Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation

Benthem, Lambertus; Keizer, Klaasjan; Wiegman, Coen; Boer, Sietse F. de; Strubbe, J.H.; Steffens, A.B.; Kuipers, Folkert; Scheurink, Antonius

doi:10.1152/ajpendo.2000.279.6.e1286

Cited by 67 publications

(58 citation statements)

References 58 publications

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“…23 One proposed mechanism is that increased sympathetic activation, a hallmark of autonomic dysfunction, leads to enhanced catecholamine release and consequent increases in circulating free fatty acids and the potential for increased insulin resistance. 24 Previous research supports this hypothesis and demonstrates stronger cross-sectional associations between autonomic dysfunction and insulin than glucose. In the Insulin Resistance and Atherosclerosis Study, heart rate was inversely associated with insulin sensitivity and directly associated with the acute insulin response to glucose and proinsulin concentration after adjustment for demographic characteristics, glucose tolerance status, and smoking.…”

Section: Temporal Sequencementioning

confidence: 78%

Prospective Investigation of Autonomic Nervous System Function and the Development of Type 2 Diabetes

Carnethon¹,

et al. 2003

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Background-Autonomic nervous system (ANS) dysfunction has been correlated with fasting insulin and glucose, independent of clinically diagnosed diabetes. We tested whether men and women (aged 45 to 64 years) from the Atherosclerosis Risk In Communities study (nϭ8185) with ANS dysfunction, estimated by high heart rate (HR) and low HR variability (HRV), were at increased risk for developing type 2 diabetes. Methods and Results-Supine HR and HRV indices were measured for 2 minutes at baseline; indices were divided into quartiles for analyses. From 1987 to 1998 (mean follow-up 8.3 years), there were 1063 cases of incident diabetes. The relative risk (RR) of developing diabetes for participants with low-frequency (LF) power (0.04 to 0.15 Hz) HRV in the lowest quartile (Ͻ7.7 ms 2 ) compared with the highest quartile (Ն38.9 ms 2 ) was 1.2 (95% CI 1.0 -1.4) after adjustment for age, race, sex, study center, education, alcohol drinking, current smoking, prevalent coronary heart disease, physical activity, and body mass index. Participants in the uppermost (Ͼ72.7 bpm) versus the lowest (Յ60.1 bpm) quartile of HR had a 60% increased risk (95% CI 33%-92%) of developing diabetes. Results were similar when the sample was restricted to participants with normal fasting glucose (glucose Ͻ6.1 mmol/L) at baseline (nϭ7192) or when adjusted for baseline glucose (HR quartile 4 versus quartile 1, RRϭ1.4, 95% CI 1.2-1.7). Conclusions-These

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Section: Temporal Sequencementioning

confidence: 78%

Prospective Investigation of Autonomic Nervous System Function and the Development of Type 2 Diabetes

Carnethon¹,

et al. 2003

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“…Thus, conditions of autonomic imbalance may result in impaired transport of blood glucose to the muscle cells, a negative feedback cycle that may continue as circulating glucose levels gradually increase. Additionally, sympathetically mediated catecholamine release increases circulating free fatty acids, which further contribute to the development of insulin resistance and diabetes (34,35). With the exception of the association between higher heart rate at baseline and incident diabetes, the associations between ECG indexes at baseline and incident diabetes were largely null.…”

Section: Incident Diabetesmentioning

confidence: 99%

The Association Among Autonomic Nervous System Function, Incident Diabetes, and Intervention Arm in the Diabetes Prevention Program

et al. 2006

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OBJECTIVE -Autonomic nervous system dysfunction, a correlate of obesity and poor cardiorespiratory fitness, is associated with the development of diabetes. We tested whether estimates of autonomic nervous system function improved in the intensive lifestyle versus metformin or placebo arms of the Diabetes Prevention Program (DPP) and whether baseline or a change in autonomic nervous system function was associated with the development of diabetes over 3.2 years.RESEARCH DESIGN AND METHODS -In 2,980 DPP participants, 12-lead electrocardiograms were measured at baseline and annually. Heart rate, heart rate variability (HRV), and QT duration were used to estimate fitness and autonomic nervous system function.RESULTS -In the lifestyle arm, heart rate and QT indexes decreased, and HRV increased over time. The magnitude of decline in heart rate and QT duration was substantially smaller in the other arms, whereas HRV did not increase. Baseline heart rate was the only index significantly (P Ͻ 0.05) associated with incident diabetes after adjustment for demographics and weight change (hazard ratio for lifestyle and metformin arms ϭ 1.19 and 1.17 per 10.6 beats/min, respectively). Decreases in heart rate and QT indexes and increases in HRV over time were associated with a lower risk of developing diabetes. The protective association between decreased heart rate and incident diabetes in the lifestyle arm remained significant after accounting for change in weight and physical activity.CONCLUSIONS -Indexes that reflect autonomic function and fitness improved (i.e., heart rate decreased and HRV increased) in the lifestyle modification arm of the DPP. Improvements in these indexes are inversely associated with the development of diabetes independent of weight change. Diabetes Care 29:914 -919, 2006A utonomic impairment has been identified at the time of diabetes diagnosis, which suggests that impairment may be present after a relatively brief exposure to hyperglycemia or develop in conjunction with obesity or insulin resistance (1,2). Cross-sectional studies in adults without diabetes provide evidence that markers of autonomic functioning are inversely associated with obesity, insulin resistance, and fasting glucose (3-6). Recent research suggesting that autonomic dysfunction predicts the development of diabetes (7,8) supports the long-held clinical suspicion that autonomic dysfunction is associated with the development of diabetes in healthy adults (9).Adults were identified as eligible to participate in the Diabetes Prevention Program (DPP) because they were at risk for developing diabetes, most commonly because of existing hyperglycemia and obesity. Thus, it is plausible that many had existing autonomic impairment at baseline in the study. At the conclusion of the trial, there was a significantly lower incidence of diabetes in the intensive lifestyle modification arm compared with that in the metformin or placebo arms (10). Lifestyle modification involved increasing physical activity and lowering dietary fat intake with a goa...

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“…Elevation of systemic or portal plasma FFA levels by intravenous lipid infusions enhances ACTH and cortisol secretion in rats (4,74). Moreover, prolonged high-fat feeding raises circulating FFA levels and basal ACTH and cortisol concentrations in rodents (63).…”

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confidence: 97%

Enhanced circadian ACTH release in obese premenopausal women: reversal by short-term acipimox treatment

Kok¹,

Kok²,

Buijs³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Several studies suggest that the hypothalamopituitary-adrenal (HPA) axis is exceedingly active in obese individuals. Experimental studies show that circulating free fatty acids (FFAs) promote the secretory activity of the HPA axis and that human obesity is associated with high circulating FFAs. We hypothesized that HPA axis activity is enhanced and that lowering of circulating FFAs by acipimox would reduce spontaneous secretion of the HPA hormonal ensemble in obese humans. To evaluate these hypotheses, diurnal ACTH and cortisol secretion was studied in 11 obese and 9 lean premenopausal women (body mass index: obese 33.5 Ϯ 0.9 vs. lean 21.2 Ϯ 0.6 kg/m 2 , P Ͻ 0.001) in the early follicular stage of their menstrual cycle. Obese women were randomly assigned to treatment with either acipimox (inhibitor of lipolysis, 250 mg orally four times daily) or placebo in a double-blind crossover design, starting one day before admission until the end of the blood-sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of plasma ACTH and cortisol concentrations. ACTH and cortisol secretion rates were estimated by multiparameter deconvolution analysis. Daily ACTH secretion was substantially higher in obese than in lean women (7,950 Ϯ 1,212 vs. 2,808 Ϯ 329 ng/24 h, P ϭ 0.002), whereas cortisol was not altered (obese 36,362 Ϯ 5,639 vs. lean 37,187 Ϯ 4,239 nmol/24 h, P ϭ 0.912). Acipimox significantly reduced ACTH secretion in the obese subjects (acipimox 5,850 Ϯ 769 ng/24 h, P ϭ 0.039 vs. placebo), whereas cortisol release did not change (acipimox 33,542 Ϯ 3,436 nmol/24 h, P ϭ 0.484 vs. placebo).In conclusion, spontaneous ACTH secretion is enhanced in obese premenopausal women, whereas cortisol production is normal. Reduction of circulating FFA concentrations by acipimox blunts ACTH release in obese women, which suggests that FFAs are involved in the pathophysiology of this neuroendocrine anomaly. adrenocorticotropic hormone; spontaneous secretion; pituitary adrenal system; free fatty acids; obesity THE ENDOCRINE ENVIRONMENT is a powerful regulator of body fat storage. For example, the hypothalamo-pituitary-adrenal (HPA) ensemble profoundly affects body composition in animals and humans. Glucocorticoid administration promotes body weight gain in rodents (19,26,77), and hypercortisolism in patients with Cushing's syndrome leads in visceral depots to excess fat, which is readily reversed by lowering plasma cortisol levels (45, 70).Obese animal models are marked by an exceedingly active HPA ensemble. Genetically obese rodents have high levels of glucocorticoids (5, 6), adrenalectomy reduces body weight in these animals (12, 21), and subsequent corticosterone replacement restores the obese state (12,22,32,61,76). Adrenalectomy also attenuates diet-induced obesity. Removal of the adrenals reduces energy intake and adipose tissue weights in diet-induced obese rodents, which is reversed by glucocorticoid replacement (18,36,48,62).Various clinical studies suggest that the HPA axis is also h...

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Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation

Cited by 67 publications

References 58 publications

Prospective Investigation of Autonomic Nervous System Function and the Development of Type 2 Diabetes

Prospective Investigation of Autonomic Nervous System Function and the Development of Type 2 Diabetes

The Association Among Autonomic Nervous System Function, Incident Diabetes, and Intervention Arm in the Diabetes Prevention Program

Enhanced circadian ACTH release in obese premenopausal women: reversal by short-term acipimox treatment

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