Fasting Free Fatty Acid Concentrations Research Articles

Effects of acute changes in fasting glucose and free fatty acid concentrations on indices of β-cell function and glucose metabolism in subjects without diabetes.

Elevated fasting free fatty acids (FFAs) and fasting glucose are additively associated with impaired glucose tolerance (IGT) and decreased β-cell function [quantified as disposition index (DI)]. We sought to examine how changes in fasting FFA and glucose alter islet function. We studied 10 subjects with normal fasting glucose (NFG) and normal glucose tolerance (NGT) on two occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG/IGT. In addition, we studied seven subjects with IFG/IGT on two occasions. On one occasion, insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG/NGT. The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and β-cell function. Elevation of overnight fasting FFA and glucose in NFG/NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 h, Saline vs. Intralipid/glucose, P = 0.55). Although overall β-cell function quantified by the Disposition Index was unchanged, the dynamic component of β-cell responsivity (ϕd) was decreased by Intralipid and glucose infusion (9 ± 1 vs. 16 ± 3 10-9, P = 0.02). In people with IFG/IGT, insulin did not alter postprandial glucose concentrations or indices of β-cell function. Endogenous glucose production and glucose disappearance were also unchanged in both groups. We conclude that acute, overnight changes in FFA, and glucose concentrations do not alter islet function or glucose metabolism in prediabetes.NEW & NOTEWORTHY This experiment studied the effect of changes in overnight concentrations of free fatty acids (FFAs) and glucose on β-cell function and glucose metabolism. In response to elevation of these metabolites, the dynamic component of the β-cell response to glucose was impaired. This suggests that in health overnight hyperglycemia and FFA elevation can deplete preformed insulin granules in the β-cell.

The association between visceral adipocyte hypertrophy and NAFLD in subjects with different degrees of adiposity.

To investigate the association between visceral adipocyte hypertrophy and the onset and development of non-alcoholic fatty liver disease (NAFLD) in subjects with different degrees of adiposity. Omental adipose tissue and liver biopsies were collected from obese subjects. NAFLD was defined according to the NASH Clinical Research Network scoring system. Adipocyte size was measured using pathological section analysis. Adipose tissue insulin resistance (Adipo-IR) was calculated as fasting insulin (pmol/L) × fasting free fatty acid concentration (mmol/L). In total, 275 obese patients were enrolled, including 158 females and 58 males with NAFLD. In females, adipocyte size was significantly larger in NAFLD participants as compared to the controls (99.37 ± 14.18 vs. 84.14 ± 12.65[Formula: see text]m, p < 0.001). Moreover, adipocyte size was larger in females with non-alcoholic steatohepatitis (NASH) as compared to those with non-alcoholic fatty liver (NAFL) (101.45 ± 12.77 vs. 95.79 ± 15.80[Formula: see text]m, p = 0.015). Mediation analysis showed that adipocyte size impacted the NAFLD activity score through Adipo-IR (b = 0.007 [95% bootstrap CI 0.002, 0.013]). Furthermore, the females were divided into: Q1 (BMI < 32.5kg/m2), Q2 (BMI 32.5-35.5kg/m2), Q3 (BMI 35.5-38.8kg/m2) and Q4 (BMI ≥ 38.8kg/m2) according to BMI quartiles. Omental adipocyte size was larger in NAFLD subjects in Q1-Q3, but not in Q4. No similar results were observed in males. For the first time, we reported that visceral adipocyte hypertrophy was associated with the onset and progression of NAFLD in mild to moderate adiposity but not in severe obesity, which may be mediated by adipose tissue insulin resistance.

1325-P: Modulation of Overnight Free Fatty Acid and Glucose Concentrations and Their Effect on Postprandial Islet Function and Glucose Metabolism

Individuals with prediabetes can be classified by fasting and glucose tolerance status. Previously we observed that elevated fasting Free Fatty Acids (FFA) are associated with Impaired Glucose Tolerance (IGT) and decreased β-cell function (quantified as Disposition Index (DI)) . Impaired Fasting glucose (IFG) is associated with further decreases in DI. To examine how changes in fasting FFA and glucose alter islet function, we studied subjects with Normal Fasting Glucose (NFG) and Normal Glucose Tolerance (NGT) on 2 occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG / IGT. In addition, we studied 7 subjects with IFG / IGT on 2 occasions. On one occasion insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG / NGT. The 2 groups were matched for Body Mass Index (BMI: 32±3 vs. 31±2 kg/m2, NFG / NGT vs. IFG / IGT respectively, p = 0.87) . The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and β-cell function. Elevation of overnight fasting FFA and glucose in NFG / NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 hrs, Saline vs. Intralipid / glucose, p = 0.55) . In people with IFG / IGT, insulin also did not alter peak and integrated glucose concentrations (2.5 ± 0.1 vs. 2.5 ± 0.2 Mol per 5 hrs, Saline vs. Insulin, p = 0.39) . Changing overnight concentrations of glucose and FFA did not alter postprandial concentrations of insulin and C-peptide in either group. While fasting Endogenous Glucose Production (EGP) differed between groups (14 ± 1 vs. 18 ± 1 μmol/kg/min, NFG / NGT vs. IFG / IGT, p &amp;lt; 0.01) , intervention did not change fasting and nadir EGP. Peak and integrated meal appearance and DI were also unchanged by intervention in either group. We conclude that acute, overnight changes in FFA and glucose concentrations do not alter islet function or glucose metabolism in prediabetes. Disclosure A.A.Welch: None. D.Schembri wismayer: None. A.M.Egan: None. R.A.Farahani: None. M.C.Laurenti: None. C.Cobelli: None. C.Dalla man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk. Funding NIH DK 078646

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.

Association of adipose tissue insulin resistance and serum free fatty acid levels with the incidence of type 2 diabetes: a retrospective cohort study

Abstract Background Insulin resistance in adipose tissue attenuates the suppression of lipolysis, leading to increased free fatty acid (FFA) release. The excess FFA may be involved in the development of type 2 diabetes. Purpose In this study, we investigated the association of adipose tissue insulin resistance and serum free fatty acid levels with the incidence of type 2 diabetes. Methods This is an observational study involving 6800 participants (3451 women, mean age 69.2 years) without diabetes who underwent 75-g oral glucose tolerance test (OGTT) at baseline. The participants were divided into the obesity and nonobesity groups on the basis of body mass index of ≥25 and &amp;lt;25 kg/m2, 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 tissue insulin resistance was assessed using adipose insulin resistance index (adipo-IR) calculated based on fasting FFA and insulin concentrations. The homeostasis model assessment of insulin resistance (HOMA-IR), and the Matsuda index were evaluated as measures of insulin resistance in the liver and whole-body, respectively. High adipo-IR, high fasting FFA, great AUCFFA high HOMA-IR, and low Matsuda index were determined based on the optimal cutoff values from ROC curve analysis. Results Over a mean 5.3-year follow-up period, 485 participants developed type 2 diabetes. Multivariate logistic regression analyses showed that high adipo-IR was a significant predicator for incident type 2 diabetes in the obesity group, but not in nonobesity group. AUCFFA, HOMA-IR, and Matsuda index were significantly associated with incident type 2 diabetes in both the two groups (Table). Conclusion Serum FFA levels after glucose loading predict the incidence of type 2 diabetes. Adipose tissue insulin resistance was associated with the risk of type 2 diabetes in individuals with obesity, but not in individuals without obesity. Funding Acknowledgement Type of funding sources: None.

Free fatty acids, glicentin and glucose-dependent insulinotropic polypeptide as potential major determinants of fasting substrate oxidation

The selection of carbohydrates or fat to generate intracellular energy is thought to be crucial for long-term metabolic health. While most studies assess fuel selection after a metabolic challenge, the determinants of substrate oxidation in the fasted state remain largely unexplored. We therefore assessed the respiratory quotient by indirect calorimetry as a read-out for substrate oxidation following an overnight fast. This cross-sectional analysis consisted of 192 (92 women, 100 men) either lean or obese participants. Following an overnight fast, the respiratory quotient (RQ) was assessed, after which a 5-point 75-g oral glucose tolerance test was performed. Unlike glucose and insulin, fasting free fatty acids (FFA) correlated negatively with fasting RQ (p < 0.0001). Participants with high levels of the ketone body β-hydroxybutyric acid had significantly lower RQ values. Fasting levels of glucose-dependent insulinotropic polypeptide (GIP) and glicentin were positively associated with fasting RQ (all p ≤ 0.03), whereas GLP-1 showed no significant association. Neither BMI, nor total body fat, nor body fat distribution correlated with fasting RQ. No relationship between the RQ and diabetes or the metabolic syndrome could be observed. In the fasting state, FFA concentrations were strongly linked to the preferentially oxidized substrate. Our data did not indicate any relationship between fasting substrate oxidation and metabolic diseases, including obesity, diabetes, and the metabolic syndrome. Since glicentin and GIP are linked to fuel selection in the fasting state, novel therapeutic approaches that target these hormones may have the potential to modulate substrate oxidation.

Decreased arterial distensibility and postmeal hyperinsulinemia in young Japanese women with family history of diabetes

IntroductionTo assess vascular function and characterize insulin secretion using a physiological approach in Japanese women with family history of type 2 diabetes (FHD).Research design and methodsStandardized mixed-meal tests were performed...

Effect of α-linolenic acid on vascular function and metabolic risk markers during the fasting and postprandial phase: A randomized placebo-controlled trial in untreated (pre-)hypertensive individuals.

Only a limited number of studies have examined the vascular and postprandial effects of α-linolenic acid (ALA, C18:3n-3). Therefore, we performed a well-controlled trial focusing specifically on the effects of ALA on vascular function and metabolic risk markers during the fasting and postprandial phase in untreated (pre-)hypertensive individuals. In a double-blind randomized, placebo-controlled parallel study, 59 overweight and obese adults (40 men and 19 women, aged 60±8 years) with a high-normal blood pressure or mild (stage I) hypertension consumed daily either 10g of refined cold-pressed flaxseed oil, providing 4.7g ALA (n=29), or 10g of high-oleic sunflower (control) oil (n=30) for 12 weeks. As compared with the high-oleic oil control, intake of flaxseed oil did not change brachial artery flow-mediated vasodilation, carotid-to-femoral pulse wave velocity, retinal microvascular calibers and plasma markers of microvascular endothelial function during the fasting and postprandial phase. Fasting plasma concentrations of free fatty acid (FFA) and TNF-α decreased by 58μmol/L (P=0.02) and 0.14pg/mL (P=0.03), respectively. No differences were found in other fasting markers of lipid and glucose metabolism, and low-grade systemic inflammation. In addition, dietary ALA did not affect postprandial changes in glucose, insulin, triacylglycerol, FFA and plasma inflammatory markers after meal intake. A high intake of ALA, about 3-5 times the recommended daily intake, for 12 weeks decreased fasting FFA and TNF-α plasma concentrations. No effects were found on other metabolic risk markers and vascular function during the fasting and postprandial phase in untreated high-normal and stage I hypertensive individuals.

The Relationship of Fasting Free Fatty Acids, Adipose Tissue, Insulin Resistance, and Fasting Glucose Concentrations with Subsequent ß-Cell Function in Nondiabetic Subjects

Elevations in both plasma free fatty acids (FFA) and glucose concentrations during fasting are associated with impaired β-cell function and predict progression from prediabetes to diabetes. Their interaction and subsequent effect on β-cell function as quantified by Disposition Index (DI) is unknown. We therefore measured total, saturated, mono-unsaturated and poly-unsaturated FFA concentrations using LC/MS in 120 nondiabetic subjects (across a range of fasting glucose &amp;lt; 6.9 mmol/l) who underwent a 2 hour oral glucose tolerance test (OGTT). Insulin secretion and action were quantified using the oral minimal model. The adipose tissue insulin resistance index (Adipo-IR) was calculated for each subject. Subjects were categorized by normal (NFG) or impaired (IFG) fasting glucose and by 2-hour glucose into normal (NGT) or impaired (IGT) glucose tolerance. Fasting total FFA were increased (p &amp;lt; 0.01) in IFG/IGT (835 ± 47 μmol/L) and in NFG/IGT (835 ± 30 μmol/L) but, intriguingly, not in IFG/NGT (593 ± 26 μmol/L) when compared to NFG/NGT (652 ± 29 μmol/L). These differences were no longer apparent within 60 minutes of OGTT and all groups suppressed FFA to the same nadir (166 ± 12 vs. 191 ± 18 vs. 184 ± 12 vs. 174 ± 17μmol/L, p = 0.59). On the other hand, an inverse relationship (p &amp;lt; 0.01) of fasting FFA (r = -0.33) and of Adipo-IR (r = -0.28) was observed with insulin action (Si). Fasting FFA did not correlate with β-cell responsivity (ϕ, r = 0.04). However, higher Adipo-IR was associated with higher values of ϕ (r = 0.36, p &amp;lt; 0.01). Fasting glucose concentrations did not alter these relationships; specifically no interaction of glucose with FFA during the fasting state to influence DI was evident. It remains to be ascertained whether the elevation in FFA reflects defects in production or in uptake, and whether the effect of changes in fasting glucose concentrations on DI is modulated by fasting FFA concentrations. Disclosure M.D. Hurtado: None. J. Adams: None. M.C. Laurenti: Other Relationship; Self; GlySens Incorporated. C. Dalla Man: None. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. R.A. Rizza: None. M.D. Jensen: Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG.

Impact of hygiene of housing conditions on performance and health of two pig genetic lines divergent for residual feed intake

Pigs selected for high performance may be more at risk of developing diseases. This study aimed to assess the health and performance of two pig lines divergently selected for residual feed intake (RFI) (low RFI (LRFI) v. high RFI (HRFI)) and housed in two contrasted hygiene conditions (poor v. good) using a 2×2 factorial design (n=40/group). The challenge period (Period 1), started on week zero (W0) when 12-week-old pigs were transferred to good or poor housing conditions. At week 6 (W6), half of the pigs in each group were slaughtered. During a recovery period (Period 2) from W6 to W13 to W14, the remaining pigs (n=20/group) were transferred in good hygiene conditions before being slaughtered. Blood was collected every three (Period 1) or 2 weeks (Period 2) to assess blood indicators of immune and inflammatory responses. Pulmonary lesions at slaughter and performance traits were evaluated. At W6, pneumonia prevalence was greater for pigs housed in poor than in good conditions (51% v. 8%, respectively, P<0.001). Irrespective of hygiene conditions, lung lesion scores were lower for LRFI pigs than for HRFI pigs (P=0.03). At W3, LRFI in poor conditions had the highest number of blood granulocytes (hygiene×line, P=0.03) and at W6, HRFI pigs in poor conditions had the greatest plasma haptoglobin concentrations (hygiene×line, P=0.02). During Period 1, growth rate and growth-to-feed ratio were less affected by poor hygiene in LRFI pigs than in HRFI pigs (hygiene×line, P=0.001 and P=0.02, respectively). Low residual feed intake pigs in poor conditions ate more than the other groups (hygiene×line, P=0.002). Irrespective of the line, fasting plasma glucose concentrations were higher in poor conditions, whereas fasting free fatty acids concentrations were lower than in good conditions. At the end of Period 2, pneumonia prevalence was similar for both housing conditions (39% v. 38%, respectively). During Period 2, plasma protein concentrations were greater for pigs previously housed in poor than in good conditions during Period 1. Immune traits, gain-to-feed ratio, BW gain and feed consumption did not differ during Period 2. Nevertheless, at W12, BW of HRFI previously housed in poor conditions was 13.4 kg lower than BW of HRFI pigs (P<0.001) previously housed in good conditions. In conclusion, health of the most feed efficient LRFI pigs was less impaired by poor hygiene conditions. This line was able to preserve its health, growth performance and its feed ingestion to a greater extent than the less efficient HRFI line.

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.

Adipose Insulin Resistance in Obese Adolescents Across the Spectrum of Glucose Tolerance.

Adipocytes represent an important insulin-responsive tissue taking an active part in glucose metabolism. This study sought to assess adipose tissue insulin resistance (IR) across the spectrum of glucose tolerance and to test its relation with free fatty acid (FFA) suppression during an oral glucose tolerance test (OGTT). A cross-sectional analysis of a pediatric clinic-derived cohort of obese adolescents. Participants age 7-20 y with a body mass index that exceeded the 95th percentile for their age and sex. A standard oral glucose tolerance test. The adipose tissue insulin resistance index (calculated as the product of fasting insulin and FFA concentrations) (Adipose IR) and the area under curve of FFAs during the OGTT were compared between glucose tolerance categories. A total of 962 obese children and adolescents participated in this study. Adipose IR significantly increased across glucose tolerance categories (P for trend < .001). Within the normal glucose tolerance participants, an increase in adipose IR was observed related to an increase in 2-hr glucose levels. In a subsample of participants who underwent abdominal imaging for determination of lipid partitioning (n = 115), a tight relation of visceral fat (r = 0.34; P < .001) and the visceral/sc fat ratio (r = 0.55; P < .001) with the Adipose IR index was evident. Greater area under the curve FFAs (lower FFA suppression) during the OGTT was evident with worsening glucose tolerance (P for trend < .001). Glucose tolerance category, degree of obesity (body mass index-z score), IL-6, and low adiponectin emerged as significant predictors of the Adipose IR. Adipose IR is associated with reduced suppression of FFAs during the OGTT and with an altered adipocytokine profile. The negative relation with insulin secretion deserves further longitudinal investigation in the context of deteriorating glucose tolerance.

A Single Session of Handcycle Exercise Can Increase Glucose Tolerance in Adolescents

We previously showed that moderate-intensity exercise before a meal resulted in increased insulin sensitivity in habitually sedentary children. That study used mostly walking and cycling; it is unclear whether those results are translatable to youth with spinal cord disorders who rely on upper body muscles for mobility. PURPOSE: To measure the impact of a single session of upper body exercise on oral glucose tolerance and insulin sensitivity METHODS: Participants were recreationally active adolescents with either spina bifida or cerebral palsy (SB/CP, 3F/4M, 15±1 y), or healthy controls (4F/7M, 15±1 y). The SB/CP group had higher body fat (SB/CP: 38±4, Control: 25±3 %, p<0.03) but cardiorespiratory fitness (VO2peak) during handcycle exercise was similar between groups (SB/CP: 18.9±2.3, Control: 20.4±2.2 ml/kg/min). A 75-gram oral glucose tolerance test was performed on two separate days. A Rest trial was completed after refraining from vigorous activity for 2 days. An Exercise trial included a 36-min bout of handcycle exercise (70% HRmax with 5 x 30-second high-intensity bursts near the end) completed 32 minutes before consuming the glucose. RESULTS: Fasting glucose (SB/CP: 87±3, Control: 89±2 mg/dl) and insulin (SB/CP: 7.3±1.8, Control: 7.4±1.9 μIU/ml) were normal in both groups. Glucose area under the curve (SB/CP: 15.3±1.2, Control: 16.1±0.9 mg-min/dl/1000) did not differ between groups on the Rest trial and declined 13% in SB/CP (6 of 7 participants, p=0.109) and 9% in Control (8 of 11 participants, p=0.045), respectively, on the Exercise trial. Insulin area under the curve (SB/CP: 10.4±2.3, Control: 9.8±1.4 μIU-min/ml/1000) did not differ between groups on the Rest trial and was not significantly altered by exercise. Fasting free-fatty acid concentration was also similar between groups (0.64±0.06 mM), equally suppressed by insulin following glucose ingestion (75±5%), and not altered by exercise. Oral glucose insulin sensitivity index was increased 16% (p=0.028) by exercise in the Control group but was not significantly changed in the SB/CP group. CONCLUSIONS: These data demonstrate that a short bout of upper body exercise improves glucose tolerance, likely through insulin-independent pathways, in adolescents with and without spinal cord disorders and could therefore reduce risk for diabetes.

Radix Astragali Improves Dysregulated Triglyceride Metabolism and Attenuates Macrophage Infiltration in Adipose Tissue in High-Fat Diet-Induced Obese Male Rats through Activating mTORC1-PPAR γ Signaling Pathway.

Increased levels of free fatty acids (FFAs) and hypertriglyceridemia are important risk factors for cardiovascular disease. The effective fraction isolated from radix astragali (RA) has been reported to alleviate hypertriglyceridemia. The mechanism of this triglyceride-lowering effect of RA is unclear. Here, we tested whether activation of the mTORC1-PPARγ signaling pathway is related to the triglyceride-lowering effect of RA. High-fat diet-induced obese (DIO) rats were fed a high-fat diet (40% calories from fat) for 9-10 weeks, and 4 g/kg/d RA was administered by gavage. RA treatment resulted in decreased fasting triglyceride levels, FFA concentrations, and adipocyte size. RA treated rats showed improved triglyceride clearance and fatty acid handling after olive oil overload. RA administration could also decrease macrophage infiltration and expression of MCP-1 and TNFα, but it may also increase the expression of PPARγ in epididymal adipose tissue from RA treated rats. Consistently, expressions of PPARγ and phospho-p70S6K were increased in differentiated 3T3-L1 adipocytes treated with RA. Moreover, RA couldnot upregulate the expression of PPARγ at the presence of rapamycin. In conclusion, the mTORC1-PPARγ signaling pathway is a potential mechanism through which RA exerts beneficial effects on the disturbance of triglyceride metabolism and dysfunction of adipose tissue in DIO rats.

Effects of Sleep Restriction on Glucose Control and Insulin Secretion During Diet‐Induced Weight Loss

Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight-loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24-hour blood glucose control during diet-induced weight loss, 10 overweight and obese adults (3F/7M; mean [SD] age 41 [5] y; BMI 27.4 [2.0] kg/m2) completed two 14-day treatments with hypocaloric diet and 8.5 or 5.5-h nighttime sleep opportunity in random order 7 [3] months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free-fatty acids (FFA), and 24-hour blood glucose, insulin, C-peptide, and counter-regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 [0.3] BMI units) during each treatment. Bedtime restriction reduced sleep by 131 [30] min/day. Recurrent sleep curtailment decreased 24-hour serum insulin concentrations (i.e. enhanced 24-hour insulin economy) without changes in oral glucose tolerance and 24-hour glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA which suppressed normally following glucose ingestion, and lower total and LDL cholesterol concentrations. Sleep-loss-related changes in counter-regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24-hour insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep-restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability.

Effects of Metformin on the Regulation of Free Fatty Acids in Insulin Resistance: A Double-Blind, Placebo-Controlled Study

Introduction. Impaired free fatty acid (FFA) metabolism is closely linked to insulin resistance. Our aim was to evaluate plasma FFA changes in insulin resistance in a physiological situation after improvement of insulin sensitivity by metformin. Methods. A double-blind, placebo-controlled intervention with metformin was carried out in patients with insulin resistance. Nineteen patients were randomized to receive metformin 850 mg b.i.d. during 6 weeks or placebo. Participants underwent a mental stress test and an oral glucose tolerance test (OGTT) before and after treatment. Results. Fasting plasma glucose, FFA, and HOMA-IR tended to decrease after metformin, suggesting improved insulin sensitivity. FFA concentrations during the mental stress test showed a similar pattern after metformin, albeit lower at all time points, in contrast to the placebo group. The decrease in fasting plasma FFAs was positively associated to the decrease in HbA1c (r = 0.70; P = 0.03) and in fasting glucose (r = 0.74; P = 0.01). The suppression of plasma FFAs during OGTT did not change by metformin or placebo. Conclusion. Metformin in insulin resistance did not lead to improved FFA dynamics despite a trend of improved insulin sensitivity. Metformin most likely decreases plasma FFAs mainly by suppressing fasting FFA concentrations and not by suppression of acute stress-induced lipolysis.

Orally Disintegrating and Oral Standard Olanzapine Tablets Similarly Elevate the Homeostasis Model Assessment of Insulin Resistance Index and Plasma Triglyceride Levels in 12 Healthy Men

Treatment with olanzapine is associated with obesity, diabetes mellitus, and dyslipidemia. Reports have indicated that orally disintegrating tablets (ODT) cause less weight gain than oral standard tablets (OST). The aim of this study was to compare the effect of short-term treatment with these 2 distinct olanzapine formulations on glucose and lipid metabolism in healthy men. Twelve healthy men (mean ± SEM age: 25.1 ± 5.5 years) received olanzapine ODT (10 mg od, 8 days), olanzapine OST (10 mg od, 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, glucose, insulin, free fatty acids (FFA), and triglyceride concentrations were measured at 10-minute intervals from 30 minutes prior to 2 hours after ingestion of standard meals. Leptin and adiponectin concentrations were measured at 20- and 30-minute intervals, respectively, between 0000h-1200h. Physical activity was assessed with an accelerometer. Fuel oxidation was measured in fasting condition by indirect calorimetry. The study was conducted from April 2006 through September 2006. Treatment with olanzapine ODT and OST equally elevated the homeostasis model assessment of insulin resistance (HOMA-IR) (P = .005). At breakfast, both formulations equally increased fasting and postprandial triglyceride concentrations (P = .013 and P = .005, respectively) while decreasing fasting and postprandial FFA concentrations (P = .004 and P = .009, respectively). Body weight, body composition, physical activity, or fuel oxidation did not differ between treatment modalities. Eight days of treatment with both olanzapine formulations similarly increased HOMA-IR and triglyceride concentrations and decreased FFA concentrations in response to standard meals without affecting anthropometrics or physical activity. These data suggest that olanzapine hampers insulin action via mechanistic routes other than body adiposity or physical inactivity. controlled-trials.com. Identifier: ISRCTN17632637.

Effects of Olanzapine and Haloperidol on the Metabolic Status of Healthy Men

A large body of evidence suggests that antipsychotic drugs cause body weight gain and type 2 diabetes mellitus, and atypical (new generation) drugs appear to be most harmful. The aim of this study was to determine the effect of short-term olanzapine (atypical antipsychotic drug) and haloperidol (conventional antipsychotic drug) treatment on glucose and lipid metabolism. Healthy normal-weight men were treated with olanzapine (10 mg/d; n = 7) or haloperidol (3 mg/d, n = 7) for 8 d. Endogenous glucose production, whole body glucose disposal (by [6,6-(2)H(2)]glucose dilution), lipolysis (by [(2)H(5)]glycerol dilution), and substrate oxidation rates (by indirect calorimetry) were measured before and after intervention in basal and hyperinsulinemic condition. Olanzapine hampered insulin-mediated glucose disposal (by 1.3 mg x kg(-1) x min(-1)), whereas haloperidol did not have a significant effect. Endogenous glucose production was not affected by either drug. Also, the glycerol rate of appearance (a measure of lipolysis rate) was not affected by either drug. Olanzapine, but not haloperidol, blunted the insulin-induced decline of plasma free fatty acid and triglyceride concentrations. Fasting free fatty acid concentrations declined during olanzapine treatment, whereas they did not during treatment with haloperidol. Short-term treatment with olanzapine reduces fasting plasma free fatty acid concentrations and hampers insulin action on glucose disposal in healthy men, whereas haloperidol has less clear effects. Moreover, olanzapine, but not haloperidol, blunts the insulin-induced decline of plasma free fatty acids and triglyceride concentrations. Notably, these effects come about without a measurable change of body fat mass.

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.

The Pro12Ala polymorphism of the PPAR-γ2 gene affects associations of fish intake and marine n−3 fatty acids with glucose metabolism

Data on associations between marine n-3 fatty acids and glucose metabolism are inconsistent. Therefore, we explored effects of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor (PPAR)-gamma2 gene on associations of fish intake and dietary and plasma eicosapentaenoic and docosahexaenoic acid with glucose metabolism. The design comprises of the cross-sectional analysis. The Pro12Ala variant in the PPAR-gamma2 (PPARG) gene was genotyped in 571 non-diabetic relatives of subjects with type II diabetes. The dietary intake was measured by a 3-day food record, and the plasma cholesterol ester fatty acid composition was analysed with gas chromatography. Associations of dietary and plasma variables with insulin resistance and fasting and 2-h glucose and free fatty acid concentrations were analysed with multiple linear regression analysis. In men, there was a significant interaction between PPARG polymorphism and plasma docosahexaenoic acid on fasting free fatty acid concentration (P=0.036), and genotype-stratified models showed an inverse association in Pro homozygotes only (P=0.028). In women, the proportion of plasma eicosapentaenoic acid was higher in Ala-allele carriers compared to Pro homozygotes (1.67 vs 1.44% respectively, P=0.006). A significant interaction between PPARG polymorphism and fish intake on 2-h glucose was found in women (P=0.021), and genotype-stratified models suggested an inverse association in Ala-allele carriers only (P=0.039). The findings suggest that PPARG polymorphism might affect the plasma proportion of eicosapentaenoic acid and modulate the associations of fish intake and marine n-3 fatty acids with glucose metabolism and fasting free fatty acids.