minutes post-ingestion were measured by qPCR. The group with T1DM had a median A1c of 8.4% (7.4, 8.9) with an average duration of 7 years. At baseline, miR-126 tended to be higher in the youth with T1DM (47%, p=0.072). In pooled groups, all three miRNAs decreased at 150 min (miR-122: -21%, p=0.036; miR-126: -37%, p=0.001; and miR-130b: -33%, p=0.023). Within the control group, miR-122 and miR-126 decreased 26% and 28% from baseline (p=0.037 and p=0.035, respectively). Within the T1DM group, miR-126 and miR-130b decreased 49% and 50% from baseline (p=0.007 and p=0.011, respectively). The decrease in miR-122 from baseline was correlated with the total energy expenditure for the meal (r=0.-0.379, p=0.017) and insulin under the curve (r=0.350, p=0.029). The decrease in miR-126 and miR-130b were negatively correlated with glucose area under the curve (r=-0.369 and -0.358, p=0.021 and 0.025, respectively), and the decrease in miR-130b was negatively correlated with baseline NEFA (r= -0.328, p=0.042). miR-122 and 130b both target AMPK, which could alter lipid metabolism, thus explaining the associations with NEFA and energy expenditure. miR-126 is known to target both IRS1 and PI3K in the insulin signaling pathway, potentially explaining the association with glucose. It is clear that the circulating abundance of these miRNAs is reduced following a high fat meal, and that response may be modified by the presence of T1DM. Disclosure J.B. Tryggestad: None. A.M. Teague: None. K.R. Short: None. Funding Harold Hamm Diabetes Center; Ardmore Institute of Health