Fasting Plasma Free Fatty Acid Research Articles

Carotid body denervation improves hyperglycemia in obese mice.

The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPRb) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of Leprb, Trpm7, and Insr gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of Leprb, Trpm7, or Insr gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB Leprb, Trpm7, and Insr had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB Leprb, Trpm7, and Insr.NEW & NOTEWORTHY This paper provides first evidence that carotid body denervation abolishes hypertension and improves fasting blood glucose levels and glucose tolerance in mice with diet-induced obesity. Furthermore, we have shown that this phenomenon is associated with increased liver glycogen content, whereas insulin sensitivity and enzymes of gluconeogenesis were not affected.

2'-fucosyllactose alone or combined with resistant starch increases circulating short-chain fatty acids in lean men and men with prediabetes and obesity.

Infusion of short-chain fatty acids (SCFA) to the distal colon beneficially affects human substrate and energy metabolism. Here, we hypothesized that the combination of 2'-fucosyllactose (2'-FL) with resistant starch (RS) increases distal colonic SCFA production and improves metabolic parameters. In this randomized, crossover study, 10 lean (BMI 20-24.9 kg/m2) and nine men with prediabetes and overweight/obesity (BMI 25-35 kg/m2) were supplemented with either 2'-FL, 2'-FL+RS, or placebo one day before a clinical investigation day (CID). During the CID, blood samples were collected after a overnight fast and after intake of a liquid high-fat mixed meal to determine plasma SCFA (primary outcomes). Secondary outcomes were fasting and postprandial plasma insulin, glucose, free fatty acid (FFA), glucagon-like peptide-1, and peptide YY concentrations. In addition, fecal SCFA and microbiota composition, energy expenditure and substrate oxidation (indirect calorimetry), and breath hydrogen excretion were determined. In lean men, supplementation with 2'-FL increased postprandial plasma acetate (P = 0.017) and fasting H2 excretion (P = 0.041) compared to placebo. Postprandial plasma butyrate concentration increased after 2'-FL and 2'-FL+RS as compared to placebo (P < 0.05) in lean men and men with prediabetes and overweight/obesity. Additionally, 2'-FL+RS decreased fasting and postprandial plasma FFA concentrations compared to placebo (P < 0.05) in lean men. Supplementation of 2'-FL with/without RS the day before investigation increased systemic butyrate concentrations in lean men as well as in men with prediabetes and obesity, while acetate only increased in lean men. The combination of 2'-FL with RS showed a putatively beneficial metabolic effect by lowering plasma FFA in lean men, indicating a phenotype-specific effect. nr. NCT04795804.

Insulin Sensitivity and β-Cell Function During Early and Late Pregnancy in Women With and Without Gestational Diabetes Mellitus.

To evaluate the metabolic alterations associated with gestational diabetes mellitus (GDM) in women with overweight or obesity. We compared fasting and postprandial plasma glucose and free fatty acid (FFA) concentrations, insulin sensitivity (IS; Matsuda index), and β-cell function (i.e., β-cell responsiveness to glucose) by using a frequently sampled oral glucose tolerance test (OGTT) at 15 and 35 weeks' gestation in women with overweight or obesity who had GDM (n = 29) or did not have GDM (No-GDM; n = 164) at 35 weeks. At 15 weeks, IS and β-cell function were lower, and fasting, 1-h, and total area-under-the-curve plasma glucose concentrations during the OGTT were higher (all P < 0.05) in the GDM than in the No-GDM group. At 35 weeks compared with 15 weeks, IS decreased, β-cell function increased, and postprandial suppression of plasma FFA was blunted in both the GDM and No-GDM groups, but the decrease in IS and the increase in postprandial FFA concentration were greater and the increase in β-cell function was less (all P ≤ 0.05) in the GDM than in the No-GDM group. A receiver operating characteristic curve analysis showed that both fasting plasma glucose and 1-h OGTT glucose concentration at 15 weeks are predictors of GDM, but the predictive power was <30%. Women with overweight or obesity and GDM, compared with those without GDM, have worse IS and β-cell function early during pregnancy and a greater subsequent decline in IS and blunted increase in β-cell function. Increased fasting and 1-h OGTT plasma glucose concentration early during pregnancy are markers of increased GDM risk, albeit with weak predictive power.

Maternal Plasma Lipids During Pregnancy, Insulin-like Growth Factor-1, and Excess Fetal Growth.

Maternal lipids during pregnancy and placental growth factors are associated with excess fetal growth. However, how these factors interact to increase the risk of delivering large-for-gestational-age (LGA) neonates remains unclear. In this study, we investigated the relationship between maternal plasma triglycerides (TGs) and free fatty acids (FFAs) during pregnancy, cord blood insulin-like growth factors (IGF), and LGA. In a cell model, we studied the effect of different FAs on placental IGF-1 secretion. This cohort study included pregnant women with term pregnancy and without diabetes or hypertensive disorders in pregnancy. Maternal fasting plasma TGs and FFAs were measured in the second trimester. Cord blood IGF-1, IGF-2, and IGF binding protein-1 and protein-3 were measured at the time of delivery. A human trophoblast cell line, 3A-sub-E, was used to evaluate the effect of different FFAs on placental IGF-1 secretion. We recruited 598 pregnant women-neonate pairs. Maternal plasma TG (180 mg/dL [152.5-185.5 mg/dL] vs 166 mg/dL [133-206 mg/dL], P = .04) and cord blood IGF-1 concentrations (72.7 ± 23.0 vs 54.1 ± 22.8 ng/mL, P < .001) were higher in the LGA group and were significantly associated with birth weight z score. Maternal plasma free palmitic acid (PA) and stearic acid (SA), but not oleic acid (OA) or linoleic acid (LA), were significantly associated with cord blood IGF-1 concentrations. In 3A-sub-E cells, treatment with PA, SA, and LA, but not OA, induced IGF-1 expression and secretion. Certain FFAs can induce placental IGF-1 secretion, which suggests a potential pathophysiology linking maternal plasma lipids and LGA.

Distinct effects of carbohydrate ingestion timing on glucose fluctuation and energy metabolism in patients with type 2 diabetes: a randomized controlled study.

This randomized, open-label, and parallel-group study aimed to investigate the effects of altering the timing of carbohydrate intake at breakfast or dinner on blood glucose fluctuations and energy metabolism. A total of 43 participants with type 2 diabetes were assigned to either the breakfast or dinner group. Participants were provided an isocaloric carbohydrate-restricted diet constituting 10% carbohydrate only at breakfast or dinner for 2 days during the study. Glucose fluctuations were compared using a continuous glucose monitoring system (iPro2) and body composition, energy expenditure, blood biochemistry, and endocrine function changes. The carbohydrate restriction either at breakfast or dinner significantly decreased postprandial glucose excursion and mean 24-h blood glucose levels. The incremental blood glucose area under the curve (AUC) for 2 h (iAUC0-2h) at lunch significantly increased in the breakfast group, whereas no significant differences were observed in the iAUC0-2h between breakfast and lunch in the dinner group. Carbohydrate restriction reduced diet-induced thermogenesis at breakfast (intragroup comparison; 223 ± 117 to 109 ± 104 kcal, p = 0.002) but did not affect diet-induced thermogenesis at dinner. However, fasting plasma free fatty acids were comparable in both groups, prelunch free fatty acids increased significantly only in the breakfast group (0.20 ± 0.09 to 0.63 ± 0.19 mEq/L, p < 0.001). Carbohydrate restriction in the diet once daily decreases mean 24-h blood glucose levels and exerts unique metabolic effects depending on the timing.

Unique Metabolic Features of Adults Discordant for Indices of Insulin Resistance.

Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Adipose Insulin Resistance index (ADIPO-IR) values are often concordant. In this study we evaluated whether there are groups discordant for HOMA-IR and ADIPOpalmitate-IR and, if so, what are their defining characteristics. The body composition, basal metabolic rate (BMR), fasting plasma lipids, insulin, glucose, and free fatty acid (FFA) palmitate concentrations data of 466 volunteers from previous research studies were abstracted and analyzed. The middle 2 population quartiles for HOMA-IR and Adipose Insulin Resistance index palmitate concentration (ADIPOpalmitate-IR) defined medium HOMA-IR and ADIPOpalmitate-IR (MH and MA), the top and bottom quartiles were defined as high/low HOMA (HH/LH), and high/low ADIPOpalmitate as HA/LA. Because ADIPOpalmitate-IR was significantly greater in women than in men, we established sex-specific quartiles for each index. We identified groups discordant for HOMA-IR and ADIPO-IR (HHMA, LHMA, MHHA, and MHLA). Body fat and fasting triglycerides (TGs) were significantly greater with higher indices in the concordant groups (HHHA > MHMA > LHLA). MHHA differed from MHLA by visceral fat (P < .01) and fasting TGs (P < .05), whereas HHMA differed (P < .01) from LHMA by BMR. By multivariate regression, the group factor contributed to BMR (P < .01) and visceral fat (P < .05). Adults discordant for HOMA-IR and ADIPO-IR have unique features including differences in visceral fat, TGs, and BMR. This suggests different forms of insulin resistance are present, which should be considered when studying insulin resistance in the future.

Deficiency in ROS-sensing nuclear factor erythroid 2-like 2 causes altered glucose and lipid homeostasis following exercise training.

Oxidative stress induced by acute exercise may regulate exercise training-induced adaptations that improve metabolic health. One of the central transcription regulatory targets of reactive oxygen species (ROS) is Nrf2 (nuclear factor erythroid-derived 2-like 2, or NFE2L2). Here, we investigated whether global deficiency of Nrf2 in mice would impact exercise training-induced changes in glucose and lipid homeostasis. We report that following 6 wk of treadmill exercise training, Nrf2-deficient mice have elevated fasting plasma triglycerides and free fatty acids and higher blood glucose levels following a meal despite having a similar fat mass to wild-type controls. This impaired glucose homeostasis appears to be related to reduced insulin sensitivity primarily in adipose and liver tissue, and although a clear mechanism was not evident, Nrf2-deficient mice had increased markers of hepatic oxidative stress and stress-related kinase activation in white adipose tissue (WAT) without overt inflammation alteration in WAT or modulation of hepatic and WAT fibroblast growth factor 21 gene expression. Our results suggest that Nrf2 facilitates exercise training-induced improvements in glucose homeostasis; however, further research is required to determine whether this occurs through direct regulation of exercise adaptations or via the maintenance of redox balance during training.

Hormone-substrate changes with exenatide plus dapagliflozin versus each drug alone: The randomized, active-controlled DURATION-8 study.

To determine the effects of individual and combined therapies on plasma insulin, glucagon, β-hydroxybutyrate (β-OH) and associated metabolites. In DURATION-8, the combination of once-weekly exenatide (EQW) + 10 mg dapagliflozin (Dapa) in patients with type 2 diabetes poorly controlled with metformin-reduced HbA1c levels and body weight (at weeks 28 and 52) was compared with EQW + placebo (Plb) or Dapa + Plb. The study included 678 patients randomized 1:1:1 to EQW + Dapa, EQW + Plb, or Dapa + Plb. Plasma insulin and glucagon were measured at fasting and 2 hours after a mixed meal. Fasting plasma free fatty acids (FFA) and β-OH concentrations were measured. The fasting insulin-to-glucagon molar ratio (I/Glg) increased with EQW + Plb only; postprandial I/Glg increased in all groups but significantly more with EQW + Plb. β-OH, FFA, and glycerol concentrations showed a parallel response: larger increments with Dapa + Plb, larger decrements with EQW + Plb, and intermediate changes with EQW + Dapa. β-OH levels and I/Glg were inversely related to one another. Patients in the top quartile of β-OH changes from baseline [median (interquartile range): +207 (305) vs. -65 (-154) μmol/L; P < .0001] were more frequently treated with Dapa + Plb, had higher urine glucose-to-creatinine ratios, and lower fasting insulin [52 (51) vs. 68 (53) pmol/L; P = .0013) and I/Glg [1.76 (1.49) vs. 2.23 (1.70) mol/mol; P = .0020]. Haematocrit increased only in the Dapa group. The EQW + Dapa combination abolished the Dapa-induced rise in β-OH, reduced the EQW-induced increase in I/Glg, maintained glycosuria, and increased haematocrit in patients with poorly controlled type 2 diabetes. The drug combination may preserve any putative benefits while mitigating the risk of ketoacidosis.

Resveratrol ameliorates high-fat diet-induced insulin resistance and fatty acid oxidation via ATM-AMPK axis in skeletal muscle.

Resveratrol (RSV) is a polyphenolic phytoalexin that exhibits diverse pharmacological actions, including its effect on the insulin resistance. However, the mechanism through which RSV improves insulin resistance is not fully understood yet. The aim of this study was to determine the mechanism through which RSV ameliorates insulin resistance in skeletal muscle of high-fat diet (HFD)-induced mouse model, as well as palmitic acid (PA) treated L6 cells, with a specific focus on the response of RSV on fatty acid oxidation. Male C57BL6/J mice were randomly divided into three groups: normal diet-fed mice (ND), the high-fat diet-fed mice (HFD), HFD supplemented with RSV (100 mg/kg body weight [BW]/day orally; n = 10). Fasting plasma glucose, insulin, total cholesterol, triglyceride (TG), and free fatty acid levels were determined. The intraperitoneal glucose tolerance test was used to measure blood glucose and area under the curve. The quantitative insulin sensitivity index was calculated to assess insulin resistance. Skeletal muscles were collected for histology study and protein expression measurement. L6 cells were cultured with PA and the glucose concentration in the culture medium, and the intracellular TG levels were tested. RSV, chloroquine, palmitoyltransferase and Ku-55933 were administered to differentiate L6 cells. The HFD fed mice showed increased BW, hyperglycemia, and hyperlipidemia. The expressions of ataxia telangiectasia mutated (ATM), 5' adenosine monophosphate-activated protein kinase (AMPK), carnitine palmitoyltransferase 1, cytochrome oxidase subunit IV protein were significantly decreased in the skeletal muscles of HFD fed mice and PA-treated L6 cells. All these effects induced by HFD and PA were reversed by RSV treatment. ATM is a key factor to improve HFD-induced lipid metabolism and insulin resistance in skeletal muscles. The effects of RSV on ameliorating HFD-induced abnormal lipid metabolism and insulin resistance mediated through ATM-AMPK pathway may due to its improvement in fatty acid oxidation efficiency and sequential reduction in ROS production in skeletal muscle. These results provide important theoretical evidence for the application of RSV in the prevention and treatment of diabetes mellitus and related metabolic diseases.

Metformin improves vascular and metabolic insulin action in insulin-resistant muscle.

Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow, and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin-resistant rats. Sprague-Dawley rats were fed a normal (ND) or high-fat (HFD) diet for 4 weeks. A separate HFD group was given metformin in drinking water (HFD + MF, 150 mg/kg/day) during the final 2 weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-h euglycaemic-hyperinsulinaemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-AKT and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole-body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-AKT phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and free fatty acid concentrations and lowered body weight and adiposity. During euglycaemic-hyperinsulinaemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-AKT phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that 2-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin-resistant rats.

Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity, and impaired glucose tolerance.

To delineate potential mechanisms for fasting hyperglucagonemia in childhood obesity by studying the associations between fasting plasma glucagon concentrations and plasma lipid parameters and fat compartments. Cross-sectional study of children and adolescents with obesity (n = 147) and lean controls (n = 43). Differences in free fatty acids (FFAs), triglycerides, insulin, and fat compartments (quantified by magnetic resonance imaging) across quartiles of fasting plasma glucagon concentration were analyzed. Differences in oral glucose tolerance test (OGTT) glucagon response was tested in high vs low FFAs, triglycerides, and insulin. Human islets of Langerhans were cultured at 5.5 mmol/L glucose and in the absence or presence of a FFA mixture with total FFA concentration of 0.5 mmol/L and glucagon secretion quantified. In children with obesity, the quartile with the highest fasting glucagon had higher insulin (201 ± 174 vs 83 ± 39 pmol/L, P < .01), FFAs (383 ± 52 vs 338 ± 109 μmol/L, P = .02), triglycerides (1.5 ± 0.9 vs 1.0 ± 0.7 mmol/L, P < .01), visceral adipose tissue volume (1.9 ± 0.8 vs 1.2 ± 0.3 dm3 , P < .001), and a higher prevalence of impaired glucose tolerance (IGT; 41% vs 8%, P = .01) than the lowest quartile. During OGTT, children with obesity and high insulin had a worse suppression of glucagon during the first 10 minutes after glucose intake. Glucagon secretion was 2.6-fold higher in islets treated with FFAs than in those not treated with FFAs. Hyperglucagonemia in childhood obesity is associated with hyperinsulinemia, high plasma FFAs, high plasma triglycerides, visceral adiposity, and IGT. The glucagonotropic effect of FFAs on isolated human islets provides a potential mechanism linking high fasting plasma FFAs and glucagon levels.

Transgenic zero-erucic and high-oleic mustard oil improves glucose clearance rate, erythrocyte membrane docosahexaenoic acid content and reduces osmotic fragility of erythrocytes in male Syrian golden hamsters

Brassica juncea, the Indian mustard variety has high erucic acid (22:1 n-9) in its oil, which causes several deleterious effects. The Centre for Genetic Manipulation of Crop Plants (India) has developed a zero-erucic and high-oleic acid transgenic mustard variety having 67% oleic acid, which is almost equivalent to that of olive oil, i.e. 71%. Therefore, we assessed its impact on erythrocyte osmotic fragility, fluidity and activities of membrane-bound enzymes and insulin sensitivity. 40 male Syrian golden hamsters of 6–8 weeks age, were divided into five groups, consisting of 8 hamsters in each and fed diet containing any one of the oils, i.e. groundnut (GNO), conventional mustard (OCM), low-erucic mustard (OLM), zero-erucic high-oleic transgenic mustard (OTM) and olive (OLO) at 10% level for 16 weeks. At the end, compared to OLO group, OTM-fed hamsters resisted osmotic shock-induced erythrocyte-haemolysis, which corroborated with higher docosahexaenoic acid (DHA; 22:6 n-3) levels in their erythrocyte membranes. However, it did affect neither the fluidity nor the activities of membrane-bound enzymes. Although fasting plasma glucose, insulin and free fatty acid levels were comparable among the various groups; during glucose challenge, OTM diet-fed animals displayed higher disposal rate of circulatory glucose, without altering the insulin levels, when compared to the conventional mustard; OCM. In conclusion, the consumption of oil from zero-erucic high-oleic transgenic mustard improved the DHA content of erythrocyte membrane, which possibly resisted haemolysis and enhanced glucose clearance during glucose overload. However, it did not affect the activities of erythrocyte membrane-bound enzymes and fluidity compared to olive oil.

Involvement of the metabolic sensor GPR81 in cardiovascular control.

GPR81 is a receptor for the metabolic intermediate lactate with an established role in regulating adipocyte lipolysis. Potentially novel GPR81 agonists were identified that suppressed fasting plasma free fatty acid levels in rodents and in addition improved insulin sensitivity in mouse models of insulin resistance and diabetes. Unexpectedly, the agonists simultaneously induced hypertension in rodents, including wild-type, but not GPR81-deficient mice. Detailed cardiovascular studies in anesthetized dogs showed that the pressor effect was associated with heterogenous effects on vascular resistance among the measured tissues: increasing in the kidney while remaining unchanged in hindlimb and heart. Studies in rats revealed that the pressor effect could be blocked, and the renal resistance effect at least partially blocked, with pharmacological antagonism of endothelin receptors. In situ hybridization localized GPR81 to the microcirculation, notably afferent arterioles of the kidney. In conclusion, these results provide evidence for a potentially novel role of GPR81 agonism in blood pressure control and regulation of renal vascular resistance including modulation of a known vasoeffector mechanism, the endothelin system. In addition, support is provided for the concept of fatty acid lowering as a means of improving insulin sensitivity.

Role of Adipose Tissue Insulin Resistance in the Natural History of Type 2 Diabetes: Results From the San Antonio Metabolism Study.

In the transition from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM), the role of β-cell dysfunction and peripheral insulin resistance (IR) is well established. However, the impact of dysfunctional adipose tissue has not been fully elucidated. The aim of this study was to evaluate the role of resistance to the antilipolytic effect of insulin (adipose tissue IR [Adipo-IR]) in a large group of subjects with NGT, impaired glucose tolerance (IGT), and T2DM. Three hundred two subjects with varying glucose tolerance received an oral glucose tolerance test (OGTT) and euglycemic insulin clamp. We evaluated Adipo-IR (fasting and mean OGTT plasma free fatty acid [FFA] × insulin concentrations), peripheral IR (1/[Matsuda index] and (M/I)-1 value), and β-cell function (calculated as the ratio of the increment in plasma insulin to glucose [OGTT/IR (ΔI/ΔG ÷ IR)]). Fasting Adipo-IR was increased twofold in obese subjects with NGT and IGT versus lean subjects with NGT (8.0 ± 1.1 and 9.2 ± 0.7 vs. 4.1 ± 0.3, respectively) and threefold in subjects with T2DM (11.9 ± 0.6; P < 0.001). Progressive decline in ΔI/ΔG ÷ IR was associated with a progressive impairment in FFA suppression during OGTT, whereas the rise in mean plasma glucose concentration only became manifest when subjects became overtly diabetic. The progressive decline in β-cell function that begins in individuals with NGT is associated with a progressive increase in FFA and fasting Adipo-IR.

Glucose tolerance and free fatty acid metabolism in adults with variations in TCF7L2 rs7903146

ObjectiveTCF7L2 variant rs7903146 is associated with increased risk for type 2 diabetes. We investigated the effect of TCF7L2 variant rs7903146 and glucose tolerance on free fatty acid (FFA) metabolism. Research Design and MethodsWe recruited 120 individuals, half homozygous for the major CC allele and half homozygous for the minor TT allele at rs7903146; each underwent a 2-h, 75g oral glucose tolerance test (OGTT). Plasma glucose, insulin and free fatty acid concentrations were measured on blood collected before and during the OGTT. ResultsTotal FFA concentrations and percent FA species during OGTT were not different in CC and TT carriers when males and females were considered together. However, monounsaturated fatty acid (MUFA) concentrations and percentages were greater in TT than CC females during the OGTT. TT carriers with high HOMA-IR had significantly greater fasting FFA concentrations, lower disposition index (DI) and greater AUC of glucose than high HOMA-IR CC carriers, whereas no such differences were observed in the low HOMA-IR group. We found that fasting (826±25 vs. 634±22μmol/L, P<0.0001) and OGTT plasma FFA concentrations were greater in IGT than NGT subjects, and the difference remained after adjusting for sex, age, BMI, and genotype. Finally, IGT subjects had greater MUFA concentrations and percentages than NGT subjects during OGTT. ConclusionsDespite similar fasting insulin and glucose, fasting plasma FFA are greater in IGT than NGT adults. Insulin resistance and sex influence plasma FFA responses amongst carriers of the minor T allele of TCF7L2 rs7903146.

Sex-related differences in the associations between plasma free fatty acid levels and clinical features in patients with hypertrophic cardiomyopathy.

BackgroundPrevious studies have indicated that inefficient energy utilization may play a pivotal role in hypertrophic cardiomyopathy (HCM). However, whether plasma free fatty acid (FFA), a main energy substrate of heart, has an effect on HCM remains unclear. Besides, several studies have suggested sex-related differences in HCM features and FFA metabolism. Here, we aimed to explore the association between plasma FFA levels and HCM and potential effects of sex on this relation.MethodsA total of 412 patients (age 47.8 ± 12.7 years, 243 males (59.0%)) with HCM were recruited. Complete medical history was collected. Echocardiography and cardiovascular magnetic resonance imaging (CMRI) were performed. Fasting plasma FFA was determined by clinical laboratory. Left ventricular mass (LVM), maximum wall thickness (MWT), and left atrium diameter (LAD) were assessed with CMRI.ResultsThe median FFA levels were 0.38 (interquartile range (IQR) 0.27–0.52) mmol/L in men and 0.40 (IQR 0.30–0.59) mmol/L in women. The FFA levels were significantly lower in men compared with those in women (p = 0.005). Compared with women, men had greater LVM index (LVMI) (96.8 ± 37.6 vs. 78.6 ± 31.5 g/m2, p < 0.001). FFA levels in male patients correlated positively with LVM, LVMI, LAD, cholesterol levels, high-density lipoprotein-cholesterol (HDL-C) levels, heart rate, and systolic blood pressure (SBP). However, none of these variables were significantly associated with sqrt (FFA) in female patients except a borderline correlation of LAD (p = 0.050). Multiple linear regression analysis was performed in male patients and revealed that HDL-C (β = 0.191, p = 0.002), heart rate (β = 0.182, p = 0.004), SBP (β = 0.167, p = 0.007), LVMI (β = 0.132, p = 0.032), and LAD (β = 0.165, p = 0.009) were independently associated with increasing FFA levels.ConclusionsIn patients with HCM, LVMI, LAD, HDL-C, SBP, and heart rate were independently associated with increasing plasma FFA levels in males, whereas not in females. These results suggest that sex may affect the pathogenesis of HCM through influencing FFA metabolism. And these sex-related differences should be taken into account in therapeutic approaches to influence myocardial FFA metabolism in HCM.

Acute Effects of Linagliptin on Progenitor Cells, Monocyte Phenotypes, and Soluble Mediators in Type 2 Diabetes.

Circulating cells, including endothelial progenitor cells (EPCs) and monocyte subtypes, are involved in diabetic complications. Modulation of these cells may mediate additional benefits of glucose-lowering medications. We assessed whether the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin acutely modifies EPCs and monocyte subsets in patients with type 2 diabetes. This was a randomized, crossover, placebo-controlled trial. The study was conducted at a tertiary referral diabetes outpatient clinic. Forty-six type 2 diabetes patients with (n = 18) or without (n = 28) chronic kidney disease (CKD) participated in the study. Intervention included a 4-day treatment with linagliptin 5 mg or placebo during two arms separated by a 2-week washout. Before and after each treatment, we determined the levels of circulating progenitor cells (CD34, CD133, KDR) and monocyte subtypes (CD14/CD16, chemokine and scavenger receptors) and the concentrations of soluble mediators. Compared with placebo, linagliptin increased CD34(+)CD133(+) progenitor cells (placebo subtracted effect 40.4 ± 18.7/10(6); P = .036), CD34(+)KDR(+) EPCs (placebo subtracted effect 22.1 ± 10.2/10(6); P = .036), and CX3CR1(bright) monocytes (placebo subtracted effect 1.7 ± 0.8%; P = .032). Linagliptin abated DPP-4 activity by greater than 50%, significantly increased active glucagon-like peptide-1 and stromal cell-derived factor-1α, and reduced monocyte chemotactic protein-1, CCL22, and IL-12. Patients with CKD, as compared with those without, had lower baseline CD133(+) and CD34(+)CD133(+) cells and had borderline reduced CD34(+) and CD34(+)KDR(+) cells. The effects of linagliptin on progenitor cells and monocyte subtypes were similar in patients with or without CKD. Fasting plasma glucose, triglycerides and free fatty acids were unaffected. DPP-4 inhibition with linagliptin acutely increases putative vasculoregenerative and antiinflammatory cells. Direct effects of DPP-4 inhibition may be important to lower vascular risk in diabetes, especially in the presence of CKD.

Effect of L-Carnitine on Insulin Sensitivity and Responsiveness in Skeletal Muscle, Adipose tissue and Hepatic tissues

Background and objectives: L-carnitine (LC) is a non-protein amino acid includes both diet and endogenous synthesis. There are no studies on the effect of LC on glucose uptake and net glucose output in muscle and hepatic tissues. So, the aim of the present work is to study the metabolic aspects of LC and to study some mechanisms that may be of help in treatment of insulin resistance. Methods: Twenty four male rats were divided into two main groups, twelve rats per each group. In vivo group was divided into control one and L-Carnitine - treated one, It was given in the dose of 3 gm carnitine/kg once every day orally for 4 weeks where fasting serum glucose and plasma free fatty acids (FFA) were measured. In vitro group included experiments on epididymal fat pad (EFP), hemidiaphragm and liver. Results: LC caused a highly significant decrease in fasting plasma FFA level (4.9 ± 1.5 mg/ dl). However, it caused a significant increase in insulin-stimulated glucose uptake by EFP in the presence of supraminimal and supramaximal insulin concentrations (2.5 ± 0.8 and 3.4± 0.4) (mg/ gm wet tissue /hour) and also by hemidiaphragm (4.9 ± 0.3 and 6 ± 0.97) (mg/ gm wet tissue /hour). Also, it increased net glucose output by liver slices in the presence of both insulin concentrations (- 4.9 ± 1.1 and – 4 ± 1.42) (mg/ gm wet tissue /hour). It decreased FFA release from EFP in the presence of both insulin concentrations (0.5 ± 0.21 and 0.4 ± 0.2 ) (mg/ gm wet tissue /hour), hemidiaphragm (0.5± 0.1 and 0.5 ±0.16) (mg/ gm wet tissue /hour) and liver slices (0.58 ± 0.19 and 0.63± 0.27) (mg/ gm wet tissue /hour). Conclusion: LC increased plasma FFA level. It potentiated the effect of insulin on glucose uptake in EFP and hemidiaphragm. It decreased hepatic insulin sensitivity and responsivity and enhanced the suppressive effect of insulin on FFA release from different peripheral tissues.

High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form with steatohepatitis (NASH) are common in patients with type 2 diabetes mellitus (T2DM). However, they are usually believed to largely affect those with elevated aminotransferases. The aim of this study was to determine the prevalence of NAFLD by the gold standard, liver magnetic resonance spectroscopy ((1)H-MRS) in patients with T2DM and normal aminotransferases, and to characterize their metabolic profile. We recruited 103 patients with T2DM and normal plasma aminotransferases (age, 60 ± 8 y; body mass index [BMI], 33 ± 5 kg/m(2); glycated hemoglobin [A1c], 7.6 ± 1.3%). We measured the following: 1) liver triglyceride content by (1)H-MRS; 2) systemic insulin sensitivity (homeostasis model assessment-insulin resistance); and 3) adipose tissue insulin resistance, both fasting (as the adipose tissue insulin resistance index: fasting plasma free fatty acids [FFA] × insulin) and during an oral glucose tolerance test (as the suppression of FFA). The prevalence of NAFLD and NASH were much higher than expected (50% and 56% of NAFLD patients, respectively). The prevalence of NAFLD was higher in obese compared with nonobese patients as well as with increasing BMI (P = .001 for trend). Higher plasma A1c was associated with a greater prevalence of NAFLD and worse liver triglyceride accumulation (P = .01). Compared with nonobese patients without NAFLD, patients with NAFLD had severe systemic (liver/muscle) and, particularly, adipose tissue (fasting/postprandial) insulin resistance (all P < .01). The prevalence of NAFLD is much higher than previously believed in overweight/obese patients with T2DM and normal aminotransferases. Moreover, many are at increased risk of NASH. Physicians should have a lower threshold for screening patients with T2DM for NAFLD/NASH.

A Novel Peroxisome Proliferator-activated Receptor (PPAR)α Agonist and PPARγ Antagonist, Z-551, Ameliorates High-fat Diet-induced Obesity and Metabolic Disorders in Mice

A novel peroxisome proliferator-activated receptor (PPAR) modulator, Z-551, having both PPARα agonistic and PPARγ antagonistic activities, has been developed for the treatment of obesity and obesity-related metabolic disorders. We examined the effects of Z-551 on obesity and the metabolic disorders in wild-type mice on the high-fat diet (HFD). In mice on the HFD, Z-551 significantly suppressed body weight gain and ameliorated insulin resistance and abnormal glucose and lipid metabolisms. Z-551 inhibited visceral fat mass gain and adipocyte hypertrophy, and reduced molecules involved in fatty acid uptake and synthesis, macrophage infiltration, and inflammation in adipose tissue. Z-551 increased molecules involved in fatty acid combustion, while reduced molecules associated with gluconeogenesis in the liver. Furthermore, Z-551 significantly reduced fasting plasma levels of glucose, triglyceride, free fatty acid, insulin, and leptin. To elucidate the significance of the PPAR combination, we examined the effects of Z-551 in PPARα-deficient mice and those of a synthetic PPARγ antagonist in wild-type mice on the HFD. Both drugs showed similar, but weaker effects on body weight, insulin resistance and specific events provoked in adipose tissue compared with those of Z-551 as described above, except for lack of effects on fasting plasma triglyceride and free fatty acid levels. These findings suggest that Z-551 ameliorates HFD-induced obesity, insulin resistance, and impairment of glucose and lipid metabolisms by PPARα agonistic and PPARγ antagonistic activities, and therefore, might be clinically useful for preventing or treating obesity and obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, and dyslipidemia.