Lower Insulin Concentrations Research Articles

Açai (Euterpe oleracea Mart.) seed flour prevents obesity-induced hepatic steatosis regulating lipid metabolism by increasing cholesterol excretion in high-fat diet-fed mice

Obesity is one of the most serious global public health challenges of the 21st century. The aim of this study was to investigate the effects of dietary incorporation of açai seed flour (ASF) on lipid metabolism of high fat diet-induced obesity mice. C57BL/6 male mice were divided into four groups (n = 10): control group (C); high fat diet (HF); high fat diet with ASF (HFA15 and HFA30, high fat diet containing 15% or 30% ASF, respectively) for 12 weeks. Body composition, lipid metabolism and excretion, hepatic and adipose tissue morphology and biochemical parameters were assayed. The incorporation of 15% or 30% ASF in mice's diet promoted protective effect upon weight gain, prevented insulin resistance and improved lipid profile of animals, which had lower concentrations of glucose, insulin and leptin. Thus, ASF reduced lipogenesis preventing the development of fatty liver disease and hypertrophic obesity. It was also observed the influence of ASF consumption on the modulation of proteins involved with cholesterol synthesis and excretion. The high fecal weight in the ASF group demonstrates a significant action of the fibers in the excretion of bile acids and cholesterol. Biochemical parameters of the nutritional status were not altered nor were signs of toxicity observed in the animals with the ASF consumption, suggesting that the flour does not present toxic or harmful effects to the animals' health. The use of ASF prevents the development of obesity and its commorbidities, especially hepatic steatosis increasing cholesterol excretion.

Insulin-Mediated Glucose Metabolism: An Atherogenic Lipid Profile of Fructose Consumption

Our laboratory has investigated two hypotheses regarding the effects of fructose consumption: 1) The endocrine effects of fructose consumption favor a positive energy balance, and 2) Fructose consumption promotes the development of an atherogenic lipid profile. In previous short- and long-term studies, we demonstrated that consumption of fructose-sweetened beverages with 3 meals results in lower 24-hour plasma concentrations of glucose, insulin, and leptin in humans compared with consumption of glucose-sweetened beverages. We have also tested whether prolonged consumption of high-fructose diets could lead to increased caloric intake or decreased energy expenditure, thereby contributing to weight gain and obesity. Results from a study conducted in rhesus monkeys produced equivocal results. Carefully controlled and adequately powered long-term studies are needed to address these hypotheses. In both short- and long-term studies we demonstrated that consumption of fructose-sweetened beverages substantially increases postprandial triacylglycerol concentrations compared with glucose-sweetened beverages. In the long-term studies, apolipoproteinB concentrations were also increased in subjects consuming fructose, but not those consuming glucose. Data from a short-term study comparing consumption of beverages sweetened with fructose, glucose, high fructose corn syrup (HFCS) and sucrose, suggest that HFCS and sucrose increase postprandial triacylglycerol to an extent comparable to that induced by 100% fructose alone. Increased consumption of fructose-sweetened beverages along with increased prevalence of obesity, metabolic syndrome, and type 2 diabetes underscore the importance of investigating the metabolic consequences fructose consumption in carefully controlled experiments.

Differences in the Postprandial Release of Appetite-Related Hormones Between Active and Inactive Men.

Active, as opposed to inactive, individuals are able to adjust their energy intake after preloads of different energy contents. The mechanisms responsible for this remain unknown. This study examined differences in plasma concentration of appetite-related hormones in response to breakfasts of different energy contents, between active and inactive men. Sixteen healthy nonobese (body mass index = 18.5-27kg/m2) adult males (nine active and seven inactive) participated in this study. Participants were given a high-energy (570kcal) or a low-energy (205kcal) breakfast in a random order. Subjective feelings of appetite and plasma concentrations of active ghrelin, active glucagon-like peptide-1, total peptide YY (PYY), cholecystokinin, and insulin were measured in fasting and every 30min up to 2.5hr, in response to both breakfasts. Mixed analysis of variance (fat mass [in percentage] as a covariate) revealed a higher concentration of active ghrelin and lower concentration of glucagon-like peptide-1, and cholecystokinin after the low-energy breakfast (p < .001 for all). Postprandial concentration of PYY was greater after the high energy compared with the low energy, but for inactive participants only (p = .014). Active participants had lower postprandial concentrations of insulin than inactive participants (p < .001). Differences in postprandial insulin between breakfasts were significantly lower in active compared with inactive participants (p < .001). Physical activity seems to modulate the postprandial plasma concentration of insulin and PYY after the intake of breakfasts of different energy contents, and that may contribute, at least partially, to the differences in short-term appetite control between active and inactive individuals.

Indices of heart rate variability as potential early markers of metabolic stress and compromised regulatory capacity in dried-off high-yielding dairy cows

High performing dairy cows experience distinct metabolic stress during periods of negative energy balance. Subclinical disorders of the cow’s energy metabolism facilitate failure of adaptational responses resulting in health problems and reduced performance. The autonomic nervous system (ANS) with its sympathetic and parasympathetic branches plays a predominant role in adaption to inadequate energy and/or fuel availability and mediation of the stress response. Therefore, we hypothesize that indices of heart rate variability (HRV) that reflect ANS activity and sympatho-vagal balance could be early markers of metabolic stress, and possibly useful to predict cows with compromised regulatory capacity. In this study we analysed the autonomic regulation and stress level of 10 pregnant dried-off German Holstein cows before, during and after a 10-h fasting period by using a wide range of HRV parameters. In addition heat production (HP), energy balance, feed intake, rumen fermentative activity, physical activity, non-esterified fatty acids, β-hydroxybutyric acid, cortisol and total ghrelin plasma concentrations, and body temperature (BT) were measured. In all cows fasting induced immediate regulatory adjustments including increased lipolysis (84%) and total ghrelin levels (179%), reduction of HP (−16%), standing time (−38%) and heart rate (−15%). However, by analysing frequency domain parameters of HRV (high-frequency (HF) and low-frequency (LF) components, ratio LF/HF) cows could be retrospectively assigned to groups reacting to food removal with increased or decreased activity of the parasympathetic branch of the ANS. Regression analysis reveals that under control conditions (feeding ad libitum) group differences were best predicted by the nonlinear domain HRV component Maxline (LMAX, R2=0.76, threshold; TS=258). Compared with cows having LMAX values above TS (>LMAX: 348±17), those with LMAX values below TS (<LMAX: 109±26) had higher basal blood cortisol levels, lower concentrations of insulin, and respond to fasting with a shift of their sympatho-vagal balance towards a much stronger dominance of the sympathetic branch of the ANS and development of stress-induced hyperthermia. The data indicate a higher stress level, reduced well-being and restricted regulatory capacity in <LMAX cows. This assumption is in accord with the lower dry matter intake and energy corrected milk yield (16.0±0.7 and 42±2 kg/day) in lactating <LMAX compared with >LMAX cows (18.5±0.4 and 47.3 kg/day). From the present study, it seems conceivable that LMAX can be used as a predictive marker to discover alterations in central autonomic regulation that might precede metabolic disturbances.

A nickel nanoparticle/carbon nanotube-modified carbon fiber microelectrode for sensitive insulin detection

A nickel nanoparticle (NiNP)/carbon nanotube (CNT)-modified carbon fiber microelectrode (NiNPs/CNTs/CFME) was fabricated using a two-step electroless plating/chemical vapor deposition method. The morphology of the NiNPs/CNTs composite structure was characterized by scanning electron microscopy, and its elemental composition was characterized by an energy dispersive spectrometer. The electrochemical behavior of the NiNPs/CNTs/CFME in aqueous alkaline solutions of insulin was investigated by cyclic voltammetry (CV), chronoamperometry, and electrochemical impedance spectroscopy in sequence. CV curves show that the NiNPs/CNTs/CFME displays a high oxidation peak current, a fast electron transfer rate, and good electrocatalytic activity towards insulin, compared to a bare CFME and a pure NiNP-modified CFME. In the chronoamperometry tests, the NiNPs/CNTs/CFME demonstrates an excellent analytical performance in detecting low concentrations of insulin, including good sensitivity (1.11 nA μM−1) and a low detection limit (270 nM). Moreover, this microelectrode exhibits great reproducibility in successive potential cycling and satisfactory long-term stability after storage at room temperature for approximately 8 weeks.

Interrelationship of the rs7903146 TCF7L2 gene variant with measures of glucose metabolism and adiposity: The NEO study

Background and aimsWe investigated the interrelationship of rs7903146-T in TCF7L2 with measures of glucose metabolism and measures of adiposity. Methods and resultsThis cross-sectional analysis was conducted in 5744 middle-aged participants (mean (standard deviation [SD]) age is 55.9 (6.0) years) from the Netherlands Epidemiology of Obesity (NEO) Study. Associations between rs7903146-T and Type 2 diabetes mellitus (T2D) were assessed with logistic regression. Additive (per-allele) associations with measures of glucose metabolism (e.g., fasting insulin) and adiposity (e.g., body mass index [BMI]) were examined with multivariable linear regression. In the total study population, rs7903146-T was associated with a higher risk of T2D (additive odds ratio: 1.42; 95% confidence interval: 1.17; 1.72), and specifically with T2D treated with insulin analogs (2.31 [1.19; 4.46]). After exclusion of participants treated with glucose-lowering medication, rs7903146-T was associated with lower mean insulin concentration (additive mean difference: −0.07 SD [−0.14; 0.00]), but not with higher mean glucose concentration (0.03 SD [−0.01; 0.07]). Furthermore, rs7903146-T was associated with, among other measures of adiposity, a lower mean BMI (−0.04 SD [−0.09; −0.00]), and a lower mean total body fat (−0.04 SD [−0.08; −0.00]). The association between rs7903146-T and T2D increased after adjustment for BMI (odds ratio: 1.51 [1.24; 1.86]); the association between rs7903146-T and fasting insulin diminished after adjustment (−0.05 SD [−0.11; 0.02]). Conclusionrs7903146-T is associated with a decreased insulin concentration and increased risk of T2D with opposing effects of adjustment for adiposity.

Relaciones entre calcio, ácidos grasos no esterificados, e insulina sanguínea en preparto y leche bovina perdida en el inicio de la lactancia

Introducción: El objetivo fue determinar la relación entre las concentraciones séricas de calcio (Ca2+), ácidos grasos no esterificados (AGNE) e insulina preparto con pérdidas en la producción de leche (PL) en el inicio de la lactancia.Método: Doscientas cuarenta y tres vacas Holstein-Friesian (780 ± 36 kg PV; con más de dos lactancias) fueron muestreadas por punción coccígea varias veces antes, durante y después del parto. Para cada muestreo y cada metabolito, las concentraciones séricas se estratificaron con umbrales y se relacionaron con la PL.Resultados: Cuando los niveles de Ca2+ fueron bajos 10 días antes del parto y se relacionaron con la PL a los 10 días posparto, se observó que el 77.11% de las vacas perdieron 2.20 kg de leche; mientras en el día 20, el 66.41% de las vacas perdieron 1.40 kg animal-1 día-1. Por el contrario, cuando los AGNE fueron altos 10 días antes de parto y se relacionaron con PL, 67.40% de las vacas mostraron riesgo de perder 0.80 kg, mientras que a los 20 días posparto, el 22.00% de las vacas perdieron aproximadamente 0.90 kg vaca-1 día-1. La determinación de insulina preparto baja y PL en los días 10 y 20 de lactancia indicó que 6.02% de las vacas perdieron 0.80 y 0.70 kg de leche animal-1 día-1 para los días 10 y 20 de lactancia.Conclusión: En conclusión, niveles bajos de calcio, AGNE alto e insulina baja en sangre, obtenidos 10 días antes de parto fueron asociados con pérdidas en producción de leche en los días 10 y 20 después del parto. También se observó que los niveles bajos de calcio podrían causar mayores pérdidas de leche que los niveles altos de ácidos grasos no esterificados y las concentraciones bajas de insulina preparto.

Sedentary Behaviors and Biomarkers Among Breast Cancer Survivors.

Sedentary behavior is associated with increased risk of poor outcomes in breast cancer survivors, but underlying mechanisms are not well understood. This pilot study explored associations between different aspects of sedentary behaviors (sitting, prolonged sitting, sit-to-stand transitions, and standing) and breast cancer risk-related biomarkers in breast cancer survivors (n = 30). Sedentary behavior variables were objectively measured with thigh-worn activPALs. Breast cancer risk-related biomarkers assessed were C-reactive protein (CRP), insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) and were measured in fasting plasma samples. Linear regression models were used to investigate associations between sedentary behavior variables and biomarkers (log CRP, insulin, and HOMA-IR). Sit-to-stand transitions were significantly associated with insulin resistance biomarkers (P < .05). Specifically, each 10 additional sit-to-stand transitions per day was associated with a lower fasting insulin concentration (β = -5.52; 95% CI, -9.79 to -1.24) and a lower HOMA-IR value (β = -0.22; 95% CI, -0.42 to -0.03). Sit-to-stand transitions were not significantly associated with CRP concentration (P = .08). Total sitting time, long sitting bouts, and standing time were not significantly associated with CRP, insulin, or HOMA-IR (P > .05). Sit-to-stand transitions may be an intervention target for reducing insulin resistance in breast cancer survivors, which may have favorable downstream effects on cancer prognosis.

A high fat breakfast attenuates the suppression of appetite and acylated ghrelin during exercise at simulated altitude

High-altitude exposure induces a negative energy balance by increasing resting energy expenditure and decreasing energy intake. This diminished energy intake is likely caused by altitude-induced anorexia and can have detrimental effects for those travelling to high-altitude. We aimed to investigate whether altering the macronutrient composition of breakfast could attenuate altitude-induced anorexia and augment energy intake at high-altitude. Twelve healthy men (aged 26 (8) years, body mass index 23.9 (2.7) kg·m−2) completed two, 305min experimental trials at 4300m simulated altitude (~11.7% O2). After an overnight fast, participants entered a normobaric hypoxic chamber and rested for one hour, before receiving either a high fat (HF; 60% fat, 25% carbohydrate) or an isocaloric high carbohydrate (HC; 60% carbohydrate, 25% fat) breakfast. One hour after breakfast, participants performed 60min of treadmill walking at 50% of relative V̇O2max. An ad-libitum buffet meal was consumed 1h 30min after exercise. Appetite perceptions, blood samples and substrate oxidation rates were measured throughout. A significantly higher area under the curve for composite appetite score was observed during exercise in HF (40 (12) mm·h−1) compared with HC (30 (17) mm·h−1, P=0.036). During exercise, lower insulin concentrations (P=0.013) and elevated acylated ghrelin concentrations (P=0.048) were observed in HF compared with HC. After exercise there was no significant difference in composite appetite score (P=0.356), acylated ghrelin (P=0.229) or insulin (P=0.513) between conditions. Energy intake at the buffet did not significantly differ between conditions (P=0.384). A HF breakfast attenuated appetite suppression during exercise at 4300m simulated altitude, however ad-libitum energy intake did not increase.

Ergogenic properties of metformin in simulated high altitude.

Metformin augments glucose/glycogen regulation and may acutely promote fatigue resistance during high-intensity exercise. In hypobaric environments, such as high altitude, the important contribution of carbohydrates to physiological function is accentuated as glucose/glycogen dependence is increased. Because hypoxia/hypobaria decreases insulin sensitivity, replenishing skeletal muscle glycogen in high altitude becomes challenging and subsequent physical performance may be compromised. We hypothesized that in conditions where glycogen repletion was critical to physical outcomes, metformin would attenuate hypoxia-mediated decrements in exercise performance. On three separate randomly ordered occasions, 13 healthy men performed glycogen-depleting exercise and ingested a low-carbohydrate dinner (1200kcals, <10% carbohydrate). The next morning, in either normoxia or hypoxia (FiO2 =0.15), they ingested a high-carbohydrate breakfast (1225kcals, 70% carbohydrate). Placebo (719mg maltodextrin) or metformin (500mg BID) was consumed 3days prior to each hypoxia visit. Subjects completed a 12.5km cycle ergometer time trial 3.5hours following breakfast. Hypoxia decreased resting and exercise oxyhemoglobin saturation (P<.001). Neither hypoxia nor metformin affected the glucose response to breakfast (P=.977), however, compared with placebo, metformin lowered insulin concentration in hypoxia 45minutes after breakfast (64.1±6.6μU/mL vs 48.5±7.8μU/mL; mean±SE; P<.001). Post-breakfast, pre-exercise vastus lateralis glycogen content increased in normoxia (+33%: P=.025) and in hypoxia with metformin (+81%; P=.006), but not in hypoxia with placebo (+27%; P=.167). Hypoxia decreased time trial performance compared with normoxia (P<.01). This decrement was similar with placebo (+2.6±0.8minutes) and metformin (+1.6±0.3minutes). These results indicate that metformin promotes glycogen synthesis but not endurance exercise performance in healthy men exposed to simulated high altitude.

Non-dipping status and selected adipokines concentration in children with primary arterial hypertension

ABSTRACTHigh blood pressure (BP) in children and adolescents is associated with increased risk of persistent hypertension (HT) in adulthood and, consequently, cardiovascular disease and target organ damage. Aim: The values of selected anthropometric parameters and laboratory test results including leptin and apelin concentration were evaluated with regard to averaged values of office BP measurements and 24-hour ABPM. Material and methods: The study included 55 children: 23-with primary HT and coexisting overweight or obese (HT-OB), 16-with primary HT and normal weight (HT-NW), and 16 healthy children (C). Results: The concentration of leptin and apelin in HT-OB children was significantly higher than in the C and HT-NW group. A similar finding for leptin level was demonstrated in comparison of HT-NW with C group. In children with HT-OB, the lack of decline in nocturnal DBP was associated with significantly higher BMI and the Cole’s Index value. Children with HT-OB and lack of decline in nocturnal SBP showed lower leptin and insulin concentrations, and lower values of HOMA-IR as compared with dipping children. Positive correlation in the whole study group was found between adipokines levels and BP measurements. In conclusion, children with primary HT show higher concentration of adipokines compared with their healthy peers. The data on relationship of serum adipokines levels with anthropometric and BP parameters in children may be helpful to clarify the sequence of disturbances in the cardiovascular system in adults, which requires further examination.

Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency.

Placental insufficiency and intrauterine growth restriction (IUGR) of the fetus affects approximately 8% of all pregnancies and is associated with short- and long-term disturbances in metabolism. In pregnant sheep, experimental models with a small, defective placenta that restricts delivery of nutrients and oxygen to the fetus result in IUGR. Low blood oxygen concentrations increase fetal plasma catecholamine concentrations, which lower fetal insulin concentrations. All of these observations in sheep models with placental insufficiency are consistent with cases of human IUGR. We propose that sustained high catecholamine concentrations observed in the IUGR fetus produce developmental adaptations in pancreatic β-cells that impair fetal insulin secretion. Experimental evidence supporting this hypothesis shows that chronic elevation in circulating catecholamines in IUGR fetuses persistently inhibits insulin concentrations and secretion. Elevated catecholamines also allow for maintenance of a normal fetal basal metabolic rate despite low fetal insulin and glucose concentrations while suppressing fetal growth. Importantly, a compensatory augmentation in insulin secretion occurs following inhibition or cessation of catecholamine signalling in IUGR fetuses. This finding has been replicated in normally grown sheep fetuses following a 7-day noradrenaline (norepinephrine) infusion. Together, these programmed effects will potentially create an imbalance between insulin secretion and insulin-stimulated glucose utilization in the neonate which probably explains the transient hyperinsulinism and hypoglycaemia in some IUGR infants.

Constitutive Activation of AKT2 in Humans Leads to Hypoglycemia Without Fatty Liver or Metabolic Dyslipidemia.

Context:The activating p.Glu17Lys mutation in AKT2, a kinase mediating many of insulin’s metabolic actions, causes hypoinsulinemic hypoglycemia and left-sided hemihypertrophy. The wider metabolic profile and longer-term natural history of the condition has not yet been reported.Objective:To characterize the metabolic and cellular consequences of the AKT2 p.Glu17Lys mutation in two previously reported males at the age of 17 years.Design and Intervention:Body composition analysis using dual-energy X-ray absorptiometry, overnight profiling of plasma glucose, insulin, and fatty acids, oral glucose tolerance testing, and magnetic resonance spectroscopy to determine hepatic triglyceride content was undertaken. Hepatic de novo lipogenesis was quantified using deuterium incorporation into palmitate. Signaling in dermal fibroblasts was studied ex vivo.Results:Both patients had 37% adiposity. One developed hypoglycemia after 2 hours of overnight fasting with concomitant suppression of plasma fatty acids and ketones, whereas the other maintained euglycemia with an increase in free fatty acids. Blood glucose excursions after oral glucose were normal in both patients, albeit with low plasma insulin concentrations. In both patients, plasma triglyceride concentration, hepatic triglyceride content, and fasting hepatic de novo lipogenesis were normal. Dermal fibroblasts of one proband showed low-level constitutive phosphorylation of AKT and some downstream substrates, but no increased cell proliferation rate.Conclusions:The p.Glu17Lys mutation of AKT2 confers low-level constitutive activity upon the kinase and produces hypoglycemia with suppressed fatty acid release from adipose tissue, but not fatty liver, hypertriglyceridemia, or elevated hepatic de novo lipogenesis. Hypoglycemia may spontaneously remit.

Effect of resistance exercise under conditions of reduced blood insulin on AMPKα Ser485/491 inhibitory phosphorylation and AMPK pathway activation.

Insulin stimulates skeletal muscle glucose uptake via activation of the protein kinase B/Akt (Akt) pathway. Recent studies suggest that insulin downregulates AMP-activated protein kinase (AMPK) activity via Ser485/491 phosphorylation of the AMPK α-subunit. Thus lower blood insulin concentrations may induce AMPK signal activation. Acute exercise is one method to stimulate AMPK activation; however, no study has examined the relationship between blood insulin levels and acute resistance exercise-induced AMPK pathway activation. Based on previous findings, we hypothesized that the acute resistance exercise-induced AMPK pathway activation would be augmented by disruptions in insulin secretion through a decrease in AMPKα Ser485/491 inhibitory phosphorylation. To test the hypothesis, 10-wk-old male Sprague-Dawley rats were administered the toxin streptozotocin (STZ; 55 mg/kg) to destroy the insulin secreting β-cells. Three days postinjection, the right gastrocnemius muscle from STZ and control rats was subjected to resistance exercise by percutaneous electrical stimulation. Animals were killed 0, 1, or 3 h later; activation of the Akt/AMPK and downstream pathways in the muscle tissue was analyzed by Western blotting and real-time PCR. Notably, STZ rats showed a significant decrease in basal Akt and AMPKα Ser485/491 phosphorylation, but substantial exercise-induced increases in both AMPKα Thr172 and acetyl-CoA carboxylase (ACC) Ser79 phosphorylation were observed. Although no significant impact on resistance exercise-induced Akt pathway activation or glucose uptake was found, resistance exercise-induced peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 α (PGC-1α) gene expression was augmented by STZ treatment. Collectively, these data suggest that circulating insulin levels may regulate acute resistance exercise-induced AMPK pathway activation and AMPK-dependent gene expression relating to basal AMPKα Ser485/491 phosphorylation.

Exercise training and metformin, but not exercise training alone, decreases insulin production and increases insulin clearance in adults with prediabetes.

Adding metformin to exercise does not augment the effect of training alone to boost whole body insulin sensitivity and lower circulating insulin concentrations. Although lower insulin concentrations (lower supply) following lifestyle and/or pharmacological interventions are primarily attributed to reductions in insulin secretion that match increases in peripheral insulin sensitivity (lower demand), it is unclear whether exercise and/or metformin exert direct effects on insulin production, extraction, or clearance. Thirty-six middle-aged, obese, sedentary adults with prediabetes were randomized to placebo (P), metformin (M), exercise and placebo (E+P), or exercise and metformin (E+M) for 12 wk. Fasting plasma proinsulin (an indicator of insulin production), C-peptide, insulin, and glucose were collected before and after the intervention. Peripheral insulin sensitivity (euglycemic clamp), hepatic insulin extraction, insulin clearance, body weight, and cardiorespiratory fitness were also measured. Fasting proinsulin was unchanged following P (19.4 ± 10.1 vs. 22.6 ± 15.0 pmol/l), E+P (15.1 ± 7.4 vs. 15.5 ± 7.4 pmol/l), or M (24.8 ± 18.9 vs. 16.7 ± 20.3 pmol/l) but was significantly reduced after E+M (18.6 ± 11.9 vs. 13.9 ± 6.7 pmol/l; P = 0.04). Insulin clearance was significantly greater following M (384.6 ± 19.4 vs. 477.4 ± 49.9; P = 0.03) and E+M (400.1 ± 32.0 vs. 482.9 ± 33.9; P = 0.02) but was unchanged in P or E+P. In this study, metformin combined with exercise training reduced circulating proinsulin, and both groups taking metformin increased insulin clearance. This suggests that adding metformin to exercise may augment or attenuate training effects depending on the outcome or organ system being assessed.NEW & NOTEWORTHY Exercise is increasingly viewed as medication, creating a need to understand its interactions with other common medications. Research suggests metformin, a widely prescribed diabetes medication, may diminish the benefits of exercise when used in combination. In this study, however, metformin combined with exercise training, but not exercise alone, lowered proinsulin concentrations and increased insulin clearance in adults with prediabetes. This may directly influence personalized prescriptions of lifestyle and/or pharmacology to reduce diabetes risk.

Systematic investigation of fabrication conditions of nanocarrier based on carboxymethyl chitosan for sustained release of insulin

pH-responsive nanoparticles (NPs) comprised of degradable carboxymethyl chitosan (CMCS) crosslinked with CaCl2 were simply prepared via ionic gelation. Fabrication conditions including insulin dosage, CMCS concentration, and crosslinking density were systematically investigated for insulin loading and release in vitro. The encapsulation efficiencies (EE), loading capacity (LC) and average size of the NPs decreased with the increasing insulin concentrations (<0.192mg/mL), while they notably increased as the insulin dosage was above 0.192mg/mL. When the concentration of CMCS increased from 0.5 to 2.0mg/mL, the EE of the NPs reduced while the size of the NPs increased. We further demonstrated that crosslinking density offered a simple method for tuning the properties of the NPs towards various insulin concentrations. The mass ratio 10:5 of CMCS to CaCl2 exhibited the optimal performance at higher insulin concentration, whereas a higher crosslinking density of 10:7 (m:m) gave the optimal performance at low insulin concentration. The cumulative release of insulin from insulin loaded NPs decreased with the elevating crosslinking density. These findings not only provided a better understanding of the synthesis of CMCS NPs but also contributed to the practical applications of insulin loading and release.

Modification of the fatty acid composition of an obesogenic diet improves the maternal and placental metabolic environment in obese pregnant mice

Peri-conceptional exposure to maternal obesogenic nutrition is associated with in utero programming of later-life overweight and metabolic disease in the offspring. We aimed to investigate whether dietary intervention with a modified fatty acid quality in an obesogenic high-calorie (HC) diet during the preconception and gestational phases can improve unfavourable effects of an adipogenic maternal environment. In NMRI mice, peri-conceptional and gestational obesity was induced by feeding a HC diet (controls), and they were compared with dams on a fat-modified (Fat-mod) HC diet of the same energy content but enriched with medium-chain fatty acids (MCFAs) and adjusted to a decreased ratio of n-6 to n-3 long-chain polyunsaturated fatty acids (LC-PUFAs). Effects on maternal and placental outcomes at delivery (day 17.5 post coitum) were investigated. Despite comparable energy assimilation between the two groups of dams, the altered fatty acid composition of the Fat-mod HC diet induced lower maternal body weight, weights of fat depots, adipocyte size, and hepatic fat accumulation compared to the unmodified HC diet group. Further, there was a trend towards lower fasting glucose, insulin and leptin concentrations in dams fed the Fat-mod HC diet. Phenotypic changes were accompanied by inhibition of transcript and protein expression of genes involved in hepatic de novo lipogenesis comprising PPARG2 and its target genes Fasn, Acaca, and Fabp4, whereas regulation of other lipogenic factors (Srebf1, Nr1h3, Abca1) appeared to be more complex. The modified diet led to a sex-specific placental response by upregulating PPARG-dependent fatty acid transport gene expression in female versus male placentae. Qualitative modification of the fatty acid spectrum of a high-energy maternal diet, using a combination of both MCFAs and n-3 LC-PUFAs, seems to be a promising interventional approach to ameliorate the adipogenic milieu of mice before and during gestation.

Investigation of miRNA-binding site variants and risk of gestational diabetes mellitus in Chinese pregnant women.

Emerging evidence suggested genetic factor attributed as a major determinant for the complex pathogenic mechanism of gestational diabetes mellitus (GDM), but the related genetic study was limited. We aimed to investigate the impact of polymorphisms in miRNA-binding sites (miR-binding SNPs) on the risk of GDM in Chinese Han pregnant women. We screened GDM susceptibility genes extensively and selected miR-binding SNPs using four bioinformatics software. TaqMan allelic discrimination assays were applied to miR-binding SNPs genotyping in 839 GDM patients and 900 controls. In total five potential miR-binding SNPs (SLC30A8 rs2466293, INSR rs1366600, INSR rs3745550, KCNJ11 rs5210 and KCNQ1 rs8234) were selected. Our results showed that SLC30A8 rs2466293 [OR 95% CI=1.455 (1.077, 1.966); P=0.014] and INSR rs1366600 [OR 95% CI=2.191 (1.077, 4.455); P=0.029] increased the risk of GDM after adjusting age in additive model. Furthermore, rs2466293 was found to significantly associate with higher levels of fasting plasma glucose (b dom=0.054, P dom=0.032), 2-h OGTT plasma glucose (b dom=0.069, P dom=0.007), lower fasting insulin concentrations (b rec=-0.082, P rec=0.003) and decreased HOMA-B (b rec=-0.067, P rec=0.015). Additionally, the correlation between rs1366600 and 2-h OGTT plasma glucose (b dom=0.078, P dom=0.001) was observed. Two miR-binding SNPs SLC30A8 rs2466293 and INSR rs1366600 increased GDM susceptibility. Functional studies were required to confirm the underlying mechanism. Our study provided additional insights into the genetic pathogenesis of GDM.

CD36 Gene Expression Induced by Fish Oil in Abdominal Adipose Tissue of Rats with Metabolic Syndrome

CD36 Gene Expression Induced by Fish Oil in Abdominal Adipose Tissue of Rats with Metabolic Syndrome Introduction: CD36 is a ubiquitously expressed transmembrane glycoprotein primarily localized in tissues with high levels of fatty acid oxidation. According to its broad binding specificity and signal transduction capabilities, CD36 is thought to be involved in several physiological and pathological events related to metabolic syndrome, which underlies diabetes and cardiovascular diseases, major causes of morbidity and mortality in most of the world. Objective and Method: The aim of this study was to evaluate the effect of dietary fish oil (n-3 PUFAs) administration on adipose tissue CD36 mRNA expression levels in rats with metabolic syndrome induced by 30% sucrose administration in drinking water during 21 weeks. Results and Discussion: After dietary fish oil administration (6 weeks), lower blood pressure and serum concentrations of insulin, non-esterified fatty acids, triacylglycerols and HOMA-IR index were observed, in combination with increased expression levels of CD36 in adipose tissue which would result in enhanced fatty acids uptake, storage and oxidation and the consequent increase in insulin sensitivity. Conclusion: our results show that the overexpression of CD36 in adipocytes could be one of the mechanisms by which fish oil is beneficial to ameliorate metabolic syndrome, through the modulation of fatty acids metabolism.

Generation of thalamic neurons from mouse embryonic stem cells.

The thalamus is a diencephalic structure that plays crucial roles in relaying and modulating sensory and motor information to the neocortex. The thalamus develops in the dorsal part of the neural tube at the level of the caudal forebrain. However, the molecular mechanisms that are essential for thalamic differentiation are still unknown. Here, we have succeeded in generating thalamic neurons from mouse embryonic stem cells (mESCs) by modifying the default method that induces the most-anterior neural type in self-organizing culture. A low concentration of the caudalizing factor insulin and a MAPK/ERK kinase inhibitor enhanced the expression of the caudal forebrain markers Otx2 and Pax6. BMP7 promoted an increase in thalamic precursors such as Tcf7l2+/Gbx2+ and Tcf7l2+/Olig3+ cells. mESC thalamic precursors began to express the glutamate transporter vGlut2 and the axon-specific marker VGF, similar to mature projection neurons. The mESC thalamic neurons extended their axons to cortical layers in both organotypic culture and subcortical transplantation. Thus, we have identified the minimum elements sufficient for in vitro generation of thalamic neurons. These findings expand our knowledge of thalamic development.