Cachexia-related consequences of glycemic metabolism: A multivariable and two-step Mendelian randomization study

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Background: Cachexia is a global burden that is caused by chronic diseases such as cancer. It is characterized by inflammation and progressive loss of muscle and adipose tissue, aggravating the patient’s health. Glycemic metabolism disorders exacerbate cachexia and mutually reinforce each other. Thus far, no research has established a connection between the two. Therefore, we aim to explore the influence of glucose metabolism on cachexia using Mendelian randomization (MR) and provide a theoretical basis for the early prediction of cachexia. Methods: We used glycemic traits (type 2 diabetes (T2D), fasting glucose (FG), fasting insulin (FI), hemoglobin A1c (HbA1c), and 2-hour postprandial glucose (2hPG)) as exposures; and cachexia traits (hand grip strength (HGS), appendicular lean mass (ALM), and walking pace (WP)) as outcomes. 22 mediators were included for mediating effects. Multivariable and mediation MR were used to assess the impact of glycemic metabolism on cachexia. Results: In univariate MR, higher FI increased HGS (β = 0.113, 95% confidence interval (CI): 0.060–0.166) and WP (β = 0.066, 95% CI: 0.021–0.112). Higher HbA1c was associated with higher ALM (β = 0.067, 95% CI: 0.017–0.117). Higher 2hPG was associated with weaker HGS (β = −0.037, 95% CI: −0.054 to −0.021). In multivariable MR, only FI maintained a relationship with HGS after adjustments for T2D (β = 0.103, 95% CI: 0.026–0.181), FG (β = 0.101, 95% CI: 0.034–0.169), HbA1c (β = 0.115, 95% CI: 0.055–0.176), and 2hPG (β = 0.101, 95% CI: 0.033–0.169). In mediation MR, three mediators were found to be significant between FI and HGS: waist circumference (WC) (48.1%), lumbar spine bone mineral density (LSBMD) (21.3%) and insulin-like growth factor 1 (IGF-1) (6.7%). Conclusions: Using multivariable and mediation MR, our finding suggests that higher FI increases HGS with an independent effect. WC, LSBMD, and IGF-1 mediate between FI and HGS. This study offers a theoretical framework for the early prediction and assessment of the prognosis of cachexia in cancer patients with glycemic metabolism disorders.

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