Metabolically healthy and unhealthy weight statuses, health issues and related costs: Findings from the 2013-2015 European Health Examination Survey in Luxembourg.

AIM: To investigate the relationship between metabolically healthy and unhealthy weight statuses and a wide range of related health issues, and healthcare and loss-of-productivity costs. METHODS: A total of 693 men and 729 women, aged 25-64 years, took part in the European Health Examination Survey conducted in Luxembourg between 2013 and 2015. Metabolically unhealthy normal-weight profiles were defined as having two or more cardiometabolic abnormalities (high blood pressure, high fasting glucose or triglycerides, low HDL cholesterol and/or previously diagnosed hypertension or diabetes) in people with normal weight. Metabolically healthy overweight/obesity was defined as having fewer than two of the above-mentioned abnormalities in people with overweight or obesity. For the present report, the participants' anthropometric, clinical, biological, sociodemographic, lifestyle and health-related data were analyzed. RESULTS: Of the participants with normal weight, 20% had a metabolically unhealthy profile, whereas 60% with overweight and 30% with obesity had a metabolically healthy profile. Comparisons between metabolically healthy and unhealthy normal weight, overweight and/or obesity status revealed that participants presented with a metabolically unhealthy profile independently of weight status (P<0.0001). People with a metabolically healthy profile were more likely to perceive their health as good (66%; P<0.0001), and to report no physical pain (64%; P=0.03), no limitations in daily activities (66%; P=0.0008), no difficulties getting in or out of a bed or chair (63%; P=0.02) or dressing and undressing (63%; P=0.003), going shopping (63%; P=0.053) or doing occasional heavy housework (64%; P=0.007); they also displayed fewer gastrointestinal (63%; P=0.02), arthrosis (64%; P=0.001) and sleep apnoea issues (63%; P=0.002) compared with those with a metabolically unhealthy profile. Healthcare- and loss-of-productivity-related costs were higher with a metabolically unhealthy profile, with differences of up to € 3000 (P=0.02). CONCLUSION: The present work has highlighted that, independently of weight status, people may develop a metabolically unhealthy profile associated with several health issues as well as higher healthcare and loss-of-productivity costs.

Subtraction of subcutaneous fat to improve the prediction of visceral adiposity: exploring a new anthropometric track in overweight and obese youth.

BACKGROUND: The efficiency of traditional anthropometric measurements such as body mass index (BMI) or waist circumference (Waist C) used to replace biomedical imaging for assessing visceral adipose tissue (VAT) is still highly controversial in youth. HYPOTHESIS AND OBJECTIVES: We evaluated the most accurate model predicting VAT in overweight/obese youth, using various anthropometric measurements and their correlation with different body fat compartments, especially by testing, for the first time in youth, the hypothesis that subtracting the anthropometric measurement the most highly correlated with subcutaneous abdominal adipose tissue (SAAT) and less correlated possible with VAT from an anthropometric abdominal measurement highly correlated with visceral and total abdominal adipose tissue (TAAT), predicts VAT with higher accuracy. SUBJECTS AND METHODS: VAT and SAAT data resulted from magnetic resonance imaging (MRI) analysis performed on 181 boys and girls (7-17 y) from Diabetes & Endocrinology Care Paediatrics Clinic in Luxembourg. Height, weight, abdominal diameters, waist, hip, and thigh circumferences were measured with a view to developing the anthropometric VAT predictive algorithms. RESULTS: In girls, subtracting proximal thigh circumference (Proximal Thigh C), the most closely correlated anthropometric measurement with SAAT, from Waist C, the most closely correlated anthropometric measurement with VAT was instrumental in improving VAT prediction, in comparison with the most accurate single VAT anthropometric surrogate. [Formula: see text] Residual analysis showed a negligible estimation error (5 cm2 ). In boys, Waist C was the best VAT predictor. CONCLUSIONS: Subtraction of abdominal subcutaneous fat is important to predict VAT in overweight/obese girls.

Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: relationship to metabolic profile, cardiac function and visceral fat.

OBJECTIVE: To assess epicardial fat volume (EFV), myocardial TG content (MTGC) and metabolic profile in severely obese patients, and to determine whether ectopic fat depots are linked to metabolic disorders or myocardial function. RESEARCH DESIGN AND METHODS: Sixty-three subjects with normal LV function and no coronary artery disease, including 33 lean (BMI: 21.4 ± 2.0 kg m(-2)) and 30 obese (BMI: 41.8 ± 6 kg m(-2)) patients, underwent 3-T cardiovascular MRI, and anthropometric, biological and visceral abdominal fat (VAT) assessments. EFV was measured by short-axis slice imaging and myocardial (intra-myocellular) TG content was measured by proton magnetic resonance spectroscopy. RESULTS: EFV and MTGC were positively correlated (r=0.52, P<0.0001), and were both strongly correlated with age, BMI, waist circumference and VAT, but not with severity of obesity. EFV and MTGC were significantly higher in obese patients than in lean controls (141 ± 18 versus 79 ± 7 ml, P=0.0001; 1.0 ± 0.1 versus 0.6 ± 0.1%, P=0.01, respectively), but some differences were found between the two cardiac depots: EFV was higher in diabetic obese subjects as compared with that in non-diabetic obese subjects (213 ± 34 versus 141 ± 18 ml, P=0.03), and was correlated with parameters of glucose tolerance (fasting plasma glucose, insulin and HOMA-IR), whereas MTGC was not. EFV and MTGC were both associated with parameters of lipid profile or inflammation (TGs, CRP). Remarkably, this was VAT-dependent, as only VAT remained independently associated with metabolic parameters (P<0.01). Concerning myocardial function, MTGC was the only parameter independently associated with stroke volume (ß=-0.38, P=0.01), suggesting an impact of cardiac steatosis in cardiac function. CONCLUSIONS: These data show that VAT dominates the relationship between EFV, MTGC and metabolic measures, and uncover specific partitioning of cardiac ectopic lipid deposition.

Ramadan fasting with diabetes: an interview study of inpatients' and general practitioners' attitudes in the South of France.

AIM: The aim of this study was to evaluate attitudes in hospital inpatients and physicians towards Ramadan fasting and diabetes in Marseille. METHODOLOGY: This cross-sectional study was conducted during the three months prior to the month of Ramadan. A total of 101 patients (age: 57±17 years) and 101 general practitioners (GPs) were recruited into the study. RESULTS: The patients had low levels of education (52% illiteracy). Of the 101 patients, 52 continued to fast during Ramadan, and only 65 patients had discussed the matter with their GP. Of these, 36 were told that fasting was forbidden, but more than half (n=19) fasted despite the medical advice. Six patients thus experienced daily hypoglycaemia because they had continued to take their hypoglycaemic agent or insulin analogue at noon. Both inadequate education and religious attitudes were found to endanger patients during the fast: 15 patients skipped the meal scheduled before dawn, five of whom persisted in taking their sulphonylurea. Also, 27% of patients refused, in spite of daytime hypoglycaemia, to ingest anything orally to avoid breaking their fast. Among the GP population, medical knowledge of Ramadan fasting with diabetes was low, leading to medically unjustified negative advice for fasting and a lack of patient education on adjusting treatments. This particular situation weakened the patient-physician relationship. CONCLUSION: This study confirms the importance of Ramadan fasting for Muslim patients, and reveals a wide cross-cultural gap between GPs and their patients. Systematic advice on treatment adjustment needs to be given. For this reason, we encourage more sensitive care of these patients and more medical training for physicians.

Effect of sleep apnea syndrome on the circadian profile of cortisol in obese men.

It has been hypothesized that sleep apnea syndrome (SAS) increases hypothalamic-pituitary-adrenal axis activity and, through increased cortisol levels, participates in the pathophysiology of metabolic and cardiovascular complications. We compared the circadian profiles of cortisol in obese men with [obSAS+; apnea-hypopnea index (AHI) >or= 20/h] and without SAS (obSAS-; AHI

[Food intake: who controls what?]. / Prise alimentaire: qui contrôle quoi?

Since the discovery of leptin and the characterization of the mechanisms leading to obesity in several animal models, considerable advance has been gained in the field of energy homeostasis. The hypothalamus plays a pivotal role in the short and long term regulatory loops that control food intake and body weight. Multiple peripheral signals, including leptin and insulin, convey information on the nutritional and metabolic status to the central nervous system. In the hypothalamus, these signals modulate several neuropeptides and intricate neuronal pathways that trigger appropriate responses of food intake and also of the autonomous nervous system and of the pituitary functions. Peripheral signals and hypothalamic neuropeptides, characterized in the last decade may represent potential targets for new pharmacological treatments of obesity. However, because of the complexity of weight regulation, such approaches may appear troublesome.

IGF-I/IGFBPs system response to endotoxin challenge in sheep.

Endotoxin (LPS), a membrane component of gram-negative bacteria produces multiple endocrine and metabolic effects that mimic those seen in acute sepsis. It induces species-dependent alterations of the growth hormone (GH) axis that may participate in the shift of the metabolism towards catabolic events. Humans and sheep show increased GH secretion in response to LPS, as opposed to rats, which have been the most studied. The purpose of our work was to evaluate the effects in intact rams of an acute intravenous administration of a high dose of LPS on the insulin-like growth factor (IGF)-I/IGF-binding proteins (IGFBPs) system and to analyse the temporal relationship of GH axis changes with those of several hormonal and metabolic parameters such as somatostatin, cortisol, insulin, and glucose. LPS induced a late moderate decrease of total IGF-I plasma levels following a 5-h steady-state period (-26.6+/-4. 2%, P<0.05, 9 h after LPS), despite a biphasic and sustained increase of GH secretion in the same animals (2.48+/-0.39 ng/ml 2 h after LPS and 2.7+/-0.37 ng/ml 5 h after LPS vs 0.77+/-0.10 before LPS; Briard et al. 1998a). Western ligand blot analysis in IGFBPs showed an early short-lasting increase in IGFBP-1 (188.8+/-39% P<0. 05, 3 h after LPS). No significant change was seen for either IGFBP-2, -3 or -4. We observed a marked and sustained increase in cortisol (128.18+/-7.21 ng/ml 3 h after LPS, vs 21.17+/-4.22 before LPS). Insulin also increased (27.69+/-3.90 microU/ml 3 h after LPS, vs 13.48+/-1.69 before LPS) and its burst coincided with that of IGFBP-1. Moderately decreased IGF-I and increased IGFBP-1 plasma levels contrasted with the sustained increase in GH secretion that we recently described, thereby suggesting that endotoxin causes a state of resistance to GH. This may be exacerbated by reduced IGF-I bioavailability and/or action, and which may participate in the pathophysiology of the catabolic state seen in sepsis. The temporal analysis of hormone responses suggests that endotoxin-induced alterations of the IGF-I/IGFBPs system may involve the prolonged and substantial somatostatin rise that we recently demonstrated, together with an increase in glucocorticoid and cytokine as more generally assumed.

Combined hypervolemia and hypoosmolality alter hypothalamic-pituitary-adrenal axis response to endotoxin stimulation.

Changes in corticotropin (ACTH) and glucocorticoid secretion have been described during disturbances of body fluid homeostasis and attributed to alterations in arginine vasopressin (AVP) secretion from magnocellular hypothalamic neurons. In order to further characterize the mechanisms involved in the interactions between body fluid alterations and pituitary adrenal function, we manipulated osmolality and volemia in sheep under stimulation of the pituitary-adrenal axis by acute injection of endotoxin. We have recently shown that endotoxin injection induces a long-lasting release of both corticotropin releasing hormone (CRH) and AVP into hypophysial portal blood, and an early stimulation of AVP secretion into peripheral vessels, thus suggesting a joint activation of magnocellular and parvocellular neurons of the PVN. We used the same experimental model to investigate the effect of combined volume loading and plasma dilution (achieved by 1-deamino-8-D-arginine (dDAVP) administration together with infusion of 2 liters of 2.5% glucose solution) on CRH, AVP, ACTH and cortisol responses to endotoxin stimulation. In volume-loaded animals, ACTH and cortisol responses to endotoxin were significantly blunted and we observed a parallel decrease in portal CRH and jugular and portal AVP levels. These data show that hypoosmolality and/or hypervolemia reduce(s) ACTH and cortisol response to stress in sheep as in other species. They strongly suggest that this reduction in ACTH and cortisol responses to endotoxin involve not only magnocellular hypothalamic neurons secreting AVP, as usually assumed, but also PVN parvocellular neurons secreting both CRH and AVP.

On the meaning of low-dose ACTH(1-24) tests to assess functionality of the hypothalamic-pituitary-adrenal axis.

To analyse further the ACTH(1-24) low-dose test, which is of clinical interest, we have examined the dose-response relationship between plasma ACTH(1-24) and cortisol concentrations after i.v. administration of increasing doses (1, 5 or 250 microg) of ACTH(1-24) as a bolus. In addition, we have measured plasma ACTH(1-39) and cortisol levels after an insulin tolerance test (ITT). Although there was a dose response relationship between plasma ACTH(1-24) immunoreactivity and the dose injected, cortisol peaks were comparable, but lower than those reached after an ITT. Under these experimental conditions, an increase in plasma ACTH as low as 13 pmol/l (i.e. the increase obtained with the 1 microg dose) induced a near maximal cortisol response. Following injection of 1 microg ACTH(1-24), peak ACTH values were short lasting, similar to physiological daily bursts. After injection of 5 microg ACTH(1-24), plasma ACTH concentrations were higher than those reached during an ITT, but clearly shorter lasting. Injection of 250 microg ACTH(1-24) induced strikingly supraphysiological levels of plasma ACTH. We conclude that neither regular nor low-dose ACTH tests can fully reproduce the ITT. Our observations strongly suggest that the low-dose ACTH(1-24) test (1 microg) can be useful to estimate the adrenal sensitivity under basal, physiological conditions.

Hypothalamic mediated action of free fatty acid on growth hormone secretion in sheep.

Experimental data suggest that elevated FFA levels play a leading role in the impaired GH secretion in obesity and may therefore contribute to the maintenance of overweight. GH has a direct lipolytic effect on adipose tissue; in turn, FFA elevation markedly reduces GH secretion. This suggests the existence of a classical endocrine feedback loop between FFA and GH secretion. However, the FFA mechanism of action is not yet understood. The involvement of somatostatin (SRIH) is controversial, and in vitro experiments suggest a direct effect of FFA on the pituitary. In sheep it is possible to collect hypophysial portal blood and quantify SRIH secretion in hypophysial portal blood under physiological conscious and unstressed conditions. In this study we determined the effects of FFA (Intralipid and heparin) infusion on peripheral GH and portal SRIH levels in intact rams chronically implanted with perihypophysial cannula and in rams actively immunized against SRIH to further determine SRIH-mediated FFA effects on GH axis. Immediately after initiation of Intralipid infusion, we observed a marked increase in the FFA concentration (2160 +/- 200 vs. 295 +/- 28 nmol/ml; P < 0.01) as well as a significant decrease in basal GH secretion (1.8 +/- 0.1 vs. 2.5 +/- 0.3 ng/ml; P < 0.05) and a drastic reduction of the GH response to i.v. GH-releasing hormone injection (4.8 +/- 0.7 ng/ml in FFA group vs. 35.8 +/- 9.7 ng/ml in saline group; P < 0.01). No change in plasma insulin-like growth factor I levels was observed. During the first 2 h of infusion, the GH decrease observed was concomitant with a significant increase in portal SRIH levels (22.1 +/- .2 vs. 13 +/- 1.6 pg/ml; P < 0.01). In rams actively immunized against SRIH, the effect of FFA on basal GH secretion was biphasic. During the first 90 min of infusion, the decrease in GH induced by FFA was significantly blunted in rams actively immunized against SRIH (57 +/- 9% for immunized rams vs. 23.5 +/- 2.5% for control rams). This corresponds to the period of increased SRIH portal levels. After this first 90-min period, no difference was seen between control and immunized rams. Our results show that FFA exert their inhibitory action on the GH axis at both pituitary and hypothalamic levels, the latter mainly during the first 90 min, through increased SRIH secretion.

Effect of endotoxin on the hypothalamic-pituitary-adrenal axis in sheep.

Endotoxin has been shown to stimulate ACTH and cortisol secretion through an action at the hypothalamic level. However, the nature of hypothalamic neurohormones, corticotropin-releasing hormone (CRH) and especially arginine vasopressin (AVP), involved in that regulation is still controversial. The purpose of this study was to determine the effects of an acute i.v. endotoxin administration on CRH and AVP secretion into hypophysial portal blood (HPB). The experiment has been performed in sheep since it is possible to collect HPB and quantify CRH and AVP secretion in this animal under physiological conditions. The release of both peptides into HPB was stimulated by endotoxin injection, the increase in portal AVP being more pronounced than that of CRH. An initial, transient, increase in jugular AVP concentrations was observed, probably due to the activation of magnocellular AVP neurons. In conclusion, our data indicate that the activation of the pituitary-adrenal axis after endotoxin injection is associated with an increased release of both CRH and AVP into HPB. Magnocellular AVP neurons are initially stimulated while parvocellular CRH and AVP neurons are stimulated throughout the experiment.

Refinement of genetic localization of the Alström syndrome on chromosome 2p12-13 by linkage analysis in a North African family.

Alström syndrome is a rare autosomal recessive disorder characterized by retinal pigment degeneration, neurogenic deafness, infantile obesity, hyperlipidemia, and non-insulin-dependent diabetes mellitus. While the disease-related gene remains unknown, studies of the genetic isolate of French Acadians provisionally locate the Alström syndrome on chromosome 2p12-13 within a 14.9-cM interval. To confirm this finding in another ethnic population and refine the candidate region we investigated by linkage analysis a consanguineous family of North African origin, in which three of seven siblings displayed all major neurological and metabolic features of Alström syndrome. Genotyping was performed on an ABI377 DNA automatic sequencer and LOD scores were obtained with the Fastlink program. Five markers previously investigated in French Acadians confirmed the involvement of the candidate region, although pairwise LOD scores were of poor significance (Zmax = 2.9). To further confirm homogeneity and refine the candidate region, 20 additional markers were investigated. Haplotype analysis and allele segregation revealed that affected children shared a single haplotype and were homozygous for the eight most centromeric markers (D2S291-D2S2114), over a 6.1-cM interval. Significative multipoint LOD scores (Zmax = 3.96) were obtained between markers D2S2110/145 and D2S286. Two clusters of known genes are present in this refined region of chromosome 2p, the most attractive candidate being the hexokinase II gene. However, except for several known polymorphisms, no mutations were detected in the coding region of this gene. In conclusion, the location of Alström syndrome on chromosome 2p12-13 is confirmed, reducing the genetic interval to 6.1 cM.

Hormonal response to stress in brittle diabetes.

Acute psychological stress may play a role in the glycaemic instability of some patients with type I diabetes through an increased secretion of insulin-counteracting hormones. To examine the validity of this hypothesis, we subjected to a video-recorded public-speaking stress seven healthy persons, six type I diabetics with stable blood glucose levels and six type I diabetics with unstable or brittle diabetes (with more than 10 hypoglycaemia/month and frequent hyperglycaemia). During the test and on a control day, heart rate, blood pressure, plasma ACTH, cortisol, catecholamines and prolactin were measured. The comparison between the stable and unstable diabetics during the stress session by two-way analysis of variance (group/time) showed a significant difference for heart rate, blood pressure, ACTH and cortisol. Psychological interview showed that most unstable diabetics perceived a link between life stress and their blood glucose control. The unstable patients had much more difficulty in verbalizing their emotions. Our study shows that the two groups of diabetic patients display distinct cardiovascular and neuroendocrine responses to psychological stress, as well as distinct psychological profiles. In conclusion, hormonal response to an acute psychological stress is more pronounced in brittle diabetes and might be one of its pathogenic factors.

Decreased Na/K ATPase ouabain binding sites in red blood cells of patients with insulin-dependent diabetes and healthy north African control subjects: relationship with diabetic neuropathy.

Like other degenerative complications occurring during diabetes, development of neuropathy is determined mainly by the duration of disease and quality of control. However, there may be some predisposing factors. Activity of Na/K ATPase has been implicated in the pathophysiology of diabetic neuropathy. A decrease in the activity of this enzyme has been observed in red blood cells of poorly controlled diabetic patients and healthy North African subjects who are predisposed to diabetic neuropathy. This study was performed to characterize abnormalities of Na/K ATPase activity in these two populations. For this purpose we measured enzyme activity (hydrolysis of ATP) and the number of enzyme units (number of binding sites for ouabain) in the red blood cells of three groups of men, i.e., healthy Caucasian subjects, healthy North African subjects and Caucasian insulin-dependent diabetic patients. The level of Na/K ATPase activity and the number of enzyme units were about 30% lower in the red blood cells of diabetic patients and North African subjects, than in healthy Caucasian controls. In healthy North African subjects predisposed to neuropathy in case of development of diabetes, the decrease in enzymatic activity was correlated with a decrease in the number of enzyme units. This correlation was not observed in diabetic patients. We speculate that the constitutional decrease in Na/K ATPase activity in healthy North African subjects corresponds to a quantitative defect, whereas the acquired decrease in diabetic patients corresponds to a qualitative defect probably related to the structure of the lipid membrane.

Effect of actively immunizing sheep against growth hormone-releasing hormone or somatostatin on spontaneous pulsatile and neostigmine-induced growth hormone secretion.

The physiological role of endogenous circulating GH-releasing hormone (GHRH) and somatostatin (SRIH) on spontaneous pulsatile and neostigmine-induced secretion of GH was investigated in adult rams actively immunized against each neuropeptide. All animals developed antibodies at concentrations sufficient for immunoneutralization of GHRH and SRIH levels in hypophysial portal blood. In the anti GHRH group, plasma GH levels were very low; the amplitude of GH pulses was strikingly reduced, although their number was unchanged. No stimulation of GH release was observed after neostigmine administration. The reduction of GH secretion was associated with a decreased body weight and a significant reduction in plasma IGF-I concentration. In the anti-SRIH group, no changes in basal and pulsatile GH secretion or the GH response to neostigmine were observed as compared to controls. Body weight was not significantly altered and plasma IGF-I levels were reduced in these animals. These results suggest that in sheep, circulating SRIH (in the systemic and hypophysial portal vasculature) does not play a significant role in pulsatile and neostigmine-induced secretion of GH. The mechanisms of its influence on body weight and production of IGF-I remain to be determined.

Effect of streptozotocin-induced diabetes on somatostatin receptors in the anterior pituitary, hypothalamus and cerebral cortex of the male rat.

In order to better understand the mechanisms underlying the reduction in GH secretion in diabetic rats, we have characterized and measured SRIH receptors in the hypothalamus and anterior pituitary gland 5 and 9 days after induction of diabetes in the rat. Experimental diabetes was induced by an intraperitoneal injection of streptozotocin (STZ) at a dose of 65 mg/kg. Basal plasma GH was significantly reduced in diabetic rats. Chronic insulin replacement therapy partly restored plasma GH and blood glucose levels in these animals. A significant reduction in SRIH receptor concentrations was demonstrated in the hypothalamus and anterior pituitary gland, 5- and 9- days after STZ injection. These changes were not significantly corrected by insulin replacement. Cerebral cortex SRIH receptor concentrations were unaffected by experimental diabetes. We conclude that hypothalamic and pituitary SRIH receptor levels are lowered in diabetic rats. These changes may contribute to aberrant GH secretion in diabetes and they indicate that pituitary sensitivity to exogenous somatostatin should be tested in diabetic patients.