Continuous glucose monitoring as a close to real life alternative to meal studies - a pilot study with a functional drink containing amino acids and chromium.

This pilot study aimed to evaluate a continuous glucose monitoring (CGM) based approach to study the effects of a functional drink containing specific amino acids and chromium picolinate (FD) and a combination of FD with a juice (FDJ) on postprandial glucose in a close to real life setting. The predefined primary endpoint for this study was the 120-min incremental area under the glucose curve (iAUC0-120min ) after meals. It was estimated that using CGM and repeated meals in 6 participants could be sufficient to match the power of the previous study in regards to the quantity of meals. Participants followed a pre-specified meal schedule over 9 days and consumed the drinks three times daily with main meals. Differences between drinks were analyzed by analysis of covariances (ANCOVA) with subject number and activity as random factors and nutrient composition as covariates. In 156 meals available for analysis, a significant 34% reduction of glucose iAUC0-120min was shown for FDJ (p < 0.001). FD did not show a significant effect on its own, but a significant reduction of 17.6% (p = 0.007) was shown in pooled data for FD and FDJ. While the differences between the two functional drinks used were not the primary focus of this study, it was sufficiently powered to detect previously described effects in 60 participants in a cross-over design under laboratory settings. The design presented defines a novel and cost-effective approach using CGM devices and app-based lifestyle tracking for studying nutritional effects on glucose at home in a close to real-life setting.

Protective Effects of Transient Glucose Exposure in Adult C. elegans.

C. elegans are used to study molecular pathways, linking high glucose levels (HG) to diabetic complications. Persistent exposure of C. elegans to a HG environment induces the mitochondrial formation of reactive oxygen species (ROS) and advanced glycation endproducts (AGEs), leading to neuronal damage and decreased lifespan. Studies suggest that transient high glucose exposure (TGE) exerts different effects than persistent exposure. Thus, the effects of TGE on ROS, AGE-formation and life span were studied in C. elegans. Four-day TGE (400 mM) as compared to controls (0mM) showed a persistent increase of ROS (4-days 286 ± 40 RLUs vs. control 187 ± 23 RLUs) without increased formation of AGEs. TGE increased body motility (1-day 0.14 ± 0.02; 4-days 0.15 ± 0.01; 6-days 0.16 ± 0.02 vs. control 0.10 ± 0.02 in mm/s), and bending angle (1-day 17.7 ± 1.55; 3-days 18.7 ± 1.39; 6-days 20.3 ± 0.61 vs. control 15.3 ± 1.63 in degree/s) as signs of neuronal damage. Lifespan was increased by 27% (21 ± 2.4 days) after one-day TGE, 34% (22 ± 1.2 days) after four-days TGE, and 26% (21 ± 1.4 days) after six-days TGE vs. control (16 ± 1.3 days). These experiments suggest that TGE in C. elegans has positive effects on life span and neuronal function, associated with mildly increased ROS-formation. From the perspective of metabolic memory, hormetic effects outweighed the detrimental effects of a HG environment.

A novel nutritional supplement containing amino acids and chromium decreases postprandial glucose response in a randomized, double-blind, placebo-controlled study.

High postprandial blood glucose levels are associated with increased mortality, cardiovascular events and development of diabetes in the general population. Interventions targeting postprandial glucose have been shown to prevent both cardiovascular events and diabetes. This study evaluates the efficacy and safety of a novel nutritional supplement targeting postprandial glucose excursions in non-diabetic adults. Sixty overweight healthy male and female participants were recruited at two centers and randomized in a double-blind, placebo-controlled, crossover design. The supplement, a water-based drink containing 2.6g of amino acids (L-Leucine, L-Threonine, L-Lysine Monohydrochloride, L-Isoleucine, L-Valine) and 250 mcg of chromium picolinate, was consumed with a standardized carbohydrate-rich meal. The primary endpoint was the incremental area under the curve (iAUC) for venous blood glucose from 0 to 120 minutes. Secondary endpoints included glucose iAUC 0-180 minutes and the maximum glucose concentration (Cmax), for both venous and capillary blood glucose. In the intention-to-treat-analysis (n = 60) the supplement resulted in a decreased venous blood glucose iAUC0-120min compared to placebo, mean (SE) of 68.7 (6.6) versus 52.2 (6.8) respectively, a difference of -16.5 mmol/L•min (95% CI -3.1 to -30.0, p = 0.017). The Cmax for venous blood glucose for the supplement and placebo were 6.45 (0.12) versus 6.10 (<0.12), respectively, a difference of -0.35 mmol/L (95% CI -0.17 to -0.53, p<0.001). In the per protocol-analysis (n = 48), the supplement resulted in a decreased Cmax compared to placebo from 6.42 (0.14) to 6.12 (0.14), a difference of -0.29 mmol/L (95% CI -0.12 to -0.47, p = 0.002). No significant differences in capillary blood glucose were found, as measured by regular bed-side glucometers. The nutritional supplement drink containing amino acids and chromium improves the postprandial glucose homeostasis in overweight adults without diabetes. Future studies should clarify, whether regular consumption of the supplement improves markers of disease or could play a role in a diet aiming at preventing the development of diabetes.

Impaired dexamethasone resorption in two patients with pseudo-Cushing after bariatric surgery: Implications for immunosuppressive treatment.

Two cases of middle-aged female patients treated by gastric bypass surgery for weight loss presented to our clinic for a follow-up examination 3-6 months after the surgical procedure (a mini gastric bypass and a modified single anastomosis sleeve-ileostomy). In both patients increased ACTH levels and either high serum cortisol or an increased urinary cortisol excretion was apparent and triggered further endocrine testing. Serum cortisol could not be suppressed adequately by 2 and 4 mg dexamethasone in the standardized oral overnight suppression test while midnight salivary cortisol dropped well below the desired cut-off. This led to the hypothesis of an impaired dexamethasone resorption and could be further substantiated by suppression of serum cortisol below the cut-off by an intravenous dexamethasone application. The data presented point to an impairment of enteral synthetic corticosteroid resorption in patients after gastric bypass surgery and could be of importance for individuals in need for immunosuppressive treatment. In view of the growing number of bariatric procedures, pharmacokinetics of corticosteroids and other drugs should be tested in clinical trials.

Dietary Intervention with Oatmeal in Patients with uncontrolled Type 2 Diabetes Mellitus - A Crossover Study.

BACKGROUND: In a pilot study, we evaluated the efficacy of two days of oatmeal on insulin resistance and glucose metabolism and found a marked decrease of insulin requirements. The most important shortcoming of that study was that the interventions were not isocaloric (diabetes adapted diet: 1500 kcal/d vs. oatmeal 1100 kcal/d). To address these drawbacks we designed the OatMeal And Insulin Resistance (OMA-IR) study. METHODS: The study was a randomized, open label crossover dietary intervention study with consecutive inclusion of 15 patients with uncontrolled type 2 diabetes. The intervention comprised two days of oatmeal on days 3 and 4 of a 5 days hospital stay. During the control period, patients received a diabetes mellitus adapted diet only. The primary endpoint was the daily insulin requirement and glycemic control. RESULTS: Upon oatmeal treatment, the required insulin dose could be significantly reduced on the third and fourth day as compared to the second day of inpatient stay (82.0±30.3 and 69.9±29.9IU versus 112±36.2IU;P<0.001). During control treatment, insulin requirement did not change. There were no significant differences in the changes of mean blood glucose or fasting glucose between both treatments. HbA1c was lower four weeks after the oatmeal intervention. CONCLUSION: In this crossover study, two days of oatmeal intervention allowed a highly significant reduction of required daily insulin doses while maintaining adequate metabolic control as compared to a diabetes adapted diet only. The beneficial effects of the intervention might last for several weeks as shown by the lower HbA1c four weeks after the intervention.

Urinary liver-type fatty acid binding protein is an independent predictor of stroke and mortality in individuals with type 1 diabetes.

AIMS/HYPOTHESIS: In type 1 diabetes, cardiovascular disease (CVD) and diabetic nephropathy progress in parallel, thereby potentiating the risk of premature death during their development. Since urinary liver-type fatty acid binding protein (L-FABP) predicts the progression of diabetic nephropathy, the aim of this study was to investigate whether urinary L-FABP also predicts cardiovascular outcomes and mortality. METHODS: We tested our hypothesis in a Finnish cohort of 2329 individuals with type 1 diabetes and a median follow-up of 14.1 years. The L-FABP to creatinine ratio was determined from baseline urine samples. The predictive value of urinary L-FABP was evaluated using Cox regression models, while its added predictive benefit for cardiovascular outcomes and mortality was evaluated using a panel of statistical indexes. RESULTS: Urinary L-FABP predicted incident stroke independently of traditional risk factors (HR 1.33 [95% CI 1.20, 1.49]) and after further adjustment for eGFR (HR 1.28 [95% CI 1.14, 1.44]) or AER (HR 1.24 [95% CI 1.06, 1.44]). In addition, it predicted mortality independently of traditional risk factors (HR 1.34 [95% CI 1.24, 1.45]), and after adjustment for eGFR (HR 1.29 [95% CI 1.18, 1.39]) or AER (HR 1.22 [95% CI 1.09, 1.36]). Urinary L-FABP was as good a predictor as eGFR or AER, and improved the AUC for both outcomes on top of traditional risk factors, with no reclassification benefit (integrated discrimination improvement/net reclassification improvement) for stroke or mortality when AER or eGFR were added to traditional risk factors. However, urinary L-FABP was not a predictor of other cardiovascular endpoints (coronary artery disease, peripheral vascular disease and overall CVD events) when adjusted for the AER. CONCLUSIONS/INTERPRETATION: Urinary L-FABP is an independent predictor of stroke and mortality in individuals with type 1 diabetes.

Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy: a likely causal link in patients with type 1 diabetes.

OBJECTIVE: We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS: We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable. RESULTS: KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (ß = -4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (ß = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (ß = -5.044; P = 0.040), suggesting a causal relationship. CONCLUSIONS: KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.

Urinary adiponectin is an independent predictor of progression to end-stage renal disease in patients with type 1 diabetes and diabetic nephropathy.

OBJECTIVE: We investigated the predictive value of urinary adiponectin (uADP) for the progression of diabetic nephropathy (DN) as well as for the principal determinants of uADP concentrations. RESEARCH DESIGN AND METHODS: uADP was measured in 2,090 patients with type 1 diabetes followed for a median of 5.8 (4.4-6.9) years and in 111 subjects without diabetes. Progression was defined as a change in albuminuria (albumin excretion rate [AER]) to a higher stage or development of end-stage renal disease (ESRD). Various Cox regression and competing risk models were used to evaluate the predictive value of uADP for DN progression. The added predictive benefit to AER or estimated glomerular filtration rate (eGFR) was estimated by the area under the receiver operating characteristic curve, integrated discrimination improvement (IDI), continuous net reclassification improvement (NRI), and other statistical indexes. The determinants of uADP were investigated by multiple regression analyses. RESULTS: uADP was an independent predictor of progression to ESRD (hazard ratio 1.60, P < 0.001) and was an even better predictor than AER (P = 0.04) or as good as eGFR (P = 0.79). Furthermore, uADP added a significant benefit when used together with AER (NRI 0.794, P = 0.03; IDI 0.115, P < 0.0001) or eGFR (NRI 0.637, P < 0.001; IDI 0.087, P < 0.0001). The common determinants of uADP were glycemic control, tubular injury, and AER. CONCLUSIONS: uADP is a strong independent predictor of DN progression from macroalbuminuria to ESRD and adds a significant predictive benefit to current biomarkers in patients with type 1 diabetes.

Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study.

BACKGROUND: Endothelial progenitor cells (EPC) are bone marrow-derived cells which can undergo differentiation into endothelial cells and participate in endothelial repair and angiogenesis. Insulin facilitates this in vitro mediated by the IGF-1 receptor. Clinical trials showed that the number of circulating EPCs is influenced by glucose control and EPC are a predictor of cardiovascular death. To study direct effects of insulin treatment on EPCs in type 2 diabetes patients, add-on basal insulin treatment was compared to an escalation of oral medication aiming at similar glucose control between the groups. METHODS: 55 patients with type 2 diabetes (61.6±5.9 years) on oral diabetes medication were randomized in a 2:2:1 ratio in 3 groups. Patients were treated additionally with insulin glargine (n=20), NPH insulin (n=22) or escalated with oral medication (n=13). Number of circulating EPC, EPC-outgrowth, intima media thickness, skin microvascular function and HbA1c were documented at baseline and/or after 4 weeks and 4 months. RESULTS: HbA1c at baseline was, 7.3+/-0.7% in the oral group, 7.3+/-0.9% and 7.5+/-0.7% in the glargine and NPH insulin respectively (p=0.713). HbA1c after 4 months decreased to 6.8+/-0.8%, 6.6+/-0.7% and 6.7+/-0.6%, in the oral, glargine and NPH insulin group respectively (p=0.61). FACS analysis showed no difference in number of circulating EPC between the groups after 4 weeks and 4 months. However, the outgrowth of EPCs as detected by colony forming assay was increased in the NPH insulin and glargine groups (29.2+/-6.4 and 29.4+/- 6.7 units respectively) compared to the group on oral medication (23.2+/-6.3, p=0.013) after 4 months of treatment. A significant decrease of IMT from 0.80mm (+/-0.14) at baseline to 0.76mm (+/-0.12) after 4 months could be observed in all patients only (p=0.03) with a trend towards a reduction of IMT after 4 months when all patients on insulin treatment were compared to the oral treatment group (p=0.06). Skin microvascular function revealed no differences between the groups (p=0.74). CONCLUSION: The study shows that a 4-month treatment with add-on insulin significantly increases the outgrowth of EPC in patients with type 2 diabetes mellitus. TRIAL REGISTRATION: (Clinical Trials Identifier: NCT00523393).

Urinary excretion of high molecular weight adiponectin is an independent predictor of decline of renal function in type 2 diabetes.

Adiponectin and urinary adiponectin excretions have been ascribed a function in glomerular physiology and seem to indicate vascular disease in diabetes. The aim of this study was to compare the urinary excretion of albumin and adiponectin as predictors for decline of renal function in patients with type 2 diabetes and early kidney disease. Over 141 patients were screened for renal function (estimated GFR, ml/min*1.73 m(2)), albumin excretion rate (AER, mg/24 h), total as well as high molecular weight (HMW) urinary adiponectin excretion (ng/mol u-creatinine). AER and adiponectin excretion were studied as predictors of renal function after 1 year. After 1 year, 36 patients were in the upper quartile of eGFR decline and defined as progressors (delta eGFR = - 12.3 ± 6.3) while the remaining 105 patients were defined as non-progressors (delta eGFR = 1.4 ± 6.0). At baseline, HMW-adiponectin excretion was positively correlated with HbA1c (p < 0.001) and negatively with eGFR (p < 0.001), but not with AER (p = 0.14). Progressors showed increased urinary HMW-adiponectin at baseline (158[IQR41/479] vs. 65[24/168] ng/mol; p < 0.01), while total adiponectin (182[101/1534] vs. 345[118/1361] ng/mol) and AER (48[23/109] vs. 46[25/108] mg/24 h) excretion showed no differences between the groups. Multivariate logistic regression showed that HMW-adiponectin excretion was an independent predictor of renal progression in all patients (OR 1.86 [95 % CI 1.34-2.59]; p < 0.01), especially in those (n = 45) with normal AER at baseline (OR 2.16 [95 % CI 1.1-4.56]; p < 0.05). Urinary HMW-adiponectin but not AER improved the prediction of progressors in ROC analysis (AUC 0.72 [95 % CI 0.63-0.81] vs. 0.80 [95 % CI 0.71-0.90], p < 0.05). In conclusion, urinary HMW-adiponectin excretion may identify diabetes patients at increased risk for progression of kidney disease.

Urinary liver-type fatty acid-binding protein and progression of diabetic nephropathy in type 1 diabetes.

OBJECTIVE: Diabetic nephropathy (DN) has mainly been considered a glomerular disease, although tubular dysfunction may also play a role. This study assessed the predictive value for progression of a tubular marker, urinary liver-type fatty acid-binding protein (L-FABP), at all stages of DN. RESEARCH DESIGN AND METHODS: At baseline, 1,549 patients with type 1 diabetes had an albumin excretion rate (AER) within normal reference ranges, 334 had microalbuminuria, and 363 had macroalbuminuria. Patients were monitored for a median of 5.8 years (95% CI 5.7-5.9). In addition, 208 nondiabetic subjects were studied. L-FABP was measured by ELISA and normalized with urinary creatinine. Different Cox proportional hazard models for the progression at every stage of DN were used to evaluate the predictive value of L-FABP. The potential benefit of using L-FABP alone or together with AER was assessed by receiver operating characteristic curve analyses. RESULTS: L-FABP was an independent predictor of progression at all stages of DN. As would be expected, receiver operating characteristic curves for the prediction of progression were significantly larger for AER than for L-FABP, except for patients with baseline macroalbuminuria, in whom the areas were similar. Adding L-FABP to AER in the models did not significantly improve risk prediction of progression in favor of the combination of L-FABP plus AER compared with AER alone. CONCLUSIONS: L-FABP is an independent predictor of progression of DN irrespective of disease stage. L-FABP used alone or together with AER may not improve the risk prediction of DN progression in patients with type 1 diabetes, but further studies are needed in this regard.

Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy.

This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.

Sustained effects of a mindfulness-based stress-reduction intervention in type 2 diabetic patients: design and first results of a randomized controlled trial (the Heidelberger Diabetes and Stress-study).

OBJECTIVE: To determine whether a mindfulness-based stress reduction (MBSR) intervention is effective for reducing psychosocial distress (i.e., depression, psychosocial stress) and the progression of nephropathy (i.e., albuminuria) and for improving the subjective health status of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes and microalbuminuria were randomized to a mindfulness-based intervention (n = 53) or a treatment-as-usual control (n = 57) group. The study is designed to investigate long-term outcomes over a period of 5 years. We present data up to the first year of follow-up (FU). RESULTS: At FU, the MBSR group showed lower levels of depression (d = 0.71) and improved health status (d = 0.54) compared with the control group. No significant differences in albuminuria were found. Per-protocol analysis also showed higher stress reduction in the intervention group (d = 0.64). CONCLUSIONS: MBSR intervention achieved a prolonged reduction in psychosocial distress. The effects on albuminuria will be followed up further.

Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve.

PURPOSE: To study myocardial perfusion reserve and myocellular metabolic alterations indicated by triglyceride content as possible causes of diastolic dysfunction in patients with type 2 diabetes mellitus, preserved systolic function, and without clinically evident coronary artery disease. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus (n = 42) underwent cardiac magnetic resonance (CMR) for quantification of 1) myocardial contractility by strain-encoded MR (SENC); 2) myocardial triglyceride content by proton magnetic resonance spectroscopy ((1) H-MRS); and 3) myocardial perfusion reserve during pharmacologic hyperemia. Age-matched healthy volunteers (n = 16) also underwent CMR to acquire normal values for myocardial strain and perfusion reserve. RESULTS: Stress CMR procedures were successfully performed in all subjects, and no regional inducible perfusion defects were observed in type 2 diabetes mellitus patients. Diastolic strain rate and myocardial perfusion reserve were significantly impaired in patients with type 2 diabetes mellitus compared to control subjects (P < 0.001 for both). Interestingly, impaired diastolic function in type 2 diabetes mellitus was not associated with impaired myocardial perfusion reserve (r = 0.12, P = NS). Conversely a significant association was observed between diastolic dysfunction and myocardial triglyceride content (r = -0.71, P < 0.001), which proved to be independent of age, gender, diabetes duration, blood pressure, and fasting blood glucose. CONCLUSION: Myocardial steatosis may represent an early marker of diabetic heart disease, triggering subclinical myocardial dysfunction irrespective of myocardial perfusion reserve.

Proximal neuropathic lesions in distal symmetric diabetic polyneuropathy: findings of high-resolution magnetic resonance neurography.

OBJECTIVE: This study investigated high-resolution magnetic resonance neurography (MRN) in distal symmetric diabetic polyneuropathy (dPNP). RESEARCH DESIGN AND METHODS: MRN comprised high-resolution transaxial imaging of peripheral nerves of the lower limbs in 20 patients with type 2 diabetes (10 with dPNP, type 2/dPNP[+], and 10 without dPNP, type 2/dPNP[-]), seven patients with type 1 diabetes (two with dPNP, type 1/dPNP[+], five without dPNP, type 1/dPNP[-]), and 10 nondiabetic control subjects. Intraneural T2 lesions, as the main diagnostic criterion of MRN, were detected visually by two independent observers and quantitatively by analysis of T2 contrast ratios. RESULTS: Multifocal fascicular, symmetric intraneural T2 lesions occurred in the proximal trunks of sciatic nerves in four patients (three with type 2/dPNP[+] and one with type 1/dPNP[+]) but not in control subjects (type 2/dPNP[-], type 1/dPNP[-], nondiabetic control subjects), which was confirmed by quantitative analysis. Clinical severity was higher in patients with T2 lesions (neuropathy deficit score: 10 vs. 7.8; P = 0.05). CONCLUSIONS: For the first time, proximal neuropathic lesions of dPNP are reported in vivo. This supports that accumulation of proximal, multifocal fascicular injury may be important in disease progression.

Determinants of troponin release in patients with stable coronary artery disease: insights from CT angiography characteristics of atherosclerotic plaque.

OBJECTIVE: To understand the determinants of troponin release in patients with stable coronary artery disease (CAD) by comparing high sensitive troponin T (hsTnT) levels with computed tomography angiography (CTA) characteristics of atherosclerotic plaque. METHODS: hsTnT was determined in 124 consecutive patients with stable angina, who underwent clinically indicated 256-slice CTA for suspected CAD. CTA was used to assess (1) coronary calcification; (2) stenosis severity; (3) non-calcified plaque volume; (4) plaque composition (soft or mixed, described as 'non-calcified' versus calcified) and (5) the presence of vascular remodeling in areas of non-calcified plaque. RESULTS: All CT scans were performed without adverse events, and diagnostic image quality was achieved in 1830/1848 available coronary segments (99.0%). In 29/124 patients, hsTnT was ≥14 pg/ml (range 14.0-34.4). Weak, albeit significant, correlations were found between hsTnT and calcium scoring (r=0.45, p<0.001), while a stronger correlation was found between hsTnT and the total non-calcified plaque burden (r=0.79, p<0.001). Patients with non-calcified plaque (n=44) yielded significantly higher hsTnT values than those with normal vessels (n=46) or those with only calcified lesions (n=26), (12.6 ± 5.2 vs 8.3 ± 2.6 and 8.8 ± 3.0 pg/ml, respectively, p<0.001). Furthermore, those with remodeled non-calcified plaque (n=8) showed even higher hsTnT values of 26.3 ± 6.5 pg/ml than all other groups (p<0.001). This allowed the identification of patients with remodeled non-calcified plaque by hsTnT with high accuracy (area under the curve=0.90, SE=0.07, 95% CI 0.84 to 0.95). CONCLUSIONS: Chronic clinically silent rupture of non-calcified plaque with subsequent microembolisation may be a potential source of troponin elevation. In light of recent imaging studies, in which patients with positively remodeled non-calcified plaque were shown to be at high risk for developing acute coronary syndromes, hsTnT may serve as a biomarker for such 'vulnerable' coronary lesions even in presumably stable CAD.

Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process: a mini-review.

Aging is a dynamic process in which its rate and subsequent longevity of an organism are dependent upon the balance between the reactive intermediates of normal cellular metabolism and the ability of the body to reduce these by-products through a multifaceted antioxidant defence system. Every disturbance of this balance constitutes a clear and present danger to the macromolecular integrity of the body. When defence mechanisms become diminished or impaired, the resulting imbalance results in accumulation of endogenous agents, such as reactive oxygen and carbonyl species, and a state of increased cellular stress, which can accelerate the rate of aging. Glycation is the non-enzymatic glycosylation of proteins, nucleotides and lipids by saccharide derivatives. Glucose and other reducing sugars are important glycating agents, but the most reactive physiological relevant glycating agents, are the dicarbonyls, in particular methylglyoxal. Endogenously formed dicarbonyl compounds can react with proteins to form advanced glycation endproducts (AGEs). Experimental models have recently provided evidence that reduced detoxification of AGE precursors by the glyoxalase system, engagement of the cellular receptor RAGE and RAGE-dependent sustained activation of the pro-inflammatory transcription factor nuclear factor κB might significantly contribute to the rate of aging and the onset of age-related neurodegenerative, musculoskeletal and vascular diseases.

Associations of fetuin-A levels with vascular disease in type 2 diabetes patients with early diabetic nephropathy.

BACKGROUND: Ambigous results exist on fetuin-A as marker for vascular disease in type 2 diabetes. This study aims to define the role of fetuin-A as marker for micro- and macrovascular disease in a high risk population of patients with type 2 diabetes mellitus and early diabetic nephropathy. METHODS: Fetuin-A serum levels were assessed by ELISA in a cross-sectional setting in 153 patients with type 2 diabetes. Associations of fetuin-A with metabolic, inflammatory and vascular markers were studied. Atherosclerotic burden was assessed by ankle-brachial-index (ABI) as well as detection of common carotid artery intima-media thickness (IMT). RESULTS: Levels of fetuin-A were lower in male than in female patients (0.49 ± 0.15 vs. 0.56 ± 0.20 g/L, p = 0.02). In addition, there was an inverse correlation with age (r = -0.20, P = 0.01). Bivariate correlations adjusted for age and gender revealed no significant correlations with metabolic parameters, except for a weak inverse correlation with serum adiponectin (r = -0.19, p = 0.02). Regarding parameters of micro- and macrovascular disease, fetuin-A was significantly associated with ABI (r = 0.18, p = 0.04), while there was no association with IMT (r = -0.07, p = n.s). Patients with an ABI < 0.9 had lower fetuin A levels than patients with an ABI 0.9-1.3 or > 1.3 (0.43 ± 0.10 vs. 0.52 ± 0.17 vs. 0.54 ± 0.18 g/L p = 0.05). Neither GFR nor albuminuria were associated with fetuin-A serum levels. Patients with prevalent neuropathy did not have altered fetuin-A levels compared to diabetic controls. In step-wise logistic regression analysis including age, gender, HbA1c, total cholesterol, glomerular filtration rate and fetuin-A, only total cholesterol (ß = 0.01, p = 0.02) and fetuin-A (ß = -5.99, p = 0.03) proved to be independent predictors of an ABI < 0.9. CONCLUSIONS: The results of this cross-sectional study suggest that lower fetuin-A levels are associated with macrovascular late complications in high-risk type 2 diabetes patients while there are no associations of fetuin-A with metabolic status or microvascular complications.

Alanine-aminotransferase levels predict impaired glucose tolerance in a worksite population.

Insulin resistance and impaired glucose tolerance precede the development of type 2 diabetes. In 2006, the BASF Occupational Medicine and Health Protection Department offered a diabetes screening program for 33,000 employees. 1,594 employees had their diabetes risk tested: 285 employees were at medium to high risk for diabetes type 2, according to the Finrisk score. Hundred and fifty-seven of these individuals underwent oral glucose tolerance testing: 22 were shown to have impaired glucose tolerance (IGT), and 5 had manifest diabetes. Thus, 18% of this worksite sample population were affected by IGT or type 2 diabetes. A total of 87% were affected by metabolic syndrome (MS) according to the International Diabetes Federation (IDF) criteria. At baseline, individuals with normal glucose tolerance and impaired glucose tolerance differed significantly with respect to fasting glucose (97 +/- 8 vs. 103 +/- 10 mg/dl, P < 0.01), HbA1c (5.5 +/- 0.3 vs. 5.7 +/- 0.4%, P < 0.01), and alanine-aminotransferase (ALT) (28 +/- 15 vs. 36 +/- 18 U/I, P < 0.05). In binary logistic regression analysis adjusted for age and gender, fasting glucose and ALT were the only independent predictors of impaired glucose tolerance (OR 4.8 [1.24-24.8] and OR 5.5 [1.2-24.8]), while age and HbA1c had only borderline significance (OR 3.9 [0.94-15.92] and OR 2.8 [0.94-8.67]). Waist circumference, BMI, triglycerides, and HDL as central components of the MS had no predictive value for impaired glucose tolerance. In summary, in this particular sample population, fasting glucose and ALT were the only significant predictors of IGT. These data point to an important role of the liver in insulin resistance and the development of impaired glucose tolerance in the relatively young and small population studied.

Association of homozygous SDF-1 3'A genotype with proliferative diabetic retinopathy.

Stromal cell-derived factor 1 (SDF-1) is involved in the development of experimental proliferative retinopathy. Since little data are available on the genetic predisposition or on biomarkers predicting the development of proliferative retinopathy, we assessed the distribution of the SDF-1 3'A genotype in 130 diabetic patients with retinopathy. In patients with proliferative retinopathy, the frequency of the homozygous SDF-1 3'A genotype was significantly higher than in patients with non-proliferative retinopathy (10.9% of PDR vs. 0 of NPDR, P = 0.01). This association was confirmed when type 2 diabetes patients were analysed separately (10.3% of PDR vs. 0 of NPDR, P = 0.03). The finding that homozygous carriers of the SDF-1 3'A genotype are more frequent in diabetes patients with proliferative retinopathy suggests a possible role of this genotype in the development of sight-threatening diabetic retinopathy.