Body Insulin Sensitivity Research Articles

Corrigendum to: The effects of a 12-week jump rope exercise program on body composition, insulin sensitivity, and academic self-efficacy in obese adolescent girls.

Background Childhood obesity is strongly associated with the development of cardiovascular disease (CVD). Exercise interventions have been used for obese children and adolescents to prevent the manifestation of CVD risks, such as hypertension and insulin resistance (IR). Additionally, obesity has been shown to be linked to low self-efficacy in adolescents, which has been shown to negatively impact academic performance. Therefore, the purpose of this study was to examine the effects of a 12-week jump rope exercise program on body composition, CVD risk factors, and academic self-efficacy (ASE) in obese adolescent girls with prehypertension. Methods Adolescent girls with prehypertension and obesity (n = 48, age 14-16 years) were randomly assigned to either the jump rope exercise group (EX, n = 24) or the control group (CON, n = 24). Body composition, blood pressure (BP), blood glucose, insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) (marker of IR), and ASE were assessed before and after 12 weeks of exercise training or control. Results There were significant group × time interactions following the 12-week exercise program for body fat percent, waist circumference (WC), systolic blood pressure (SBP), blood glucose, insulin levels, and HOMA-IR, which were all significantly reduced (p < 0.05). A significant improvement (p <0.05) was observed in task difficulty preference (TDP) and self-regulatory efficacy (SRE) following exercise training. Additionally, ASE was strongly correlated (r = -0.58) with body composition. Conclusions This study provides evidence that jump rope exercise intervention can be a useful therapeutic treatment to improve CVD risk factors and ASE in obese adolescent girls with prehypertension.

Effects of metformin on metabolism of white and brown adipose tissue in obese C57BL/6J mice

BackgroundTo investigate effects of metformin on the regulation of proteins of white adipose tissue (WAT) and brown adipose tissue (BAT) in obesity and explore the underlying mechanisms on energy metabolism.MethodsC57BL/6J mice were fed with normal diet (ND, n = 6) or high-fat diet (HFD, n = 12) for 22 weeks. HFD-induced obese mice were treated with metformin (MET, n = 6). After treatment for 8 weeks, oral glucose tolerance test (OGTT) and hyperinsulinemic–euglycemic clamp were performed to evaluate the improvement of glucose tolerance and insulin sensitivity. Protein expressions of WAT and BAT in mice among ND, HFD, and MET group were identified and quantified with isobaric tag for relative and absolute quantification (iTRAQ) coupled with 2D LC–MS/MS. The results were analyzed by MASCOT, Scaffold and IPA.ResultsThe glucose infusion rate in MET group was increased significantly compared with HFD group. We identified 4388 and 3486 proteins in WAT and BAT, respectively. As compared MET to HFD, differential expressed proteins in WAT and BAT were mainly assigned to the pathways of EIF2 signaling and mitochondrial dysfunction, respectively. In the pathways, CPT1a in WAT, CPT1b and CPT2 in BAT were down-regulated by metformin significantly.ConclusionsMetformin improved the body weight and insulin sensitivity of obese mice. Meanwhile, metformin might ameliorate endoplasmic reticulum stress in WAT, and affect fatty acid metabolism in WAT and BAT. CPT1 might be a potential target of metformin in WAT and BAT.

The effect of pregnancy on nitrogen retention, maternal insulin sensitivity, and mRNA abundance of genes involved in energy and amino acid metabolism in gilts.

Twenty-one of each pregnant (P) and nonserviced, nonpregnant (NP) sister-pairs of gilts were selected to investigate the effect of pregnancy on protein deposition (Pd; whole body and maternal), insulin sensitivity, and mRNA abundance of genes involved in energy and AA metabolism. Between breeding (study day 0) and day 111, P and NP gilts received 2.16 kg of the experimental diet (3.34 Mcal ME/kg, 17.6% crude protein, 0.78% standardized ileal digestible lysine) that was formulated to meet the estimated ME requirements of pregnant gilts (and meet or exceed AA requirements). Nitrogen balances were conducted on day 63 and 102 ± 0.2 of the study during 4-d periods. Blood samples were collected on day 43, 56, 71, 85, 98, and 108 ± 0.3 of the study to determine plasma concentrations of fasted IGF-1, estradiol (E2), and estrone sulfate (E1S). Frequently sampled intravenous glucose tolerance tests (FSIGTT) were conducted on day 75 ± 0.7 in 6 P and 5 NP gilts and on day 107 ± 0.4 in 17 P and 17 NP gilts and the MINMOD approach was applied to evaluate whole body insulin sensitivity and pancreatic responsiveness. Longissimus muscle (LM) and s.c. adipose tissue (AD) samples were excised from 12 P and 12 NP gilts at day 111 ± 0.4 of the study after euthanasia to determine mRNA abundance of key genes. Whole body Pd was greater (P < 0.001) at day 102 and maternal Pd was lower (P < 0.002) at day 63 and 102 for P compared to NP gilts. Plasma concentrations of E1S and E2 increased (P < 0.05) with study day for P gilts and remained constant for NP gilts, which coincided with reduced plasma concentrations of IGF-1 and increased estrogen receptor alpha (ESR1) mRNA abundance in LM of P gilts. Glucose effectiveness was not different between P and NP gilts, but whole body insulin sensitivity was lower (P = 0.004) in P compared to NP gilts on day 75 and 107, which corresponded with reduced mRNA abundances of SLC2A4, HK2, SREBF1, and FASN, and increased abundances of PDK4 and PPARGC1A in LM and AD. When fed identically, P gilts had greater whole body Pd at day 102, which reflects Pd in the pregnancy-associated tissues (at the expense of maternal Pd), likely driven by estrogen-stimulated insulin resistance in peripheral tissue and subsequent modulation of gene expression relating to glucose metabolism.

Longitudinal association of biomarkers of pesticide exposure with cardiovascular disease risk factors in youth with diabetes

BackgroundCardiovascular disease (CVD) is the leading cause of death among individuals with diabetes, but little is known about the role of exposures to environmental chemicals such as pesticides in the early development of CVD risk in this population. ObjectivesTo describe changes over time in concentrations of pesticide biomarkers among youth with diabetes in the United States and to estimate the longitudinal association between these concentrations and established risk factors for CVD. MethodsPesticide biomarkers were quantified in urine and serum samples from 87 youth with diabetes participating in the multi-center SEARCH cohort study. Samples were obtained around the time of diagnosis (baseline visit, between 2006 and 2010) and, on average, 5.4 years later (follow-up visit, between 2012 and 2015). We calculated geometric mean (95% CI) pesticide biomarker concentrations. Eight CVD risk factors were measured at these two time points: body mass index (BMI) z-score, HbA1c, insulin sensitivity, fasting C-peptide (FCP), LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Linear regression models were used to estimate the associations between each pesticide biomarker at baseline and each CVD risk factor at follow-up, adjusting for baseline health outcome, elapsed time between baseline and follow up, sex, age, race/ethnicity, and diabetes type. ResultsParticipants were, on average, 14.2 years old at their baseline visit, and most were diagnosed with type 1 diabetes (57.5%). 4-nitrophenol, 3-phenoxybenzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol, 2,2-bis(4-chlorophenyl)-1,1-dichloroethene, and hexachlorobenzene were detected in a majority of participants at both time points. Participants in the highest quartile of 2,4-D and 4-nitrophenol at baseline had HbA1c levels at follow-up that were 1.05 percentage points (95% CI: −0.40, 2.51) and 1.27 percentage points (0.22, 2.75) higher, respectively, than participants in the lowest quartile of these pesticide biomarkers at baseline. These participants also had lower log FCP levels (indicating reduced beta-cell function) compared to participants in the lowest quartile at baseline: beta (95% CI) for log FCP of −0.64 (−1.17, −0.11) for 2,4-D and −0.39 (−0.96, 0.18) for 4-nitrophenol. In other words, participants in the highest quartile of 2,4-D had a 47.3% lower FCP level compared to participants in the lowest quartile, and those in the highest quartile of 4-nitrophenol had a 32.3% lower FCP level than those in the lowest quartile. Participants with trans-nonachlor concentrations in the highest quartile at baseline had HbA1c levels that were 1.45 percentage points (−0.11, 3.01) higher and log FCP levels that were −0.28 (−0.84, 0.28) lower than participants in the lowest quartile at baseline, that is to say, participants in the highest quartile of trans-nonachlor had a 24.4% lower FCP level than those in the lowest quartile. While not all of these results were statistically significant, potentially due to the small same size, clinically, there appears to be quantitative differences. No associations were observed between any pesticide biomarker at baseline with BMI z-score or insulin sensitivity at follow-up. ConclusionsExposure to select pesticides may be associated with impaired beta-cell function and poorer glycemic control among youth with diabetes.

Physical Exercise and Selective Autophagy: Benefit and Risk on Cardiovascular Health.

Physical exercise promotes cardiorespiratory fitness, and is considered the mainstream of non-pharmacological therapies along with lifestyle modification for various chronic diseases, in particular cardiovascular diseases. Physical exercise may positively affect various cardiovascular risk factors including body weight, blood pressure, insulin sensitivity, lipid and glucose metabolism, heart function, endothelial function, and body fat composition. With the ever-rising prevalence of obesity and other types of metabolic diseases, as well as sedentary lifestyle, regular exercise of moderate intensity has been indicated to benefit cardiovascular health and reduce overall disease mortality. Exercise offers a wide cadre of favorable responses in the cardiovascular system such as improved dynamics of the cardiovascular system, reduced prevalence of coronary heart diseases and cardiomyopathies, enhanced cardiac reserve capacity, and autonomic regulation. Ample clinical and experimental evidence has indicated an emerging role for autophagy, a conservative catabolism process to degrade and recycle cellular organelles and nutrients, in exercise training-offered cardiovascular benefits. Regular physical exercise as a unique form of physiological stress is capable of triggering adaptation while autophagy in particular selective autophagy seems to be permissive to such cardiovascular adaptation. Here in this mini-review, we will summarize the role for autophagy in particular mitochondrial selective autophagy namely mitophagy in the benefit versus risk of physical exercise on cardiovascular function.

Depressive symptoms in adolescent girls at-risk for type 2 diabetes and their parents

ABSTRACTFew studies have characterized the relation between parent’s depression symptoms and adolescent’s depression symptoms in adolescents at-risk for type 2 diabetes (T2D). We evaluated the associations of parental depression symptoms with the depression symptoms and metabolic functioning of adolescent offspring at-risk for T2D. One-hundred sixteen parents and adolescent girls with a family history of diabetes completed surveys of depression symptoms. Adolescents’ degree of metabolic risk for T2D was estimated from body mass index (BMI; kg/m2) standard score, percent adiposity from dual-energy x-ray absorptiometry scan, and whole body insulin sensitivity index determined from glucose/insulin concentrations during a two-hour oral glucose tolerance test. Parents’ and adolescents’ depression symptoms were significantly associated, even after accounting for race/ethnicity, age, puberty, body composition, and parental diabetes/BMI. Adjusting for similar covariates, parent depression symptoms also were positively related to adolescents’ BMI standard score and had a trend-level association with adiposity. There was an inverse relation between parental depression symptoms and adolescent insulin sensitivity, which was entirely accounted for by adolescent body composition. The associations of parental depression symptoms with more elevated depression symptoms and higher BMI in adolescents at-risk for T2D has potential implications for interventions addressing these co-morbid health conditions.

Effects of Securigera Securidaca seed extract in combination with glibenclamide on antioxidant capacity, fibroblast growth factor 21 and insulin resistance in hyperglycemic rats.

Undesired effects of synthetic antidiabetic agents have made researchers to seek for safer and healthier resources. With this aspect, herbal materials have attracted substantial research interest and are being extensively investigated. Considering that herb-drug interactions can be a double-edged sword presenting both risks and benefits, investigation of such interactions is greatly in demand. to investigate possible beneficial effects of hydroalcoholic extract of SecurigeraSecuridaca seed (HESS) on antioxidant capacity, fibroblast growth factor 21 (FGF21) and insulin resistance in Streptozotocin (STZ)-induced diabetic rats, alone and in combination with glibenclamide. Forty male Wistar rats were randomly divided in to eight equal groups including healthy and diabetic controls and six treated groups with a various doses of HESS alone and in combination with glibenclamide, for 35 consecutive days. Serum samples were taken and analyzed for biochemical profile, HOMA indexes, FGF21, oxidative/nitrosative stress and inflammatory biomarkers as compared with the controls. Moreover, total phenolic and flavonoid contents of herbal extract were assessed. The herbal extract was found to be rich in flavonoid and phenolic components. Both of glibenclamide and the HESS decreased glucose and insulin resistance, as well as increased body weight and insulin sensitivity. Moreover, the extract could mitigate oxidative/nitrosative stress and inflammation dose-dependently, however, the standard drug was less effective than HESS. Induction of diabetes increased FGF21 levels and both of the treatments could reduce its contents, however, glibenclamide was more effective than HESS. The results clearly show that there is no contradiction between HESS and glibenclamide. Moreover, the herbal extract could augment antioxidant and anti-inflammatory properties of the standard drug.

A410 A dose-dependent effect of aqueous leaf extract of Annona squamosal (L.) leaves on body weight gain, food intake and insulin sensitivity in high-fat diet-induced obesity.

A410 A dose-dependent effect of aqueous leaf extract of Annona squamosal (L.) leaves on body weight gain, food intake and insulin sensitivity in high-fat diet-induced obesity.

One week of continuous corticosterone exposure impairs hepatic metabolic flexibility, promotes islet β-cell proliferation, and reduces physical activity in male C57BL/6 J mice

Clinical glucocorticoid use, and diseases that produce elevated circulating glucocorticoids, promote drastic changes in body composition and reduction in whole body insulin sensitivity. Because steroid-induced diabetes is the most common form of drug-induced hyperglycemia, we investigated mechanisms underlying the recognized phenotypes associated with glucocorticoid excess. Male C57BL/6 J mice were exposed to either 100ug/mL corticosterone (cort) or vehicle in their drinking water. Body composition measurements revealed an increase in fat mass with drastically reduced lean mass during the first week (i.e., seven days) of cort exposure. Relative to the vehicle control group, mice receiving cort had a significant reduction in insulin sensitivity (measured by insulin tolerance test) five days after drug intervention. The increase in insulin resistance significantly correlated with an increase in the number of Ki-67 positive β-cells. Moreover, the ability to switch between fuel sources in liver tissue homogenate substrate oxidation assays revealed reduced metabolic flexibility. Furthermore, metabolomics analyses revealed a decrease in liver glycolytic metabolites, suggesting reduced glucose utilization, a finding consistent with onset of systemic insulin resistance. Physical activity was reduced, while respiratory quotient was increased, in mice receiving corticosterone. The majority of metabolic changes were reversed upon cessation of the drug regimen. Collectively, we conclude that changes in body composition and tissue level substrate metabolism are key components influencing the reductions in whole body insulin sensitivity observed during glucocorticoid administration.

Carbohydrate-restricted Diet and Exercise Increase Brain-derived Neurotrophic Factor and Cognitive Function: A Randomized Crossover Trial.

IntroductionMetabolic syndrome (MetS) has been recognized as one of the most important clinical challenges and global health issues of today. Growing evidence suggests that mechanisms of energy metabolism may also play a key role in mediating aspects of cognitive function. Brain-derived neurotrophic factor (BDNF) is one such factor well known for its critical role in neuronal plasticity, including memory and learning, and more recently metabolic processes. BDNF levels have been shown separately to be dependent on diet and exercise programming.PurposeThe purpose of this study was to investigate the effect of diet and exercise on BDNF levels and cognitive functioning with any metabolic association in individuals characterized with MetS.MethodsTwelve subjects with MetS followed a randomized crossover design with two four-week interventions, including a carbohydrate (CHO)-restricted Paleolithic-based diet (CRPD; <50gCHO) with sedentary activity (CRPD-Sed) and CRPD with high intensity interval training (HIIT; CRPD-Sed), separated by a four-week washout period. The HIIT exercise consisted of 10 x 60 s cycling intervals interspersed with 60 s of active recovery 3 day/week for four-week. Serum BDNF was detected and quantified via enzyme-linked immunosorbent assay (ELISA). Cognitive executive function (Stroop Test) and self-perceived cognitive symptoms and function (MOS-CFS) were quantified. A two-way analysis of variance with repeated measures was performed with post-hoc analysis using simple effects analysis with a Bonferroni adjustment. The level of statistical significance was established a priori as P < 0.05.ResultsCompared to baseline, CRPD-Sed and CRPD-Ex improved variables for cognitive function, including increased peripheral serum BDNF levels (20% and 38%), psychomotor speed and cognitive flexibility (-14%, -14%), and self-perceived cognitive symptoms and functioning (+8%, +16%), respectively. BDNF inversely correlated with %body fat (r = -0.35, P < 0.05), fasting glucose (r = -0.64, P < 0.05), triglycerides (r = -0.55, P < 0.05), and insulin sensitivity (r = -0.25, P < 0.05).ConclusionThis study shows the short-term beneficial effects of carbohydrate-restricted diet on serum BDNF and executive function in those individuals characterized with MetS. We have shown that the addition of exercise can further improve neuroprotection and cognitive function beyond the results of diet alone.

Puerariae lobatae root extracts and the regulation of brown fat activity

Background: Obesity is one of the major health problems worldwide. The induction of brown adipocyte formation and activity represents a promising therapeutic option by increasing energy expenditure. Asian herbs have the potential to treat obesity, however, pharmacological effects should be well documented at the molecular level first. Hypothesis: A novel hypothesis-driven screening approach identified the root of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep (PLR) to have potential effects on obesity by stimulating brown adipocytes. Study design: This study explored the metabolic effects of PLR water extract (PLRE) in a high-fat diet-induced obesity mouse model and characterized its secondary metabolite composition. Methods: Animals were orally treated daily for two weeks and the bioactivity of PLRE evaluated by measuring various parameters including body weight, circulating metabolites, energy expenditure and insulin sensitivity. The chemical composition of the mains components was obtained by HPLC–MS–ELSD–PDA. Based on the dereplication results and semi-quantitative estimation, pure molecules were selected for tests on adipocytes in vitro. Results: PLRE induces brown adipocyte activity and triggers the formation of brown-like cells in inguinal fat tissue, weight loss, and improved glucose metabolism. These effects are primarily caused by cell-autonomous activation of brown adipocytes and not by autonomic nervous system regulation. Even though the analysis of PLRE revealed puerarin as the most abundant secondary metabolite, it showed no effect on brown adipocyte formation and function. Brown adipocyte activity was induced dose-dependently by two other isoflavones, daidzein, and genistein. Daidzein is present in a very small amount in PLRE, but various glycosidic isoflavones, including puerarin, may release daidzein after metabolism. Conclusion: This approach demonstrated the positive effects of PLRE on a diet-induced obesity mouse model and provided clues on the mode of action of PLRE at the molecular level.

The Short-Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity.

The interplay of gut microbiota, host metabolism, and metabolic health has gained increased attention. Gut microbiota may play a regulatory role in gastrointestinal health, substrate metabolism, and peripheral tissues including adipose tissue, skeletal muscle, liver, and pancreas via its metabolites short-chain fatty acids (SCFA). Animal and human data demonstrated that, in particular, acetate beneficially affects host energy and substrate metabolism via secretion of the gut hormones like glucagon-like peptide-1 and peptide YY, which, thereby, affects appetite, via a reduction in whole-body lipolysis, systemic pro-inflammatory cytokine levels, and via an increase in energy expenditure and fat oxidation. Thus, potential therapies to increase gut microbial fermentation and acetate production have been under vigorous scientific scrutiny. In this review, the relevance of the colonically and systemically most abundant SCFA acetate and its effects on the previously mentioned tissues will be discussed in relation to body weight control and glucose homeostasis. We discuss in detail the differential effects of oral acetate administration (vinegar intake), colonic acetate infusions, acetogenic fiber, and acetogenic probiotic administrations as approaches to combat obesity and comorbidities. Notably, human data are scarce, which highlights the necessity for further human research to investigate acetate’s role in host physiology, metabolic, and cardiovascular health.

Obesity as the Main Risk Factor for Metabolic Syndrome in Children.

Obesity in childhood is the main determinant of whole body reduced insulin sensitivity. This association has been demonstrated in multiple adult and pediatric cohorts. The mechanistic link explaining this association is the pattern of lipid partitioning in the face of excess calories and energy surplus. A tight relation exists between typical lipid deposition patterns, specifically within the skeletal muscle and liver, as well as the intra-abdominal compartment and whole body insulin sensitivity. The impact of lipid deposition within insulin responsive tissues such as the liver and skeletal muscle relates to the ability of fatty acid derivates to inhibit elements of the insulin signal transduction pathway. Strengthening the relation of obesity and reduced insulin sensitivity are the observations that weight gain reduces insulin sensitivity while weight loss increases it. This manifests as the appearance of cardiovascular risk factor clustering with weight gain and its recovery in the face of weight loss. Both obesity per se, via the adipocytokine profile it induces, and low insulin sensitivity, are independent determinants of the adverse metabolic phenotype characteristic of the metabolic syndrome.

Insulin Resistance in Nonobese Renal Allograft Recipients on Maintenance Doses of Cyclosporine or Tacrolimus

PurposeIn comparison to cyclosporine (CsA), tacrolimus (Tac) seems to be more diabetogenic in renal transplant recipients, and post-transplant diabetes mellitus is more common in patients using Tac, especially during the first year after transplantation. However, at maintenance doses, there are no comparative data of insulin resistance (IR) in patients using Tac or CsA. The purpose of this study was to investigate the IR indexes in patients on maintenance doses of CsA or Tac. MethodsForty-five nondiabetic and nonobese renal transplant recipients participated in the study (M:F, 30:15; age, 36 ± 9 years); 27 patients were on CsA, and 18 were on Tac. All had stable graft function, were transplanted at least 6 months previously, and were receiving maintenance doses of steroids (5.0 mg/d), azathioprine or mycophenolate mofetil, and calcineurin inhibitors (CsA [2.14 ± 0.46 mg/kg/d] or Tac [0.06 ± 0.03 mg/kg/d]). IR was evaluated by the homeostasis model assessment (HOMA) index and composite body insulin sensitivity index. ResultsWe did not determine any significant difference in the HOMA and composite body insulin sensitivity index levels among patients using CsA or Tac (1.5 ± 1.3 vs 1.5 ± 1.1, P > .05, and 9.9 ± 5.8 vs 14.6 ± 11.7, P > .05, respectively). There was a significant correlation between creatinine and HOMA values. ConclusionThere was no difference in IR indexes in renal transplant recipients receiving maintenance doses of either CsA or Tac.

Simulation of gastric bypass effects on glucose metabolism and non-alcoholic fatty liver disease with the Sleeveballoon device

BackgroundGastric bypass surgery is a very effective treatment of obesity and type 2 diabetes. However, very few eligible patients are offered surgery. Some patients also prefer less invasive approaches.We aimed to study the effects of the Sleeveballoon – a new device combining an intragastric balloon with a connecting sleeve, which covers the duodenal and proximal jejunal mucosa – on insulin sensitivity, glycemic control, body weight and body fat distribution. MethodsWe compared the effects of Sleeveballoon, Roux-en-Y Gastric-Bypass (RYGB) and sham-operation in 30 high-fat diet (HFD) fed Wistar rats. Whole body and hepatic insulin sensitivity and insulin signaling were studied. Transthoracic echocardiography was performed using a Vevo 2100 system (FUJIFILM VisualSonics Inc., Canada). Gastric emptying was measured using gastrografin. FindingsHepatic (P = .023) and whole-body (P = .011) insulin sensitivity improved in the Sleeveballoon and RYGB groups compared with sham-operated rats. Body weight reduced in both Sleeveballoon and RYGB groups in comparison to the sham-operated group (503.1 ± 8.9 vs. 614.4 ± 20.6 g, P = .006 and 490.0 ± 17.7 vs. 614.4 ± 20.6 g, P = .006, respectively). Ectopic fat deposition was drastically reduced while glycogen content was increased in both liver and skeletal muscle. Gastric emptying (T1/2) was longer (157.7 ± 29.2 min, P = .007) in the Sleeveballoon than in sham-operated rats (97.1 ± 26.3 min), but shorter in RYGB (3.5 ± 1.1 min, P < .0001). Cardiac function was better in Sleeveballoon and RYGB versus sham-operated rats. InterpretationThe Sleeveballoon reduces peripheral and hepatic insulin resistance, glycaemia, body weight and ectopic fat deposition to a similar level as RYGB, although the contribution of gastric emptying to blood glucose reduction is different.

Beige Fat, Adaptive Thermogenesis, and Its Regulation by Exercise and Thyroid Hormone.

While it is now understood that the proper expansion of adipose tissue is critically important for metabolic homeostasis, it is also appreciated that adipose tissues perform far more functions than simply maintaining energy balance. Adipose tissue performs endocrine functions, secreting hormones or adipokines that affect the regulation of extra-adipose tissues, and, under certain conditions, can also be major contributors to energy expenditure and the systemic metabolic rate via the activation of thermogenesis. Adipose thermogenesis takes place in brown and beige adipocytes. While brown adipocytes have been relatively well studied, the study of beige adipocytes has only recently become an area of considerable exploration. Numerous suggestions have been made that beige adipocytes can elicit beneficial metabolic effects on body weight, insulin sensitivity, and lipid levels. However, the potential impact of beige adipocyte thermogenesis on systemic metabolism is not yet clear and an understanding of beige adipocyte development and regulation is also limited. This review will highlight our current understanding of beige adipocytes and select factors that have been reported to elicit the development and activation of thermogenesis in beige cells, with a focus on factors that may represent a link between exercise and ‘beiging’, as well as the role that thyroid hormone signaling plays in beige adipocyte regulation.

Reductions in body weight and insulin resistance are not associated with changes in grey matter volume or cortical thickness during the PREVIEW study

IntroductionThe effect of changes in body weight or insulin resistance on grey matter volume and cortical thickness change are unclear. The present observational study assessed effects of an 8-week weight loss period (≥8% of body weight), and a subsequent 22-month weight maintenance period on grey matter volume and cortical thickness. MethodsA total of 24 participants (12f/12 m; age 52.8 ± 10.6 years) with overweight/obesity and pre-diabetes were recruited. T1-weighted magnetic resonance imaging was used to determine grey matter volume and cortical thickness at baseline, after the weight loss period and after a medium to high dietary protein weight maintenance period. ResultsAt baseline, global grey matter volume was inversely associated with HOMA-IR, adjusted for sex and age (r = −0.42; p = .049). During the weight loss period participants decreased their BMI (32.1 ± 3.3 to 28.1 ± 2.8 kg/m2, p < .01), body-fat (41.6 ± 6.4 to 35.0 ± 8.0%, p < .01) and insulin resistance (HOMA-IR: 4.0 ± 2.0 to 1.8 ± 0.9, p < .01). During the 22-month weight maintenance period, these parameters gradually increased again (BMI: 29.3 ± 3.8 kg/m2; body-fat: 37.8 ± 9.3%; HOMA-IR: 2.9 ± 1.4, p < .01). Global grey matter volume and cortical thickness did not change significantly during the weight loss or weight maintenance period. Changes in body weight, body-fat percentage or insulin sensitivity were not associated with changes in global grey matter volume. ConclusionIn conclusion, we confirmed that global grey brain matter volume was inversely associated with insulin resistance at baseline, yet an intervention yielding a decrease in insulin resistance did not lead to changes in global grey brain matter volume or cortical thickness. Trial registrationThe trial is registered with ClinicalTrials.gov, NCT01777893.

769-P: Short-Term Dietary Reduction of Branched-Chain Amino Acids Reduces Meal-Induced Insulin Secretion and Modifies Microbiome Composition in Overweight Patients with Type 2 Diabetes

Increased levels of branched-chain amino acids (BCAA) associate with insulin resistance and type 2 diabetes (T2D), which could result from dietary habits, gut microbiome composition or direct effects on cellular energy metabolism. We hypothesized that reduced dietary intake of BCAA improves whole body insulin sensitivity and hyperinsulinemia in patients with T2D. In a randomized, placebo-controlled, double-blinded, cross over trial, 12 metabolically well-controlled patients with T2D received an isocaloric diet (protein: 1 g/kg body weight), containing either the complete amino acid set (BCAA+) or a 60% reduction in BCAA (BCAA-) for 1 week each. Effects on glucose homeostasis were assessed from mixed meal tolerance tests (MMT) and hyperinsulinemic-euglycemic clamps (HEC, M-value), and pathways affecting insulin signaling were analyzed in muscle and adipose tissue biopsies. Microbiome composition was assessed by next generation sequencing. After the BCAA- diet, MMT-derived insulin secretion was 28% lower compared to the BCAA+ diet (p&amp;lt;0.05). After the BCAA- diet, MMT-derived insulin sensitivity (PREDIM, the validated predicted HEC-derived M-value from meal data), turned 23% higher (p&amp;lt;0.01), whereas HEC-derived insulin sensitivity (M-value) remained unchanged. Respiratory control ratio was 1.7-fold higher in adipose tissue (p&amp;lt;0.05), but unchanged in skeletal muscle. Mechanistic target of rapamycin (mTOR) was downregulated by 13% in adipose tissue (p&amp;lt;0.05). BCAA- diet was associated with a 40% increase of fecal Bacteroidetes and a 11% decrease of Firmicutes (both p&amp;lt;0.05). In conclusion, a short-term dietary reduction of BCAA decreases insulin secretion, increases postprandial insulin sensitivity, which may relate to adipocyte mitochondrial efficiency and altered gut microbiome composition in patients with T2D. Disclosure Y. Karusheva: None. T. van Gemert: None. K. Strassburger: None. D.F. Markgraf: Research Support; Self; Sanofi. T. Jelenik: None. L. Mastrototaro: None. M. Simon: None. O.P. Zaharia: None. K. Bodis: None. F. Bärenz: None. D. Schmoll: Employee; Self; Sanofi-Aventis Deutschland GmbH. V. Burkart: None. K. Muessig: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. Funding Sanofi Aventis Deutschland GmbH

274-OR: Beta-Cell Dysfunction Is Associated with Impaired Insulin-Mediated Suppression of Glucagon in Obese Hispanic Americans

Recent studies have demonstrated an increase in the glucagon:insulin ratio in lean versus obese subjects. We assessed insulin-mediated suppression of plasma glucagon levels in 260 obese Hispanic Americans (59 NGT, HbA1c= 5.1±0.1%, BMI= 32.6±0.7; 109 Prediabetes, HbA1c= 5.8±0.1%, BMI= 33.8±0.5; 92 T2D, HbA1c= 7.3±0.2%, BMI= 34±0.5) with varying glucose tolerance. Subjects participated in a 2-h OGTT with measurement of plasma glucose, insulin, glucagon concentrations. During the OGTT, we quantitated insulin-mediated suppression of plasma glucagon concentration, Matsuda Index of insulin sensitivity, and the insulin secretion/insulin sensitivity (disposition) index using plasma C-peptide concentration. There was no difference in fasting plasma glucagon level between obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D). However, there was a progressive decrease in fasting glucagon:insulin ratio from NGT to prediabetes to T2D (8.71±0.72 vs. 6.92±0.53 vs. 5.66±0.41, P&amp;lt;0.01). During OGTT at 60 min, glucagon:insulin ratio increased from NGT to T2D (0.93±0.09 vs. 0.89±0.07 vs. 2.33±0.20, P&amp;lt;0.001), and the suppression of plasma glucagon (compared to basal value) was markedly decreased (10.3±3.4% vs. 9.3±1.9% vs. 2.5±2.8%, P&amp;lt;0.05). At 120 min (OGTT), glucagon:insulin ratio was increased in T2D versus NGT (1.28±0.17 vs. 2.0±0.20, P&amp;lt;0.01). The glucagon:insulin ratio was closely correlated with whole body insulin sensitivity and β-cell function during the fasting state (Matsuda Index, r= 0.51, P&amp;lt;0.001; Disposition Index, r= 0.30, P&amp;lt;0.001) and with Disposition Index during the OGTT at 60 and 120 min (r= -0.41, P&amp;lt;0.001; r= -0.21, P&amp;lt;0.01), respectively. Collectively, these findings indicate that insulin-mediated suppression of glucagon secretion is impaired with increasing severity of glucose intolerance in obese Hispanic Americans and is closely associated with insulin resistance and β-cell dysfunction. Disclosure X. Chen: None. E.R. Maldonado Corchado: None. A. Merovci: None. E. Case: None. 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 &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.

1764-P: Insulin Sensitive Induction of Adipogenesis

Healthy adipose tissue has a remarkable ability to adapt to energy intake through contraction and expansion. A large body of evidence pin-points the ability expand adipose tissue as vital to maintain whole body lipid homeostasis and insulin sensitivity in humans as well as in mice. Increases in fat mass can be driven by expansion of existing adipocytes or by recruitment of new adipocytes from adipose tissue pre-courser cells or preadipocytes (Adipogenesis). Failure to expand adipose tissues as well as appearance of dysfunctional large adipocytes both result in local and systemic insulin resistance. Conversely, strategies to preserve adipocyte function during tissue expansion through enhanced adipogenesis could preserve insulin function in the face of obesity or high caloric intake. In order to study the hormonal control of adipose tissue expansion we have examined the ability of insulin and IGF-1 to induce adipogenesis in isolated rodent primary SVF cells. We find that both insulin and IGF-1 dose dependently induce lipid droplet accumulation and expression of adipocyte genes in primary cells isolated from mouse epididymal and subcutaneous adipose depots. Surprisingly, adipogenesis in mouse SVF cells is a very insulin sensitive process and more specifically we identify CD45neg/Ly6c low SVF cells isolated from epididymal fat pads as extremely sensitive to insulin induced adipogenesis. These results indicate that insulin signaling directly in preadipocytes could drive adipocyte differentiation in vivo e.g., during high insulin levels in serum in response to prolonged periods of high caloric intake or lipid induced insulin resistance. Disclosure T.Å. Pedersen: Employee; Spouse/Partner; Cook Medical. Employee; Self; Novo Nordisk A/S. J. Peics: Employee; Self; Novo Nordisk A/S. G.S. Olsen: Employee; Self; Novo Nordisk A/S.