Fasting Free Fatty Acid Levels Research Articles

Metabolic characteristics of transmembrane prolyl 4-hydroxylase (P4H-TM) deficient mice.

Transmembrane prolyl 4-hydroxylase (P4H-TM) is an enigmatic enzyme whose cellular function and primary substrate remain to be identified. Its loss-of-function mutations cause a severe neurological HIDEA syndrome with hypotonia, intellectual disability, dysautonomia and hypoventilation. Previously, P4H-TM deficiency in mice was associated with reduced atherogenesis and lower serum triglyceride levels. Here, we characterized the glucose and lipid metabolism of P4h-tm-/- mice in physiological and tissue analyses. P4h-tm-/- mice showed variations in 24-h oscillations of energy expenditure, VO2 and VCO2 and locomotor activity compared to wild-type (WT) mice. Their rearing activity was reduced, and they showed significant muscle weakness and compromised coordination. Sedated P4h-tm-/- mice had better glucose tolerance, lower fasting insulin levels, higher fasting lactate levels and lower fasting free fatty acid levels compared to WT. These alterations were not present in conscious P4h-tm-/- mice. Fasted P4h-tm-/- mice presented with faster hepatic glycogenolysis. The respiratory rate of conscious P4h-tm-/- mice was significantly lower compared to the WT, the decrease being further exacerbated by sedation and associated with acidosis and a reduced ventilatory response to both hypoxia and hypercapnia. P4H-TM deficiency in mice is associated with alterations in whole-body energy metabolism, day-night rhythm of activity, glucose homeostasis and neuromuscular and respiratory functions. Although the underlying mechanism(s) are not yet fully understood, the phenotype appears to have neurological origins, controlled by brain and central nervous system circuits. The phenotype of P4h-tm-/- mice recapitulates some of the symptoms of HIDEA patients, making this mouse model a valuable tool to study and develop tailored therapies.

FRI029 Chronic Free Fatty Acid Elevation Is Associated With An Overcompensatory Increase In Hepatic Mitochondrial Function In Patients With Overweight Or Obesity

Abstract Disclosure: F. Bril: None. S. Kalavalapalli: None. K. Cusi: None. The obesity epidemic has resulted in a significant increase in the prevalence of nonalcoholic fatty liver disease (NAFLD). Some patients with NAFLD progress to more severe forms of the disease, such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Our central hypothesis is that the inability of hepatic mitochondria to enhance nutrient oxidation in the setting of nutrient oversupply plays a key role in the progression of NAFLD. Specifically, the aim of this study was to assess if free fatty acid (FFA) excess contributes to hepatic mitochondrial dysfunction in patients with overweight or obesity. Patients with BMI ≥ 25kg/m2, without diabetes were included in the study. Patients underwent a 2-hour oral glucose tolerance test (OGTT) and a liver proton magnetic resonance spectroscopy (1H-MRS) to measure liver fat. In vivo hepatic mitochondrial ATP levels were measured by phosphorus (31P)-MRS every 30 minutes during a 2-hour oral fructose challenge (OFC). Due to unregulated phosphorylation of fructose upon entering hepatocytes, the OFC provides a dynamic measurement of hepatic ATP consumption and re-synthesis. Hepatic ATP levels were estimated as β-ATP/total phosphorus. A total of 37 patients were recruited for this study (age: 54 ± 11 years; sex: 43% male/57% female; BMI: 34.4 ± 6.3 kg/m2; A1c: 5.7 ± 0.4%; NAFLD: 51%). No differences were found in hepatic ATP levels in patients with or without NAFLD (0.019 ± 0.015 vs. 0.016 ± 0.012, p=0.44). Patients were then divided in three groups (tertiles) based on fasting FFA levels. We did not observe any significant differences among these three groups in key clinical variables, such as age, sex, BMI, A1c or prevalence of NAFLD. At baseline (pre OFC), we did not observe any difference in hepatic ATP levels (i.e., β-ATP/total phosphorus) among FFA tertiles (0.020 ± 0.015, 0.020 ± 0.012, and 0.012 ± 0.012, p=0.25). During the OFC, we estimated changes over time in hepatic ATP levels as the decremental area under the curve (AUROC) of β-ATP/total phosphorus. We observed that the decremental AUROC of hepatic ATP levels during OFC was significantly different among groups (0.57 ± 0.86, 0.14 ± 0.59, -0.40 ± 0.54, p=0.006). Patients in the highest tertile of FFAs showed no consumption of ATP after the OFC, but rather an overall increase in ATP AUROC over time. Plasma FFA levels correlated well with hepatic ATP AUROC during the OFC (-0.47, p =0.007). Conclusion: Chronic elevations in FFA levels are associated with changes in hepatic mitochondrial ATP synthesis, which were unmasked after an oral fructose challenge. While long-term, FFA elevations may impair mitochondrial function, in our study we observed an overcompensatory response in patients with high plasma FFA, characterized by an increase in hepatic ATP levels over time after fructose consumption. At what point this compensation is overwhelmed leading to inflammation and cellular lipotoxicity remains to be determined. Presentation: Friday, June 16, 2023

Association of obesity with serum free fatty acid levels in individuals at different stages of prediabetes

We investigated the associations of prediabetes categories and obesity with serum free fatty acid (FFA) levels and adipose tissue insulin resistance. This study included 5006 male participants (1779, 1025, 629, 874, and 699 with normal fasting glucose/normal glucose tolerance, isolated impaired fasting glucose [IFG], isolated impaired glucose tolerance [IGT], IFG plus IGT, and diabetes, respectively). Serum FFA levels were assessed before and 30, 60, and 120 min after glucose ingestion, and the total area under the FFA curve (AUCFFA ) was calculated. Adipose insulin resistance index (adipo-IR) was assessed based on fasting FFA and insulin concentrations. Isolated IFG was associated with high fasting FFA levels (OR, 1.35; p < 0.001) and high adipo-IR (OR, 1.82; p < 0.001) only in the nonobesity group. Isolated IGT, IFG plus IGT, and diabetes were associated with high fasting FFA levels, regardless of obesity. Obesity was significantly associated with AUCFFA , and the duration of obesity-related impairment in lipolysis inhibition after glucose ingestion was prolonged in IFG plus IGT and diabetes. These results suggest that IFG and obesity may overlap in their effects on FFA metabolism whereas IGT has significant effects on FFA independent of obesity. Obesity impact on lipolysis may be involved in worsening glucose metabolism.

Postprandial Free Fatty Acids at Mid-Pregnancy Increase the Risk of Large-for-Gestational-Age Newborns in Women with Gestational Diabetes Mellitus.

Background To investigate the association between free fatty acid (FFA) level at mid-pregnancy and large-for-gestational-age (LGA) newborns in women with gestational diabetes mellitus (GDM).Methods We enrolled 710 pregnant women diagnosed with GDM from February 2009 to October 2016. GDM was diagnosed by a ‘two-step’ approach with Carpenter and Coustan criteria. We measured plasma lipid profiles including fasting and 2-hour postprandial FFA (2h-FFA) levels at mid-pregnancy. LGA was defined if birthweights of newborns were above the 90th percentile for their gestational age.Results Mean age of pregnant women in this study was 33.1 years. Mean pre-pregnancy body mass index (BMI) was 22.4 kg/m2. The prevalence of LGA was 8.3% (n=59). Levels of 2h-FFA were higher in women who delivered LGA newborns than in those who delivered non-LGA newborns (416.7 μEq/L vs. 352.5 μEq/L, P=0.006). However, fasting FFA was not significantly different between the two groups. The prevalence of delivering LGA newborns was increased with increasing tertile of 2h-FFA (T1, 4.3%; T2, 9.8%; T3, 10.7%; P for trend <0.05). After adjustment for maternal age, pre-pregnancy BMI, and fasting plasma glucose, the highest tertile of 2h-FFA was 2.38 times (95% confidence interval, 1.11 to 5.13) more likely to have LGA newborns than the lowest tertile. However, there was no significant difference between groups according to fasting FFA tertiles.Conclusion In women with GDM, a high 2h-FFA level (but not fasting FFA) at mid-pregnancy is associated with an increasing risk of delivering LGA newborns.

Prevalence and Features of Impaired Glucose Tolerance in Young Underweight Japanese Women.

In Japan, while it is known that underweight women over the age of 40 years have a high risk for type 2 diabetes, there is a lack of clarity on the association between glucose tolerance and underweight in younger women. Accordingly, we investigate the prevalence and features of impaired glucose tolerance (IGT) in young underweight Japanese women. In this cross-sectional study, we recruited 56 normal weight and 98 underweight young Japanese women and evaluated their glucose tolerance levels using an oral glucose tolerance test. Then, we compared the clinical characteristics associated with normal glucose tolerance (NGT) and IGT in the underweight women. Insulin secretion, whole-body insulin sensitivity, and adipose tissue insulin resistance values were measured using the insulinogenic index, whole-body insulin sensitivity index (Matsuda index), and adipose insulin resistance index (Adipo-IR), respectively. Fitness level (peak VO2) was measured using an ergometer. The prevalence of IGT was higher in the underweight women than the normal weight women (13.3% vs 1.8%). The underweight women with IGT showed a lower insulinogenic index, lower peak VO2, and Matsuda index and a higher fasting free fatty acid level and Adipo-IR than those with NGT. The whole-body composition was comparable between the NGT and IGT groups. The prevalence of IGT was higher in young Japanese women with underweight than those with a normal weight. The underweight women with IGT showed impaired early-phase insulin secretion, low fitness levels, and reduced whole-body and adipose tissue insulin sensitivity levels.

Basal insulin ameliorates post-breakfast hyperglycemia via suppression of post-breakfast proinsulin/C-peptide ratio and fasting serum free fatty acid levels in patients with type 2 diabetes.

In general, basal insulin targets fasting plasma glucose (FPG) levels, and prandial insulin targets postprandial glucose (PPG) levels. However, the effects of basal insulin on PPG levels are controversial. We investigated the effect of basal insulin on postprandial hyperglycemia using a test meal at breakfast as well as compared differences between degludec and glargine. A total of 20 participants with type 2 diabetes were randomly assigned to degludec (n = 10) or glargine (n = 10). We initiated basal-bolus insulin therapy and titrated only basal insulin until FPG was < 6.1mmol/L. We evaluated changes in post-breakfast glucose levels and changes in clinical parameters such as serum C-peptide (CPR), proinsulin (PI), and free fatty acids (FFA) levels between the pre- and post-titration periods. Differences between degludec and glargine in the post-titration period were also evaluated. Post-breakfast glucose levels significantly decreased by 46.1% in the post-titration period compared with the pre-titration period (n = 20, p < 0.001). These decreases correlated positively with decreases in the post-breakfast PI/CPR ratio (r = 0.692, p < 0.001) and in fasting FFA levels (r = 0.720, p < 0.001). There were no significant differences in post-breakfast glucose levels between degludec and glargine. However, the hypoglycemic rate with degludec was significantly lower than with glargine. Our results suggest that basal insulin with either degludec or glargine decreases the incidence of post-breakfast hyperglycemia accompanied by decreasing the post-breakfast PI/CPR ratio and fasting FFA levels in patients with type 2 diabetes.

Free fatty acids, cardiovascular disease, and mortality in the Multi-Ethnic Study of Atherosclerosis

Fasting free fatty acid (FFA) levels may be associated with cardiovascular disease (CVD) and mortality, but research among generally healthy adults, females, and racially/ethnically diverse populations is lacking. The primary aim of this project was to investigate prospective associations between fasting FFAs and coronary heart disease (CHD) and CVD incidence and CVD-specific and all-cause mortality in a generally healthy age, sex, and racially/ethnically heterogeneous population. This study was conducted in the Multi-Ethnic Study of Atherosclerosis cohort using baseline (2000-2002) fasting FFAs and outcome data through 2015 (N=6678). Cox proportional hazards regression was used to calculate hazard ratios for associations between FFAs and CHD, CVD, CVD-specific mortality, and all-cause mortality. Interactions by age, sex, race/ethnicity, and metabolic syndrome were evaluated by stratification and cross-product terms. A secondary analysis was conducted to evaluate associations between FFAs, and inflammatory and endothelial activation biomarkers were evaluated using linear regression (analytic N range: 964-6662). FFA levels were not associated with CHD or CVD incidence. Higher FFAs were associated with CVD-specific and all-cause mortality, but associations were attenuated in fully adjusted models with a borderline significant association remaining only for all-cause mortality (fully adjusted, per standard deviation increase hazard ratio=1.07, 95% confidence interval: 1.00-1.14). Associations did not differ by age, sex, race/ethnicity, or metabolic syndrome. Fasting FFAs were not associated with CHD, CVD, or CVD-specific mortality and were modestly associated with all-cause mortality, regardless of age, sex, race/ethnicity, or metabolic syndrome status.

1386-P: A Comparison of Ectopic Fat Stores and Insulin Sensitivity among Women With and Without Gestational Diabetes

Background: We assessed relationships between ectopic lipid stores [intrahepatic (IHL), intramyocellular (IMCL), and extramyocellular (EMCL)] and parameters of insulin sensitivity in women with gestational diabetes (GDM) compared with BMI-matched controls. Methods: We performed a case-control analysis nested within a prospective cohort study of 54 pregnant women with normal weight, overweight, and obesity without pregestational diabetes. From the prospective cohort, 7 women developed GDM. Three additional women with GDM were recruited in late pregnancy to increase sample size. All women underwent insulin clamps to assess insulin disposal (Rd) and endogenous glucose production (EGP); 1H magnetic resonance spectroscopy to assess IHL, IMCL, and EMCL content; MRI to assess subcutaneous abdominal (SAT) and visceral adipose tissue (VAT) volume, BODPOD to assess % body fat, fat mass, and fat free mass; and measurement of fasting free fatty acid levels. Measures were performed in early and late pregnancy [mean (minute-max), 15.5 (12.4-17.6) and 34.1 (31.6-37.3) weeks gestation, respectively]. Results: Women with GDM were matched on BMI to women in the prospective cohort who did not develop GDM. In early pregnancy, compared to controls, women with GDM had greater % body fat (P=.02), fasting free fatty acids (P&amp;lt;.01), and insulin resistance (lower Rd, P&amp;lt;.01), but did not significantly differ in amounts of VAT, SAT, IHL, EGP, IMCL, or EMCL. In late pregnancy, cases and controls did not significantly differ by body composition or free fatty acid levels, but insulin resistance remained greater among women with GDM (P=.02). Conclusion: Women who would be later diagnosed with GDM exhibited greater percent body fat, insulin resistance, and fasting free fatty acid levels early in pregnancy, but not visceral or ectopic fat stores. Accumulation of excess lipids in VAT and ectopic fat stores does not appear to play an important role in distinguishing women who develop GDM from those that do not. Disclosure K. Vesco: None. M.C. Leo: None. M. Francisco: None. N.E. Marshall: None. W. Rooney: None. E. Baetscher: None. A.M. Valent: None. J.Q. Purnell: Advisory Panel; Self; Novo Nordisk A/S. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098707)

The Association between Free Fatty Acid Level at Midpregnancy and Postpartum Glucose Intolerance in Women with Gestational Diabetes Mellitus

Free fatty acid (FFA) is correlated with fetal growth during pregnancy and with neonatal fat mass in women with gestational diabetes mellitus (GDM). However, there are few studies between FFA level and postpartum glucose metabolism in women with GDM. The aim of this study was to evaluate the association between FFA level at mid-pregnancy and postpartum glucose intolerance in women with GDM. We enrolled 769 pregnant women diagnosed with GDM from February 2009 to October 2016. FFA levels (fasting and postprandial 2-h) were measured during 24-32 gestational weeks and 75-g OGTT was performed at 6-12 weeks after delivery. High FFA was defined by more than the median level of FFA at mid-pregnancy. Postpartum glucose intolerance was defined as fasting plasma glucose (FPG) ≥ 100 mg/dL or 2-h plasma glucose (2-h PG) ≥ 140 mg/dL. Mean age was 33.1 years and mean pre-pregnancy BMI was 22.4 kg/m2. The prevalence of postpartum glucose intolerance was 48.0% (n = 369). Although postprandial 2-h FFA level and FFA difference (between fasting and postprandial 2-h FFA) were not significantly different between two groups, women with postpartum glucose intolerance had higher fasting FFA level at mid-pregnancy than those with normal glucose tolerance (733.7 μEq/L vs. 700.6 μEq/L, P = 0.049). Compared to women with low fasting FFA, women with high fasting FFA had higher postpartum glucose intolerance (51.8% vs. 44.1%, P = 0.033). After adjustment for maternal age, pre-pregnancy BMI, parity, family history of diabetes, FPG, and lipid measures (total cholesterol, triglyceride, HDL-cholesterol), women with high fasting FFA were 1.47 times (95% CI 1.07-2.01) more likely to have postpartum glucose intolerance than those with low fasting FFA. In women with GDM, high fasting FFA level at mid-pregnancy is associated with elevated risk of postpartum glucose intolerance. Disclosure K. Kim: None. S. Kim: None. Y. Cho: None. S. Park: None.

Higher Fasting and Postprandial Free Fatty Acid Levels Are Associated With Higher Muscle Insulin Resistance and Lower Insulin Secretion in Young Non-Obese Women

BackgroundTo assess the relationship of the shape of glucose concentration curve during a standardized meal test to serum free fatty acid (FFA) concentrations, insulin resistance and insulin secretion in young non-obese women.MethodsThirty-five young women had a standardized meal for breakfast with measurement of glucose, insulin and FFA concentrations at 0 (fasting), 30, 60 and 120 min; the areas under the concentration curves were calculated (AUCg, AUCi and AUCffa, respectively). Meal-induced insulin response (MIR) was calculated as the ratio between the incremental insulin and glucose concentrations during the first 30 min of meal tests. In two women (group A), post-breakfast glucose (PBG) returned to levels below fasting plasma glucose (FPG) at 30 min; in 15 and 11 women, PBG returned to levels below FPG at 60 and 120 min (groups B and C, respectively). In the remaining seven women (group D), PBG never fell below FPG.ResultsDespite no difference in fasting insulin and AUCi, fasting FFA, AUCg and AUCffa were the lowest in group A, increased linearly from group B to C and plateaued in group D, whereas MIR might be the highest in group A, decreased from group B to C and plateaued in group D.ConclusionYoung women whose PBG returned to FPG more slowly had higher muscle insulin resistance and lower MIR associated with higher fasting and postprandial FFA levels compared with young women whose PBG returned to baseline more quickly.

Metabolic complications and selected cytokines in HIV‑infected individuals

Human immunodeficiency virus (HIV)-infected individuals are at a higher risk of developing metabolic disturbances. The pathogenesis of these complications is complex and not fully explored. The aim of the study was to investigate the effect of HIV infection and antiretroviral (ARV) therapy on the development of metabolic changes and adipocytokine concentrations. The analysis of the differences in the investigated parameters among lipodystrophic and nonlipodystrophic patients was also performed. A total of 42 HIV‑infected patients on ARV therapy (HIV[+]ARV[+]), 13 HIV‑infected ARV naive patients (HIV[+]ARV[-]), and 20 healthy controls were included in the study. A lipid profile, fasting free fatty acids (FFAs), glucose, insulin, and insulin resistance (homeostasis model assessment of insulin resistance--HOMA‑IR) were tested. Serum concentrations of tumor necrosis factor α (TNF‑α), interleukin 6 (IL‑6), adiponectin, leptin, and fatty acid-binding protein 4 (FABP4) were determined. Increased FFA levels were observed in HIV(+)ARV(-) patients. HIV(+)ARV(+) patients had significantly higher triglycerides and insulin level compared with controls. HOMA‑IR showed a tendency to be higher in HIV(+)ARV(+) patients compared with the other study groups. The ARV therapy longer than 2 years resulted in more pronounced metabolic abnormalities. HIV infection itself had a significant effect on inflammation expressed by elevated TNF‑α and IL‑6 levels. We did not observe differences in adiponectin and FABP4 concentrations among the study groups, while the leptin concentration was significantly lower in HIV‑infected lipodystrophic than in nonlipodystrophic patients. HIV infection induces lipid disorders, especially associated with fatty acid turnover augmented by ARV therapy. Compared with FABP4, leptin is a better biological marker of metabolic complications in HIV‑infected patients.

Genetic Variation in NR1H4 Encoding the Bile Acid Receptor FXR Determines Fasting Glucose and Free Fatty Acid Levels in Humans

Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models. To understand the role of FXR in human metabolism, we investigated associations of common single-nucleotide polymorphisms (SNPs) in the FXR-encoding gene NR1H4 with glucose and lipid metabolism, body fat mass, and liver fat content. We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of common genetic variation (minor allele frequency > 10%). Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by (1)H-magnetic resonance spectroscopy were performed. SNP rs4764980 was significantly associated with fasting glycemia (P = .0043) and nominally associated with fasting and postglucose load free fatty acid (FFA) levels (P = .01). Upon interrogation of publicly available Meta-Analyses of Glucose and Insulin-related traits Consortium data, the association of rs4764980 with fasting glycemia was replicated (Meta-Analyses of Glucose and Insulin-related traits Consortium, P = .005). Additionally, SNP rs11110390 showed significant associations with fasting (P = .0054) and postload (P = .0051) FFA levels. For none of the investigated SNPs, associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected. We conclude that FXR contributes to fasting glucose and FFA levels in humans independent of unhealthy body fat accumulation. The receptor represents an interesting target to influence lipid and glucose metabolism.

Higher Fasting Plasma Free Fatty Acid Levels Are Associated with Lower Insulin Secretion in Children and Adults and a Higher Incidence of Type 2 Diabetes

There are limited data in humans on the association between fasting free fatty acid (FFA) levels and pancreatic β-cell function. Our objective was to examine this association in children and adults with normal glucose tolerance and to explore fasting FFA levels in relation to subsequent risk of impaired glucose tolerance (IGT) and type 2 diabetes (T2D). We measured FFA, glucose, and insulin levels after an overnight fast and 30 min after an oral glucose load in 797 children aged 8 yr in the Avon Longitudinal Study of Parents and Children and 770 adults aged 44-71 yr in the Medical Research Council Ely Study. We calculated the homeostasis model assessment to estimate fasting insulin sensitivity, the insulinogenic index to estimate insulin secretion, and the disposition index to assess insulin secretion corrected for insulin sensitivity. Higher fasting FFA levels were associated with lower insulin secretion in children (boys, P = 0.03; girls, P = 0.001) and adults (men, P = 0.03, women, P = 0.04). Associations with insulin sensitivity were more variable, but after adjustment for insulin sensitivity, higher fasting FFA levels remained associated with lower insulin secretion (disposition index). Compared with adults in the lowest tertile of fasting FFA levels, those in the middle and highest tertiles had a 3-fold higher incidence of IGT or T2D over the following 5-8 yr. Higher fasting FFA levels were consistently associated with lower insulin secretion in children and adults with normal glucose tolerance. Furthermore, higher fasting FFA levels were prospectively associated with a greater risk of subsequent IGT and T2D.

Race differences in the association of oxidative stress with insulin sensitivity in African- and European-American women.

Excessive metabolism of glucose and/or fatty acids may impair insulin signaling by increasing oxidative stress. The objective of this study was to examine the association between insulin sensitivity and protein carbonyls, a systemic marker of oxidative stress, in healthy, nondiabetic women, and to determine if the relationship differed with race. Subjects were 25 African-Americans (AA, BMI 28.4 ± 6.2 kg/m(2), range 18.8-42.6 kg/m(2); age 33.1 ± 13.5 years, range 18-58 years) and 28 European-Americans (EA, BMI 26.2 ± 5.9 kg/m(2), range 18.7-48.4 kg/m(2); age 31.6 ± 12.4 years, range 19-58 years). Insulin sensitivity was determined using an intravenous glucose tolerance test incorporating [6,6-(2)H(2)]-glucose, and a two-compartment mathematical model. Multiple linear regression results indicated that insulin sensitivity was inversely associated with protein carbonyls in AA (standardized regression coefficient -0.47, P < 0.05) but not EA (0.01, P = 0.945), after adjusting for %body fat. In contrast, %body fat was significantly and positively associated with insulin sensitivity in EA (-0.54, P < 0.01) but not AA (-0.24, P = 0.196). Protein carbonyls were associated with free fatty acids (FFA) in AA (r = 0.58, P < 0.01) but not EA (r = -0.11, P = 0.59). When subjects were divided based on median levels of fasting glucose and FFA, those with higher glucose/FFA concentrations had a significantly greater concentration of circulating protein carbonyls compared to those with lower glucose/FFA concentrations (P < 0.05). These results suggest that oxidative stress independently contributes to insulin sensitivity among AA women. Further, this association in AA may be mediated by circulating FFA and/or glucose.

The impact of Ephedra and green tea combination mesotherapy on localized fat: A randomized-controlled clinical trial

Aim of the studyThe goal of this study was to evaluate the efficacy of mesotherapy treatment with Ephedra and green tea extract in combination on localized fat of overweight women subjects. Materials and methodsTwenty-five overweight women, 20–35-years-of-age, body mass index ≥ 23kg/m2 were randomly assigned into active (Ephedra+green tea, n=13) and placebo (saline, n=12) groups. A total eight herbal or saline mesotherapy administrations were performed into the thighs alternatively in two phases, each one comprising of four consecutive treatments on one thigh on weekly basis. Body composition parameters, circumference and subcutaneous fat area of thighs were measured before and after each phase, in addition to evaluating fasting free fatty acid (FFA) level of blood as well as adverse events of the therapy in volunteers. ResultsThere were no significant changes in the body weight, BMI, body fat, and subcutaneous fat area of thigh within or between the groups, but the change in thigh circumference within the active group was significantly lower compared to that within the placebo group. The blood FFA level at 1h after the first herbal therapy was significantly higher than that recorded at other time points of pre- and post-treatment measurements. ConclusionsThe herbal mesotherapy treatment produced a significant effect on thigh circumference and fasting-FFA level within the active group. Future studies that compensate for the limitations of this trial are required to fully ascertain the efficacy and safety of the proposed mesotherapy, and a very careful consideration is needed until then.

GH Does Not Modulate the Early Fasting-Induced Release of Free Fatty Acids in Mice

Fasting results in the mobilization of adipose stores and the elevation of levels of free fatty acids (FFA). In humans, this process is driven by a release in GH. Little is known regarding the role of GH in modulating this process during early stages of fasting in the mouse. Confirmation of the role of GH in modulating FFA release in the fasting mouse is of particular importance given the frequent use of mouse models to study metabolic mechanisms. Here, we correlate the initial release of FFA throughout fasting in mice with pulsatile GH secretion. Observations illustrate the rapid release of FFA in response to food withdrawal. This does not correlate with a rise in GH secretion. Rather, we observed a striking loss in pulsatile secretion of GH throughout the first 6 h of fasting, suggesting that GH does not modulate the initial release of FFA in the mouse in response to fasting. This was confirmed in GH receptor knockout mice, in which we observed a robust fasting-induced rise in FFA. We further illustrate the dynamic relationship between the orexigenic and anorexigenic hormones ghrelin and leptin during fasting in the mouse. Our findings show an initial suppression of leptin and the eventual rise in circulating levels of acyl-ghrelin with fasting. However, altered acyl-ghrelin and leptin secretion occurs well after the rise in FFA and the suppression of GH secretion. Consequently, we conclude that although acyl-ghrelin and leptin may modulate the physiological response to drive food intake, these changes do not contribute to the initial loss of pulsatile GH secretion. Rather, it appears that the suppression of GH secretion in fasting may occur in response to an elevation in fasting levels of FFA or physiological stress. Observations highlight a divergent role for GH in modulating FFA release between man and mouse.

Beta-Cell Dysfunction and Insulin Resistance after Subarachnoid Haemorrhage

Background: Hyperglycaemia is a common finding and an independent risk factor for increased morbidity and mortality in aneurysmal subarachnoid haemorrhage (SAH). Although in these patients hyperglycaemia is commonly ascribed to insulin resistance, there is little understanding of underlying mechanisms. Aims: To prospectively study temporal disturbances of glucose metabolism after aneurysmal SAH in patients without known abnormalities of glucose metabolism and to explore possible correlations with markers of stress. Methods: In consecutive aneurysmal SAH patients not subjected to insulin therapy, in-hospital and follow-up oral glucose tolerance tests (OGTTs) and assessments of insulin resistance, pancreatic β-cell function, free fatty acids (FFA) and cortisol were performed and compared with reference values. Results: We included 13 patients. In the first 2 weeks of admission, median fasting glucose and FFA levels were elevated while insulin levels were not. OGTTs were indicative of glucose intolerance in all patients at days 3 and 7, while on follow-up 1 patient had glucose intolerance and all patients had normal fasting glucose levels. Pancreatic β-cell function was impaired throughout the first week and insulin resistance from day 4 to 10. Levels of cortisol correlated with higher fasting glucose and increased FFA. FFA in turn correlated with pancreatic β-cell dysfunction. Conclusions: Aneurysmal SAH patients have transient abnormalities of glucose metabolism. During the first week, it appears to result predominantly from transient pancreatic β-cell dysfunction, in combination with insulin resistance.

Effects of rosiglitazone and aspirin on experimental model of induced type 2 diabetes in rats: focus on insulin resistance and inflammatory markers

Both insulin resistance and decreased insulin secretion are major features of the pathophysiology of type 2 diabetes. Inflammatory pathways are found to be critical in mechanisms underlying insulin resistance, which is a major determinant of increased risk of cardiovascular complications in type 2 diabetes, and so, it is a potential therapeutic target. Thiazolidinediones (e.g., rosiglitazone) act primarily as insulin sensitizers and were discovered to have anti-inflammatory effects leading to reevaluation of their potential use in treatment of diabetes. Acetyl salicylic acid (aspirin), which is currently recommended for cardiovascular disease (CVD) or even CVD risk factors, is shown to ameliorate diabetic process. This work aimed to study correlation between homeostasis model assessment estimate of insulin resistance (HOMA-IR) with serum levels of inflammatory markers tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), C-reactive protein (CRP), and free fatty acids (FFAs) in experimental model of induced type 2 diabetes in rats, with evaluation of effects of rosiglitazone and aspirin (low or high dose), alone or in combination. There is significant elevation of insulin resistance and serum levels of fasting glucose, insulin, TNF-α, IL-6, CRP, and FFAs in the diabetic group when compared to the normal group, with positive significant correlation between levels of each of TNF-α, IL-6, CRP, and FFAs with insulin resistance (HOMA-IR). Administration of rosiglitazone, low-dose aspirin, or high-dose aspirin to diabetic rats caused nonsignificant lowering in insulin level with significant reduction of levels of other parameters when compared to the diabetic group. Also, there is no significant difference in the measured parameters between diabetic rats administered a combination of rosiglitazone with high-dose aspirin and those administered a combination of rosiglitazone with low-dose aspirin. It was concluded that aspirin and rosiglitazone offer unique approaches for treatment of type 2 diabetes due to their insulin-sensitizing and anti-inflammatory properties, and their combination was found to provide augmented beneficial effects. Also, in view of the potential dose-dependent adverse effects of aspirin, with no achievement of further benefit by high dose in this study, it is strongly recommended to use low-dose aspirin as a safe and effective medication for diabetes.

Effects of prolonged fasting and sustained lipolysis on insulin secretion and insulin sensitivity in normal subjects.

Normal beta-cells adjust their function to compensate for any decrease in insulin sensitivity. Our aim was to explore whether a prolonged fast would allow a study of the effects of changes in circulating free fatty acid (FFA) levels on insulin secretion and insulin sensitivity and whether any potential effects could be reversed by the antilipolytic agent acipimox. Fourteen (8 female, 6 male) healthy young adults (aged 22.8-26.9 yr) without a family history of diabetes and a body mass index of 22.6 +/- 3.2 kg/m(2) were studied on three occasions in random order. Growth hormone and FFA levels were regularly measured overnight (2200-0759), and subjects underwent an intravenous glucose tolerance test in the morning (0800-1100) on each visit. Treatment A was an overnight fast, treatment B was a 24-h fast with regular administrations of a placebo, and treatment C was a 24-h fast with regular ingestions of 250 mg of acipimox. The 24-h fast increased overnight FFA levels (as measured by the area under the curve) 2.8-fold [51.3 (45.6-56.9) vs. 18.4 (14.4-22.5) *10(4) micromol/l*min, P < 0.0001], and it led to decreases in insulin sensitivity [5.7 (3.6-8.9) vs. 2.6 (1.3-4.7) *10(-4) min(-1) per mU/l, P < 0.0001] and the acute insulin response [16.3 (10.9-21.6) vs. 12.7 (8.7-16.6) *10(2) pmol/l*min, P = 0.02], and therefore a reduction in the disposition index [93.1 (64.8-121.4) vs. 35.5 (21.6-49.4) *10(2) pmol/mU, P < 0.0001]. Administration of acipimox during the 24-h fast lowered FFA levels by an average of 20% (range: -62 to +49%; P = 0.03), resulting in a mean increase in the disposition index of 31% (P = 0.03). In conclusion, the 24-h fast was accompanied by substantial increases in fasting FFA levels and induced reductions in the acute glucose-simulated insulin response and insulin sensitivity. The use of acipimox during the prolonged fast increased the disposition index, suggesting a partial reversal of the effects of fasting on the acute insulin response and insulin sensitivity.

Incorporation of the fasting free fatty acid concentration into quantitative insulin sensitivity check index improves its association with insulin sensitivity in adults, but not in children

Based on fasting insulin and glucose, several indices of insulin sensitivity have been developed in adults. Recently, it has been demonstrated that incorporation of the fasting free fatty acid (FFA) concentration improves the association with insulin sensitivity in adults. We investigated the association of clamp-derived insulin sensitivity with indices of insulin sensitivity derived from fasting blood in prepubertal children and adults, with and without incorporation of FFAs. We studied 59 healthy adults and 29 of them are prepubertal children. We measured insulin sensitivity with the euglycemic-hyperinsulinemic clamp. Based on fasting insulin and glucose, we estimated insulin sensitivity with the homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI), and the revised QUICKI after the incorporation of FFAs. The associations of HOMA and QUICKI with clamp-derived insulin sensitivity in children (r=-0.55 and 0.54 respectively; P<0.01) were similar to those in adults (r=-0.54 and 0.53 respectively; P<0.01). However, incorporation of FFAs into the QUICKI model resulted in an increase in the association in adults, but not in children (r=0.68 and 0.48 respectively; P<0.01). Adding FFA levels to a regression model with glucose and insulin as independent variables resulted in an increase in the explained variance in clamp-derived insulin sensitivity in adults, but not in children (P value 0.004 in adults and 0.3 in children). HOMA and QUICKI are associated with clamp-derived insulin sensitivity in both children and adults. Incorporating fasting levels of FFAs into the QUICKI model improves the association with clamp-derived insulin sensitivity in adults, but not in children.