Acylated Ghrelin and The Regulation of Lipid Metabolism in The Intestine.

Acylated ghrelin (AG) is a gastrointestinal (GI) peptide mainly secreted by the stomach that promotes cytosolic lipid droplets (CLD) hypertrophy in adipose tissues and liver. However, the role of AG in the regulation of lipid metabolism in the intestine remains unexplored. This study aimed at determining whether AG influences CLD production and chylomicron (CM) secretion in the intestine. The effects of AG and oleic acid on CLD accumulation and CM secretion were first investigated in cultured Caco-2/15 enterocytes. Intestinal lipid metabolism was also studied in Syrian Golden Hamsters submitted to conventional (CD) or Western (WD) diets for 8 weeks and continuously administered with AG or physiological saline for the ultimate 2 weeks. In cultured Caco-2/15 enterocytes, CLD accumulation influenced CM secretion while AG reduced fatty acid uptake. In WD hamsters, continuous AG treatment amplified chylomicron output while reducing postprandial CLD accumulation in the intestine. The present study supports the intimate relationship between CLD accumulation and CM secretion in the intestine and it underlines the importance of further characterizing the mechanisms through which AG exerts its effects on lipid metabolism in the intestine.

Impact of 5-week high-intensity interval training on indices of cardio metabolic health in men.

PURPOSE: To compare the acute and chronic effects of high-intensity intermittent training (HIIT) and moderate-intensity continuous training (MICT) on indices of cardio-metabolic health: (HDL-c, total cholesterol, triglycerides, heart ratio, and phase angle/PhA) in physically active men. METHODS: Twenty active men were randomly allocated to HIIT (n = 10), or MICT (n = 10) for 5 weeks, three times per week. HIIT consisted of running 5 km with 1-min at 100% of maximal aerobic speed interspersed by 1-min passive recovery while subjects in MICT group ran continuously the same 5 km at 70% of maximal aerobic speed. Blood samples were collected at different moments during the first and last exercise session. Before and after 5 weeks of both exercise training protocols, heart ratio (during exercise session) and PhA were measured pre and post-exercise training. RESULTS: Fasting HDL-c levels did not change after 5 weeks of HIIT or MICT. Perceptual variation of HDL pre and post training (fed state) tended to differ between HIIT and MICT (p = 0.09). All lipoproteins parameters (HDL-c, total cholesterol, triglycerides and non-HDL) were increased in post-acute exercise session compared to pre-exercise during the first and last training session, these being observed after both training protocols. PhA and heart rate measured at different times during the first and last training session were not affected in both training protocols. CONCLUSION: These results indicate that HIIT and MICT modify the post-exercise lipoprotein profile acutely. On the other hand, only HIIT tended to increase HDL-c levels chronically.

Two weeks of high-fat feeding disturb lipid and cholesterol molecular markers.

Metabolic disorders are often associated with liver steatosis and increased plasma cholesterol levels. However, the link between excessive lipid accumulation and impairments in cholesterol metabolism remains uninvestigated in the liver. Short term of high-fat diet (HFD) was previously shown to promote excessive lipid accumulation prior to the development of metabolic disorders. The present study intended to characterize how increases in liver fat alter the expression of several key regulators of hepatic cholesterol metabolism in response to a short-term HFD. Wistar rats were randomly submitted either to HFD (n = 8) or a regular chow diet (n = 8) for 14 days. Increases in triglycerides were highly significant (P < 0.01) in the liver but marginal in the plasma of HFD rats. In contrast, the HFD resulted in higher (P < 0.01) cholesterol levels in plasma but not in liver samples. Gene expression of key markers involved in cholesterol uptake (LDL particles) including low-density lipoprotein receptor-related protein-1 (LRP-1) and protein convertase subtilisin/kexin type 9 (PCSK9) along with ATP-binding cassette, superfamily G, member 5 (ABCG5) involved in cholesterol exportation via bile ducts was found to be higher (P < 0.05) in response to the HFD. In contrast, expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), involved in cholesterol synthesis, was downregulated in the liver. The data support the concept that excessive accumulation of lipids promptly alters the expression of key genes regulating cholesterol metabolism in the liver. On a clinical point of view, this indicates that increases in plasma cholesterol occur after a short-term HFD.

Adverse effects of weight loss: Are persistent organic pollutants a potential culprit?

Health professionals commonly recommend weight loss to individuals with obesity. However, unexpected adverse health effects after a weight-loss program have been reported in several studies. The factors that could explain this phenomenon are currently poorly understood. However, one potential factor that has emerged is persistent organic pollutants (POPs). Due to their lipophilic nature, POPs are known to accumulate in the adipose tissue and their concentrations are found to be higher in obese individuals than lean subjects. There is evidence to suggest that weight loss induces a significant increase in POPs levels in the bloodstream. Furthermore, the increases in plasma POPs levels after weight loss are even greater with an intensive weight loss. Thus, a critical question that remains unresolved is whether POPs released from the adipose tissue to the bloodstream during intensive weight loss could increase the risk of cardiometabolic disturbances. In turn, the accumulation of POPs released in response to an intensive weight loss may impair energy metabolism and stimulate a subsequent weight regain. Thus, the purpose of this review is to provide insights about the role of POPs on cardiometabolic risk factors during weight loss and weight regain that could potentially explain, at least in part, the adverse effects observed in certain weight-loss studies. We will also discuss the potential synergistic or antagonistic POPs-dependent risks following weight-loss programs. Ultimately, this may lead in establishing new therapeutic boundaries to minimize potential health hazards related to weight loss.

Plasma glucose kinetics and response of insulin and GIP following a cereal breakfast in female subjects: effect of starch digestibility.

BACKGROUND/OBJECTIVES: Foods with high contents of slowly digestible starch (SDS) elicit lower glycemic responses than foods with low contents of SDS but there has been debate on the underlying changes in plasma glucose kinetics, that is, respective contributions of the increase in the rates of appearance and disappearance of plasma glucose (RaT and RdT), and of the increase in the rate of appearance of exogenous glucose (RaE) and decrease in endogenous glucose production (EGP). SUBJECTS/METHODS: Sixteen young healthy females ingested in random order four types of breakfasts: an extruded cereal (0.3% SDS: Lo-SDS breakfast) or one of three biscuits (39-45% SDS: Hi-SDS breakfasts). The flour in the cereal products was labeled with (13)C, and plasma glucose kinetics were measured using [6,6-(2)H2]glucose infusion, along with the response of plasma glucose, insulin and glucose-dependent insulinotropic peptide (GIP) concentrations. RESULTS: When compared with the Lo-SDS breakfast, after the three Hi-SDS breakfasts, excursions in plasma glucose, the response of RaE, RaT and RdT, and the reduction in EGP were significantly lower (P<0.05). The amount of exogenous glucose absorbed over the 4.5-h postprandial period was also significantly lower by ~31% (P<0.001). These differences were associated with lower responses of GIP and insulin concentrations. CONCLUSIONS: Substituting extruded cereals with biscuits slows down the availability of glucose from the breakfast and its appearance in peripheral circulation, blunts the changes in plasma glucose kinetics and homeostasis, reduces excursions in plasma glucose, and possibly distributes the glucose ingested over a longer period following the meal.

The GH-releasing effect of acylated ghrelin in normal subjects is refractory to GH acute auto-feedback but is inhibited after short-term GH administration inducing IGF1 increase.

OBJECTIVE: GH secretion is regulated by an interplay between GH-releasing hormone (GHRH), somatostatin (SST), and other central and peripheral signals. Acylated ghrelin (AG) amplifies GH pulsatility acting, at least partially, independently from GHRH and SST. The GH response to GHRH is inhibited by recombinant human GH (rhGH), likely due to a SST-mediated negative GH auto-feedback. The effect of exogenous rhGH on the GH-releasing effect of AG has never been tested. DESIGN AND METHODS: In six healthy volunteers, we studied the GH response to acute AG administration (1.0 µg/kg i.v.) during saline or rhGH infusion (4.0 µg/kg per h i.v.) or after 4-day rhGH (10.0 µg/kg s.c.) administration. RESULTS: Compared with saline, rhGH infusion increased GH levels (P<0.01). During saline, acute i.v. AG induced a marked increase (P<0.01) in GH levels similar to those observed after AG administration during rhGH infusion. During s.c. rhGH, IGF1 levels rose from day 0 to day 5 (P<0.01). After 4-day s.c. rhGH, i.v. AG increased (P<0.01) GH levels, though significantly (P<0.05) less than on day 0. CONCLUSIONS: The marked somatotroph-releasing effect of AG is refractory to a direct GH auto-feedback whereas is markedly inhibited after 4-day rhGH administration, suggesting the possibility of a selective IGF1-mediated inhibitory feedback.

Effect of secretin on preadipocyte, differentiating and mature adipocyte functions.

OBJECTIVE: Several gastrointestinal peptides are now recognized to have target functions beyond the intestinal wall, including effects on adipocytes. Secretin (SEC), one of the first identified, has not been evaluated in this context. METHODS: Using cultured 3T3-L1 preadipocytes, adipocytes and primary rat adipocytes we evaluated the effect of SEC on cell proliferation, mitochondrial activity, differentiation, triglyceride (TG) synthesis, lipolysis as well expression of the SEC receptor (SCTR) in rodent and human adipose tissues. RESULTS: In preadipocytes, SEC significantly increased mitochondrial activity (115%; P<0.01), thymidine incorporation (149.7%; P<0.05) and C/EBPß expression (123.4%; P<0.05). During standard differentiation, SCTR mRNA increased up to a maximum of ninefold (P<0.001). In human adipose tissue, SCTR correlated with body mass index and plasma insulin, and SCTR mRNA expression was also detected in rat adipose tissues. SEC supplementation during differentiation enhanced TG accumulation (+138%; P<0.01). In mature adipocytes, SEC increased fatty acid (FA) uptake (186%; P<0.01), adiponectin and monocyte chemotactic protein-1 secretion (+142% and +149%, respectively; P<0.05) and mRNA expression of PPARγ (+206%; P<0.01), FABP4 (+164%; P<0.001), DGAT-1 (+144%; P<0.01), adiponectin (+138%; P<0.001) and CD36 (+149%; P<0.05). In primary rat adipocytes, SEC also increased FA uptake (137%; P<0.05). Pretreatment with a SEC antagonist impaired SEC-induced FA uptake and cAMP accumulation. SEC treatment simultaneously stimulated lipolysis measured as glycerol release in 3T3-L1 adipocytes and rat adipose tissue. CONCLUSION: The present results suggest that SEC is a potent modulator of adipocyte functions, demonstrating overall a role in enhanced substrate cycling.

Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats.

BACKGROUND: Levodopa (L-dopa) is the most commonly used treatment for alleviating symptoms of Parkinson's disease. However, L-dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents L-dopa action on gastric emptying and enhances circulating L-dopa in rats. METHODS: Gastric emptying of non-nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) L-dopa, or intravenous (i.v.) ghrelin 10 min before orogastric L-dopa. Plasma L-dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 µg kg(-1)) 10 min before i.p. L-dopa. KEY RESULTS: Levodopa (5 and 15 mg kg(-1)) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 µg kg(-1), i.v.) completely prevented L-dopa's (15 mg kg(-1), orogastrically) inhibitory action on gastric emptying and enhanced plasma L-dopa and dopamine levels compared with vehicle 15 min after orogastric L-dopa. Levodopa (5 mg kg(-1)) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg(-1), i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. CONCLUSIONS & INFERENCES: Ghrelin counteracts L-dopa-induced delayed gastric emptying but not Fos induction in the brain and enhances circulating L-dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson's disease patients treated with L-dopa remain to be investigated.

Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans.

OBJECTIVE: To clarify the metabolic effects of an overnight i.v. infusion of unacylated ghrelin (UAG) in humans. UAG exerts relevant metabolic actions, likely mediated by a still unknown ghrelin receptor subtype, including effects on ß-cell viability and function, insulin secretion and sensitivity, and glucose and lipid metabolism. DESIGN: We studied the effects of a 16-h infusion (from 2100 to 1300  h) of UAG (1.0  µg/kg per h) or saline in eight normal subjects (age (mean±s.e.m.), 29.6±2.4 years; body mass index (BMI), 22.4±1.7  kg/m(2)), who were served, at 2100 and 0800  h respectively, with isocaloric balanced dinner and breakfast. Glucose, insulin, and free fatty acid (FFA) levels were measured every 20  min. RESULTS: In comparison with saline, UAG induced significant (P<0.05) changes in glucose, insulin, and FFA profiles. UAG infusion decreased glucose area under the curve (AUC) values by 10% (UAG(0 - 960  min): 79.0±1.7×10(3)  mg/dl per min vs saline(0- 960  min): 87.5±3.8×10(3)  mg/dl per min) and the AUC at night by 14% (UAG(180)(-)(660  min): 28.4±0.5×10(3)  mg/dl per min vs saline(180 - 660  min): 33.2±1.1×10(3)  mg/dl per min). The overall insulin AUC was not significantly modified by UAG infusion; however, insulin AUC observed after meals was significantly increased under the exposure to UAG with respect to saline at either dinner or breakfast. The FFA AUC values were decreased by 52% under the exposure to UAG in comparison with saline (UAG(0 - 960  min): 0.3±0.02×10(3)  mEq/l per min vs saline(0 - 960  min): 0.6±0.05×10(3)  mEq/l per min). CONCLUSIONS: Exposure to the i.v. administration of UAG improves glucose metabolism and inhibits lipolysis in healthy volunteers. Thus, in contrast to the diabetogenic action of AG, UAG displays hypoglycemic properties.

The metabolic response to the activation of the beta-adrenergic receptor by salbutamol is amplified by acylated ghrelin.

BACKGROUND: It is well recognized that beta-adrenergic receptors mediate important endocrine and metabolic actions. In fact, beta-adrenergic receptor activation negatively influences GH secretion while exerting relevant metabolic actions such as the stimulation of insulin secretion, glycogenolysis, and lipolysis. AIM: We have already shown that the activation of the GH secretagogue receptor (GHS-R)-1a by acylated ghrelin (AG) counteracts the inhibitory effect of salbutamol (SALB), a beta2-adrenergic agonist, on GH release. The aim of the present study in humans was to clarify whether the metabolic response to SALB is affected by the infusion of AG, also known to exert significant metabolic actions. METHODS: Six healthy young male volunteers underwent the following testing sessions in random order at least 5 days apart: a) SALB (0.06 microg/kg/min iv from 0 to 60 min) alone; b) SALB in combination with AG (1.0 microg/kg/min iv from -60 to 60 min); c) isotonic saline. Insulin, glucose, and free fatty acids (FFA) levels were evaluated every 15 min. RESULTS: As expected, with respect to saline, SALB administration tended to increase both insulin secretion [Delta area under the curve (DeltaAUC): 0.16+/-0.09 vs 0.003+/-0.077 x 10(3) microU/ml/min; p>0.05] and FFA levels (DeltaAUC: 8.0+/-7.3 vs -4.0+/-4.0 mEq/l/min; p>0.05), while glucose levels did not change. The metabolic response to SALB was significantly modified under the exposure of AG. In fact, under AG infusion, SALB elicited a more marked increase of FFA (DeltaAUC: 22.3+/-3.2 vs 8.0+/-7.3 mEq/l/min; p<0.05) as well as a slight elevation in insulin (DeltaAUC: 0.37+/-0.11 vs 0.16+/-0.09 x 10(3) microU/ml/min; p>0.05). Under AG, the baseline glucose levels were more elevated but, again, in combination with AG, SALB did not significantly modify glucose levels. CONCLUSIONS: Beta-adrenergic receptors and AG are likely to interact at the metabolic level. In humans, the lypolitic response to a beta2-adrenergic agonist such as SALB is amplified by AG. Meanwhile, during the co-treatment, the marginal insulinotropic effect was not associated with an increase in glycemia.

Circulating obestatin levels in normal and Type 2 diabetic subjects.

BACKGROUND: Obestatin has been discovered as a new product of the ghrelin gene. Its physiological actions are still a matter of debate, but it seems that this peptide is likely to be involved in the control of insulin secretion and action as well as of adipocyte function. It has been already shown that obestatin secretion in humans is negatively modulated by food intake. AIM: To clarify obestatin secretion in normal subjects and in patients with Type 2 diabetes (T2D) in basal conditions and after a standardized meal. SUBJECTS/METHODS: Five normal subjects and 5 T2D patients were studied during infusion of saline (iv for over 5 h from -120 to +180 min). A standardized lunch was served at 0 min. Obestatin, glucose, and insulin levels were assayed at -120, -90, -60, -45, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150, and 180 min. RESULTS: From -120 to 0 min, obestatin levels in normal and T2D subjects were similar (area under the curve: 32.3+/-5.6 pg/ml/min vs 31.1+/-1.0 pg/ml/min). After the meal, circulating obestatin levels underwent a clear decrease in normal subjects (0 min: 300.6+/-34.7 pg/ml vs nadir at 60 min: 161.8+/-29.4 pg/ml; p=0.002) but not in diabetic patients (0 min: 267.2+/-16.5 pg/ml vs nadir at 180 min: 226.0+/-10.5 pg/ml). CONCLUSION: This study shows that normal and diabetic subjects display similar levels of circulating obestatin in fasting condition. However patients with T2D look refractory to the inhibitory effect of meal on obestatin secretion.

Secretin: Should we revisit its metabolic outcomes?

Metabolic pathologies such as Type 2 Diabetes have become a major health problem for worldwide populations. Unfortunately, efforts to cure and especially to prevent these significant global problems have so far been met with disappointment. Recently, the involvement of the gut-derived hormonal dysregulation in the development of obesity-related disturbances has been intensively studied. For instance, studies of gut-derived peptides such as peptide YY 3-36, glucagon-like peptide-1, oxyntomodulin and, more recently, ghrelin have significantly improved our understanding of mechanisms underlying weight and metabolic regulation. Even though early reports of the existence of secretin, the first peptide hormone to be described, date back as far as 1825, so much and yet so little is still known about its physiological role in mammals, including humans. However, recent years have provided a better understanding of how the release of secretin is regulated by enteral secretagogues. On the other hand, most basic questions about its role in the post-prandial regulation of metabolic functions in normal and pathophysiological conditions remain to be elucidated. The present work intends to review the physiology of secretin along with its central and peripheral outcomes on metabolic functions.

Lack of obestatin effects on food intake: should obestatin be renamed ghrelin-associated peptide (GAP)?

Obestatin is a newly identified ghrelin-associated peptide (GAP) that is derived from post-translational processing of the prepro-ghrelin gene. Obestatin has been reported initially to be the endogenous ligand for the orphan receptor G protein-coupled receptor 39 (GPR39), and to reduce refeeding- and ghrelin-stimulated food intake and gastric transit in fasted mice, and body weight gain upon chronic peripheral injection. However, recent reports indicate that obestatin is unlikely to be the endogenous ligand for GPR39 based on the lack of specific binding on GRP39 receptor expressing cells and the absence of signal transduction pathway activation. In addition, a number of studies provided convergent evidence that ghrelin injected intracerebroventricularly or peripherally did not influence food intake, body weight gain, gastric transit, gastrointestinal motility, and gastric vagal afferent activity, as well as pituitary hormone secretions, in rats or mice. Similarly, obestatin did not alter ghrelin-induced stimulation of food intake or gastric transit. Therefore, the present state-of-knowledge on obestatin and GPR39 is leaving many unanswered questions that deserve further consideration. Those relate not only to redefining the biological action of obestatin that should be renamed GAP, but also the identification of the native ligand for GPR39.

Lack of interaction between peripheral injection of CCK and obestatin in the regulation of gastric satiety signaling in rodents.

Obestatin is a new peptide for which anorexigenic effects were recently reported in mice. We investigate whether peripheral injection of obestatin or co-injection with cholecystokinin (CCK) can modulate food intake, gastric motor function (intragastric pressure and emptying) and gastric vagal afferent activity in rodents. Obestatin (30, 100 and 300 microg/kg, i.p.) did not influence cumulative food intake for the 2h post-injection in rats or mice nor gastric emptying in rats. In rats, obestatin (300 microg/kg) did not modify CCK (1 microg/kg, i.p.)-induced significant decrease in food intake (36.6%) and gastric emptying (31.0%). Furthermore, while rats injected with CCK (0.3 microg/kg, i.v.) displayed gastric relaxation, no change in gastric intraluminal pressure was elicited by obestatin (300 microg/kg, i.v.) pre- or post-CCK administration. In in vitro rat gastric vagal afferent preparations, 20 units that had non-significant changes in basal activity after obestatin at 30 microg responded to CCK at 10 ng by a 182% increase. These data show that obestatin neither influences cumulative food intake, gastric motility or vagal afferent activity nor CCK-induced satiety signaling.

Lifestyle behaviours and components of energy balance as independent predictors of ghrelin and adiponectin in young non-obese women.

AIM: Dysregulation of the normal levels of ghrelin, leptin and adiponectin in young non-obese subjects could promote food intake, diabetes and cardiovascular disease in later stages of life. Little information is available on how plasmatic concentrations of these hormones may be influenced by eating habits and/or components of energy balance in a young population, which if known, could facilitate their voluntary regulation. METHODS: In this cross-sectional study we examined the predictors of fasting plasma ghrelin, adiponectin and leptin in a population of well-characterized young non-obese women (N = 63). Energy intake was assessed by 24-hour dietary recall, resting metabolic rate (RMR) by indirect calorimetry, physical activity energy expenditure (PAEE) by tri-axial accelerometer, physical fitness by VO(2 peak), and eating behaviors by self administrated questionnaire. RESULTS: Lower RMR and higher HDL-cholesterol were independent predictors of higher plasma ghrelin explaining 17.6% of its variation even after correcting for BMI. Higher total or central fat mass was the only predictor of higher plasma leptin, and no other variable added any power to the prediction equation. Finally, higher energy intake and waist circumference and lower PAEE predicted lower plasma adiponectin in young non-obese women, explaining 43% of the variation in its concentrations even after correcting for total or central fat mass. CONCLUSION: Components of the energy balance (ie: energy intake and/or expenditure) influence adiponectin and ghrelin circulating levels. That is, higher energy intake and lower physical activity independently predict lower adiponectin concentrations, whereas lower resting metabolic rate independently predicts higher ghrelin levels in young non-obese women. Prospective studies are needed to examine whether circulating concentrations of ghrelin and adiponectin can be voluntarily regulated by lifestyle interventions.

Surrogate indexes vs. euglycaemic-hyperinsulinemic clamp as an indicator of insulin resistance and cardiovascular risk factors in overweight and obese postmenopausal women.

BACKGROUND: There is considerable interest in validating the most convenient method to estimate insulin sensitivity in clinical research protocols that could best indicate cardiovascular risk factors. To address this issue we examined the interrelationships of several cardiovascular risk factors with surrogate indexes such as fasting insulin, the homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI) and the revised QUICKI vs the euglycaemic-hyperinsulinemic (EH) clamp in a non-diabetic overweight or obese postmenopausal female population. DESIGN: Cross-sectional study involving 88 obese postmenopausal women (age: 57.5+/-5.0 yrs; body mass index: 32.52+/-4.4 kg/m2; percent body fat: 46.35+/-4.9%). METHODS: Insulin sensitivity was determined by the EH clamp technique as well as by surrogate indexes such as fasting insulin, HOMA, log HOMA, QUICKI and revised QUICKI. Body composition and body fat distribution were measured using dual energy x-ray absorptiometry and computed tomography, respectively. RESULTS: Correlations between insulin resistance indexes (fasting insulin, revised QUICKI, QUICKI, log HOMA, HOMA) vs glucose disposal were similar (range of r's=0.40 to 0.49), suggesting that no index was superior to another with respect to its relationship with the EH clamp. Correlations between the insulin resistance indexes with plasma lipids were comparable among all indexes, however, systolic blood pressure, visceral fat and C-reactive protein were moderately superior with index vs the EH clamp. CONCLUSION: Surrogate measures of insulin resistance, in particular fasting insulin, are simple tools appropriate for epidemiological studies that can be used as substitutes for the EH clamp to estimate glucose disposal and cardiovascular risk factors in overweight and obese postmenopausal women.

Degradation in insulin sensitivity with increasing severity of the metabolic syndrome in obese postmenopausal women.

AIM: We investigated the relationship between insulin sensitivity and the graded increase in the number of features of the metabolic syndrome in a cross-sectional sample of obese postmenopausal women. We hypothesized that insulin sensitivity would deteriorate with an increased number of metabolic syndrome phenotypes. METHODS: Insulin sensitivity was measured in 75 obese postmenopausal women (age: 57.3 +/- 5.3 years; BMI: 32.8 +/- 4.5 kg/m2) by using both the hyperinsulinaemic-euglycaemic clamp and the homeostasis model assessment (HOMA-IR). Features of the metabolic syndrome included visceral fat (>130 cm2), HDL-cholesterol (<1.29 mmol/l), fasting triglycerides (> or =1.7 mmol/l), blood pressure (> or =130/> or =85 mmHg) and fasting glucose (> or =6.1 mmol/l). Participants were classified into three categories based on the presence of metabolic syndrome phenotypes: 0-1 vs. 2 vs. > or =3 features of the metabolic syndrome. RESULTS: We found that insulin sensitivity decreased in a graded fashion (12.19 +/- 3.2 vs. 11.80 +/- 2.3 vs. 9.29 +/- 2.6 mg/min/FFM) and HOMA-IR increased in a similar manner (2.95 +/- 1.1 vs. 3.28 +/- 1.3 vs. 4.65 +/- 2.2), as the number of features of the metabolic syndrome increased from 0-1 to > or =3. When insulin sensitivity was statistically adjusted for visceral fat (as measured by computed tomography) and plasma triglycerides, the differences among groups were abolished. CONCLUSIONS: These findings suggest that a decreased insulin sensitivity is associated with increased features of the metabolic syndrome in obese postmenopausal women and that visceral fat as well as plasma triglyceride accumulation might be potential mediators of this relationship.