Serum levels of advanced glycation end products (AGEs) are independent correlates of insulin resistance in nondiabetic subjects.
ABSTRACT Advanced glycation end products (AGEs) evoke oxidative stress generation and inflammatory reactions, thus being involved in vascular complications in diabetes. Since oxidative stress and inflammation impair insulin actions as well, it is conceivable that AGEs may play some role in insulin resistance. However, there is no clinical study to examine the relationship between serum levels of AGEs and insulin resistance. This study investigated whether serum AGE levels were independent correlates of insulin resistance in humans.
Three hundred twenty-two nondiabetic Japanese subjects (216 male and 106 female; mean age 61.5 ± 9.1 years) underwent a complete history and physical examination, determinations of blood chemistries, anthropometric and metabolic variables, including AGEs. Serum AGE levels were examined with an enzyme-linked immunosorbent assay.
Mean serum AGE levels were 8.96 ± 2.57 U/mL. In univariate analysis, waist circumference, diastolic blood pressure (BP), mean BP, AGEs, low-density lipoprotein (LDL) cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol (inversely), hemoglobin A1c (GHb), creatinine clearance, uric acid, and high sensitivity C-reactive protein were significantly associated with insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) index. After performing multiple regression analysis, waist circumference (P < 0.001), GHb (P < 0.001), triglycerides (P < 0.001), and AGEs (P < 0.01) still remained significant independently. When age-adjusted HOMA-IR levels stratified by AGE tertiles were compared using ANCOVA, a significant trend was demonstrated in both males and females.
The present study demonstrated for the first time that serum AGE levels were one of the independent correlates of HOMA-IR index, thus suggesting that AGEs may play some pathological role in insulin resistance in humans.
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ABSTRACT: The prevalence, prognostic import, and impact of renal insufficiency on the benefits of ACE inhibitors and beta-blockers in community-dwelling patients with heart failure are uncertain. We analyzed data from a prospective cohort of 754 patients with heart failure who had ejection fraction, serum creatinine, and weight measured at baseline. Median age was 69 years, and 43% had an ejection fraction > or =35%. By the Cockcroft-Gault equation, 118 patients (16%) had creatinine clearances < or =30 mL/min and 301 (40%) had creatinine clearances between 30 and 59 mL/min. During follow-up (median 926 days), 385 patients (37%) died. Even after adjustment for all other prognostic factors, survival was significantly associated with renal function (P=0.002) in patients with either systolic or diastolic dysfunction; patients exhibited a 1% increase in mortality for each 1-mL/min decrease in creatinine clearance. The associations with 1-year mortality reductions were similar for ACE inhibitors (OR 0.46 [95% CI 0.26 to 0.82] versus OR 0.28 [95% CI 0.11 to 0.70]) and beta-blockers (OR 0.40 [95% CI 0.23 to 0.70] versus OR 0.41 [95% CI 0.19 to 0.85]) in patients with creatinine clearances <60 mL/min versus > or =60 mL/min, although these drugs were used less frequently in patients with renal insufficiency. Renal insufficiency is more prevalent in patients with heart failure than previously reported and is an independent prognostic factor in diastolic and systolic dysfunction. ACE inhibitors and beta-blockers were associated with similar reductions in mortality in patients with and without renal insufficiency.Circulation 04/2004; 109(8):1004-9. · 15.20 Impact Factor
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ABSTRACT: Type 2 diabetes is a result of derangement of homeostatic systems of metabolic control and immune defense. Increases in visceral fat and organ adipose, environmental factors and genetic predisposition create imbalances of these homeostatic mechanisms, ultimately leading to a condition in which the oxidative environment cannot be held in check. A significant imbalance between the production of reactive oxygen species and antioxidant defenses, a condition called to oxidative stress, ensues, leading to alterations in stress-signalling pathways and potentially end-organ damage. Oxidative stress and metabolic inflammation upregulate the expression pro-inflammatory cytokines, including tissue necrosis factor alpha, monocyte chemoattractant protein-1 and interleukin-6, as well as activating stress-sensitive kinases, such as c-Jun N-terminal kinase (JNK), phosphokinase C isoforms, mitogen-activated protein kinase and inhibitor of kappa B kinase. The JNK pathway (specifically JNK-1) appears to be a regulator that triggers the oxidative-inflammation cascade that, if left unchecked, can become chronic and cause abnormal glucose metabolism. This can lead to insulin resistance and dysfunction of the vasculature and pancreatic beta-cell. The series of events set in motion by the interaction between metabolic inflammation and oxidative stress constitutes an 'oxidative-inflammatory cascade', a delicate balance driven by mediators of the immune and metabolic systems, maintained through a positive feedback loop. Modulating an oxidative-inflammation cascade may improve glucose metabolism, insulin resistance and vascular function, thereby slowing the development and progression to cardiovascular diseases and type 2 diabetes.International Journal of Clinical Practice 08/2008; 62(7):1087-95. · 2.43 Impact Factor
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ABSTRACT: Diabetic complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis. Chronic hyperglycemia is initially involved in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic derangements. High glucose increased production of various types of advanced glycation end-products (AGEs). Recently, we found that glyceraldehyde-derived AGEs (AGE-2) play an important role in the pathogenesis of angiopathy in diabetic patients. There is considerable interest in receptor for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGE-2 (predominantly structure of toxic AGEs; TAGE) with RAGE alters intracellular signaling, gene expression, release of pro-inflamatory molecules and production of reactive oxygen species (ROS) that contribute towards the pathology of diabetic complications. We propose three pathways for the in vivo formation of AGE-2 precursor, glyceraldehyde, such as i) glycolytic pathway, ii) polyol pathway, and iii) fructose metabolic pathway. Glyceraldehyde can be transported or can leak passively across the plasma membrane. It can react non-enzymatically with proteins to lead to accelerated formation of TAGE at both intracellularly and extracellularly. In this review, we discuss the molecular mechanisms of diabetic complications, especially focusing on toxic AGEs (TAGE) and their receptor (RAGE) system.Current Molecular Medicine 06/2006; 6(3):351-8. · 4.20 Impact Factor