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Reduced insulin clearance is linked to subclinical atherosclerosis in individuals at risk for type 2 diabetes mellitus

Medicine and Health

Reduced insulin clearance is linked to subclinical atherosclerosis in individuals at risk for type 2 diabetes mellitus

E. Randrianarisoa, A. Lehn-stefan, et al.

This study explores the intriguing link between glycemic traits and carotid intima-media thickness (cIMT), revealing that reduced insulin clearance correlates with early signs of vascular damage. Conducted by a team of researchers from the Institute of Diabetes Research and Metabolic Diseases and the University Hospital of Tübingen, it sheds light on potential early markers for those at risk of type 2 diabetes.

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Playback language: English
Introduction
Type 2 diabetes mellitus (T2D) significantly increases the risk of cardiovascular disease (CVD) through the development of atherosclerosis. Elevated carotid intima-media thickness (cIMT) is a well-established indicator of subclinical atherosclerosis, reflecting structural changes in blood vessels years before overt CVD. While hyperglycemia and insulin resistance are implicated in vascular damage, their precise roles and the contribution of other metabolic factors remain unclear. This study aimed to systematically investigate the relative contributions of multiple glycemic traits (fasting and oral glucose tolerance test (oGTT)-derived) to cIMT in individuals at increased risk of T2D. The rationale for focusing on insulin clearance stems from its known association with atherosclerosis, independent of insulin-stimulated glucose disposal. Understanding the relative contributions of different pathophysiological mechanisms, including insulin clearance, is crucial for early identification and intervention strategies for CVD in high-risk individuals.
Literature Review
Existing literature demonstrates a strong association between hyperglycemia and CVD risk, observed not only in patients with overt diabetes but also in prediabetic states. However, insulin resistance and hyperinsulinemia, hallmarks of T2D, also contribute to vascular damage. Hepatic insulin clearance plays a significant role in regulating systemic insulin levels, with reduced clearance leading to elevated circulating insulin. Previous research indicates a link between reduced insulin clearance and atherosclerosis, but the relative contribution of this factor compared to other risk factors remains less well-defined. Therefore, a systematic examination of glycemia, insulin secretion, sensitivity, clearance, and classical cardiovascular risk factors on cIMT was needed.
Methodology
This cross-sectional study analyzed data from the Tübingen Lifestyle Intervention Program, encompassing individuals at increased risk for T2D. Participants with known diabetes or a history of CVD were excluded. Inclusion criteria included family history of T2D, BMI > 27 kg/m², or a previous diagnosis of impaired glucose tolerance or gestational diabetes. A total of 667 participants (417 women, 250 men; mean age 44.1 years) with complete datasets were included. Following a 10-hour overnight fast, a 75g oral glucose tolerance test (oGTT) was conducted with frequent blood sampling. Glucose, insulin, C-peptide, and proinsulin were measured. Insulin sensitivity and secretion indices were calculated. Carotid intima-media thickness (cIMT) was measured by high-resolution ultrasound. Additional parameters measured included blood pressure, lipids, hsCRP, HbA1c, and estimated glomerular filtration rate. Liver fat content was assessed in a subgroup using proton magnetic resonance spectroscopy. Univariate and multivariate linear regression analyses, including stepwise regression with cross-validation, were used to determine the association between cIMT and the various metabolic and clinical parameters. Subgroup analyses were performed based on glucose tolerance status. Statistical significance was set at p < 0.05.
Key Findings
Univariate analysis confirmed the association of classical CVD risk factors (waist circumference, blood pressure, dyslipidemia) with increased cIMT. Glucose and insulin levels were positively, and insulin sensitivity negatively, associated with cIMT. Glucose-stimulated insulin clearance showed a significant inverse correlation with cIMT (r = -0.17, p < 0.0001). Stepwise multivariate regression analysis identified age, glucose-stimulated insulin clearance, systolic blood pressure, BMI, gender, and fasting serum insulin as significant determinants of cIMT. Even after adjusting for traditional CVD risk factors, glucose-stimulated insulin clearance remained a significant independent predictor of cIMT (β = -0.16, p < 0.001). Subgroup analysis revealed a significant association between insulin clearance and cIMT in participants with newly diagnosed diabetes and those without diabetes, but not consistently across all glucose tolerance subgroups, possibly due to small sample sizes. No significant interactions were found between gender, liver fat content, or estimated glomerular filtration rate and the association between insulin clearance and cIMT.
Discussion
This study demonstrates a robust and independent association between reduced insulin clearance and increased cIMT, suggesting a potential link between impaired insulin clearance and early vascular damage. This relationship was observed even in individuals with normal glucose tolerance, indicating that the association is not solely dependent on hyperglycemia or overt diabetes. The mechanism may involve alterations in insulin signaling pathways at the vessel wall, with reduced clearance leading to hyperinsulinemia and a shift towards pro-inflammatory and pro-atherogenic signaling. While peripheral and hepatic insulin clearance could contribute, liver fat content did not explain the independent association in this study. The findings support the idea that reduced insulin clearance could serve as an early marker for vascular damage, preceding the development of T2D.
Conclusion
Reduced insulin clearance is independently associated with subclinical atherosclerosis, as evidenced by increased cIMT, in individuals at risk for T2D. This suggests that impaired insulin clearance may be an early and independent marker of vascular damage and a potential target for future CVD prevention strategies. Further prospective studies are needed to validate these findings and elucidate the precise mechanisms underlying this association. The use of standardized methods for assessing insulin clearance, like the euglycemic clamp, should also be explored in future research.
Limitations
This study is cross-sectional, limiting the ability to establish causality. The assessment of insulin clearance using an oGTT, rather than a gold-standard glucose clamp, could affect the precision of the measurements. The potential influence of medication use on the results could not be completely controlled for, given that drug intake wasn’t systematically analyzed. Subgroup analyses in some glucose tolerance strata had limited statistical power due to small sample sizes.
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