Markers Of Insulin Sensitivity Research Articles

Plasma adiponectin levels and type 2 diabetes risk: a nested case-control study in a Chinese population and an updated meta-analysis

Results from previous prospective studies assessing the relation between adiponectin and type 2 diabetes (T2D) were not entirely consistent, and evidence in Chinese population is scarce. Moreover, the last meta-analysis did not examine the impact of metabolic variables on the adiponectin-T2D association. Therefore, we prospectively evaluated the adiponectin-T2D association among 571 T2D cases and 571 age-sex-matched controls nested within the Singapore Chinese Health Study (SCHS). Furthermore, we conducted an updated meta-analysis by searching prospective studies on Pubmed till September 2016. In the SCHS, the odds ratio of T2D, comparing the highest versus lowest tertile of adiponectin levels, was 0.30 (95% confidence interval: 0.17, 0.55) in the fully-adjusted model. The relation was stronger among heavier participants (body mass index ≥23 kg/m2) compared to their leaner counterparts (P for interaction = 0.041). In a meta-analysis of 34 prospective studies, the pooled relative risk was 0.53 (95% confidence interval: 0.47, 0.61) comparing the extreme tertiles of adiponectin with moderate heterogeneity (I2 = 48.7%, P = 0.001). The adiponectin-T2D association remained unchanged after adjusting for inflammation and dyslipidemia markers, but substantially attenuated with adjustment for insulin sensitivity and/or glycaemia markers. Overall evidence indicates that higher adiponectin levels are associated with decreased T2D risk in Chinese and other populations.

Gut Microbiota Interacts with Markers of Adipose Tissue Browning, Insulin Action and Plasma Acetate in Morbid Obesity.

To examine the potential relationship among gene expression markers of adipose tissue browning, gut microbiota, and insulin sensitivity in humans. Gut microbiota composition and gene markers of browning are analyzed in subcutaneous (SAT) and visceral (VAT) adipose tissue from morbidly obese subjects (n = 34). Plasma acetate is measured through 1 H NMR and insulin sensitivity using euglycemic hyperinsulinemic clamp. Subjects with insulin resistance show an increase in the relative abundance (RA) of the phyla Bacteroidetes and Proteobacteria while RA of Firmicutes is decreased. In all subjects, Firmicutes RA is negatively correlated with HbA1c and fasting triglycerides, whereas Proteobacteria RA was negatively correlated with insulin sensitivity. Firmicutes RA is positively associated with markers of brown adipocytes (PRDM16, UCP1, and DIO2) in SAT, but not in VAT. Multivariate regression analysis indicates that Firmicutes RA contributes significantly to SAT PRDM16, UCP1, and DIO2 mRNA variance after controlling for age, BMI, HbA1c , or insulin sensitivity. Interestingly, Firmicutes RA, specifically those bacteria belonging to the Ruminococcaceae family, is positively associated with plasma acetate levels, which are also linked to SAT PRDM16 mRNA and insulin sensitivity. Gut microbiota composition is linked to adipose tissue browning and insulin action in morbidly obese subjects, possibly through circulating acetate.

Comparison between euglycemic hyperinsulinemic clamp and surrogate indices of insulin sensitivity in children with growth hormone deficiency

ObjectiveData about the impact of growth hormone treatment (GHT) on insulin sensitivity in children are quite controversial, due to the different surrogate indices that have been used. DesignWe evaluated insulin sensitivity through the euglycemic hyperinsulinemic clamp, considered the gold standard technique, in 23 children affected by growth hormone deficiency (GHD) at baseline and after 12months of GHT and in 12 controls with short stature at baseline, and we compared the clamp-derived index (M-value) with the most commonly used surrogate index of insulin sensitivity, as ISI Matsuda, and with circulating plasma markers of insulin sensitivity, as adiponectin and resistin levels. ResultsAt baseline, no significant difference in all metabolic parameters between GHD children and control subjects was found. After 12months of GHT, GHD children showed a significant increase in fasting insulin (p<0.001) and resistin (p=0.028) and a decrease in ISI Matsuda (p<0.001) and M-value (p<0.001), without significant change in fasting glucose, HbA1c and adiponectin. In GHD children, M-value showed a significant but weak correlation with ISI Matsuda (rho 0.418, p=0.047) at baseline, while no correlation with other parameters was found. After 12months of GHT, M-value did not show any significant correlation with any other metabolic parameter analyzed. ConclusionsThis study highlights the limit of the evaluation of insulin sensitivity performed through surrogate indices or circulating markers, which may lead to controversial data and do not correlate with the gold standard technique to evaluate insulin sensitivity.

Associations of Physical Activity Intensities with Markers of Insulin Sensitivity.

Objectively measured physical activity (PA) intensity has traditionally been categorized as light, moderate, and vigorous using laboratory calibrated cut points. The relative contribution of time spent across a spectrum of accelerometer-determined intensities on health outcomes is less clear. This study aimed to assess the relationship between objectively measured PA intensity on a continuous scale and markers of insulin sensitivity (IS). Participants at high risk of type 2 diabetes mellitus were recruited from primary care (Leicestershire, UK). PA was measured using an ActiGraph accelerometer. Fasting and postchallenge glucose and insulin levels were assessed using an oral glucose tolerance test. IS was calculated using the Matsuda-IS and the HOMA-IS indices. Log-linear regression modeling was used to assess the relationship between PA intensity, in increments of 500 counts per minute, with markers of IS. Models were controlled for known confounders. Complete data were available for 569 participants. PA intensity was favorably associated with fasting and 2 h of insulin and IS, with the association increasing in magnitude with each increment of 500 counts per minute. Differences in HOMA-IS per 10 min of PA ranged from 12.4% (95% confidence interval = 3.7%-21.8%) to 26.8% (11.0%-44.7%) within the moderate-intensity PA category (from 2000-2499 to 3500-3999 counts per minute). For Matsuda-IS, these differences were 22.0% (10.3%-34.9%) and 34.7% (13.9%-59.3%), respectively. Significant associations for fasting insulin were no longer observed after controlling for body mass index, whereas differences associated with 2-h insulin and IS were attenuated but still significant. PA of any intensity may positively influence glucose regulation and insulin sensitivity in individuals at high risk of type 2 diabetes mellitus in a dose-response manner. Further research is required to identify the intensity thresholds at which clinically relevant benefits occur in this population.

Assessment of disturbed glucose metabolism and surrogate measures of insulin sensitivity in obese children and adolescents

BackgroundWith the rising prevalence of obesity and type 2 diabetes (T2D) in obese children, it is becoming imperative to detect disturbed glucose metabolism as early as possible in order to prevent T2D development.Subjects/MethodsCross-sectional study of 92 obese children (median age 11.7 years, 51% female) and 7 lean children (median age 11.4 years, 57% female) who underwent an oral glucose tolerance test (OGTT) in a tertiary pediatric care center. Glucose tolerance was assessed and different indices for β-cell function, insulin sensitivity and insulin secretion were calculated.ResultsNineteen obese children were identified with prediabetes (PD, 12 impaired glucose tolerance, 4 increased fasting glucose and 3 combined). Compared with the 73 obese children with normal glucose tolerance (nGT), subjects with PD had higher insulin resistance, but lower insulin sensitivity and β-cell function, although their glycated hemoglobin (HbA1c) levels were comparable. The Whole Body Insulin Sensitivity Index (WBISI) and β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) strongly correlated with the OGTT glucose area under the curve 0–120 min (r = 0.392, p < 0.0002; r = 0.547, p < 0.0001, respectively). When testing the relation between early insulin response during OGTT by insulinogenic index and insulin sensitivity assessed by WBISI, a hyperbolic relationship between insulin secretion and insulin sensitivity was found. The calculated disposition index was lower in subjects with PD vs. nGT (median 459 vs. 792, p = 0.004). We identified the OGTT 30-min/120-min insulin ratio as a simple marker, which is significantly lower in obese children with vs. without PD (median 0.87 vs. 1.29, p = 0.021) and which has a better sensitivity and specificity for detecting PD than HbA1c among obese children.ConclusionsChildren with identified PD had changes of several markers for β-cell function, insulin sensitivity and resistance before changes in HbA1c occurred. The lower disposition index indicates that these children have already inadequate β-cell compensation for the degree of insulin resistance.

Adiponectin levels may help assess the clinical repercussions of obesity irrespective of body mass index.

Adiponectin is the major product of adipose tissue. The aim of this study was to associate adiponectin levels with adipose tissue and metabolic indices. Plasma samples of 274 non-diabetic volunteers were collected to evaluate for adiponectin, inflammatory markers, insulin and lipid parameters. Body fat composition was measured by DEXA. As expected, adiponectin levels correlated with body mass index (BMI) and gender but a wide scattering was evident. When the population was divided into two groups per median levels of adiponectin (11.94 μg/mL), adiponectin was correlated with various metabolic indices. Persons displaying relatively high adiponectin levels [17.7(CI:14.8-21.0]μg/mL; MEDIAN (25%-75%)] exhibited lower levels of inflammatory markers (hs-CRP, plasminogen, erythrocyte sedimentation rate), circulating lipids and markers of insulin sensitivity (fasting blood glucose, insulin, HbA1c and HOMA-IR) compared to those individuals displaying low-adiponectin levels [8.9(CI:6.9-10.6)μg/mL]. The percentage of high-adiponectin individuals decreased from 69.6% in the normal-BMI group to 36.5% in the obese-BMI group. Average adiponectin levels in the high-adiponectin normal-BMI group were significantly higher compared to the high-adiponectin obese-BMI group (p=0.014). Regarding body fat, only the individuals with high adiponectin levels in either the combined population or within the obese-BMI group displayed low levels of waist-to-hip ratio. Interestingly, high-adiponectin levels within the obese-BMI group were associated with higher legs fat than trunk fat as compared to the low-adiponectin obese-BMI group. Our data suggest that the distribution of adiponectin above or below a cutoff level may offer additional clinical information over and above that of BMI grouping regarding inflammatory profile, insulin-sensitivity and adiposity.

Increased Free Testosterone Levels in Men with Uncontrolled Type 2 Diabetes Five Years After Randomization to Bariatric Surgery.

Hypogonadism frequently occurs in male patients with type 2 diabetes (T2DM) and is linked to insulin resistance and inflammation. Testosterone levels rise acutely in obese patients following bariatric surgery, though long-term changes have not been investigated in a randomized controlled trial. This study evaluated obese men with T2DM randomized to either bariatric surgery or medical therapy. Testosterone, gonadotropins, body composition, insulin sensitivity, and inflammatory markers were evaluated in 32 patients at baseline and at 5years. Surgical patients had 47.4% increase in free testosterone compared to medical therapy patients who had 2.2% decrease (P=0.013). Increase in free testosterone correlated with reduction in body weight, high-sensitivity C-reactive protein (hsCRP), and leptin levels. Prolonged improvements in testosterone levels after bariatric surgery in T2DM are found to be related to reduction in body weight and adipogenic inflammation.

“2-(4-Fluorobenzamido)-4-methylthiazole-5-carboxylic acid” a novel thiazole compound, ameliorates insulin sensitivity and hyperlipidaemia in streptozotocin-induced diabetic rats: Plausible role of inflammatory and oxidative stress markers

Emerging evidence suggests that thiazole compounds are of great interest due to their protective effect against DM. Protective effects of thiazole derivatives against hyperglycemia have been demonstrated in earlier in vitro and in vivo studies. Previously, anti-oxidant and free radical scavenging activities of 2-(4-Fluorobenzamido)-4-methylthiazole-5-carboxylicacid, a newly developed thiazole derivative (NDTD), have been well-documented. Current study investigated the pharmacological effect of NDTD on hyperglycaemia, insulin sensitivity, lipid profile, anti-inflammatory and oxidative stress markers in an animal model. T2DM was induced in neonatal rats using single i.p. injection of STZ at a dose of 100mg/kg. As a result, significant increase in serum glucose, insulin and HOMA-IR, lipid and pro-inflammatory cytokines levels were observed in STZ diabetic rats compared to normal control rats. Administration of NDTD for 4 weeks reversed the increased levels of above mentioned parameters to normal. Increased serum TG, TC, LDL-C and VLDL-C levels were significantly lowered, while reduction of serum HDL-C was alleviated after administration of NDTD. In addition, NDTD attenuated oxidative stress markers by increasing levels of GSH, CAT, SOD and lowering the level of MDA. Similarly, NDTD showed its pharmacological effects against hepatic and renal injury markers via restoring the alleviated level of ALT, AST, BUN, CRE and uric acid. In addition, all the results obtained from the biochemical estimations were supported by the histopathological examination. Pancreatic histopathological study demonstrated reduction in the size of pancreatic islets as well as the number of β-cells, per islet in the STZ control group and diabetic rats exposed to NDTD normalized the morphology of islets. Furthermore, histopathological study of liver suggests the protective role of NDTD against hepatic injury, as diabetic rats exposed with NDTD shows significantly reduction in inflammation and lesion as compared to STZ control rats. Our findings concluded, NDTD attenuated hyperglycaemia, glucose intolerance and insulin resistance through its anti-oxidant and anti-inflammatory effects. Thus, we suggest NDTD as potential therapeutic candidate for T2DM. In addition, the current study also investigated the beneficial effects of NDTD against inflammation, hyperlipidemia, renal and hepatic injury.

β-Cell Function Over Time in Adolescents With New Type 2 Diabetes and Obese Adolescents Without Diabetes

PurposeThe progression of β-cell function in newly diagnosed adolescents with type 2 diabetes mellitus (T2DM) is not well documented. We hypothesized that at the time of diagnosis with T2DM, adolescents would have impaired β-cell function as demonstrated by the disposition index (calculated as: insulin secretion adjusted for insulin sensitivity), and this would be followed by a rapid decline of function despite standard medical management. MethodsThirty-nine adolescents with recently diagnosed T2DM and 32 obese adolescent controls with normal glucose tolerance had acute insulin response to glucose, homeostatic model assessment of insulin resistance, and disposition index measured serially over 2 years. ResultsIn the adolescent T2DM group, fasting glucose increased over 2 years (p = .04), while DI was impaired at baseline and showed an overall relative decline of 25% per year. The mean Hemoglobin A1c remained below 8% (64 mmol/mol). Differences were observed between the T2DM and control adolescents in the way DI changed over time (p = .02). Conclusionsβ-cell function in adolescents with recently diagnosed T2DM was impaired with no improvement of β-cell function over the 2 years of study despite stable Hemoglobin A1c, body mass index markers of insulin sensitivity, and standard treatment of hyperglycemia.

Effects of Descending Stair Walking on Health and Fitness of Elderly Obese Women.

Eccentric exercise training produces positive fitness and health outcomes, but whether this is also the case for descending stair walking (DSW) is unknown. This study investigated the hypothesis that DSW would improve insulin sensitivity, lipid profiles and physical fitness better than ascending stair walking (ASW). Elderly (≥60 yr) obese women were placed to either DSW or ASW group (n = 15 per group). An elevator was used to eliminate ascending stairs for DSW, and descending stairs for ASW. Descending stair walking and ASW were performed twice a week for 12 wk by increasing the repetitions gradually. Overnight fasting blood samples were taken 3 d before the first training session and 4 d after the last training session, and analyzed for insulin sensitivity and lipid profile markers. Resting HR, systolic blood pressure, and diastolic blood pressure, bone mineral density, knee extensor maximal voluntary isometric contraction strength and several functional physical fitness measures were taken before and after the intervention. Average HR during DSW (88.6 ± 7.8 bpm) was lower (P < 0.05) than that of ASW (113.7 ± 10.9 bpm). Resting HR (-10%) and systolic blood pressure (-9%) decreased greater after DSW than ASW (-4% for both), and bone mineral density increased (6%) only for DSW (P < 0.05). Decreases in serum triacylglycerols, total and low-density lipoprotein cholesterols, glucose, insulin, homeostasis model assessment and whole blood glycosylated hemoglobin, and increases in high-density lipoprotein cholesterols were greater (P < 0.05) after DSW than ASW. Maximal voluntary isometric contraction strength increased greater for DSW (34%) than ASW (15%), and many of functional physical fitness measures showed greater (P < 0.05) improvement for DSW than ASW. These results supported the hypothesis and suggest that DSW is an effective exercise intervention for elderly obese women to improve their health and fitness.

Beneficial metabolic effects of dietary epigallocatechin gallate alone and in combination with exendin-4 in high fat diabetic mice

ObjectiveSignificant attempts are being made to generate multifunctional, hybrid or peptide combinations as novel therapeutic strategies for type 2 diabetes, however this presents key challenges including design and pharmaceutical development. In this study, we evaluated metabolic properties of oral nutritional supplement epigallocatechin gallate (EGCG) in combination with GLP-1 agonist exendin-4 in a mouse model of dietary-induced diabetes and obesity. MethodsEGCG, exendin-4 or combination of both were administered twice-daily over 28 days to high fat (HF) mice on background of low-dose streptozotocin. Energy intake, body weight, fat mass, glucose tolerance, insulin sensitivity, lipid profile, biochemical and hormone markers, and islet histology were examined. ResultsAll treatment groups exhibited significantly reduced body weight, fat mass, circulating glucose and insulin concentrations, and HbA1c levels which were independent of changes in energy intake. Similarly, there was marked improvement in glycaemic control, glucose-stimulated insulin release, insulin sensitivity, total cholesterol and triglycerides, with most prominent effects observed following combination therapy. Circulating corticosterone concentrations and 11beta-hydroxysteroid dehydrogenase type1 (11β-HSD1) staining (in pancreas) were beneficially decreased without changes in circulating interleukin 6 (IL-6), alanine transaminase (ALT) and glutathione reductase. Combination therapy resulted in increased islet area and number, beta cell area, and pancreatic insulin content. Generally, metabolic effects were much more pronounced in mice which received combination therapy. ConclusionsEGCG alone and particularly in combination with exendin-4 exerts positive metabolic properties in HF mice. EGCG may be useful dietary adjunct alongside GLP-1 mimetics in treatment of diabetes and related disorders.

Adipose tissue and liver.

Adipose tissue and liver are central tissues in whole body energy metabolism. Their composition, structure, and function can be noninvasively imaged using a variety of measurement techniques that provide a safe alternative to an invasive biopsy. Imaging of adipose tissue is focused on quantitating the distribution of adipose tissue in subcutaneous and intra-abdominal (visceral) adipose tissue depots. Also, detailed subdivisions of adipose tissue can be distinguished with modern imaging techniques. Adipose tissue (or adipocyte) accumulation or infiltration of other organs can also be imaged, with intramuscular adipose tissue a common example. Although liver fat content is now accurately imaged using standard magnetic resonance imaging (MRI) techniques, inflammation and fibrosis are more difficult to determine noninvasively. Liver imaging efforts are therefore concerted on developing accurate imaging markers of liver fibrosis and inflammatory status. Magnetic resonance elastography (MRE) is presently the most reliable imaging technique for measuring liver fibrosis but requires an external device for introduction of shear waves to the liver. Methods using multiparametric diffusion, perfusion, relaxometry, and hepatocyte-specific MRI contrast agents may prove to be more easily implemented by clinicians, provided they reach similar accuracy as MRE. Adipose tissue imaging is experiencing a revolution with renewed interest in characterizing and identifying distinct adipose depots, among them brown adipose tissue. Magnetic resonance spectroscopy provides an interesting yet underutilized way of imaging adipose tissue metabolism through its fatty acid composition. Further studies may shed light on the role of fatty acid composition in different depots and why saturated fat in subcutaneous adipose tissue is a marker of high insulin sensitivity.

Increased Adipose and Muscle Insulin Sensitivity Without Changes in Serum Adiponectin in Young Female Collegiate Athletes.

Background: Effects of endurance training on adipose insulin sensitivity in association with body composition, circulating adipokines, and markers of inflammation have been studied less in young Asian subjects.Methods: Adipose insulin sensitivity/resistance was compared between 170 female Japanese collegiate athletes and 311 nonathletes (18–24 years), who underwent measurements of serum adipokines, markers of insulin sensitivity, inflammation, and dual-energy X-ray absorptiometry. Two separate subsamples of two groups of women underwent either a 75-gram oral glucose tolerance test or a standardized meal test, but not both.Results: As compared with nonathletes, athletes, characterized by higher skeletal muscle mass and lower percentage of body fat (both P < 0.001), had lower adipose insulin resistance (IR) (a product of fasting insulin and nonesterified fatty acid (NEFA) and lower leptin/adiponectin ratio (both P < 0.001). Although athletes had lower postmeal/postglucose insulinemia (P = 0.009 and 0.01, respectively), the two groups did not differ in postmeal percentage NEFA suppression and postmeal/postglucose glycemia, suggesting increased insulin sensitivity in adipose tissue and skeletal muscle, respectively. Serum leptin (P < 0.001) and tumor necrosis factor-α (P = 0.01) were lower in athletes, whereas adiponectin and homeostasis model assessment IR did not differ.Conclusions: Endurance training was associated with increased insulin sensitivity in adipose tissue as well as skeletal muscle without changes in circulating adiponectin even in young, normal-weight Japanese women.

Rifaximin in non-alcoholic steatohepatitis: An open-label pilot study.

Gut microbial dysbiosis is implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH). We investigated downstream effects of gut microbiota modulation on markers of hepatic inflammation, steatosis, and hepatic and peripheral insulin sensitivity in patients with NASH using rifaximin therapy. Patients with biopsy-proven NASH and elevated aminotransferase values were included in this open-label pilot study, all receiving 6weeks rifaximin 400mg twice daily, followed by a 6-week observation period. The primary endpoint was change in alanine aminotransferase (ALT) after 6weeks of rifaximin. Secondary endpoints were change in hepatic lipid content and insulin sensitivity measured with a hyperinsulinemic-euglycemic clamp. Fifteen patients (13 men and 2 women) with a median (range) age of 46 (32-63)years were included. Seven had diabetes on oral hypoglycemic medications and 8 had no diabetes. After 6weeks of therapy, no differences were seen in ALT (55 [33-191] vs. 63 [41-218]IU/L, P = 0.41), peripheral glucose uptake (28.9 [19.4-48.3] to 25.5 [17.7-47.9]μmol/kg/min, P = 0.30), hepatic insulin sensitivity (35.2 [15.3-51.7]% vs. 30.0 [10.8-50.5]%, P = 0.47), or hepatic lipid content (21.6 [2.2-46.2]% vs. 24.8 [1.7-59.3]%, P = 0.59) before and after rifaximin treatment. After 12weeks from baseline, serum ALT increased to 83 (30-217)IU/L, P = 0.02. There was a significant increase in the homeostasis model assessment-estimated insulin resistance index (P = 0.05). The urinary metabolic profile indicated a significant reduction in urinary hippurate with treatment, which reverted to baseline after cessation of rifaximin, although there was no consistent difference in relative abundance of fecal microbiota with treatment. These data do not indicate a beneficial effect of rifaximin in patients with NASH.

The effects of 100% wild blueberry (Vaccinium angustifolium) juice consumption on cardiometablic biomarkers: a randomized, placebo-controlled, crossover trial in adults with increased risk for type 2 diabetes

BackgroundWild blueberries have a high content of polyphenols, but there is limited data evaluating their health benefits in adults at risk for type 2 diabetes. The objective of the study was to investigate whether consumption of 100% wild blueberry juice improves cardiometabolic biomarkers associated with type 2 diabetes risk.MethodsA single-blind, randomized, placebo-controlled, crossover design trial was conducted in which adults (women, n = 19, ages 39–64 y) at risk for type 2 diabetes consumed 240 mL of wild blueberry juice or a placebo beverage as part of their free-living diet for 7 days. Blood was collected to determine various biomarkers such as fasting plasma glucose, fasting serum insulin, surrogate markers of insulin sensitivity, triglycerides, inflammation (interleukin-6, interleukin-10, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, serum amyloid A), adhesion molecules (soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1), oxidative stress (LDL-oxidation, total 8-isoprostanes), and nitric oxide. Endothelial function and blood pressure were also assessed.ResultsWild blueberry juice consumption for 7 days produced no significant changes in glucose, insulin, insulin sensitivity, triglycerides, inflammatory markers, adhesion molecules, oxidative stress, endothelial function or blood pressure. However, wild blueberry juice consumption showed a trend for lowering systolic blood pressure: 120.8 ± 2.2 mmHg in the placebo group vs 116.0 ± 2.2 mmHg in the blueberry juice group (P = 0.088). Serum concentrations of nitrates and nitrites, an index of nitric oxide production, increased from 2.9 ± 0.4 μM after placebo drink to 4.1 ± 0.4 μM after drinking wild blueberry juice (P = 0.039).ConclusionsShort-term consumption of wild blueberry juice may promote cardioprotective effects, by improving systolic blood pressure, possibly through nitric oxide production, in adults at risk for type 2 diabetes. This outcome warrants longer-term human studies of blueberries, including defined amounts of either the whole fruit or juice, to clarify whether polyphenol-rich foods can be efficacious for improving cardiometabolic biomarkers in adults at risk for type 2 diabetes.Trial registrationNCT02139878, clinicaltrials.gov; date of registration: May 4, 2014.

0071 ROLE OF SLEEP RESTRICTION IN ADIPOCYTE INSULIN SENSITIVITY DURING AN INTRAVENOUS GLUCOSE TOLERANCE TEST IN HEALTHY ADULT MEN

Sleep restriction, or chronic partial sleep loss, increases obesity and diabetes risk by disrupting glucose metabolism and reducing whole-body insulin sensitivity without a compensatory increase in insulin secretion. Healthy adipocytes suppress hormone sensitive lipase (HSL) activity in response to insulin, which severely limits non-esterified fatty acid (NEFA) release. Elevated overnight NEFA levels are correlated with the reduction in insulin sensitivity that occurs in sleep restriction. Additionally, subcutaneous adipose biopsies from sleep-restricted subjects have reduced pAKT, evidence that sleep restriction decreases insulin sensitivity in adipocytes. The objective of this pilot study was to extend previous findings of the effects of sleep restriction on plasma glucose to mechanistic shifts within adipocyte metabolism. Subjects (20–35 y/o) were enrolled in an 11-day in-lab protocol; light exposure, activity, temperature, and diet were carefully controlled. An intravenous glucose tolerance test (IVGTT) was performed at three time points: after three nights of baseline sleep (10 hrs/night), after five nights of sleep restriction (5 hrs/night), and after two nights of recovery sleep (10 hrs/night). NEFA were quantified (Wako Diagnostics) and parameters describing NEFA kinetics (i.e. rate of NEFA production, utilization, suppression threshold) in the Boston and Moate minimal model were calculated using WinSAAM Compartmental Modeling software. Five subjects completed the sleep restriction protocol; one did not complete IVGTT procedures for safety reasons. Preliminary results from four subjects show the fractional rate of NEFA utilization was increased by 0.024 [0.009, 0.039] min-1 in the restricted condition (p=0.008). Restriction also increased the modifier of the inhibitory effect of remote glucose on NEFA production by 4.3 fold [1.2, 15.9] from baseline (p=0.04). Sleep restriction induces symmetrical changes in both glucose and lipid markers of insulin sensitivity in vivo. Preliminary evidence indicates that NEFA rate of utilization is increased in response to sleep restriction. In the context of whole-body metabolism, this indicates a shift in Randle cycle fuel selection by metabolic tissues. Additionally, a greater concentration of glucose was required to initiate NEFA suppression, evidence that sleep restriction functionally impairs HSL activity. UL1TR000127 (Chang PI) T32GM108563 (to KMN; Korzick PI).

Strawberry and cranberry polyphenols improve insulin sensitivity in insulin-resistant, non-diabetic adults: a parallel, double-blind, controlled and randomised clinical trial.

Plant-derived foods rich in polyphenols are associated with several cardiometabolic health benefits, such as reduced postprandial hyperglycaemia. However, their impact on whole-body insulin sensitivity using the hyperinsulinaemic-euglycaemic clamp technique remains under-studied. We aimed to determine the effects of strawberry and cranberry polyphenols (SCP) on insulin sensitivity, glucose tolerance, insulin secretion, lipid profile, inflammation and oxidative stress markers in free-living insulin-resistant overweight or obese human subjects (n 41) in a parallel, double-blind, controlled and randomised clinical trial. The experimental group consumed an SCP beverage (333 mg SCP) daily for 6 weeks, whereas the Control group received a flavour-matched Control beverage that contained 0 mg SCP. At the beginning and at the end of the experimental period, insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, and glucose tolerance and insulin secretion by a 2-h oral glucose tolerance test (OGTT). Insulin sensitivity increased in the SCP group as compared with the Control group (+0·9 (sem 0·5)×10-3 v. -0·5 (sem 0·5)×10-3 mg/kg per min per pmol, respectively, P=0·03). Compared with the Control group, the SCP group had a lower first-phase insulin secretion response as measured by C-peptide levels during the first 30 min of the OGTT (P=0·002). No differences were detected between the two groups for lipids and markers of inflammation and oxidative stress. A 6-week dietary intervention with 333 mg of polyphenols from strawberries and cranberries improved insulin sensitivity in overweight and obese non-diabetic, insulin-resistant human subjects but was not effective in improving other cardiometabolic risk factors.

Effects of Renal Denervation on Insulin Sensitivity and Inflammatory Markers in Nondiabetic Patients with Treatment-Resistant Hypertension

Increased sympathetic activity is important in the pathogenesis of hypertension and insulin resistance. Afferent signaling from the kidneys elevates the central sympathetic drive. We investigated the effect of catheter-based renal sympathetic denervation (RDN) on glucose metabolism, inflammatory markers, and blood pressure in nondiabetic patients with treatment-resistant hypertension. Eight subjects were included in an open-labelled study. Each patient was studied before and 6 months after RDN. Endogenous glucose production was assessed by a 3-3H glucose tracer, insulin sensitivity was examined by hyperinsulinemic euglycemic clamp, hormones and inflammatory markers were analyzed, and blood pressure was measured by office blood pressure readings and 24-hour ambulatory blood pressure monitoring. Insulin sensitivity (M-value) increased nonsignificantly from 2.68 ± 0.28 to 3.07 ± 0.41 (p = 0.12). A significant inverse correlation between the increase in M-value and BMI 6 months after RDN (p = 0.03) was found, suggesting beneficial effects on leaner subjects. Blood pressure decreased significantly, but there were no changes in hormones, inflammatory markers, or endogenous glucose production. Our results indicate that RDN may improve insulin sensitivity in some patients with treatment-resistant hypertension, albeit confirmation of these indications of beneficial effects on leaner subjects awaits the outcome of larger randomized controlled studies.

Vitamin D supplementation, the metabolic syndrome and oxidative stress in obese children.

Previous studies suggest that vitamin D may play a role in cardiovascular and metabolic health. Oxidative stress has also been implicated in the development of cardiovascular disease. Evidence suggests that vitamin D deficiency may contribute to the occurrence of oxidative stress. This study aimed to determine whether treatment and correction of vitamin D deficiency in obese children led to changes in their metabolic profile, independent of changes in adiposity. In addition, we aimed to determine whether vitamin D deficiency and oxidative stress are causally related in obese children. In the retrospective arm, chart review identified 32 obese children who experienced normalization of vitamin D deficiency or insufficiency with vitamin D supplementation. We then correlated laboratory and anthropometric data with vitamin D levels. In the prospective arm of the study, urinary 8-isoprostane and hydrogen peroxide were measured before and after correction of vitamin D deficiency/insufficiency and correlated to vitamin D levels in seven patients. In our predominantly Hispanic population of obese children in an urban setting, we demonstrated a cause-effect relationship between vitamin D deficiency and oxidative stress. In contrast, we found no association between vitamin D status, adiposity, and markers of insulin sensitivity, nor any effect of vitamin D treatment on the same parameters. These discordant findings suggest a differential effect of vitamin D on cardiovascular risk factors such as oxidative stress and insulin resistance. To confirm these findings, further prospective studies with larger sample size and longer follow-up are warranted.

Phytochemical Pharmacokinetics and Bioactivity of Oat and Barley Flour: A Randomized Crossover Trial.

While dietary fiber plays an important role in the health benefits associated with whole grain consumption, other ingredients concentrated in the outer bran layer, including alkylresorcinols, lignans, phenolic acids, phytosterols, and tocols, may also contribute to these outcomes. To determine the acute bioavailability and pharmacokinetics of the major phytochemicals found in barley and oats, we conducted a randomized, three-way crossover trial in 13 healthy subjects, aged 40–70 years with a body mass index (BMI) of 27–35.9 kg/m2. After a two-day run-in period following a diet low in phytochemicals, subjects were randomized to receive muffins made with either 48 g whole oat flour, whole barley flour, or refined wheat flour plus cellulose (control), with a one-week washout period between each intervention. At the same time, an oral glucose tolerance test was administered. In addition to plasma phytochemical concentrations, glucose and insulin responses, biomarkers of antioxidant activity, lipid peroxidation, inflammation, and vascular remodeling were determined over a 24-h period. There was no significant effect on acute bioavailability or pharmacokinetics of major phytochemicals. Administered concurrently with a glucose bolus, the source of whole grains did not attenuate the post-prandial response of markers of glucoregulation and insulin sensitivity, inflammation, nor vascular remodeling compared to the refined grain control. No significant differences were observed in the bioavailability or postprandial effects between whole-oat and whole-barley compared to a refined wheat control when administered with a glucose challenge. These null results may be due, in part, to the inclusion criteria for the subjects, dose of the whole grains, and concurrent acute administration of the whole grains with the glucose bolus.