CAMKK1 in Obesity and Type 2 Diabetes Mellitus: Evidence of Interaction With Appetite-Regulating, Metabolic and Inflammatory Factors

Introduction: Calcium/calmodulin-dependent protein kinase kinase 1 (CAMKK1) regulates energy homeostasis through AMP-activated protein kinase (AMPK). CAMKK1 has been implicated in appetite and satiety regulation; however, its role in obesity or type 2 diabetes mellitus (T2DM) remains unexplored. In this cross-sectional study, the primary aim was to confirm whether CAMKK1 is elevated in individuals with diabetes. The secondary aim was to investigate CAMKK1's molecular correlates. Methods: CAMKK1 serum levels in individuals with obesity (n = 3,061), patients with T2DM (n = 4,910) and controls (n = 44,257) were retrieved and compared (age, body mass index—BMI and sex-adjusted ANCOVA). Pearson correlation coefficients and linear regression coefficients (age and BMI-adjusted) were computed. The moderation effect of diagnostic groups was also assessed. The interaction between factors was explored by mixed graphical models. Results: CAMKK1 was elevated in patients with T2DM, in comparison to both individuals with obesity and controls (post hoc comparison, Tukey-adjusted p = 0.010 and p = 0.044, respectively). Across diagnostic groups, positive associations were observed between CAMKK1 and AMPK (min β > 0.400, max p < 0.001) or TNFα (min > β 0.070, max p < 0.001). A positive association with leptin (β = 0.010, p = 0.002) and ghrelin (β = 0.005, p = 0.048) was observed only within controls. Multivariate multivariable models confirmed that specific interactions between factors were disrupted in patients with T2DM (p < 0.001). Conclusion: These findings provide new insights into the role of CAMKK1 in obesity and T2DM. Future research may further explore CAMKK1's interplay with inflammatory pathways. © 2025 The Author(s). Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.