Sergio A. Burgos

Context: The metabolic mechanisms underlying insulin resistance are not fully understood. Metabolomic profiling can reveal compartment-specific variations and identify individuals at risk for type 2 diabetes (T2D). Objective: To characterize insulin-induced metabolomic changes during a hyperinsulinemic–euglycemic clamp and evaluate a derived risk score's predictive value for T2D. Design, Setting, and Participants: Clamp studies were conducted in 80 adults (38 with T2D, 42 without) to measure plasma and muscle metabolites in fasting and hyperinsulinemic states. An insulin resistance metabolomic score was developed and tested in a prospective case–control study (367 cases, 910 controls) from the Women's Health Initiative (28.5-year follow-up). Main Outcome Measures: Metabolite changes during hyperinsulinemia and incident T2D. Results: Hyperinsulinemia altered 79.5% of plasma metabolites (notably fatty acids, lactate, and pyruvate) and 15.8% of muscle metabolites (eg, branched-chain and aromatic amino acids). T2D was associated with higher triglycerides and lower tricarboxylic acid intermediates during clamp. Adiposity amplified insulin-induced increases in plasma lipids. The risk score predicted incident T2D (hazard ratio, 1.20 per SD; 95% CI, 1.09-1.32; P = 7.4 × 10−4). Conclusion: Compartment-specific metabolic responses to insulin are shaped by adiposity and predict future T2D risk, supporting use of metabolomic signatures for early identification and prevention.

Dietary guidelines emphasize the consumption of plant protein foods, but the implications of replacing animal with plant sources on a combination of diet sustainability dimensions are unknown. Using a combination of data from a national nutrition survey, greenhouse gas emissions from dataFIELD and relative risks from the Global Burden of Disease Study 2017, we assess the impact of partially substituting red and processed meat or dairy with plant protein foods in Canadian self-selected diets on nutrition, health and climate outcomes. The substitutions induced minor changes to the percentage of the population below requirements for nutrients of concern, but increased calcium inadequacy by up to 14% when dairy was replaced. Replacing red and processed meat or dairy increased life expectancy by up to 8.7 months or 7.6 months, respectively. Diet-related greenhouse gas emissions decreased by up to 25% for red and processed meat and by up to 5% for dairy replacements. Co-benefits of partially substituting red and processed meat with plant protein foods among nutrition, health and climate outcomes are relevant for reshaping consumer food choices in addressing human and planetary health.

Although the cyclin-dependent kinases CDK4 and CDK6 play fundamental roles in cancer, the specific pathways and downstream targets by which they exert their tumorigenic effects remain elusive. In this study, we uncover distinct and novel functions for these kinases in regulating tumor formation and metastatic colonization in various solid tumors, including those of the breast, prostate, and pancreas. Combining in vivo CRISPR-based CDK4 and CDK6 gene editing with pharmacologic inhibition approaches in orthotopic transplantation and patient-derived xenograft preclinical models, we defined clear functions for CDK4 and CDK6 in facilitating tumor growth and progression in metastatic cancers. Transcriptomic profiling of CDK4/6 CRISPR knockouts in breast cancer revealed these two kinases to regulate cancer progression through distinct mechanisms. CDK4 regulated prometastatic inflammatory cytokine signaling, whereas CDK6 mainly controlled DNA replication and repair processes. Inhibition of CDK6 but not CDK4 resulted in defective DNA repair and increased DNA damage. Multiple CDK6 DNA replication/repair genes were not only associated with cancer subtype, grades, and poor clinical outcomes, but also facilitated primary tumor growth and metastasis in vivo. CRISPR-based genomic deletion of CDK6 efficiently blocked tumor formation and progression in preestablished cell- and patient-derived xenograft preclinical models of breast cancer, providing a potential novel targeted therapy for these deadly tumors.Significance:In-depth transcriptomic analysis identifies cyclin-dependent kinases CDK4 and CDK6 as regulators of metastasis through distinct signaling pathways and reveals the DNA replication/repair pathway as central in promoting these effects.