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Increased serum GGT and ALT levels are independent, additive risk factors for the development of type 2 diabetes mellitus in subjects without fatty liver or hepatic dysfunction.

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Abstract. As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies revealed advanced glycation end products (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes and the receptor for AGE (RAGE) as the major genic factor that responds to them. AGE fractions that caused the vascular derangement were proved to be RAGE ligands. When made diabetic, RAGE transgenic mice exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A) ϩ RNA, a novel splice variant coding for a soluble RAGE protein was found and was named endogenous secretory RAGE. Endogenous secretory RAGE was able to capture AGE ligands and to neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE-RAGE system, therefore, should be a candidate molecular target for overcoming this life-and quality-of-life-threatening disease.In 1912, Maillard (1) reported the generation of browncolored substances by a nonenzymatic reaction between reducing sugars and amino acids. It begins with linkage between the carbonyl group and the amino group to form Schiff bases and then Amadori compounds, finally yielding irreversibly crosslinked products termed "mélanoïdine." The series of the chemical reactions was named after the discoverer and has been one of the major themes in food chemistry, because melanoidines constitute an essential component of colors, odors, and tastes of a wide variety of foods. The Maillard reaction, however, does not occur merely on kitchen ranges. In 1981, Monnier and Cerami (2) documented that it can take place within our bodies. Because it proceeds as we age, the final products were then termed "AGE." The AGE formation and accumulation are most accelerated under diabetes.The major sources of the carbonyl group in the glycation reaction in vivo include glucose and carbonyl compounds, such as glyceraldehyde, glyoxal, glycolaldehyde, methylglyoxal, and 3-deoxyglucosone, which are derived from glucose, Schiff bases, and Amadori compounds (3) (Figure 1). Long half-lived proteins, such as serum albumin, lens crystallin, and collagen in the extracellular matrix, are akin to be glycated. AGE Actions on Vascular CellsMicrovessels, which are first deranged in diabetic retinopathy and nephropathy, are composed of endothelial cells (EC) and pericytes. By co-culture experiments, Yamagishi et al. (4,5) showed that pericytes not only regulate the growth of neighboring EC but also preserve EC-specific functions, including the production of prostacyclin, an antithrombogenic prostanoid. This indicates that when the pericyte-EC interaction is impaired, angiogenesis and thrombogenesis should result. Such a ...

We examined the effects of high-fat diet (HFD) and exercise training on insulin-stimulated whole body glucose fluxes and several key steps of glucose metabolism in skeletal muscle. Rats were maintained for 3 wk on either low-fat (LFD) or high-fat diet with or without exercise training (swimming for 3 h per day). After the 3-wk diet/exercise treatments, animals underwent hyperinsulinemic euglycemic clamp experiments for measurements of insulin-stimulated whole body glucose fluxes. In addition, muscle samples were taken at the end of the clamps for measurements of glucose 6-phosphate (G-6-P) and GLUT-4 protein contents, hexokinase, and glycogen synthase (GS) activities. Insulin-stimulated glucose uptake was decreased by HFD and increased by exercise training (P < 0.01 for both). The opposite effects of HFD and exercise training on insulin-stimulated glucose uptake were associated with similar increases in muscle G-6-P levels (P < 0.05 for both). However, the increase in G-6-P level was accompanied by decreased GS activity without changes in GLUT-4 protein content and hexokinase activities in the HFD group. In contrast, the increase in G-6-P level in the exercise-trained group was accompanied by increased GLUT-4 protein content and hexokinase II (cytosolic) and GS activities. These results suggest that HFD and exercise training affect insulin sensitivity by acting predominantly on different steps of intracellular glucose metabolism. High-fat feeding appears to induce insulin resistance by affecting predominantly steps distal to G-6-P (e.g., glycolysis and glycogen synthesis). Exercise training affected multiple steps of glucose metabolism both proximal and distal to G-6-P. However, increased muscle G-6-P levels in the face of increased glucose metabolic fluxes suggest that the effect of exercise training is quantitatively more prominent on the steps proximal to G-6-P (i.e., glucose transport and phosphorylation).

OBJECTIVEThe relationship between impaired fasting glucose (IFG) and risk of cardiovascular disease (CVD) or ischemic heart disease (IHD) varies widely according to sex and ethnicity. We evaluated the relationship between IFG and CVD or IHD among Korean men and women.RESEARCH DESIGN AND METHODSA total of 408,022 individuals who underwent voluntary private health examinations in 17 centers in South Korea were followed for 10 years. Data regarding CVD or IHD events were obtained from the Korean National Health Insurance database. IFG was categorized as grade 1 (fasting glucose 100–109 mg/dL) or grade 2 (110–125 mg/dL).RESULTSIncidence rates of CVD (per 100,000 person-years) were 2,203 for diabetes. Age-adjusted hazard ratios (HRs) for CVD were 1.17 (95% CI 1.13–1.20) for grade 1 IFG, 1.30 (1.24–1.35) for grade 2 IFG, and 1.81 (1.75–1.86) for diabetes. The increased risk for women was similar to that of men. Age-adjusted HRs for IHD and ischemic stroke were also significantly increased for men and women with IFG and diabetes. After multivariate adjustment of conventional risk factors (hypertension, dyslipidemia, smoking, obesity, and family history of CVD), the overall risk of CVD was greatly attenuated in all categories. However, the HRs for IHD and ischemic stroke remained significantly increased in men for grade 2 IFG but not in women.CONCLUSIONSIn Korea, grade 2 IFG is associated with increased risk of IHD and ischemic stroke, independent of other conventional risk factors, in men but not in women.

BackgroundWe investigated the relationships of adiponectin/leptin (A/L) ratio with cardiovascular risk factors, insulin resistance index, and metabolic syndrome (MS) in apparently healthy Korean male adults.MethodsSixty-eight male subjects were enrolled among the participants of an annual health check-up program (mean age, 55.1 years). Percent body fat (%) was measured using a bioelectric impedance analyzer. Serum leptin level was measured via radioimmunoassay, and adiponectin level was measured using an enzyme-linked immunosorbent assay. Homeostasis model assessment (HOMA)-insulin resistance (IR) index was calculated, and the presence of metabolic syndrome was assessed.ResultsAdiponectin, leptin, and A/L ratio showed significant correlations with percent body fat, lipid profile, and HOMA-IR. Mean leptin and HOMA-IR levels were significantly higher, while A/L ratio was significantly lower in subjects with MS. With increasing number of MS components, the mean values of leptin and HOMA-IR increased and the A/L ratio decreased. In multiple regression analysis, HOMA-IR was significantly correlated with triglyceride, fasting glucose, and A/L ratio, while A/L ratio was significantly correlated with body mass index and HOMA-IR. HOMA-IR and A/L ratio were significant predictors for each other after adjustment for other factors.ConclusionA/L ratio correlated well with lipid profile, HOMA-IR, and the presence and number of MS components in Korean male subjects.

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