Metabolic Insulin Sensitivity Research Articles

Investigating The Effectiveness Of A Healthy Diet On Metabolic Flexibility And Insulin Sensitivity - A Challenge-Based Human Trial

Investigating The Effectiveness Of A Healthy Diet On Metabolic Flexibility And Insulin Sensitivity - A Challenge-Based Human Trial

Effect of Ellagic Ácid on the Components of Metabolic Syndrome, Insulin Sensitivity and Insulin Secretion

Effect of Ellagic Ácid on the Components of Metabolic Syndrome, Insulin Sensitivity and Insulin Secretion

1962-P: Comparison of the Effects of Three SGLT2 Inhibitors on Metabolic Parameters and Insulin Sensitivity in a Nondiabetic Rat Model of Metabolic Syndrome

Studies directly comparing metabolic efficacy of various sodium glucose cotransporter-2 inhibitors (SGLT2i) are scarce. To this end, we compared the effect of SGLT2i: Empagliflozin (EMP), Canagliflozin (CAN) and Dapagliflozin (DAP) on biometric, metabolic and hormonal parameters and insulin sensitivity in hereditary hypertriglyceridemic rats (hHTG) - a non-obese model of metabolic syndrome characterized by dyslipidemia, insulin resistance and increased blood pressure. Male rats, 4 months old, were fed standard diet (C) or standard diet enriched by EMP (10mg/kg b.w./day), CAN (100mg/kg b.w./day) or DAP (10mg/kg b.w./day) for 6 weeks. All SGLT2i induced glycosuria which was 8-fold higher in CAN and DAP as compared to EMP group (Mean±SD: EMP:53±6; CAN:416±4; DAP:376±32 mmol/l; P<0.001). CAN decreased body weight relative to C while EMP and DAP had no significant effect. Visceral fat weight decreased in CAN and DAP compared to C (P<0.01). Relative weight of kidneys (g/100g b.w.) was increased in all SGLT2i groups compared to C with a less pronounced effect of EMP relative to CAN and DAP (P<0.01). CAN decreased both fasting and postprandial glycemia relative to other groups. Postprandial triglyceride levels were decreased by all SGLT2i compared to C (EMP: -32%; P<0.01; CAN: -55%; DAP -48%, P<0.001). 14C-palmitic acid oxidation decreased in the myocardium of CAN and DAP compared to C, whereas no significant effect of EMP was noted. CAN and EMP administration reduced liver glycogen content compared to C (P<0.05). Leptin levels decreased in CAN (-79%) and DAP (-56%) compared to C. GLP-1 levels increased in CAN compared to other groups while C-peptide was lower in CAN vs. C group. In conclusion, our results suggest higher efficacy of CAN compared to DAP and EMP in improving insulin sensitivity and decreasing glucose levels in a non-obese model of metabolic syndrome. The differences could be related to higher SGLT1 inhibition activity of CAN. Disclosure J. Trnovska: None. M. Hüttl: None. I. Marková: None. O. Oliyarnyk: None. H. Malinska: None. D. Miklankova: None. H. Kratochvilova: None. P. Svoboda: None. A. Cinkajzlova: None. I. Lankova: None. M. Mraz: None. M. Haluzik: None. Funding MH CZ - DRO; Institute for Clinical and Experimental Medicine (IN00023001)

1840-P: Pioglitazone Increases Metabolic Insulin Clearance (MCRI) in IGT Subjects: The ACT NOW Study

Recent studies have documented that the MCRI plays a major role in determining the plasma insulin response to ingested glucose. We evaluated the long-term effect of pioglitazone (PIO) on MCRI in 441 IGT subjects (ACT NOW study) who were randomized to PIO (45 mg/day) or placebo and followed for an average of 2.4 years. OGTT was performed at baseline and study end. 50 placebo-treated subjects developed type 2 diabetes versus 15 PIO-treated subjects (p<0.005). Insulin secretion rate (ISR) was measured from deconvolution of plasma C-peptide curve. MCRI was measured as ISR/mean insulin conc during OGTT. Data were correlated with changes in liver enzymes and peripheral insulin sensitivity measured with the Matsuda index (MI). Results: PIO improved MI from to 3.9 ±1 to 7.5 ±3 (p<0.0001), glucose tolerance (mean glucose OGTT from 172±2to 148±1mg/dl, p<0.0001) and reduced ALT(from 30±1 to 24±1, p<0.0001). Fasting insulin secretion increased in the placebo group (420 ±14 to 558 ±21 pmol/min, p < 0.0001 vs. baseline) and did not change in the PIO group (411 ±14 to 446 ± 19; p <0.0001, PIO vs. placebo). During the OGTT (0- 120 min) ISR increased in both groups (PIO, 165 ±3 to 189 ± 5 nmol; placebo, 167 ±3 to 202 ±6; p < 0.0001 vs. baseline in both groups; p = NS, PIO vs. placebo).The MCRI increased in both groups but the increase was much greater in PIO (3.5 ± 0.2 to 6.0±0.2 ml/min; placebo, 3.5 ± 0.1 to 4.7±0.2; p < 0.0001 vs. baseline in both groups; p <0.0001, PIO vs. placebo). In the whole dataset the improvement in insulin clearance was associated with improvement in peripheral insulin sensitivity (r=0.62, p<0.0001), the reduction in mean plasma glucose concentration during OGTT (r=-0.31, p<0.0001) and decrease in ALT (r=-0.14, p<0.009). Conclusion: PIO treatment results in an increase in MCRI that is associated with improved hepatic function, glucose metabolism and peripheral insulin sensitivity. Disclosure A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. D. Tripathy: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.

Understanding Human Physiological Limitations and Societal Pressures in Favor of Overeating Helps to Avoid Obesity.

Fat gain in our United States (US) environment of over-abundant, convenient, and palatable food is associated with hypertension, cardiovascular disease, diabetes, and increased mortality. Fuller understanding of physiological and environmental challenges to healthy weight maintenance could help prevent these morbidities. Human physiological limitations that permit development of obesity include a predilection to overeat palatable diets, inability to directly detect energy eaten or expended, a large capacity for fat storage, and the difficulty of losing body fat. Innate defenses resisting fat loss include reduced resting metabolism, increased hunger, and high insulin sensitivity, promoting a regain of fat, glycogen, and lean mass. Environmental challenges include readily available and heavily advertised palatable foods, policies and practices that make them abundant, less-than-ideal recommendations regarding national dietary macronutrient intake, and a frequently sedentary lifestyle. After gaining excess fat, some metabolic burdens can be mitigated though thoughtful selection of nutrients. Reduced dietary salt helps lower hypertension, less dietary sugar lowers risk of cardiovascular disease and obesity, and reducing proportion of dietary carbohydrates lowers post-meal insulin secretion and insulin resistance. Food intake and exercise should also be considered thoughtfully, as exercise in a fasted state and before the meals raises glucose intolerance, while exercising shortly after eating lowers it. In summary, we cannot directly detect energy eaten or expended, we have a genetic predisposition to eat palatable diets even when not hungry, and we have a large capacity for fat storage and a difficult time permanently losing excess fat. Understanding this empowers individuals to avoid overeating and helps them avoid obesity.

A Novel Role of Growth Differentiation Factor 3 for the Regulation of Muscle Metabolism

Insulin resistance has become a major global health problem, and current insulin sensitization treatments have the unfortunate effect of also increasing adiposity. One solution to mitigate these side effects would be to selectively stimulate skeletal muscle metabolism to reduce fasting glucose levels and improve insulin sensitivity. Previous studies have described growth differentiation factor 3 (GDF3) as an adipokine, however our recent studies have identified GDF3 as a macrophage derived factor that stimulates myoblast fusion and promotes muscle regeneration. Thus, we hypothesize that GDF3 might also stimulate myocyte metabolism and skeletal muscle insulin sensitivity. We first assessed whether recombinant GDF3 treatment can stimulate glucose uptake in vitro. Differentiated C2C12 myotubes were treated with rGDF3 and [H3] 2-deoxy-D-glucose uptake was found to be increased upon GDF3 treatment. Next, we tested whether GDF3 could stimulate insulin sensitivity in vivo. GDF3 was adenovirally overexpressed in mice fed a high fat diet for 8 weeks and insulin sensitivity was assessed by insulin tolerance tests. GDF3 overexpression reduced fasting glucose levels and also demonstrated a tendency for improved insulin tolerance. Collectively, these data suggest that GDF3 could act as a potential insulin sensitizing agent and provide mechanistic insights into skeletal muscle glucose regulation. Disclosure T.T. Hays: None. A. Patsalos: None. D. Hammers: None. C. Huang: None. I. Restrepo: None. M. Hajian: None. J. Ayala: None. L. Nagy: None.

Genetic Nicotinamide N-Methyltransferase Deficiency Improves Insulin Sensitivity in DIO Mice

Nicotinamide N-methyltransferase (NNMT) is expressed in most tissues including muscle, adipose tissue, liver and digestive organs. Recent research suggests the involvement of NNMT in the pathogenesis of obesity, insulin resistance and related metabolic disease. Antisense oligonucleotide (ASO) knockdown in high-fat diet (HFD)-fed mice led to reduced weight gain, relative fat mass, plasma insulin levels and improved glucose tolerance. We tested the hypothesis, that genetic NNMT deletion protects mice on HFD and Western diet (WD) against obesity and explored the metabolic effects of NNMT. Using NNMT ASO treatment and a NNMT knockout mouse (NNMT-/-), we investigate the effects of NNMT deletion on energy metabolism, glucose homeostasis and the development of obesity. We also examined data from a human study concerning NNMT expression and 1-methylnicotinamide (MNA) levels regarding weight reduction. In WD-fed mice, NNMT ASO treatment improved acute glucose tolerance, reduced weight gain and fat mass increase and, consequently, lowered plasma insulin levels. NNMT-/- mice exhibited virtually no MNA but threefold higher nicotinamide levels. Whereas NNMT-/- male and female mice on normal chow revealed no metabolic phenotype, NNMT-/- males on HFD showed improved glucose infusion rates, nearly complete insulin-mediated suppression of endogenous glucose production and an enhanced glucose uptake during a hyperinsulinemic-euglycemic clamp. Furthermore, NNMT-/- females on WD showed reduced weight gain, less fat mass and lower plasma insulin levels compared to controls. While NNMT gene expression in human fat biopsies increased over weight loss, corresponding plasma MNA levels significantly declined after weight reduction, suggesting that other mechanisms rather than adipose NNMT expression modulate circulating MNA levels during weight reduction. In conclusion, we observed an improvement of basal metabolic parameters and insulin sensitivity in NNMT-deficient mouse models. Disclosure S. Brachs: Research Support; Self; Sanofi-Aventis Deutschland GmbH. J. Polack: None. M. Brachs: Research Support; Spouse/Partner; Sanofi. K. Jahn-Hofmann: None. R. Elvert: Employee; Self; Sanofi. A. Pfenninger: None. F. Bärenz: None. D. Margerie: Employee; Self; Sanofi-Aventis Deutschland GmbH. K. Mai: None. A. Kannt: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J. Spranger: Research Support; Self; Sanofi R&D.

Insulin Resistance, Hyperinsulinemia, and LH: Relative Roles in Peripubertal Obesity-Associated Hyperandrogenemia.

Peripubertal obesity is associated with variable hyperandrogenemia, but precise mechanisms remain unclear. To assess insulin resistance, hyperinsulinemia, and LH roles in peripubertal obesity-associated hyperandrogenemia. Cross-sectional analysis. Academic clinical research unit. Eleven obese (body mass index for age ≥95%) peripubertal girls. Blood samples were taken during a mixed-meal tolerance test (1900 to 2100), overnight (2100 to 0700), while fasting (0700 to 0900), and during an 80 mU/m2/min hyperinsulinemic-euglycemic clamp (0900 to 1100). The dependent variable was morning free testosterone level; independent variables were insulin sensitivity index (ISI), estimated 24-hour insulin, and estimated 24-hour LH levels. All participants demonstrated insulin resistance and hyperinsulinemia. ISI, but not estimated 24-hour insulin level, correlated positively with morning free testosterone level when correcting for estimated 24-hour LH level and Tanner stage (rs = 0.68, P = 0.046). The correlation between estimated 24-hour LH and free testosterone levels approached significance after adjusting for estimated 24-hour insulin level and Tanner stage (rs = 0.63, P = 0.067). Estimated 24-hour insulin level did not correlate with free testosterone level after adjusting for estimated 24-hour LH level and Tanner stage (rs = 0.47, P = 0.20). In insulin-resistant obese girls with hyperinsulinemia, free testosterone levels correlated positively with insulin sensitivity and, likely, circulating LH concentrations but not with circulating insulin levels. In the setting of relatively uniform hyperinsulinemia, variable steroidogenic-cell insulin sensitivity may correlate with metabolic insulin sensitivity and contribute to variable free testosterone concentrations.

Aldosterone Is Not Associated With Metabolic and Microvascular Insulin Sensitivity in Abdominally Obese Men.

Impaired insulin-mediated muscle microvascular recruitment (IMMR) may add to the development of insulin resistance and hypertension. Increased aldosterone levels have been linked to these obesity-related complications in severely to morbidly obese individuals and to impaired microvascular function in experimental studies. To investigate whether aldosterone levels are associated with IMMR, insulin sensitivity, and blood pressure in lean and moderately abdominally obese men, and to study the effect of weight loss. In 25 lean and 53 abdominally obese men, 24-hour blood pressure measurement was performed, and aldosterone levels were measured using ultra-performance liquid chromatography tandem mass spectrometry. Insulin sensitivity was assessed by determining whole-body glucose disposal during a hyperinsulinemic clamp. IMMR in forearm skeletal muscle was measured with contrast-enhanced ultrasonography. These assessments were repeated in the abdominally obese men following an 8-week weight loss or weight stable period. Sodium excretion and aldosterone levels were similar in lean and abdominally obese participants, but sodium excretion was inversely associated with aldosterone concentration only in the lean individuals [lean, β/100 mmol sodium excretion (adjusted for age and urinary potassium excretion) = -0.481 (95% confidence interval, -0.949 to -0.013); abdominally obese, β/100 mmol sodium excretion = -0.081 (95% confidence interval, -0.433 to 0.271); P for interaction = 0.02]. Aldosterone was not associated with IMMR, insulin sensitivity, or blood pressure and was unaffected by weight loss. In moderately abdominally obese men, the inverse relationship between sodium excretion and aldosterone concentration is less than that in lean men but does not translate into higher aldosterone levels. The absolute aldosterone level does not explain differences in microvascular and metabolic insulin sensitivity and blood pressure between lean and moderately abdominally obese men.

880 The effect of partial replacement of corn with a high-lipid, high-fiber byproduct pellet on hepatic indicators of metabolic efficiency and insulin sensitivity in beef steers throughout the finishing period

880 The effect of partial replacement of corn with a high-lipid, high-fiber byproduct pellet on hepatic indicators of metabolic efficiency and insulin sensitivity in beef steers throughout the finishing period

Docosahexaenoic acid enrichment in NAFLD is associated with improvements in hepatic metabolism and hepatic insulin sensitivity: a pilot study

Background/Objective:Treatment of subjects with non-alcoholic fatty liver disease (NAFLD) with omega-3 polyunsaturated fatty acids (FAs) suggests high levels of docosahexaenoic acid (DHA) tissue enrichment decrease liver fat content. We assessed whether changes in erythrocyte DHA enrichment (as a surrogate marker of changes in tissue enrichment) were associated with alterations in hepatic de novo lipogenesis (DNL), postprandial FA partitioning and hepatic and peripheral insulin sensitivity in a sub-study of the WELCOME trial (Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD (non-alcoholic fatty liver disease) with OMacor thErapy).Subjects/Methods:Sixteen participants were randomised to 4 g/day EPA+DHA (n=8) or placebo (n=8) for 15–18 months and underwent pre- and post-intervention measurements. Fasting and postprandial hepatic FA metabolism was assessed using metabolic substrates labelled with stable-isotope tracers (2H2O and [U13C]palmitate). Insulin sensitivity was measured by a stepped hyperinsulinaemic-euglycaemic clamp using deuterated glucose. Participants were stratified according to change in DHA erythrocyte enrichment (< or ⩾2% post intervention).Results:Nine participants were stratified to DHA⩾2% (eight randomised to EPA+DHA and one to placebo) and seven to the DHA<2% group (all placebo). Compared with individuals with erythrocyte <2% change in DHA abundance, those with ⩾2% enrichment had significant improvements in hepatic insulin sensitivity, reduced fasting and postprandial plasma triglyceride concentrations, decreased fasting hepatic DNL, as well as greater appearance of 13C from dietary fat into plasma 3-hydroxybutyrate (all P<0.05).Conclusions:The findings from our pilot study indicate that individuals who achieved a change in erythrocyte DHA enrichment ⩾2% show favourable changes in hepatic FA metabolism and insulin sensitivity, which may contribute to decreasing hepatic fat content.

Abstract P073: Chemerin Receptor Antagonism Improves Vascular Insulin Signaling in Diabetic Mice

Adipose tissue releases many adipokines, including chemerin, which produces its effects through activation of chemokine-like receptor 1 (ChemR23). Chemerin influences major aspects of the metabolic syndrome, including adipogenesis and insulin sensitivity in adipocytes and skeletal muscle cells. Considering that chemerin impairs vascular reactivity and that amongst its many actions, insulin also influences vascular function, we postulate that chemerin decreases insulin-induced vasodilatation, by reducing PI3K/Akt signaling, and impairs glucose uptake by vascular smooth muscle cells (VSMC). Mesenteric arteries, endothelial cells (EC) or VSMC from C57Bl6 mice were incubated with chemerin (0.5 ng/mL, 1 h) or vehicle (veh). Chemerin decreased insulin-induced relaxation (0.1 - 3000 ng/mL, pD2: chemerin: 94.5±0.1 vs. veh: 23.6±0,1), which was prevented by the ChemR23 antagonist CCX 832 (pD2: veh= 16.9±0.1; chem= 174.1±0.1, CCX+chem= 37.4±0.1) and a PI3K activator (YS-49) (pD2: veh= 23.0±0.1; chem= 108.5±0.1, YS-49+chem= 28.5±0.1). Chemerin also decreased PI3K (0.8±0.1 vs. veh 1.1±0.1), Akt (0.8±0.1 vs. veh 1.2±0.1) and AMPK [0.7±0.2 vs. veh 1.0 ±0.1] phosphorylation in VSMC. IRS1 and IRS2 gene expression was decreased in VSMC stimulated with chemerin. In addition, chemerin decreased insulin-stimulated NO production in EC through activation of ChemR23 and PI3K and inhibited insulin-stimulated glucose uptake by VSMC (counts per minute: 5668±729.0 vs. veh 9923±662.7), which was mediated by ChemR23, AMPK and PI3K. Importantly, ChemR23 antagonism in diabetic (db/db) mice partially reversed decreased insulin-induced vasodilatation (mesenteric resistance arteries; pD2: db/m: 6.1±1.0; db/db: 7.3±0.2; db/db+CCX832: 6.9±0.3). In conclusion, chemerin decreases vascular insulin responses by reducing PI3K/Akt and AMPK signaling. Moreover, chemerin/ChemR23 system plays a crucial role in impaired vascular insulin signaling in diabetes, suggesting its involvement in the pathogenesis of vascular insulin resistance. Our study may contribute to a better understanding of the role of chemerin in vascular insulin dysfunction in diabetes- and obesity-associated diseases. Financial Support: FAPESP, Brazil.

Abstract 1871: Circulating cis- and trans- palmitoleic acid in relation to prostate cancer-specific mortality among prostate cancer patients

Abstract Background: Palmitoleic acid (16:1n-7c), a lipokine, and its trans isomer (16:1n-7t), a fatty acid found in foods of ruminant origin, have been associated with metabolic regulation and insulin sensitivity, which have in turn been related to prostate cancer progression and survivorship. Objective: To investigate whether circulating cis- and trans-palmitoleate, measured before and after prostate cancer diagnosis, are related to prostate cancer-specific mortality among men diagnosed with non-metastatic prostate cancer. Methods: We employed a prospective study using pre-diagnostic whole blood samples collected in 1982 in 518 men who were later diagnosed with prostate cancer and followed for mortality. Proportional hazards regression was used to estimate relative risk (RR) and 95% confidence interval (CI) of prostate cancer-specific mortality across quartiles of pre-diagnostic palmitoleate concentrations. The multivariable model was adjusted for age at diagnosis, BMI, smoking status, clinical characteristics and time interval between blood drawn and prostate cancer diagnosis. Using a nested case-control design, we also assayed 148 post-diagnostic red blood cell samples collected in 1997 among 74 patients who subsequently died of the disease and 74 survivors, matched with age at diagnosis and risk scores. Conditional logistic regression was used to estimate the RR (95%CI) of prostate cancer-specific mortality across tertiles of post-diagnostic palmitoleate levels after adjusting for BMI and smoking status. trans- and cis-palmitoleic acid concentrations were measured by gas chromatography. Results: Pre-diagnostic whole blood trans-palmitoleic acid and post-diagnostic red blood cell trans-palmitoleic acid levels were associated with lower prostate cancer-specific mortality. The adjusted RR (95%CI) of prostate cancer-specific mortality comparing top to bottom quartiles of pre-diagnostic 16:1n-7t was 0.35 (0.16-0.79; p-trend = 0.03). The adjusted RR (95%CI) comparing top to bottom tertiles of post-diagnostic 16:1n-7t levels was 0.26 (0.08-0.84; p-trend = 0.02). In contrast, cis-palmitoleic acid levels measured before and after prostate cancer diagnosis were unrelated to disease-specific mortality. The pre-diagnostic cis-isomer, however, was significantly correlated with a lower level of adiponectin and higher levels of C-peptide, insulin-like growth factor binding protein 3, and pro-insulin. Conclusions: Pre- and post- diagnostic circulating trans-palmitoleic acid, but not cis-palmitoleic acid, was associated with lower prostate cancer-specific mortality among prostate cancer patients. Citation Format: Meng Yang, Stacey A. Kenfield, Hannia Campos, Howard D. Sesso, Jing Ma, Meir J. Stampfer, Jorge E. Chavarro. Circulating cis- and trans- palmitoleic acid in relation to prostate cancer-specific mortality among prostate cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1871. doi:10.1158/1538-7445.AM2015-1871

Globular adiponectin ameliorates metabolic insulin resistance via AMPK‐mediated restoration of microvascular insulin responses

Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague-Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ∼60%. However, supplementing gAd fully rescued insulin's microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats.

Insulin-induced changes in skeletal muscle microvascular perfusion are dependent upon perivascular adipose tissue in women.

Aims/hypothesisObesity increases the risk of cardiovascular disease and type 2 diabetes, partly through reduced insulin-induced microvascular vasodilation, which causes impairment of glucose delivery and uptake. We studied whether perivascular adipose tissue (PVAT) controls insulin-induced vasodilation in human muscle, and whether altered properties of PVAT relate to reduced insulin-induced vasodilation in obesity.MethodsInsulin-induced microvascular recruitment was measured using contrast enhanced ultrasound (CEU), before and during a hyperinsulinaemic–euglycaemic clamp in 15 lean and 18 obese healthy women (18–55 years). Surgical skeletal muscle biopsies were taken on a separate day to study perivascular adipocyte size in histological slices, as well as to study ex vivo insulin-induced vasoreactivity in microvessels in the absence and presence of PVAT in the pressure myograph. Statistical mediation of the relation between BMI and microvascular recruitment by PVAT was studied in a mediation model.ResultsObese women showed impaired insulin-induced microvascular recruitment and lower metabolic insulin sensitivity compared with lean women. Microvascular recruitment was a mediator in the association between obesity and insulin sensitivity. Perivascular adipocyte size, determined in skeletal muscle biopsies, was larger in obese than in lean women, and statistically explained the difference in microvascular recruitment between obese and lean women. PVAT from lean women enhanced insulin-induced vasodilation in isolated skeletal muscle resistance arteries, while PVAT from obese women revealed insulin-induced vasoconstriction.Conclusions/interpretationPVAT from lean women enhances insulin-induced vasodilation and microvascular recruitment whereas PVAT from obese women does not. PVAT adipocyte size partly explains the difference in insulin-induced microvascular recruitment between lean and obese women.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3606-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Metabolic flexibility, insulin sensitivity and genetic variations in newly diagnosed patients with type 2 diabetes

Metabolic flexibility, insulin sensitivity and genetic variations in newly diagnosed patients with type 2 diabetes

The metabolic syndrome and insulin sensitivity in lean and obese children and adolescents

The metabolic syndrome and insulin sensitivity in lean and obese children and adolescents

Effect of magnesium supplementation on metabolic control and insulin sensitivity in type 2 diabetic patients

Effect of magnesium supplementation on metabolic control and insulin sensitivity in type 2 diabetic patients

Effect of resveratrol administration on metabolic syndrome, insulin sensitivity and insulin secretion

Effect of resveratrol administration on metabolic syndrome, insulin sensitivity and insulin secretion

Blueberry Tea Enhances Insulin Sensitivity by Augmenting Insulin-Mediated Metabolic and Microvascular Responses in Skeletal Muscle of High Fat Fed Rats

Background: The aim of the current study was to determine whether a unique blueberry tea (BT) ameliorates insulin resistance by improving metabolic and vascular actions of insulin in skeletal muscle. Methods: Male Sprague Dawley rats were fed normal (4.8% fat wt/wt, ND) or high (22.6% fat wt/wt, HFD) fat diets for 4 weeks. A second group of HFD rats was provided BT (4.0% wt/vol) in the drinking water during the final 2 weeks. Animals were subjected to an intraperi toneal glucose tolerance test (1g glucose/kg IPGTT) or euglycaemic hyperinsulinaemic clamp (10mU/min/kg x 2hr). Results: HFD rats displayed significantly (p<0.05) higher plasma glucose levels at 15 and 30 mins following the IPGTT compared to ND, and this increase was completely abolished by BT treatment. Glucose infusion rate, muscle glucose uptake, and microvascular perfusion in muscle were significantly (p<0.05) impaired during clamps in HFD and all markedly improved (p<0.05) with BT treatment. Insulin-mediated changes in femoral artery blood flow were unaffected by HFD or BT treatment. Conclusions: We conclude that BT treatment ameliorates glucose intolerance and insulin resistance by restoring both metabolic and microvascular insulin sensitivity in high fat-fed rats. Therefore, BT consumption may have therapeutic implications for insulin resistance and type 2 diabetes.