The relationship between adiposopathy and glucose-insulin homeostasis is not affected by moderate-intensity aerobic training in healthy women with obesity

The contribution of adiposopathy to glucose-insulin homeostasis remains unclear. This longitudinal study examined the potential relationship between the adiponectin/leptin ratio (A/L, a marker of adiposopathy) and insulin resistance (IR: homeostasis model assessment (HOMA)), insulin sensitivity (IS: Matsuda), and insulin response to an oral glucose tolerance test before and after a 16-week walking program, in 29 physically inactive pre- and postmenopausal women with obesity (BMI, 29-35 kg/m2; age, 47-54 years). Anthropometry, body composition, VO2max, and fasting lipid-lipoprotein and inflammatory profiles were assessed. A/L was unchanged after training (p = 0.15), despite decreased leptin levels (p < 0.05). While the Matsuda index tended to increase (p = 0.07), HOMA decreased (p < 0.05) and fasting insulin was reduced (p < 0.01) but insulin area under the curve (AUC) remained unchanged (p = 0.18) after training. Body fatness and VO2max were improved (p < 0.05) while triacylglycerols increased and HDL-CHOL levels decreased after training (p < 0.05). At baseline, A/L was positively associated with VO2max, HDL-CHOL levels, and Matsuda (0.37 < ρ < 0.56; p < 0.05) but negatively with body fatness, HOMA, insulin AUC, IL-6, and hs-CRP levels (− 0.41 < ρ < − 0.66; p < 0.05). After training, associations with fitness, HOMA, and inflammation were lost. Multiple regression analysis revealed A/L as an independent predictor of IR and IS, before training (partial R2 = 0.10 and 0.22), although A/L did not predict the insulin AUC pre- or post-intervention. A significant correlation was found between training-induced changes to A/L and IS (r = 0.38; p < 0.05) but not with IR or insulin AUC. Although changes in the A/L ratio could not explain improvements to glucose-insulin homeostasis indices following training, a relationship with insulin sensitivity was revealed in healthy women with obesity

The relationship between adiposopathy and glucose-insulin homeostasis is not affected by moderate-intensity aerobic training in healthy women with obesity.

The contribution of adiposopathy to glucose-insulin homeostasis remains unclear. This longitudinal study examined the potential relationship between the adiponectin/leptin ratio (A/L, a marker of adiposopathy) and insulin resistance (IR: homeostasis model assessment (HOMA)), insulin sensitivity (IS: Matsuda), and insulin response to an oral glucose tolerance test before and after a 16-week walking program, in 29 physically inactive pre- and postmenopausal women with obesity (BMI, 29-35 kg/m2; age, 47-54 years). Anthropometry, body composition, VO2max, and fasting lipid-lipoprotein and inflammatory profiles were assessed. A/L was unchanged after training (p = 0.15), despite decreased leptin levels (p < 0.05). While the Matsuda index tended to increase (p = 0.07), HOMA decreased (p < 0.05) and fasting insulin was reduced (p < 0.01) but insulin area under the curve (AUC) remained unchanged (p = 0.18) after training. Body fatness and VO2max were improved (p < 0.05) while triacylglycerols increased and HDL-CHOL levels decreased after training (p < 0.05). At baseline, A/L was positively associated with VO2max, HDL-CHOL levels, and Matsuda (0.37 < ρ < 0.56; p < 0.05) but negatively with body fatness, HOMA, insulin AUC, IL-6, and hs-CRP levels (- 0.41 < ρ < - 0.66; p < 0.05). After training, associations with fitness, HOMA, and inflammation were lost. Multiple regression analysis revealed A/L as an independent predictor of IR and IS, before training (partial R2 = 0.10 and 0.22), although A/L did not predict the insulin AUC pre- or post-intervention. A significant correlation was found between training-induced changes to A/L and IS (r = 0.38; p < 0.05) but not with IR or insulin AUC. Although changes in the A/L ratio could not explain improvements to glucose-insulin homeostasis indices following training, a relationship with insulin sensitivity was revealed in healthy women with obesity.

Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle.

Lipid droplets (LD) play a central role in lipid homeostasis by controlling transient fatty acid (FA) storage and release from triacylglycerols stores, while preventing high levels of cellular toxic lipids. This crucial function in oxidative tissues is altered in obesity and type 2 diabetes. Perilipin 5 (PLIN5) is a LD protein whose mechanistic and causal link with lipotoxicity and insulin resistance has raised controversies. We investigated here the physiological role of PLIN5 in skeletal muscle upon various metabolic challenges. We show that PLIN5 protein is elevated in endurance-trained (ET) subjects and correlates with muscle oxidative capacity and whole-body insulin sensitivity. When overexpressed in human skeletal muscle cells to recapitulate the ET phenotype, PLIN5 diminishes lipolysis and FA oxidation under basal condition, but paradoxically enhances FA oxidation during forskolin- and contraction- mediated lipolysis. Moreover, PLIN5 partly protects muscle cells against lipid-induced lipotoxicity. In addition, we demonstrate that down-regulation of PLIN5 in skeletal muscle inhibits insulin-mediated glucose uptake under normal chow feeding condition, while paradoxically improving insulin sensitivity upon high-fat feeding. These data highlight a key role of PLIN5 in LD function, first by finely adjusting LD FA supply to mitochondrial oxidation, and second acting as a protective factor against lipotoxicity in skeletal muscle.

Associations Between Serum 25-Hydroxyvitamin D, Insulin Sensitivity, Insulin Secretion, and ß-Cell Function According to Glucose Tolerance Status.

BACKGROUND: The objective of this study was to determine whether glucose tolerance status influences the associations between serum 25-hydroxyvitamin D [25(OH)D], insulin sensitivity, insulin secretion, and ß-cell function. METHODS: This cross-sectional study included 112 French Canadian postmenopausal women with normal glucose tolerance (NGT; n = 65) or abnormal glucose tolerance (AGT; n = 47). Estimates of insulin sensitivity [homeostasis model assessment of insulin sensitivity (HOMA %S) and glucose disposal rate (GDR)], insulin secretion [area under the curve of C-peptide (AUC C-peptide)], and ß-cell function (GDR × AUC C-peptide) were derived from a 2-hr euglycemic-hyperinsulinemic clamp and a 75-gram 3-hr oral glucose tolerance test (OGTT). Measures of adiposity were taken (waist circumference, body mass index, fat mass by the hydrostatic weighting technique, and computed tomography (CT)-derived total and visceral adiposity), questionnaires on physical activity, dietary calcium, and vitamin D intake were administered, and blood was sampled for measurement of parathyroid hormone, interleukin-6, and adiponectin. RESULTS: AGT status was significantly associated with lower insulin sensitivity and ß-cell function (P ≤ 0.01 for all) but not with insulin secretion. Lower serum 25(OH)D concentrations were significantly associated with lower insulin sensitivity and secretion (P ≤ 0.01 for all) but not with ß-cell function. The interaction between glucose tolerance status and serum 25(OH)D concentration was not significant for either insulin sensitivity, insulin secretion, or ß-cell function, even after adjustment for potential confounders. CONCLUSION: Vitamin D and glucose tolerance status are both independently associated with measures of insulin sensitivity, insulin secretion, and ß-cell function. However, the association between serum 25(OH)D and these surrogate markers of type 2 diabetes mellitus risk is not influenced by glucose tolerance status.

Modulation of Strawberry/Cranberry Phenolic Compounds Glucuronidation by Co-Supplementation with Onion: Characterization of Phenolic Metabolites in Rat Plasma Using an Optimized µSPE-UHPLC-MS/MS Method.

Plant phenolic compounds are suggested to exert pharmacological activities in regards to obesity and type-2 diabetes, but their mode of action is poorly understood due to a lack of information about their bioavailability. This work aimed to study the bioavailability of GlucoPhenol phenolic compounds, a strawberry-cranberry extracts blend, by characterizing plasma phenolic profile in obese rats. A comparison was performed by co-supplementation with an onion extract. Using an optimized µSPE-UHPLC-MS/MS method, 21 phenolic metabolites were characterized, mostly conjugated metabolites and microbial degradation products of the native phenolic compounds. Their kinetic profiles revealed either an intestinal or hepatic formation. Among identified metabolites, isorhamnetin glucuronide sulfate was found in greater amount in plasma. Three glucuronidated conjugates of strawberry-cranberry phenolic compounds, p-hydroxybenzoic acid glucuronide, catechins glucuronide, and methyl catechins glucuronide were found in higher quantities when GlucoPhenol was ingested together with onion extract (+252%, +279%, and +118% respectively), suggesting a possible induction of glucuronidation processes by quercetin. This work allowed the characterization of actual phenolic metabolites generated in vivo following a phenolic intake, the analysis of their kinetics and suggested a possible synergistic activity of phenolic compounds for improving bioavailability.

Impact of a moderate-intensity walking program on cardiometabolic risk markers in overweight to obese women: is there any influence of menopause?

OBJECTIVE: The aim of this study was to examine the effect of brisk walking on cardiometabolic risk profile and on the gene expression (ie, messenger RNA [mRNA] levels) of inflammatory and thrombotic markers in abdominal and femoral subcutaneous adipose tissues (SATs) among sedentary overweight to obese women with different menopause statuses. METHODS: Sixteen late premenopausal (mean [SD] age, 49 [3] y; mean [SD] body mass index, 31.9 [3.0] kg/m) and 14 early postmenopausal (53 [2] y; 30.8 [1.9] kg/m) women were involved in a 16-week walking program (three sessions of 45 min/wk at 60% of heart rate reserve). Glucose-insulin homeostasis, lipid-lipoprotein profile, and inflammatory (tumor necrosis factor-α, interleukin-6 [IL-6], and adiponectin) and thrombotic (plasminogen activator inhibitor-1) SAT mRNA and plasma levels were measured before and after the intervention. RESULTS: Glucose area under the curve was reduced in all participants (P = 0.03) after the walking program. Increases in plasma tumor necrosis factor-α were observed in both groups (P = 0.001), whereas increases in plasminogen activator inhibitor-1 levels were found in postmenopausal women only (P = 0.014). However, plasma IL-6 and adiponectin levels remained unchanged after the intervention (0.07 < P < 0.98). Although femoral SAT adiponectin mRNA levels decreased in postmenopausal women only (P = 0.008), abdominal SAT IL-6 mRNA levels were reduced in both groups (P = 0.01). CONCLUSIONS: Taken together, our results show that, despite a reduced abdominal SAT IL-6 expression, brisk walking does not seem to exert a favorable impact on the cardiometabolic risk profile of overweight to obese women, irrespective of their menopause status.

Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly.

It has been suggested that treatment with adequate dose titration of pegvisomant, a GH antagonist, up to a maximum of 40 mg daily, can achieve IGF-1 normalisation in virtually all patients with acromegaly. On the other hand, temozolomide (TMZ), an alkylating cytostatic agent, has been reported to reduce pituitary tumour size and hormone hypersecretion in a small number of aggressive pituitary macroadenomas. In this paper we report the case of a patient resistant to very high doses of pegvisomant used in combination with somatostatin analogs (SSA) and to TMZ therapy. The patient, initially a 22 year-old man with an invasive GH-secreting pituitary macroadenoma (IGF-1, 371% upper limit of normal), had active acromegaly despite a repeat transsphenoidal surgery followed by radiotherapy and SSA (octreotide 800 µg sc daily) (IGF-1, 262% ULN). In combination with SSA, pegvisomant was started at 20 mg daily and doses were titrated up to 60 mg daily. IGF-1 was moderately reduced and stabilized at 200% ULN after 1 year of treatment. Serum pegvisomant level was 30,500 ng/l, the denaturalized GHBP concentration 1,120 pM and the endogenous GH level was 220 µg/l. Pegvisomant was stopped and TMZ therapy was given for 5 cycles. However, the patient reported an increase of acromegaly symptoms and the serum IGF-1 was raised to the same level prior to pegvisomant therapy. Consequently, pegvisomant was tried again with doses up to 100 mg daily finally resulting in normalisation of serum IGF-1 level and improvement of acromegaly symptoms and patient well-being. We conclude that in some patients with severe acromegaly refractory to multimodal therapy, biochemical control may be difficult to attain with conventional doses of pegvisomant or TMZ therapy.

Impact of walking on adipose tissue lipoprotein lipase activity and expression in pre- and postmenopausal women.

OBJECTIVE: The aim of this study was to examine regional variation in adipose tissue lipoprotein lipase (AT-LPL) activity and expression in pre-and postmenopausal women, before and after training, once differences in chronological age or obesity degree are taken into account. METHODS: Sixteen late pre- and 14 early postmenopausal (49 +/- 2 vs. 52 +/- 2 years; p < 0.001) moderately obese women (body mass index 29-35 kg/m(2)) were subjected to a 16-week walking program (3 sessions/week of 45 min at 60% heart rate reserve). Abdominal and femoral AT-LPL activity and expression, fasting lipid-lipoprotein profile, body composition, and cardiorespiratory fitness (CRF) were measured before and after our intervention. Statistical analyses were performed using covariance analysis for age differences. RESULTS: AT-LPL activity and expression, lipid-lipoprotein metabolism, body fatness, and CRF were similar at baseline, irrespective of the group considered. Slight reductions in plasma cholesterol and high-density lipoprotein (HDL) cholesterol levels, fat mass and waist girth reductions, CRF increases as well as femoral AT-LPL activity and expression decreases after our intervention were comparable, regardless of menopausal status (0.0001 < p < 0.05). CONCLUSIONS: Lipid storage is decreased in the femoral depot after walking, regardless of menopausal status. Reduction in AT-LPL activity or expression does not lead to a more deleterious lipid-lipoprotein profile, despite the modest decrease noted in HDL cholesterol concentrations.

Impact of walking on eating behaviors and quality of life of premenopausal and early postmenopausal obese women.

OBJECTIVE: Aerobic exercise is known to improve health-related quality of life (QoL). The aim of this study was to compare the effects of a 16-week walking program on eating behaviors and QoL between late premenopausal and early postmenopausal obese and sedentary women, once chronological aging is taken into account. METHODS: Sixteen women 49 +/- 2 years old and 14 women 53 +/- 2 years old, whose body mass index ranged between 29 and 35 kg/m, were subjected to three sessions per week of 45-minute walking at 60% of their heart rate reserve. Fat mass and lean mass (bioelectrical impedance), cardiorespiratory fitness estimated by maximum oxygen consumption (2-km walking test), eating behaviors (Three-Factor Eating Questionnaire), and QoL, estimated by the Short Form-36 Health Survey, Pittsburgh Sleep Quality Index, and Perceived Stress Scale-10 questionnaires, were recorded before and after exercise. RESULTS: With the exception of a higher attitude of self-regulation in postmenopausal than in premenopausal women (P = 0.05), no between-group differences were observed in body composition, eating behaviors, and QoL at baseline. In all participants, body weight and fat mass decreased, whereas cardiorespiratory fitness increased after walking (0.001 < P < 0.0001). Situational susceptibility was the only eating behavior reduced after training in all women (P = 0.02). Neither the sleep quality index nor the perceived stress score changed in response to endurance exercise. Finally, in all women, Short Form-36 physical and mental scores increased after walking (0.001 < P < 0.05). CONCLUSIONS: Despite modest body weight and fat mass losses, a 16-week walking program seems to be sufficient to improve physical and mental well-being, irrespective of menopause status.

Interaction between HNF4A polymorphisms and physical activity in relation to type 2 diabetes-related traits: results from the Quebec Family Study.

AIMS: To test for associations between type 2 diabetes mellitus (T2DM)-related traits and polymorphisms (SNPs) in the hepatocyte nuclear factor 4-alpha gene (HNF4A) in the Quebec Family Study cohort, and determine whether these associations are modulated by physical activity (PA). METHODS: Two HNF4A SNPs (rs1885088 G>A; rs745975 C>T), previously reported to be associated with T2DM, were studied in 528 non-diabetic subjects who underwent a 75g oral glucose tolerance test (OGTT). Glucose, insulin and C-peptide plasma levels, measured in the fasting state and during the OGTT, were used in the analysis. The amount (hours per week) of PA was assessed by questionnaire. RESULTS: The HNF4A rs1885088 SNP was not independently associated with T2DM-related traits, whereas the rs745975 was associated with fasting insulin, HOMA-IR and 2-h glucose levels (p<0.05 for all). Genotype by PA interactions were found for glucose homeostasis (p<0.0001) and insulin secretion (p2h/week) was associated with smaller glucose area under the curve (AUC) and 2-h glucose levels in rs1885088 A/A homozygotes and with lower fasting C-peptide and insulin AUC in rs745975 T/T homozygotes. CONCLUSION: These results indicate that the associations of HNF4A rs1885088 with glucose tolerance and rs745975 with insulin secretion are modulated by PA. Our finding therefore suggests that the effect of HNF4A polymorphisms on the risk of T2DM is influenced by PA.

Cardiorespiratory fitness and components of the metabolic syndrome in sedentary men.

OBJECTIVE: To investigate the relationships between fitness and components of the metabolic syndrome in sedentary men. SUBJECTS AND METHODS: 39 subjects (34-53 years) were evaluated for fitness (VO(2max)) and anthropometric, metabolic, and skeletal muscle phenotypes. VO(2max) was assessed on a bicycle ergometer whereas other variables were obtained from an oral glucose tolerance test (OGTT), hydrostatic weighing, and a muscle biopsy. RESULTS: Pearson and partial correlations adjusted for fat mass (FM), waist circumference (WC), muscle enzyme activities (citrate synthase (CS), cytochrome c oxidase (COX)), and capillary density were used to investigate the independent relationships be tween variables. Negative correlations between VO(2max) and WC as well as blood pressure and OGTT test were observed. When adjusted for FM, correlations remained between VO(2max) and WC (r = -0.46, p < 0.01) and systolic blood pressure (r = -0.35, p < 0.05). When adjusted for WC and CS activity, all correlations were lost except for high-sensitivity C-reactive protein (hs-CRP) (r = -0.34, p < 0.05) which remained when adjusted for CS activity. Adjustment for COX activity failed to remove correlations with hs-CRP (r = -0.36, p < 0.05), age (r = 0.34, p < 0.05), WC (r = -0.35, p < 0.05), and blood pressure. Negative correlations persisted when fitness was adjusted for the mean number of capillaries. CONCLUSION: The effects of fitness on components of the metabolic syndrome in sedentary men are explained by abdominal obesity and muscle phenotypes.