Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest. 97, 2859-2865

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 06/1996; 97(12):2859-65. DOI: 10.1172/JCI118742
Source: PubMed


To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (approximately 5.2 mM) hyperinsulinemic (approximately 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be approximately 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a approximately 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to approximately 50% of control values (4.0 +/- 1.0 vs. 9.3 +/- 1.6 mumol/[kg.min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at approximately 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an approximately 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation.

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    • "Additionally, postoperative hyperglycemia is also seen in patients due to an increase in insulin resistance and its decreased secretion caused by surgical trauma, a phenomenon called 'surgical/stress diabetes' or 'diabetes of injury' (Vanhorebeek &amp; Langouche, 2009). It is also claimed that increased lipolysis due to the stress hormones results in increased free fatty acid (FFA) levels that produce insulin-resistance in diabetic and non-diabetic patients, further contributing to stress-related hyperglycemia (Roden et al., 1996).There is a greater chance of severe hypoglycemic episodes in patients who are obese, hypertensive and have an atherogenic lipid profile. These characteristics are very common in cardiac surgery patients (Weintraub, Wenger, Jones, Craver, &amp; Guyton, 1993). "
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    ABSTRACT: Perioperative hyperglycemia has been shown to be related to higher levels of morbidity and mortality in patients on cardiopulmonary bypass (CPB) undergoing coronary artery bypass grafting (CABG), both diabetic and non-diabetic. Blood electrolytes, like sodium, potassium, calcium, and chloride play a very important role in the normal functioning of the body and can lead to a variety of clinical disorders if they become deficient. A minimal number of studies have been conducted on the simultaneous perioperative changes in both blood glucose and electrolyte levels during CPB in Pakistan. Therefore, our aim is to record and compare the changes in blood glucose and electrolyte levels during CPB in diabetic and non-diabetic patients.MATERIALS & METHODS: This was a prospective, observational study conducted on 200 patients who underwent CABG with CPB, from October 2014 to March 2015. The patients were recruited from the Cardiac Surgery Ward, Civil Hospital Karachi after they complied with the inclusion criteria. Repeated-measures analysis of variance (ANOVA) was used to compare the trend of the changes perioperatively for the two groups.RESULTS: There was no significant difference in changes in blood glucose between the two groups (P = 0.62). The only significant difference detected between the two groups was for PaCO2 (P = 0.001). Besides, further analysis revealed insignificant group differences for the trend changes in other blood electrolytes (P > 0.05).CONCLUSION: Our findings highlighted that there is no significant difference in blood electrolytes changes and the increase in blood glucose levels between diabetic and non-diabetic patients.
    Full-text · Article · Jan 2016 · Global journal of health science
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    • "During the availability of sufficient amounts of free FA, serum concentrations of ET1 have been reported to increase and insulin resistance is thus observed (e.g. obese and insulin resistant diabetes) [107] [108]. Increasing concentrations of ET1 in the sputum of stable COPD patients have been observed [83] [109] [110] [111] [112]. "

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    • "In this study involving seven healthy adults, it has been demonstrated that four consecutive days of PSD (4.5 h night À1 ) reduced the ability of insulin to stimulate intracellular downstream pathways in subcutaneous adipose tissue by approximately 30% (Broussard et al., 2012). In another study involving 19 young non-diabetic men, PSD for 4 consecutive nights (4.5 h in bed night À1 ) resulted in increased circulating concentrations of free fatty acids (FFAs) (Broussard et al., 2015), which are known to impair insulin-stimulated muscle uptake of glucose in humans (Roden et al., 1996). To what extent such biochemical alterations may have contributed to Table 1 Sleep characteristics of the two experimental sleep conditions "
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    ABSTRACT: The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin’s anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25-hr sleep) versus one night of full sleep (8.5-hr sleep). In the morning following each sleep condition, subjects’ oral cavity was rinsed with a 1-molar sucrose solution for 45 seconds, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (-3, +3, +5, +7, +10, and +20 minutes). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P=0.025). In contrast, no CPIR was observed in any of the sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. Contrarily, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans.
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