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  • Author: Coen D A Stehouwer x
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Richard G Ijzerman, Coen D A Stehouwer, Erik H Serné, Jasper J Voordouw, Yvo M Smulders, Henriette A Delemarre-van de Waal and Mirjam M van Weissenbruch

Objective

Based on fasting insulin and glucose, several indices of insulin sensitivity have been developed in adults. Recently, it has been demonstrated that incorporation of the fasting free fatty acid (FFA) concentration improves the association with insulin sensitivity in adults. We investigated the association of clamp-derived insulin sensitivity with indices of insulin sensitivity derived from fasting blood in prepubertal children and adults, with and without incorporation of FFAs.

Design and methods

We studied 59 healthy adults and 29 of them are prepubertal children. We measured insulin sensitivity with the euglycemic–hyperinsulinemic clamp. Based on fasting insulin and glucose, we estimated insulin sensitivity with the homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI), and the revised QUICKI after the incorporation of FFAs.

Results

The associations of HOMA and QUICKI with clamp-derived insulin sensitivity in children (r=−0.55 and 0.54 respectively; P<0.01) were similar to those in adults (r=−0.54 and 0.53 respectively; P<0.01). However, incorporation of FFAs into the QUICKI model resulted in an increase in the association in adults, but not in children (r=0.68 and 0.48 respectively; P<0.01). Adding FFA levels to a regression model with glucose and insulin as independent variables resulted in an increase in the explained variance in clamp-derived insulin sensitivity in adults, but not in children (P value 0.004 in adults and 0.3 in children).

Conclusions

HOMA and QUICKI are associated with clamp-derived insulin sensitivity in both children and adults. Incorporating fasting levels of FFAs into the QUICKI model improves the association with clamp-derived insulin sensitivity in adults, but not in children.

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Johanna W M Nin, Isabel Ferreira, Casper G Schalkwijk, Martin H Prins, Nish Chaturvedi, John H Fuller, Coen D A Stehouwer and EURODIAB Prospective Complications Study Group

Context and objective

High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro- and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein.

Design and methods

This was a cross-sectional nested case–control study of 463 patients (226 women; mean age 40±10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study. We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors.

Results

Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised β=0.07 (95% confidence interval (CI): 0.02–0.12) and β=0.08 (95% CI: 0.02–0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro- and macroalbuminuria: odds ratio (OR)=1.24 (95% CI: 0.90–1.71) and OR=1.61 (95% CI: 1.15–2.25) respectively, P for trend=0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however.

Conclusions

In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes.

Free access

Iris J G Ketel, Mariken N M Volman, Jacob C Seidell, Coen D A Stehouwer, Jos W Twisk and Cornelis B Lambalk

Objective: To determine which anthropometric measurement is the most reliable alternative for fat distribution as measured by dual-energy X-ray absorptiometry (DXA).

Design: Population-based survey carried out in Amsterdam, The Netherlands.

Subjects and methods: A total of 376 individuals (200 women) with a mean age of 36.5 years and mean body mass index (BMI) of 24.0 (±3.1) kg/m2 underwent various anthropometric and DXA measurements of central (CFM) and peripheral fat mass (PFM). Furthermore, for the assessment of apple-shaped body composition, CFM-to-PFM ratio was calculated. Anthropometric measurements were waist and hip circumference, waist-to-hip ratio (WHR), BMI, waist/length and the skinfold thickness of biceps, triceps, suprailiacal (SI), subscapular (SS) and upper leg. We determined whether equations of combined anthropometrics were even more reliable for the assessment of fat mass.

Results: In both women and men, reliable alternatives for CFM are central skinfolds and waist (Pearson’s correlation (r) ≥ 0.8). Peripheral skinfolds are the best predictors of PFM (r ≥ 0.8). In contrast, WHR correlated only marginally with any of the DXA measurements. Equations based on several anthropometric variables correlate with CFM even better (R 2 ≥ 0.8). CFM-to-PFM ratio has the highest correlation with the ratio (SS+SI)/BMI in women (r = 0.66) and waist/length in men (r = 0.71). Equations are reasonable alternatives of CFM-to-PFM ratio (R 2 ≥ 0.5).

Conclusion: Waist and skinfolds are reliable alternatives for the measurement of body fat mass in a cohort of Caucasian adults. WHR is not appropriate for the measurement of fat distribution.

Free access

Lian Engelen, Søren S Lund, Isabel Ferreira, Lise Tarnow, Hans-Henrik Parving, Jørgen Gram, Kaj Winther, Oluf Pedersen, Tom Teerlink, Rob Barto, Coen D A Stehouwer, Allan A Vaag and Casper G Schalkwijk

Objective

Metformin has been reported to reduce α-dicarbonyls, which are known to contribute to diabetic complications. It is unclear whether this is due to direct quenching of α-dicarbonyls or to an improvement in glycemic control. We therefore compared the effects of metformin versus repaglinide, an antihyperglycemic agent with an insulin-secreting mechanism, on the levels of the α-dicarbonyl 3-deoxyglucosone (3DG).

Methods

We conducted a single-center, double-masked, double-dummy, crossover study involving 96 nonobese patients with type 2 diabetes. After a 1-month run-in on diet-only treatment, patients were randomized to either repaglinide (6 mg daily) followed by metformin (2 g daily) or vice versa each during 4 months with a 1-month washout between interventions.

Results

3DG levels decreased after both metformin (−19.3% (95% confidence interval (CI): −23.5, −14.8)) and repaglinide (−20.8% (95% CI: −24.9, −16.3)) treatments, but no difference was found between treatments (1.8% (95% CI: −3.8, 7.8)). Regardless of the treatment, changes in glycemic variables were associated with changes in 3DG. Specifically, 3DG decreased by 22.7% (95% CI: 19.0, 26.5) per s.d. decrease in fasting plasma glucose (PG), by 20.0% (95% CI: 16.2, 23.9) per s.d. decrease in seven-point mean plasma glucose, by 22.5% (95% CI: 18.6, 26.6) per s.d. decrease in area under the curve for PG, by 17.2% (95% CI: 13.8, 20.6) per s.d. decrease in HbAlc, and by 10.9% (95% CI: 6.4, 15.5) per s.d. decrease in Amadori albumin. In addition, decreases in 3DG were associated with decreases in advanced glycation endproducts and endothelial markers.

Conclusion

Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in 3DG levels in nonobese individuals with type 2 diabetes. This may constitute a shared metabolic pathway through which both treatments have a beneficial impact on the cardiovascular risk.

Free access

Søren S Lund, Lise Tarnow, Coen D A Stehouwer, Casper G Schalkwijk, Tom Teerlink, Jørgen Gram, Kaj Winther, Merete Frandsen, Ulla M Smidt, Oluf Pedersen, Hans-Henrik Parving and Allan A Vaag

Objective

In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti-hyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients.

Design and methods

Single-centre, double-masked, double-dummy, crossover study during 2×4 months involving 96 non-obese (body mass index≤27 kg/m2) insulin-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions.

Results

Levels of tumour necrosis factor-α, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment effects.

Conclusions

In non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments.

Free access

Dirk van Moorsel, Marleen M J van Greevenbroek, Nicolaas C Schaper, Ronald M A Henry, Charlotte C Geelen, Elisabeth F C van Rossum, Giel Nijpels, Leen M 't Hart, Casper G Schalkwijk, Carla J H van der Kallen, Hans P Sauerwein, Jacqueline M Dekker, Coen D A Stehouwer and Bas Havekes

Objective

Excess glucocorticoids are known to cause hypertension and cardiovascular disease (CVD). The BclI glucocorticoid receptor (GR) polymorphism increases glucocorticoid sensitivity and is associated with adverse metabolic effects. Previous studies investigating cardiovascular implications have shown inconsistent results. Therefore, the aim of the present study was to investigate the association of the BclI polymorphism with blood pressure, atherosclerosis, low-grade inflammation, endothelial dysfunction, and prevalent CVD.

Design

Observational cohort study, combining two cohort studies designed to investigate genetic and metabolic determinants of CVD.

Methods

We genotyped 1228 individuals (aged 64.7 years±8.5) from the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study and Hoorn study for the BclI polymorphism. We measured blood pressure, ankle–brachial index (ABI), and carotid intima–media thickness (cIMT). Low-grade inflammation and endothelial dysfunction scores were computed by averaging Z-scores of six low-grade inflammation markers and four endothelial dysfunction markers respectively. Prevalent CVD was assessed with questionnaires, hospital records, ECG, and ABI.

Results

Homozygous carriers (GG) had higher mean arterial pressure (103.8±12.4 mmHg vs 101.6±12.2 mmHg (mean±s.d.); P<0.05) compared with non-carriers (CC). Homozygous carriers had lower ABI compared with heterozygous carriers (CG) (1.08±0.13 vs 1.11±0.14; P<0.05). After adjustment for all covariates in the full model, the association with ABI was no longer significant. BclI was not associated with systolic blood pressure, cIMT, low-grade inflammation, endothelial dysfunction, and prevalent CVD.

Conclusions

The BclI polymorphism of the GR gene may contribute to an unfavorable cardiovascular profile; however, the effects on cardiovascular variables appear to be limited and partly mediated by the metabolic phenotype exerted by BclI.