Yan Fang

Background/Objectives: Obesity is a major risk factor for diabetes, but the underlying mechanisms remain incompletely understood. Obesity is associated with alterations in circulating lipids. This study aimed to determine whether, and to what extent, circulating lipids mediate the diabetogenic effect of obesity. Methods: This mediation analysis included 26,627 adult participants. Parallel mediation analysis included total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides as simultaneous mediators. Low-density lipoprotein (LDL) cholesterol was excluded from the parallel model due to collinearity with total cholesterol and was assessed separately using simple mediation analysis adjusted for confounders. Results: After adjustment for tested confounders, parallel mediation analysis showed that increases in triglycerides and reductions in HDL cholesterol mediated 24.0% (indirect effect coefficient = 0.23; 95% CI: 0.20–0.26; p < 0.05) and 3.8% (indirect effect coefficient = 0.04; 95% CI: 0.01–0.06; p < 0.05) of the diabetogenic effect of obesity, respectively. An increase in total cholesterol modestly attenuated the diabetogenic effect of obesity by 2.3% (indirect effect coefficient = −0.02; 95% CI: −0.03 to −0.01; p < 0.05), a magnitude that is unlikely to be clinically meaningful. Simple mediation analysis indicated that LDL cholesterol was not a significant mediator. Conclusions: Triglycerides are the most influential circulating lipid in mediating the diabetogenic effect of obesity, accounting for 24% of the total effect. Targeting triglyceride levels might represent an underrecognized therapeutic strategy to reduce obesity-related diabetes risk.

Background/Objectives: Obesity is a major risk factor for diabetes, but the underlying mechanisms remain incompletely understood. Obesity is associated with alterations in circulating lipids. This study aimed to determine whether, and to what extent, circulating lipids mediate the pro-diabetic effect of obesity. Methods: We analyzed data from 26,627 US adults. Mediation analysis was performed using the PROCESS Version 4.3 Macro for SPSS. Parallel mediation analysis included total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides as simultaneous mediators. Low-density lipoprotein (LDL) cholesterol was excluded from the parallel model due to collinearity with total cho-lesterol and was assessed separately using simple mediation analysis adjusted for con-founders. Results: After adjustment for tested confounders, parallel mediation analysis showed that increases in triglycerides and reductions in HDL cholesterol mediated 24.0% (indirect effect coefficient = 0.23; 95% CI: 0.20–0.26; p < 0.05) and 3.8% (indirect effect coef-ficient = 0.04; 95% CI: 0.01–0.06; p < 0.05) of the pro-diabetic effect of obesity, respectively. An increase in total cholesterol negatively mediated the effect by 2.3% (indirect effect coef-ficient = -0.02; 95% CI: -0.03 to -0.01; p < 0.05). Simple mediation analysis indicated that LDL cholesterol was not a significant mediator. Conclusions: Triglycerides are the most influential circulating lipid in mediating the pro-diabetic effect of obesity, accounting for 24% of the total effect. Targeting triglyceride levels may represent an underrecognized therapeutic strategy to reduce obesity-related diabetes risk.

Sympathetic nerves innervate bone marrow and various immune organs, where norepinephrine—the primary sympathetic neurotransmitter—directly interacts with immune cells that express adrenergic receptors. This article reviewed the key molecular pathways triggered by sympathetic activation and explored how sympathetic activity influences immune cell migration. Norepinephrine serves as a chemoattractant for monocytes, macrophages, and stem cells, promoting the migration of myeloid cells while inhibiting the migration of lymphocytes at physiological concentrations. We also examined the role of immune cell infiltration in cardiovascular diseases and cancer. Evidence suggests that sympathetic activation increases myeloid cell infiltration into target tissues across various cardiovascular diseases, including atherosclerosis, hypertension, cardiac fibrosis, cardiac hypertrophy, arrhythmia, myocardial infarction, heart failure, and stroke. Conversely, inhibiting sympathetic activity may serve as a potential therapeutic strategy to treat these conditions by reducing macrophage infiltration. Furthermore, sympathetic activation promotes macrophage accumulation in cancer tissues, mirroring its effects in cardiovascular diseases, while suppressing T lymphocyte infiltration into cancerous sites. These changes contribute to increased cancer growth and metastasis. Thus, inhibiting sympathetic activation could help to protect against cancer by enhancing T cell infiltration and reducing macrophage presence in tumors.

Sympathetic nerves innervate bone marrow and various immune organs, where norepinephrine—the primary sympathetic neurotransmitter—directly interacts with immune cells that express adrenergic receptors. This article reviewed the key molecular pathways triggered by sympathetic activation and explored how sympathetic activity influences immune cell migration. Norepinephrine serves as a chemoattractant for monocytes, macrophages, and stem cells, promoting the migration of myeloid cells while inhibiting the migration of lymphocytes at physiological concentrations. We also examined the role of immune cell infiltration in cardiovascular diseases and cancer. Evidence suggests that sympathetic activation increases myeloid cell infiltration into target tissues across various cardiovascular diseases, including atherosclerosis, hypertension, cardiac fibrosis, cardiac hypertrophy, arrhythmia, myocardial infarction, heart failure, and stroke. In contrast, inhibiting sympathetic activity may serve as a potential therapeutic strategy to treat these conditions by reducing macrophage infiltration. Furthermore, sympathetic activation suppresses T lymphocyte infiltration and promotes macrophage accumulation in cancer tissues, which are linked to increased cancer growth and metastasis. Thus, inhibiting sympathetic activation could help protect against cancer by enhancing T cell infiltration and reducing macrophage presence in tumors.

Postprandial plasma glucose between 4 and 7.9 hours is associated with the diagnosis of diabetes, diabetes mortality, and cardiovascular mortality. However, it is unknown whether 2-hour plasma glucose during the oral glucose tolerance test conducted in this postprandial period (4–7.9 hours), termed as 2-h PGOGTT@4–7.9h, can accurately classify diabetes diagnosis and predict mortality risks. This study aimed to address these questions using 2,347 adult participants. Diabetes was defined as HbA1c ≥6.5%, and the ability of 2-h PGOGTT@4–7.9h to classify diabetes was analyzed using receiver operating characteristic curves. Cox proportional hazards models were employed to estimate mortality hazard ratios (HRs) and 95% confidence intervals (CIs). The results showed that 2-h PGOGTT@4–7.9h could classify diabetes with 92% accuracy. Participants were followed up for a mean of 21.4 years. A 1-natural-log higher 2-h PGOGTT@4–7.9h was associated with an increased risk of mortality from diabetes (adjusted HR, 21.1; 95% CI, 9.2–48.0) and cardiovascular disease (adjusted HR, 1.47; 95% CI, 1.13–1.91). Simulation analysis indicated that future studies may require at least 100 participants to investigate 2-h PGOGTT@4–7.9h for diabetes diagnosis. In conclusion, 2-h PGOGTT@4–7.9h may be useful for diabetes classification and prediction of mortality risk.

Postprandial glucose levels between 4 and 7.9 h (PPG_4–7.9h) correlate with mortality from various diseases, including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG_4–7.9h could diagnose diabetes. Two groups of participants were involved: Group 1 (4420 participants) had actual PPG_4–7.9h, while Group 2 (8422 participants) lacked this measure but had all the diabetes diagnostic measures. Group 1 underwent multiple linear regression to predict PPG_4–7.9h using 30 predictors, achieving accuracy within 11.1 mg/dL in 80% of the participants. Group 2 had PPG_4–7.9h predicted using this model. A receiver operating characteristic curve analysis showed that predicted PPG_4–7.9h could diagnose diabetes with an accuracy of 87.3% in Group 2, with a sensitivity of 75.1% and specificity of 84.1% at the optimal cutoff of 102.5 mg/dL. A simulation on 10,000 random samples from Group 2 revealed that 175 participants may be needed to investigate PPG_4–7.9h as a diabetes diagnostic marker with a power of at least 80%. In conclusion, predicted PPG_4–7.9h appears to be a promising diagnostic indicator for diabetes. Future studies seeking to ascertain its definitive diagnostic value might require a minimum sample size of 175 participants.

This study aimed to investigate whether non-fasting plasma triglycerides were associated with diabetes mortality. It included 7312 US adult participants. Diabetes mortality data were obtained via the linkage to National Death Index (NDI) records. Hazard ratios of non-fasting plasma triglycerides for diabetes mortality were assessed using Cox proportional hazards models, adjusting for age, gender, ethnicity, obesity, poverty–income ratio, education levels, physical activity, alcohol consumption, cigarette smoking status, survey period, hypercholesterolemia, hypertension, diabetes, and family history of diabetes. Among these participants, 1180 had diabetes. A total of 420 diabetes-caused deaths were recorded during a mean follow-up of 16.8 years. A 1-natural-log-unit increase in non-fasting plasma triglycerides was associated with a 41% higher diabetes mortality risk (hazard ratio, 1.41; 95% confidence interval, 1.19–1.67). Participants with non-fasting plasma triglycerides in the highest quintile, versus those in the lowest quintile, had a 141% higher diabetes mortality risk (hazard ratio, 2.41; 95% confidence interval, 1.46–3.97). The positive association of non-fasting plasma triglycerides with diabetes mortality was independent of diabetes status at the baseline. In conclusion, this study demonstrated that non-fasting plasma triglycerides were positively associated with diabetes mortality, independent of diabetes status at baseline. Non-fasting triglycerides may be a therapeutic target for diabetes-related complications.

This study aimed to investigate whether non-fasting plasma triglycerides were associated with diabetes mortality. It included 7,312 US adult participants. Diabetes mortality data were obtained via linkage to the National Death Index (NDI) records. Hazard ratios of non-fasting plasma triglycerides for diabetes mortality were assessed using Cox proportional hazards models, adjusting for age, gender, ethnicity, obesity, poverty-income ratio, education levels, physical activity, alcohol consumption, cigarette smoking status, survey period, hypercholesterolemia, hypertension, diabetes, and family history of diabetes. Among these participants, 1,180 had diabetes. A total of 420 diabetes-caused deaths were recorded during a mean follow-up of 16.8 years. A 1-natural-log-unit increase in non-fasting plasma triglycerides was associated with a 41% higher diabetes mortality risk (hazard ratio, 1.41; 95% confidence interval, 1.19-1.67). Participants with non-fasting plasma triglycerides in the highest quintile, versus those in the lowest quintile, had a 144% higher diabetes mortality risk (hazard ratio, 2.44; 95% confidence interval, 1.49-4.02). The positive association of non-fasting plasma triglycerides with diabetes mortality was independent of diabetes status at the baseline. In conclusion, this study demonstrated that non-fasting plasma triglycerides were positively associated with diabetes mortality, independent of diabetes status at the baseline. Non-fasting triglycerides may be a therapeutic target for diabetes-related complications.

Postprandial glucose levels between 4 and 7.9 hours (PPG4–7.9h) correlate with mortality from various diseases including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG4–7.9h could diagnose diabetes. Two groups of participants were involved: Group 1 (4420 participants) had actual PPG4–7.9h, while Group 2 (8422 participants) lacked this measure but had all the diabetes diagnostic measures. Group 1 underwent multiple linear regression to predict PPG4–7.9h using 30 predictors, achieving accuracy within 11.1 mg/dL in 80% of the participants. Group 2 had PPG4–7.9h predicted using this model. Receiver operating characteristic curve analysis showed that predicted PPG4–7.9h could diagnose diabetes with an accuracy of 87.3% in Group 2, with a sensitivity of 75.1% and specificity of 84.1% at the optimal cutoff of 102.5 mg/dL. Simulation on 10,000 random samples from Group 2 revealed that 175 participants may be needed to investigate PPG4–7.9h as a diabetes diagnostic marker with a power of at least 80%. In conclusion, predicted PPG4–7.9h appears to be a promising diagnostic indicator for diabetes. Future studies seeking to ascertain its definitive diagnostic value might require a minimum sample size of 175 participants.

Elevated circulating triglyceride levels have been linked to an increased risk of diabetes, although the precise mechanisms remain unclear. This study aimed to investigate whether low-density lipoprotein (LDL) cholesterol, homeostatic model assessment (HOMA) for insulin resistance, and C-reactive protein (CRP) served as mediators in this association across a sample of 18,435 US adults. Mediation analysis was conducted using the PROCESS Version 4.3 Macro for SPSS. Simple mediation analysis revealed that all three potential mediators played a role in mediating the association. However, in parallel mediation analysis, where all three mediators were simultaneously included, HOMA for insulin resistance remained a significant mediator (indirect effect coefficient, 0.47; 95% confidence interval [CI], 0.43–0.52; p < 0.05) after adjusting for all tested confounding factors. Conversely, LDL cholesterol (indirect effect coefficient, −0.13; 95% CI, −0.31–0.05; p > 0.05) and C-reactive protein (indirect effect coefficient, 0.01; 95% CI, −0.003–0.02; p > 0.05) ceased to be significant mediators. HOMA for insulin resistance accounted for 49% of the association between triglycerides and diabetes. In conclusion, HOMA for insulin resistance was the dominant mediator underlying the association between triglycerides and diabetes. Therefore, reducing triglyceride levels may hold promise for improving insulin sensitivity in diabetic patients.