Increased plasma free fatty acid (FFA) concentrations are typically associated with many insulin-resistant states including obesity and type 2 diabetes mellitus (1-3). Furthermore, raising plasma FFA levels in healthy humans, by triglyceride/heparin infusions, can also acutely induce insulin resistance (4-11). Over thirty years ago, Randle et al. (12,13) demonstrated that FFAs compete with glucose for oxidation in isolated rat heart and diaphragmatic muscle preparations, and they speculated that increased fat oxidation may cause the insulin resistance associated with diabetes and obesity. They proposed that increased FFA oxidation leads to an increase in the intramitochondrial acetyl-coenzyme A (acetyl-CoA) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD + ) ratios, resulting in inactivation of pyruvate dehydrogenase activity. The consequent increase in intracellular citrate concentration causes inhibition of phosphofructokinase resulting in an increase in glucose-6-phosphate levels. The elevated glucose-6-phosphate levels would inhibit hexokinase II activity and then lead to decreased glucose uptake. However, recent studies by our group (14) and others (15,16) have called this mechanism into question. Boden and coworkers have shown that a reduction in carbohydrate oxidation was responsible for only one-third of the fatty acid-dependent decrease in glucose uptake, while impaired non-oxidative glucose metabolism accounted for the remainder (16). These workers suggested that two different defects might contribute to the impairment in nonoxidative glucose metabolism. At FFA concentrations of ∼0.75 mM, they found an increase in glucose-6-phosphate concentrations in muscle biopsies, suggesting an inhibitory effect of FFA on glycogen synthase activity, whereas at lower FFA concentrations (∼0.50 mM) they observed no difference in intramuscular glucose-6-phosphate concentration. In contrast, using carbon-13/phosphorous-31 nuclear magnetic resonance (NMR) spectroscopy under increased plasma FFA concentrations (∼1.8 mM), we observed a decrease in intramuscular glucose-6-phosphate concentration associated with a 50% reduction in insulin-stimulated muscle glycogen synthesis (14). These data suggest that acute elevations in plasma FFA levels in humans cause insulin resistance by initial inhibition of glucose transport and/or phosphorylation activity that is concurrently followed by a reduction in the rate of both muscle glycogen synthesis and glucose oxidation. Because glucose-6-phosphate (and not intracellular glucose) concentration was measured, it was not possible to distinguish between To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. I...

To examine the mechanism by which free fatty acids (FFAs) induce insulin resistance in vivo, awake chronically catheterized rats underwent a hyperinsulinemic-euglycemic clamp with or without a 5-h preinfusion of lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted in insulin resistance as reflected by a approximately 35% reduction in the glucose infusion rate (P < 0.05 vs. control). The insulin resistance was associated with a 40-50% reduction in 13C nuclear magnetic resonance (NMR)-determined rates of muscle glycogen synthesis (P < 0.01 vs. control) and muscle glucose oxidation (P < 0.01 vs. control), which in turn could be attributed to a approximately 25% reduction in glucose transport activity as assessed by 2-[1,2-3H]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induced decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a approximately 50% reduction in insulin-stimulated insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 2) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a four-fold increase in membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control). We conclude that acute elevations of plasma FFA levels for 5 h induce skeletal muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity. These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta.

Universal screening for GDM is superior to risk factor based screening-detecting more cases, facilitating early diagnosis and is associated with improved pregnancy outcome.

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The two-step spin crossover in mononuclear iron(III) complex [Fe(salpm)2 ]ClO4 ⋅0.5 EtOH (1) is shown to be accompanied by a structural phase transition as concluded from (57) Fe Mössbauer spectroscopy and single crystal X-ray diffraction, with spin-state ordering on just one of two sub-lattices in the intermediate magnetic and structural phase. The complex also exhibits thermal- and light-induced spin-state trapping (TIESST and LIESST), and relaxation from the LIESST and TIESST excited states occurs via the broken symmetry intermediate phase. Two relaxation events are evident in both experiments, that is, two T(LIESST) and two T(TIESST) values are recorded. The change in symmetry which accompanies the TIESST effect was followed in real time using single crystal diffraction. After flash freezing at 15 K the crystal was warmed to 40 K at which temperature superstructure reflections were observed to appear and disappear within a 10 000 s time range. In the frame of the international year of crystallography, these results illustrate how X-ray diffraction makes it possible to understand complex ordering phenomena.

Acknowledgments-We acknowledge the superb technical assistance of Vincenzo Cinapri and Stefano Quilici. References 1. Matteucci E, Giampietro O: Oxidative stress in families of type 1 diabetic patients. Diabetes Care 23:1182-1186, 2000 2. Cutaia M, Parks N: Oxidant stress decreases Na ϩ /H ϩ antiport activity in bovine pulmonary artery endothelial cells.

Summary The increased risk of atherosclerotic disease in diabetic subjects may be due to enhanced foam cell formation following an increased susceptibility of low density lipoprotein to oxidative modification. This study has compared fatty acid content and lipoprotein oxidisability in 10 non-insulin-dependent diabetic subjects with that in 10 control subjects. Both groups were normocholesterolaemic and the diabetic subjects had higher triglyceride levels (2.2 + 0.4 vs 1.2 + 0.2 mmol/1, p < 0.05). The fatty acid composition was compared in low density lipoprotein following Folch extraction, separation by thin layer chromatography (for the lipid classes) and analysis by gas liquid chromatography. Low density lipoprotein oxidisability was assessed by conjugated diene and thiobarbituric acid reacting substance formation in the presence of copper ions. The esterified/free cholesterol ratio was higher in the low density lipoprotein from patients compared to control subjects (2.9 _+ 0.1 vs 1.9 + 0.3, p < 0.05). Linoleic acid in the cholesteryl ester fraction of the lipoprotein was higher in the patients than in the control subjects (48.2 + 2.2 % vs 42.4 + 3.4 %,p < 0.05) as was the total quantity of linoleic acid in the cholesteryl ester fraction (317.8 + 68.0 vs 213.2 + 28.0 vg/mg protein, p < 0.05) and in the low-density lipoprotein as a whole (443.2 + 70.0 vs 340.2 + 28.2 ~g/mg protein, p<0.05). Lipoprotein oxidisability was also increased in the diabetic group with increased formation of thiobarbituric acid reacting substances (35.6 + 7.2 vs 22.3 + 3.5 nmol/mg protein, p < 0.05, increased total diene formation (502 + 60 vs 400 + 30 nmol/mg protein, p < 0.05) and increased rate of diene formation (7.2 + 0.6 vs 5.1 + 0.9 nmol diene 9 mg protein -1. min -1, p < 0.05). This study indicates that low-density lipoprotein from diabetic subjects is more susceptible to oxidation. This could, in vivo, accelerate foam-cell formation thereby increasing atherosclerotic risk in diabetic subjects. [Diabetologia (1995[Diabetologia ( ) 38: 1300[Diabetologia ( -1306 Key words Non-insulin-dependent diabetes mellitus, low-density lipoprotein oxidation, dietary fatty acids, low-density lipoprotein composition, glycated lowdensity lipoprotein.Although hypercholesterolaemia is an important risk factor in both diabetic and non-diabetic subjects, lowdensity lipoprotein (LDL) cholesterol levels are of- ten normal in patients with atherosclerosis. In this study attention has been focused on abnormalities in the composition of LDL the major cholesterol-carrying particle, rather than the quantity. These investigations have been prompted by the finding that oxidised rather than native LDL delivers cholesterol to the macrophage [1], the precursor of the foam cell and the maj or cholesterol-containing cell in the atherosclerotic plaque. Therefore, the potential for LDL to be oxidised in the vessel wall may be of importance in atherogenesis. Babiy et al. [2] have shown that LDL from non-insulin-dependent diabetic (NIDDM)