Fat Oxidation,Fitness and Skeletal Muscle Expression of Oxidative/Lipid Metabolism Genes in South Asians: Implications for Insulin Resistance?

Background

South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures.

Methodology/Principal Findings

Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO_2max (40.6±6.6 vs 52.4±5.7 ml.kg⁻¹.min⁻¹, p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77±2.02 vs 6.55±2.60 mg.kg⁻¹.min⁻¹ at 55% VO_2max, p = 0.013), and absolute (3.46±2.20 vs 6.00±1.93 mg.kg⁻¹.min⁻¹ at 25 ml O₂.kg⁻¹.min⁻¹, p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO_2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO_2max or fat oxidation during exercise explaining 10–13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity.

Conclusions/Significance

These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes.     

Cardiometabolic plasticity in response to a short-term diet and exercise intervention in young Hispanic and nonHispanic white adults

Background

Young adult Mexican Americans (MA) exhibit lower insulin sensitivity (Si) than nonHispanic whites (NHW), even when controlling for fitness and adiposity. It is unclear if MA are as responsive to the same lifestyle intervention as NHW.

Objective

We developed a model to examine cardiometabolic plasticity (i.e., changes in Si and plasma lipids) in MA compared to NHW adults in response to a diet-exercise intervention.

Design

Sedentary subjects (20 NHW: 11F, 9M, 23.0 y, 25.5 kg/m²; 17 MA: 13F, 4M, 22.7 y, 25.4 kg/m²) consumed their habitual diets and remained sedentary for 7 days, after which fasting blood samples were obtained, and a 3-h intravenous glucose tolerance test (IVGTT) was performed with the insulin area under the curve (IAUC) used to estimate Si. Subjects then completed a 7-day diet/exercise intervention (diet: low saturated fat, low added sugar, high fiber; exercise: cycling, six total sessions lasting 40–45 min/session at 65% VO₂ max). Pre-intervention tests were repeated.

Results

Pre intervention IAUC was 28% higher (p<0.05) in MA (IAUC pre  =  2298 µU*180 min/mL) than in NHW (IAUC = 1795 µU*180 min/mL). Following the intervention, there was a significant reduction in IAUC in MA (29%) and NHW (32%), however, the IAUC remained higher (p<0.05) for MA (post  = 1635 µU*180 min/mL) than for NHW (post = 1211 µU*180 min/mL). Pre test plasma lipids were not different in MA compared to NHW. Plasma cholesterol and TG concentrations significantly improved in both groups, but concentrations of low density lipoprotein-cholesterol and small dense LDL particles significantly improved only in the NHW.

Conclusion

With a short-term diet-exercise intervention, the magnitude of improvements in Si and serum cholesterol and TG in Hispanics are similar to those in NHW. However, because at the outset MA were less insulin sensitive compared to NHW, within the short timeframe studied the ethnic gap in insulin sensitivity remained.     

Variance of the SGK1 gene is associated with insulin secretion in different European populations: results from the TUEF, EUGENE2, and METSIM studies

Hypothesis

Serum- and Glucocorticoid-inducible Kinase 1 (SGK1) is involved in the regulation of insulin secretion and may represent a candidate gene for the development of type 2 diabetes mellitus in humans.

Methods

Three independent European populations were analyzed for the association of SGK1 gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally, the detected associations were validated in the METSIM study, providing 3798 non-diabetic and 659 diabetic (type 2) individuals.

Results

Carriers of the minor G allele in rs9402571 had significantly higher C-peptide levels in the 2 h OGTT (+10.8%, p = 0.04; dominant model) and higher AUC_C-Peptide/AUC_Glc ratios (+7.5%, p = 0.04) compared to homozygous wild type TT carriers in the screening population. As interaction analysis for BMI×rs9402571 was significant (p = 0.04) for the endpoint insulin secretion, we stratified the TUEF cohort for BMI, using a cut off point of BMI = 25. The effect on insulin secretion only remained significant in lean TUEF participants (BMI≤25). This finding was replicated in lean EUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUC_Ins/AUC_Glc (TT: 226±7, XG: 246±9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type 2 diabetes (OR: 0.85; 95%CI: 0.71–1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers.

Conclusions

The rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three independent European populations supports the conclusion that SGK variability affects diabetes risk.     

Circulating Irisin Levels Are Positively Associated with Metabolic Risk Factors in Sedentary Subjects

Introduction

A physically active life-style plays an independent role in the protection against type 2 diabetes and cardiovascular diseases. Irisin, a novel exercise-induced myokine, activates thermogenesis in rodents through increasing beige fat cells abundance within white fat. We aimed to investigate circulating irisin levels in association with the degree of physical activity and various metabolic parameters in humans.

Methods

Circulating irisin levels (ELISA) and metabolic parameters were analyzed in 428 subjects (195 men/233 women). Participants were classified according to their self-reported physical activity and to their area of residence.

Results

Circulating irisin levels were higher in active than in sedentary subjects (p= 0.006). Rural inhabitants showed higher circulating irisin levels than urban subjects (p < 0.0001). The increase in irisin levels related to an active lifestyle was only observed in rural citizens (p = 0.014). Among sedentary participants, irisin levels were positively associated with metabolic risk factors (BMI, fasting insulin, HOMA and fasting triglycerides). The area of residence (β= - 0.592, p= < 0.0001) contributed independently to circulating irisin levels variance after controlling for age, gender, BMI, HOMA_IR, triglycerides and physical activity.

Conclusions

In sedentary participants, circulating irisin levels were positively associated with parameters related to an increased cardiometabolic risk. The present study confirmed that an active lifestyle increases circulating irisin levels, but only among subjects living in a rural environment. Area of residence might be a determinant of irisin levels.     

A cross-sectional characterization of insulin resistance by phenotype and insulin clamp in East Asian Americans with type 1 and type 2 diabetes

Objective

Classic features of type 1 and type 2 diabetes may not apply in Asian Americans, due to shared absence of common HLA DR-DQ genotype, low prevalence of positive anti-islet antibodies and low BMI in both types of diabetes. Our objective was to characterize diabetic phenotypes in Asian Americans by clamp and clinical features.

Materials/Methods

This was a cross-sectional study conducted in a referral center. Thirty East young Asian American adult volunteers (27.6±5.5 years) with type 1, type 2 diabetes or controls underwent hyperinsulinemic euglycemic clamp to assess insulin resistance and DEXA to assess adiposity.

Results

Gender, BMI, waist/hip ratio, leptin, LDL, anti-GAD, anti-IA2 antibodies and C-reactive protein were similar among three groups. Serum C-peptide, adiponectin, free fatty acid, HDL concentrations and truncal fat by DEXA, were different between diabetic groups. Glucose disposal rate by clamp was lowest in type 2 diabetes, followed by type 1 diabetes and controls (5.43±2.70, 7.62±2.59, 8.61±2.37 mg/min/kg, respectively, p = 0.001). Free fatty acid concentration universally plummeted during steady state of the clamp procedure regardless of diabetes types in all three groups. Adipocyte fatty acid binding protein in the entire cohort (r = −0.625, p = 0.04) and controls (r = −0.869, p = 0.046) correlated best with insulin resistance, independent of BMI.

Conclusions

Type 2 diabetes in Asian Americans was associated with insulin resistance despite having low BMI as type 1 diabetes, suggesting a potential role for targeting insulin resistance apart from weight loss. Adipocyte fatty acid binding protein, strongly associated with insulin resistance, independent of adiposity in the young Asian American population, may potentially serve as a biomarker to identify at-risk individuals. Larger studies are needed to confirm this finding.     

Consequences of obstructive sleep apnea on metabolic profile: A Population‐Based Survey

Objective:

Epidemiologic studies that control for potential confounders are needed to assess the independent associations of obstructive sleep apnea (OSA) with metabolic abnormalities. The aim of our study was to evaluate the associations of OSA with metabolic abnormalities among the adult population of Sao Paulo, Brazil.

Design and Methods:

Questionnaires were applied face‐to‐face, full night polysomnography (PSG) was performed, and blood samples were collected in a population‐based survey in Sao Paulo, Brazil, adopting a probabilistic three‐stage cluster sample method. The metabolic profile included fasting glucose, insulin, and lipid levels. The hepatic insulin resistance index was assessed by the homeostasis model assessment‐estimated insulin resistance (HOMA_IR).

Results:

A total of 1,042 volunteers underwent PSG. Mild OSA and moderate to severe OSA comprised 21.2% and 16.7% of the population, respectively. Subjects with severe to moderate OSA were older, more obese, had higher fasting glucose, HOMA_IR, and triglycerides (TG) levels than did the mild and non‐OSA group (P < 0.001). Multivariate regression analyses showed that an apnea‐hypopnea index (AHI) ≥15 and a time of oxy‐hemoglobin saturation <90% were independently associated with impaired fasting glucose, elevated TG, and HOMA_IR.

Conclusions:

The results of this large cross‐sectional epidemiological study showed that the associations of OSA and metabolic abnormalities were independent of other risk factors.     

Habitual physical activity in mitochondrial disease

Purpose

Mitochondrial disease is the most common neuromuscular disease and has a profound impact upon daily life, disease and longevity. Exercise therapy has been shown to improve mitochondrial function in patients with mitochondrial disease. However, no information exists about the level of habitual physical activity of people with mitochondrial disease and its relationship with clinical phenotype.

Methods

Habitual physical activity, genotype and clinical presentations were assessed in 100 patients with mitochondrial disease. Comparisons were made with a control group individually matched by age, gender and BMI.

Results

Patients with mitochondrial disease had significantly lower levels of physical activity in comparison to matched people without mitochondrial disease (steps/day; 6883±3944 vs. 9924±4088, p = 0.001). 78% of the mitochondrial disease cohort did not achieve 10,000 steps per day and 48%were classified as overweight or obese. Mitochondrial disease was associated with less breaks in sedentary activity (Sedentary to Active Transitions, % per day; 13±0.03 vs. 14±0.03, p = 0.001) and an increase in sedentary bout duration (bout lengths / fraction of total sedentary time; 0.206±0.044 vs. 0.187±0.026, p = 0.001). After adjusting for covariates, higher physical activity was moderately associated with lower clinical disease burden (steps / day; r_s = −0.49; 95% CI −0.33, −0.63, P<0.01). There were no systematic differences in physical activity between different genotypes mitochondrial disease.

Conclusions

These results demonstrate for the first time that low levels of physical activity are prominent in mitochondrial disease. Combined with a high prevalence of obesity, physical activity may constitute a significant and potentially modifiable risk factor in mitochondrial disease.     

Effect of different doses of aerobic exercise on total white blood cell (WBC) and WBC subfraction number in postmenopausal women: results from DREW

Background

Elevated total white blood cell (WBC) count is associated with an increased risk of coronary heart disease and death. Aerobic exercise is associated with lower total WBC, neutrophil, and monocyte counts. However, no studies have evaluated the effect of the amount of aerobic exercise (dose) on total WBC and WBC subfraction counts.

Purpose

To examine the effects of 3 different doses of aerobic exercise on changes in total WBC and WBC subfraction counts and independent effects of changes in fitness, adiposity, markers of inflammation (IL-6, TNF-α, C-reactive protein), fasting glucose metabolism, and adiponectin.

Methods

Data from 390 sedentary, overweight/obese postmenopausal women from the DREW study were used in these analyses. Women were randomized to a non-exercise control group or one of 3 exercise groups: energy expenditure of 4, 8, or 12 kcal kg⁻¹⋅week⁻¹ (KKW) for 6 months at an intensity of 50% VO_2peak.

Results

A dose-dependent decrease in total WBC counts (trend P = 0.002) was observed with a significant decrease in the 12KKW group (−163.1±140.0 cells/µL; mean±95%CI) compared with the control (138.6±144.7 cells/µL). A similar response was seen in the neutrophil subfraction (trend P = 0.001) with a significant decrease in the 12KKW group (−152.6±115.1 cells/µL) compared with both the control and 4KKW groups (96.4±119.0 and 21.9±95.3 cells/µL, respectively) and in the 8KKW group (−102.4±125.0 cells/µL) compared with the control. When divided into high/low baseline WBC categories (median split), a dose-dependent decrease in both total WBCs (P = 0.003) and neutrophils (P<0.001) was observed in women with high baseline WBC counts. The effects of exercise dose on total WBC and neutrophil counts persisted after accounting for significant independent effects of change in waist circumference and IL-6.

Conclusion

Aerobic exercise training reduces total WBC and neutrophil counts, in a dose-dependent manner, in overweight/obese postmenopausal women and is especially beneficial for those with systemic low grade inflammation.

Clinical Trials Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00011193","term_id":"NCT00011193"}}NCT00011193

     

Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle

Background

The pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots.

Methodology/Principal Findings

To explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL) were assessed by DXA, MRI and ¹H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36±0.23 vs. 0.78±0.10 OD units, P<0.05), while there was no evidence for activation of p38 MAPK or IKKβ. IRS-1 serine phosphorylation was increased (1.30±0.09 vs. 0.22±0.03 OD units, P<0.005) while insulin-stimulated tyrosine phosphorylation decreased (10.97±0.95 vs. 0.89±0.50 OD units, P<0.005). IMCL levels were twice as high in insulin resistant subjects (3.26±0.48 vs. 1.58±0.35% H₂O peak, P<0.05), who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls.

Conclusions

This is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired insulin signaling in this population.     

Characteristics of Glucose Metabolism in Nordic and South Asian Subjects with Type 2 Diabetes

Background

Insulin resistance and type 2 diabetes are more prevalent in people of South Asian ethnicity than in people of Western European origin. To investigate the source of these differences, we compared insulin sensitivity, insulin secretion, glucose and lipid metabolism in South Asian and Nordic subjects with type 2 diabetes.

Methods

Forty-three Nordic and 19 South Asian subjects with type 2 diabetes were examined with intra-venous glucose tolerance test, euglycemic clamp including measurement of endogenous glucose production, indirect calorimetry measuring glucose and lipid oxidation, and dual x-ray absorptiometry measuring body composition.

Results

Despite younger mean ± SD age (49.7±9.4 vs 58.3±8.3 years, p = 0.001), subjects of South Asian ethnicity had the same diabetes duration (9.3±5.5 vs 9.6±7.0 years, p = 0.86), significantly higher median [inter-quartile range] HbA_1c (8.5 [1.6] vs 7.3 [1.6] %, p = 0.024) and lower BMI (28.7±4.0 vs 33.2±4.7 kg/m², p<0.001). The South Asian group exhibited significantly higher basal endogenous glucose production (19.1 [9.1] vs 14.4 [6.8] µmol/kgFFM⋅min, p = 0.003). There were no significant differences between the groups in total glucose disposal (39.1±20.4 vs 39.2±17.6 µmol/kgFFM⋅min, p = 0.99) or first phase insulin secretion (AUC_{0–8 min}: 220 [302] vs 124 [275] pM, p = 0.35). In South Asian subjects there was a tendency towards positive correlations between endogenous glucose production and resting and clamp energy expenditure.

Conclusions

Subjects of South Asian ethnicity with type 2 diabetes, despite being younger and leaner, had higher basal endogenous glucose production, indicating higher hepatic insulin resistance, and a trend towards higher use of carbohydrates as fasting energy substrate compared to Nordic subjects. These findings may contribute to the understanding of the observed differences in prevalence of type 2 diabetes between the ethnic groups.     

Concentration-dependent dual effects of hydrogen peroxide on insulin signal transduction in H4IIEC hepatocytes

Background

Oxidative stress induced by the accumulation of reactive oxygen species (ROS) has a causal role in the development of insulin resistance, whereas ROS themselves function as intracellular second messengers that promote insulin signal transduction. ROS can act both positively and negatively on insulin signaling, but the molecular mechanisms controlling these dual actions of ROS are not fully understood.

Methodology/Principal Findings

Here, we directly treated H4IIEC hepatocytes with hydrogen peroxide (H2O2), a representative membrane-permeable oxidant and the most abundant ROS in cells, to identify the key factors determining whether ROS impair or enhance intracellular insulin signaling. Treatment with high concentrations of H2O2 (25–50 µM) for 3 h reduced insulin-stimulated Akt phosphorylation, and increased the phosphorylation of both JNK and its substrate c-Jun. In contrast, lower concentrations of H2O2 (5–10 µM) enhanced insulin-stimulated phosphorylation of Akt. Moreover, lower concentrations suppressed PTP1B activity, suggesting that JNK and phosphatases such as PTP1B may play roles in determining the thresholds for the diametrical effects of H2O2 on cellular insulin signaling. Pretreatment with antioxidant N-acetyl-L-cysteine (10 mM) canceled the signal-promoting action of low H2O2 (5 µM), and it canceled out further impairment of insulin of insulin signaling induced by high H₂O₂ (25 µM).

Conclusions/Significance

Our results demonstrate that depending on its concentration, H2O2 can have the positive or negative effect on insulin signal transduction in H4IIEC hepatocytes, suggesting that the concentration of intracellular ROS may be a major factor in determining whether ROS impair or enhance insulin signaling.     

Is a sedentary lifestyle an independent predictor for hospital and early mortality after elective cardiac surgery?

Objective

This study evaluates whether a sedentary lifestyle is an independent predictor for increased mortality after elective cardiac surgery.

Methods

Three thousand one hundred fifty patients undergoing elective cardiac surgery between January 2007 and June 2012 completed preoperatively the Corpus Christi Heart Project questionnaire concerning physical activity (PA). Based on this questionnaire, 1815 patients were classified as active and 1335 patients were classified as sedentary. The endpoints of the study were hospital mortality and early mortality.

Results

The study population had a mean age of 69.7 ± 10.1 (19–95) years and a mean logistic EuroSCORE risk of 5.1 ± 5.6 (0.88–73.8). Sedentary patients were significantly older (p = 0.001), obese (p = 0.001), had a higher EuroSCORE risk (p = 0.001), and a higher percentage of complications. Hospital mortality (1.1 % versus 0.4 % (p = 0.014)) and early mortality (1.5 % versus 0.6 % (p = 0.006)) were significantly higher in the sedentary group compared with the active group. However, a sedentary lifestyle was not identified as an independent predictor for hospital mortality (p = 0.61) or early mortality (p = 0.70).

Conclusion

Sedentary patients were older, obese and had a higher EuroSCORE risk. They had significantly more postoperative complications, higher hospital mortality and early mortality. Despite these results, sedentary behaviour could not be identified as an independent predictor for hospital or early mortality.     

Beneficial effects of resistance exercise on glycemic control are not further improved by protein ingestion

Purpose

To investigate the mechanisms underpinning modifications in glucose homeostasis and insulin sensitivity 24 h after a bout of resistance exercise (RE) with or without protein ingestion.

Methods

Twenty-four healthy males were assigned to a control (CON; n = 8), exercise (EX; n = 8) or exercise plus protein condition (EX+PRO; n = 8). Muscle biopsy and blood samples were obtained at rest for all groups and immediately post-RE (75% 1RM, 8×10 repetitions of leg-press and extension exercise) for EX and EX+PRO only. At 24 h post-RE (or post-resting biopsy for CON), a further muscle biopsy was obtained. Participants then consumed an oral glucose load (OGTT) containing 2 g of [U-¹³C] glucose during an infusion of 6, 6-[²H₂] glucose. Blood samples were obtained every 10 min for 2 h to determine glucose kinetics. EX+PRO ingested an additional 25 g of intact whey protein with the OGTT. A final biopsy sample was obtained at the end of the OGTT.

Results

Fasted plasma glucose and insulin were similar for all groups and were not different immediately post- and 24 h post-RE. Following RE, muscle glycogen was 26±8 and 19±6% lower in EX and EX+PRO, respectively. During OGTT, plasma glucose AUC was lower for EX and EX+PRO (75.1±2.7 and 75.3±2.8 mmol·L⁻¹∶120 min, respectively) compared with CON (90.6±4.1 mmol·L⁻¹∶120 min). Plasma insulin response was 13±2 and 21±4% lower for EX and CON, respectively, compared with EX+PRO. Glucose disappearance from the circulation was ∼12% greater in EX and EX+PRO compared with CON. Basal 24 h post-RE and insulin-stimulated PAS-AS160/TBC1D4 phosphorylation was greater for EX and EX+PRO.

Conclusions

Prior RE improves glycemic control and insulin sensitivity through an increase in the rate at which glucose is disposed from the circulation. However, co-ingesting protein during a high-glucose load does not augment this response at 24 h post-exercise in healthy, insulin-sensitive individuals.     

Control of muscle mitochondria by insulin entails activation of Akt2-mtNOS pathway: implications for the metabolic syndrome

Background

In the metabolic syndrome with hyperinsulinemia, mitochondrial inhibition facilitates muscle fat and glycogen accumulation and accelerates its progression. In the last decade, nitric oxide (NO) emerged as a typical mitochondrial modulator by reversibly inhibiting citochrome oxidase and oxygen utilization. We wondered whether insulin-operated signaling pathways modulate mitochondrial respiration via NO, to alternatively release complete glucose oxidation to CO₂ and H₂O or to drive glucose storage to glycogen.

Methodology/Principal Findings

We illustrate here that NO produced by translocated nNOS (mtNOS) is the insulin-signaling molecule that controls mitochondrial oxygen utilization. We evoke a hyperinsulinemic-normoglycemic non-invasive clamp by subcutaneously injecting adult male rats with long-lasting human insulin glargine that remains stable in plasma by several hours. At a precise concentration, insulin increased phospho-Akt2 that translocates to mitochondria and determines in situ phosphorylation and substantial cooperative mtNOS activation (+4–8 fold, P<.05), high NO, and a lowering of mitochondrial oxygen uptake and resting metabolic rate (−25 to −60%, P<.05). Comparing in vivo insulin metabolic effects on gastrocnemius muscles by direct electroporation of siRNA nNOS or empty vector in the two legs of the same animal, confirmed that in the silenced muscles disrupted mtNOS allows higher oxygen uptake and complete (U-¹⁴C)-glucose utilization respect to normal mtNOS in the vector-treated ones (respectively 37±3 vs 10±1 µmolO₂/h.g tissue and 13±1 vs 7.2±1 µmol ³H₂O/h.g tissue, P<.05), which reciprocally restricted glycogen-synthesis by a half.

Conclusions/Significance

These evidences show that after energy replenishment, insulin depresses mitochondrial respiration in skeletal muscle via NO which permits substrates to be deposited as macromolecules; at discrete hyperinsulinemia, persistent mtNOS activation could contribute to mitochondrial dysfunction with insulin resistance and obesity and therefore, to the progression of the metabolic syndrome.     

Brain-derived neurotrophic factor gene Val66Met polymorphism modulates reversible cerebral vasoconstriction syndromes

Background

Reversible cerebral vasoconstriction syndrome (RCVS) could be complicated by cerebral ischemic events. Hypothetical mechanisms of RCVS involve endothelial dysfunction and sympathetic overactivity, both of which were reported to be related to brain-derived neurotrophic factor (BDNF). The study investigated the association between functional BDNF Val66Met polymorphism and RCVS.

Methods

Patients with RCVS and controls were prospectively recruited and genotyped for the BDNF Val66Met polymorphism. Magnetic resonance angiography (MRA) and transcranial color-coded Doppler sonography were employed to evaluate cerebral vasoconstriction. Genotyping results, clinical parameters, vasoconstriction scores, mean flow velocities of the middle cerebral artery (V_MCA), and Lindegaard indices were analyzed. Split-sample approach was employed to internally validate the data.

Principal Findings

Ninety Taiwanese patients with RCVS and 180 age- and gender-matched normal controls of the same ethnicity completed the study. The genotype frequencies did not differ between patients and controls. Compared to patients with Met/Met homozygosity, patients with Val allele had higher mean vasoconstriction scores of all arterial segments (1.60±0.72 vs. 0.87±0.39, p<0.001), V_MCA values (116.7±36.2 vs. 82.7±17.9 cm/s, p<0.001), and LI (2.41±0.91 vs. 1.89±0.41, p = 0.001). None of the Met/Met homozygotes, but 38.9% of the Val carriers, had V_MCA values of >120 cm/s (p<0.001). Split-sample validation by randomization, age, entry time or residence of patients demonstrated concordant findings.

Conclusions

Our findings link BDNF Val66Met polymorphism with the severity of RCVS for the first time and implicate possible pathogenic mechanisms for vasoconstriction in RCVS.     

Exercise Intensity Modulates Glucose-Stimulated Insulin Secretion when Adjusted for Adipose,Liver and Skeletal Muscle Insulin Resistance

Little is known about the effects of exercise intensity on compensatory changes in glucose-stimulated insulin secretion (GSIS) when adjusted for adipose, liver and skeletal muscle insulin resistance (IR). Fifteen participants (8F, Age: 49.9±3.6yr; BMI: 31.0±1.5kg/m²; VO₂peak: 23.2±1.2mg/kg/min) with prediabetes (ADA criteria, 75g OGTT and/or HbA_1c) underwent a time-course matched Control, and isocaloric (200kcal) exercise at moderate (MIE; at lactate threshold (LT)), and high-intensity (HIE; 75% of difference between LT and VO₂peak). A 75g OGTT was conducted 1 hour post-exercise/Control, and plasma glucose, insulin, C-peptide and free fatty acids were determined for calculations of skeletal muscle (1/Oral Minimal Model; SM_IR), hepatic (HOMA_IR), and adipose (ADIPOSE_IR) IR. Insulin secretion rates were determined by deconvolution modeling for GSIS, and disposition index (DI; GSIS/IR; DI_SMIR, DI_HOMAIR, DI_ADIPOSEIR) calculations. Compared to Control, exercise lowered SM_IR independent of intensity (P<0.05), with HIE raising HOMA_IR and ADIPOSE_IR compared with Control (P<0.05). GSIS was not reduced following exercise, but DI_HOMAIR and DI_ADIPOSEIR were lowered more following HIE compared with Control (P<0.05). However, DI_SMIR increased in an intensity based manner relative to Control (P<0.05), which corresponded with lower post-prandial blood glucose levels. Taken together, pancreatic insulin secretion adjusts in an exercise intensity dependent manner to match the level of insulin resistance in skeletal muscle, liver and adipose tissue. Further work is warranted to understand the mechanism by which exercise influences the cross-talk between tissues that regulate blood glucose in people with prediabetes.     

Maternal cigarette smoke exposure contributes to glucose intolerance and decreased brain insulin action in mice offspring independent of maternal diet

Background

Maternal smoking leads to intrauterine undernutrition and is associated with low birthweight and higher risk of offspring obesity. Intrauterine smoke exposure (SE) may alter neuroendocrine mediators regulating energy homeostasis as chemicals in cigarette smoke can reach the fetus. Maternal high-fat diet (HFD) consumption causes fetal overnutrition; however, combined effects of HFD and SE are unknown. Thus we investigated the impact of combined maternal HFD and SE on adiposity and energy metabolism in offspring.

Method

Female Balb/c mice had SE (2 cigarettes/day, 5 days/week) or were sham exposed for 5 weeks before mating. Half of each group was fed HFD (33% fat) versus chow as control. The same treatment continued throughout gestation and lactation. Female offspring were fed chow after weaning and sacrificed at 12 weeks.

Results

Birthweights were similar across maternal groups. Faster growth was evident in pups from SE and/or HFD dams before weaning. At 12 weeks, offspring from HFD-fed dams were significantly heavier than those from chow-fed dams (chow-sham 17.6±0.3 g; chow-SE 17.8±0.2 g; HFD-sham 18.7±0.3 g; HFD-SE 18.8±0.4 g, P<0.05 maternal diet effect); fat mass was significantly greater in offspring from chow+SE, HFD+SE and HFD+sham dams. Both maternal HFD and SE affected brain lactate transport. Glucose intolerance and impaired brain response to insulin were observed in SE offspring, and this was aggravated by maternal HFD consumption.

Conclusion

While maternal HFD led to increased body weight in offspring, maternal SE independently programmed adverse health outcomes in offspring. A smoke free environment and healthy diet during pregnancy is desirable to optimize offspring health.     

Effects of short-term continuous subcutaneous insulin infusion on fasting plasma fibroblast growth factor-21 levels in patients with newly diagnosed type 2 diabetes mellitus

Background

To investigate the effects of short-term continuous subcutaneous insulin infusion (CSII) on plasma fibroblast growth factor-21 (FGF-21) levels in patients with newly diagnosed type 2 diabetes mellitus (nT2DM).

Method

Sixty-eight patients with nT2DM (nT2DM group), and 52 gender-, age- and body mass index (BMI) -matched normal glucose tolerance (NGT group) controls participated in the study. 30 nT2DM patients with FBG≥14.0 mmol/L were treated with CSII for 2 weeks, and were underwent a euglycemic–hyperinsulinemic clamp pre- and post-treatment. Plasma FGF-21 concentrations were measured with a commercial ELISA kit. The relationship between plasma FGF-21 levels and metabolic parameters was also analyzed.

Results

Fasting plasma FGF-21 levels were higher in the nT2DM group than in NGT groups (1.60±0.08 vs. 1.13±0.26 µg/L, P<0.01). In nT2DM patients, fasting plasma FGF-21 concentrations were significantly decreased after CSII treatment for 2 weeks (1.60±0.08 vs.1.30±0.05 µg/L, P<0.05), accompanied by a significant increase in the whole body glucose uptake (M value) and blood glucose control. The changes in plasma FGF-21 levels (ΔFGF-21) were positively associated with the amelioration of insulin resistance shown by the changes in M value.

Conclusion

Plasma FGF-21 level is associated with whole body insulin sensitivity and significantly reduced following short-term CSII treatment.     

Effects of a flaxseed-derived lignan supplement in type 2 diabetic patients: a randomized, double-blind, cross-over trial

Background

Flaxseed consumption has been shown to improve blood lipids in humans and flaxseed-derived lignan has been shown to enhance glycemic control in animals. The study aimed to investigate the effect of a flaxseed-derived lignan supplement on glycemic control, lipid profiles and insulin sensitivity in type 2 diabetic patients.

Methodology/Principal Findings

This was a randomized, double-blind, placebo-controlled, cross-over trial and it was conducted between April and December 2006 in Shanghai, China. Seventy-three type 2 diabetic patients with mild hypercholesterolemia were enrolled into the study. Patients were randomized to supplementation with flaxseed-derived lignan capsules (360 mg lignan per day) or placebo for 12 weeks, separated by an 8-week wash-out period. HbA1c, lipid profiles, insulin resistance index and inflammatory factors were measured. Sixty-eight completed the study and were included in the analyses. The lignan supplement significantly improved glycemic control as measured by HbA_1c (-0.10±0.65 % vs. 0.09±0.52 %, P = 0.001) compared to placebo; however, no significant changes were observed in fasting glucose and insulin concentrations, insulin resistance and blood lipid profiles. Urinary excretion of lignan metabolites (enterodiol and enterolactone) was significantly higher after the lignan supplement intervention compared to baseline (14.2±18.1 vs. 1.2±2.4 µg/mL, P<0.001). Data also suggested minimal competition between lignan and isoflavones for bioavailability when measured by the excretion concentrations.

Conclusions/Significance

Daily lignan supplementation resulted in modest, yet statistically significant improvements in glycemic control in type 2 diabetic patients without apparently affecting fasting glucose, lipid profiles and insulin sensitivity. Further studies are needed to validate these findings and explore the efficacy of lignans on type 2 diabetes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00363233","term_id":"NCT00363233"}}NCT00363233