In Chinese patients with early-onset T2DM, CGM-derived metrics are independently associated with early DKD, with TIR and GRI showing opposite associations and CV exhibiting a U-shaped relationship, and the observed association involving triglycerides suggests that lipid metabolism may be a correlate of glycemic control in relation to renal injury.
Abstract
Background The rising prevalence of early-onset type 2 diabetes (T2DM) has become a major public health concern, with these patients facing a particularly high risk of early diabetic kidney disease (DKD). Although continuous glucose monitoring (CGM)-derived metrics have shown promise in predicting complications in later-onset T2DM, their utility in early-onset T2DM, a more aggressive phenotype characterized by rapid β-cell decline and heightened complication risk, remains unclear. Moreover, the relationship between glycemic variability and renal injury, as well as the mechanisms underlying the associations between CGM metrics and DKD, have not been fully elucidated. This study aimed to evaluate the associations of time in range (TIR), coefficient of variation (CV), and glycemic risk index (GRI) with early DKD in Chinese patients with early-onset T2DM, and to explore the potential mediating role of triglycerides. Methods This cross-sectional study included 810 individuals with early-onset T2DM, defined as diagnosis before age 40. All participants underwent ≥7 days of CGM. Early DKD was defined as a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m². Multivariable logistic regression, restricted cubic splines, and mediation analysis were used to evaluate independent associations, nonlinear relationships, and the mediating role of triglycerides (TG), respectively. Results Among the participants, 183 (22.59%) had early DKD. After full adjustment including HbA1c, higher TIR was associated with lower odds of early DKD (per 1% increase: OR 0.99, 95% CI 0.98–0.99, P < 0.001), whereas higher GRI was associated with increased odds (per 1-unit increase: OR 1.01, 95% CI 1.01–1.02, P < 0.001). A U-shaped relationship was observed between CV and early DKD risk, with the nadir observed at approximately 20–30% CV. In mediation analysis, TG statistically accounted for 13.01% of the association between TIR and early DKD, and 11.92% of the association between GRI and early DKD. Conclusions In Chinese patients with early-onset T2DM, CGM-derived metrics are independently associated with early DKD, with TIR and GRI showing opposite associations and CV exhibiting a U-shaped relationship. The observed association involving triglycerides suggests that lipid metabolism may be a correlate of glycemic control in relation to renal injury. These findings support a multidimensional strategy integrating glucose control, glycemic stability, and lipid management for renal protection in this high-risk population.
Background The role of short‑term glycemic variability (GV) in early diabetic kidney disease (DKD) among patients with type 2 diabetes (T2D) remains controversial. This study aims to investigate the independent association between continuous glucose monitoring (CGM)-derived GV indices and early DKD in T2D patients. Methods This cross-sectional study included 315 patients with T2D. Early DKD was identified as persistent microalbuminuria (urine albumin-to-creatinine ratio 30–300 mg/g) with preserved renal function (eGFR≥60 mL/min/1.73 m2). GV metrics, including mean amplitude of glycemic excursions (MAGE) and glucose standard deviation (SDBG), were derived from CGM data. Multivariate logistic regression and generalized additive models (GAMs) were used to assess associations, with subgroup analyses and interaction tests. Results Participants with early DKD had significantly higher MAGE and SDBG (both P<0.001). After full adjustment for HbA1c, medication use, and other covariates, both MAGE (OR =1.58, 95% CI: 1.31–1.89, P<0.001) and SDBG (OR =2.14, 95% CI: 1.39–3.30, P = 0.001) were independently associated with early DKD. Compared with the lowest tertile, the highest tertiles of MAGE and SDBG were associated with a 5.78-fold (95% CI: 2.83–11.81) and 3.56-fold (95% CI: 1.77–7.18) higher risk, respectively (all P< 0.001). BMI was a significant effect modifier of the MAGE-DKD association (P for interaction = 0.014), which was present only in overweight/obese individuals. GAM analysis demonstrated a linear positive relationship for MAGE and a non-linear U-shaped association for SDBG. Conclusion CGM-derived short-term GV indices MAGE and SDBG are independently associated with early DKD in T2D patients, with distinct dose-response patterns: MAGE shows a linear positive relationship, whereas SDBG exhibits a U-shaped association. Moreover, the MAGE–DKD association is confined to overweight individuals. Prospective studies are needed to establish causality and to verify whether personalized targeting of short‑term GV might be associated with lower DKD risk.
Nan Chen, Nuo-Jin Wang, Hao Duan et al.· Diabetes, Metabolic Syndrome...· 0 citations
Background Diabetic kidney disease (DKD) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation has been implicated in the development and progression of DKD. The systemic inflammatory response index (SIRI), a novel composite inflammatory biomarker, has demonstrated prognostic value in various inflammatory and metabolic disorders. However, evidence regarding the association between SIRI and DKD remains limited. Methods This retrospective cross-sectional study included 2421 hospitalized patients with T2DM. DKD was defined according to established clinical criteria. Multivariable logistic regression models were used to evaluate the association between SIRI and DKD after adjustment for demographic and clinical covariates. Restricted cubic spline (RCS), receiver operating characteristic (ROC), subgroup, sensitivity, and mediation analyses were additionally performed. Results Among the 2,421 participants, 892 (36.8%) were diagnosed with DKD. Higher SIRI levels were significantly associated with increased odds of DKD in multivariable logistic regression analyses. Participants in the highest SIRI category had substantially greater odds of DKD compared with those in the lowest category. RCS analysis demonstrated a nonlinear positive association between SIRI and DKD risk. ROC analysis showed that the combination of age, sex, and SIRI had better discrimination ability for DKD than SIRI alone. Subgroup analyses demonstrated generally consistent associations across predefined subgroups, although significant interactions were observed for age and HbA1c status. Mediation analysis indicated that eGFR partially mediated the association between SIRI and DKD, accounting for approximately 46% of the total effect. Conclusion Elevated SIRI was independently associated with increased odds of DKD in patients with T2DM. The association appeared nonlinear and was partially mediated through renal function impairment. SIRI may serve as a convenient inflammatory biomarker for identifying patients at higher risk of DKD.
Xuan Li, Binquan Fang, Kainuo Yu et al.· Diabetes, Metabolic Syndrome...· 0 citations
Background Diabetic kidney disease (DKD) is a prevalent microvascular complication of type 2 diabetes mellitus (T2DM) and contributes substantially to end-stage renal disease. The atherogenic index of plasma (AIP) has exhibited biomarker utility. However, its relationship with DKD remains uncertain. Methods This cross-sectional investigation included 10,112 T2DM subjects from the National Metabolic Management Center of Yuhuan Second People’s Hospital between September 2017 and February 2025 and 5,573 individuals in NHANES cohort (1999–2020). AIP values were calculated and categorized into quartiles. Multivariable logistic regression, restricted cubic spline, and stratified subgroup analyses were applied for assessing the link between AIP and DKD. The area under the curve (AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI) was used to assess the discriminative ability of AIP. Results After adjustment for confounding factors, each one-unit AIP rise resulted in a 72% higher likelihood of DKD (OR: 1.72, 95% CI: 1.51–1.96, p < 0.001). Relative to the lowest AIP quartile, the highest quartile showed a 54% higher odds DKD (OR: 1.54, 95% CI: 1.36–1.75, p < 0.001), with a clear dose–response effect (P for trend <0.001). Spline modeling indicated a positive linear link between AIP and DKD, which was apparent in all examined subgroups (all P for interaction >0.05) and externally validated in NHANES. Incorporating AIP into the baseline model modestly improved discrimination, increasing the area under the curve from 68.42 to 68.76%, with a continuous NRI of 0.118 (95% CI: 0.079–0.157, p < 0.001) and an IDI of 0.006 (95% CI: 0.004–0.007, p < 0.001). Conclusion AIP shows an independent positive association with DKD in individuals with T2DM, demonstrating a linear dose–response relationship, but the incremental predictive value is limited. The association between AIP and DKD still needs to be further validated by larger-scale prospective studies.
Jinghan Zheng, J. Chi, K. Che et al.· Frontiers in Nutrition· 0 citations
Background An elevated triglyceride-glucose (TyG) index is strongly linked to an increased risk of cardiovascular events in patients with acute coronary syndrome (ACS) and type 2 diabetes mellitus (T2DM). However, the potential impact of increasing diabetes duration on the association between the TyG index and cardiovascular risk remains unclear. Methods Consecutive patients admitted for ACS with T2DM received PCI between March 2016 and March 2020 were enrolled in the analysis. A total of 7093 patients were categorized into tertiles according to the TyG index and T2DM duration. The primary outcome was ischemic events, composed of cardiac death, myocardial infarction, and/or stroke at 5 years. The main secondary outcomes were 5-year cardiac death and all-cause death. Interaction terms and non-linear associations of the TyG index with the clinical outcomes were examined across diabetes durations. Results Over 5 years, 753 (10.6%) experienced ischemic events, 375 (5.3%) cardiac death, and 636 (9.0%) all-cause death. Higher TyG index and longer diabetes duration independently associated with all outcomes. Compared with the lowest TyG tertile, the highest tertile had adjusted hazard ratios (HRs) of 1.55 (95% CI: 1.29–1.88) for ischemic events and 1.23 (1.10–1.38) for all-cause death. The association between TyG index and ischemic events was strongest in the shortest duration group (HR: 1.43), with significant interaction for ischemic and cardiac death (both p < 0.05). Conclusions A higher TyG index was independently associated with an increased risk of ischemic events and mortality among patients with ACS and T2DM. This association appeared to be attenuated with longer diabetes duration, suggesting that the prognostic relevance of the TyG index may vary according to the chronicity of diabetes.
CONTEXT
Youth-onset type 2 diabetes (T2D) is characterized by accelerated β-cell decline and early treatment failure, and there is an urgent need to improve the understanding of molecular drivers of loss of glycemic control (LOGC).
OBJECTIVE
To identify multiprotein signatures associated with loss of glycemic control (LOGC) in youth-onset T2D.
DESIGN
Longitudinal observational study with a mean follow-up of 10.8 ± 3.8 years using data from the TODAY study, with external validation in three youth cohorts and one adult-onset T2D cohort.
SETTING
Multicenter clinical research study.
PARTICIPANTS
Participants from the TODAY study (N = 374; age 14 ± 2 years; 37% male), of whom 72% experienced LOGC over 10.8 ± 3.8 years.
INTERVENTIONS
None.
MAIN OUTCOME MEASURE
LOGC, defined as HbA1c ≥ 8% for ≥6 months or inability to discontinue insulin after acute metabolic decompensation.
RESULTS
Plasma proteomics quantified 7604 aptamers representing 6596 proteins using the SomaScan 7 K platform. Sixty-seven proteins were associated with LOGC after false discovery rate correction and multivariable adjustment. Key proteins included plexin-B2 (HR: 1.46 [95% CI: 1.29-1.66]) and semaphorin-6A (HR: 1.31 [1.18-1.47]), which were also associated with glycemic outcomes in independent youth and adult cohorts. Enrichment analyses implicated pathways related to axon guidance, immune response, inflammation, and metabolism.
CONCLUSIONS
Novel proteins involved in axon guidance, immune response, inflammation, and metabolism associated with LOGC in youth-onset T2D with proteins demonstrating consistent associations across the lifespan and proteomic platforms.
K. Tommerdahl, Kristen R Miller, Jian-Jun Liu et al.· Journal of Clinical Endocrin...· 0 citations
Cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). While statin therapy is universally recommended for cardiovascular disease prevention, its potential adverse effects on glycemic progression remain controversial, particularly in patients with newly diagnosed disease. This study aimed to evaluate the dual effects of statin initiation on glycemic control and major adverse cardiovascular events (MACEs) in a retrospective cohort of patients with new-onset T2D.
We conducted a retrospective cohort study in which patients who were newly diagnosed with T2D between January 2018 and December 2020 were screened. The primary outcome was the change in the glycated hemoglobin (HbA1c) levels. Secondary outcomes included fasting plasma glucose (FPG) levels, 2-hour post-prandial glucose (2hPG) levels, diabetes therapy intensification, insulin initiation, hyperglycemic crisis, and MACEs. Longitudinal glycemic trajectories were assessed using two-way repeated-measures ANOVA. The MACE risk was evaluated with a Kaplan–Meier analysis and multivariable Cox regression model.
A total of 604 eligible patients were classified into a statin group (n = 458) and a nonstatin group (n = 146). At the 6-month follow-up, both groups exhibited improved glycemic indices, but this improvement was significantly attenuated in the statin group. Similar attenuated improvements were observed in the FPG and 2hPG levels at 6 months. Group × time interaction effects were significant for FPG, 2hPG, and HbA1c levels at 6 months. By 60 months, between-group differences in HbA1c levels were no longer significant. During the median (interquartile range) follow-up of 73 (68–80) months, statin therapy was associated with higher frequencies of diabetes therapy intensification (33.3% vs. 22.6%, p = 0.016), insulin initiation (21.5% vs. 12.3%, p = 0.015), and hyperglycemic crisis (8.5% vs. 3.4%, p = 0.039). Despite these metabolic disadvantages, statin therapy was independently associated with a lower MACE risk according to the multivariable Cox regression analysis (HR 0.41, 95% CI 0.21–0.83; p = 0.013).
In patients with new-onset T2D, early statin initiation is associated with worse short-term glycemic improvement and a greater need for escalating glucose-lowering therapy; however, it is also associated with a substantial reduction in the long-term MACE risk.
Ying Ran, Lili Jiang, Jing Ran et al.· Frontiers in Endocrinology· 0 citations
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