Effect of androgen deprivation therapy on cognitive functioning in men with prostate cancer: A systematic review.

The objective of this study was to review publications assessing cognitive functioning in patients with prostate cancer treated with androgen deprivation therapy. We conducted a systematic review of the literature published in PubMed, Embase, Web of Science, Cochrane Library, and PsycINFO up to February 2020. A total of 31 studies were included. Half of the studies (n = 16) demonstrated that androgen deprivation therapy in patients with prostate carcinoma did not result in a negative effect on cognitive functioning, however, still a substantial proportion of the studies (n = 11) reported a negative effect on cognitive functioning. In four studies the results were inconclusive. In the three studies using additional functional magnetic resonance imaging, no significant effect on neuropsychological tests was found, but grey matter volume, brain activity, and brain connectivity were affected. Given the substantial number of studies showing a significant negative effect of androgen deprivation therapy on cognitive functioning, clinicians should be aware of this side effect. Furthermore, future research should focus on the further examination of brain characteristics using functional magnetic resonance imaging, since these techniques might be more sensitive in detecting brain abnormalities as a result of androgen deprivation therapy.

Lipid droplet dynamics and insulin sensitivity upon a 5-day high-fat diet in Caucasians and South Asians.

A 5-day High-Fat High-Calorie diet (HFHC-diet) reduces insulin-stimulated glucose disposal (Rd) in South Asian, but not Caucasian healthy lean males. We aimed to investigate if differences in myocellular lipid handling are underlying this differential response. A two-step hyperinsulinemic-euglycemic clamp and muscle biopsies were performed in 12 healthy lean Caucasian and South Asian males (BMI < 25 kg/m2, 19-25 years) before and after a 5-day HFHC-diet (regular diet + 375 mL cream/day; 1275 kcal/day; 94% fat). Triglyceride extractions and Western Blots for lipid droplet and mitochondrial proteins were performed. Intramyocellular lipid content and HFHC-diet response were similar between ethnicities (group effect: P = 0.094; diet effect: +~30%, P = 0.044). PLIN5 protein content increased upon the HFHC-diet (P = 0.031) and tended to be higher in South Asians (0.87 ± 0.42 AU vs. 1.35 ± 0.58 AU, P = 0.07). 4-HNE tended to increase in South Asians upon the HFHC-diet (interaction effect: P = 0.057). In Caucasians ΔPLIN5 content correlated with ΔRd (Caucasians: r = 0.756, P = 0.011; South Asians: r = -0.085, P = 0.816), while in South Asians Δ4-HNE associated with ΔPLIN5 content (Caucasians: r = 0.312, P = 0.380; South Asians: r = 0.771, P = 0.003). These data indicate that in Caucasians, PLIN5 may be protective against HFHC-diet induced insulin resistance, which for reasons not yet understood is not observed in South Asians, who possess increased lipid peroxidation levels.

Middle-aged overweight South Asian men exhibit a different metabolic adaptation to short-term energy restriction compared with Europeans.

AIMS/HYPOTHESIS: South Asians have a higher risk of developing type 2 diabetes than Europeans. The underlying cause of this excess risk is still poorly understood but might be related to differences in the regulation of energy/nutrient-sensing pathways in metabolic tissues and subsequent changes in whole-body substrate metabolism. In this study, we investigated the whole-body and skeletal muscle metabolic adaptations to short-term energy restriction in South Asian and European volunteers. METHODS: Twenty-four middle-aged overweight South Asian and European men underwent a two-step hyperinsulinaemic-euglycaemic clamp, with skeletal muscle biopsies and indirect calorimetry before and after an 8 day diet very low in energy (very low calorie diet [VLCD]). Abdominal fat distribution and hepatic triacylglycerol content were assessed using MRI and MR spectroscopy. RESULTS: South Asian men had higher hepatic triacylglycerol content than European men, and exhibited elevated clamp insulin levels that probably reflect a lower insulin clearance rate. Despite higher insulin levels, endogenous glucose production rate was similar and glucose disposal rate (Rd) and nonoxidative glucose disposal rate (NOGD) were significantly lower in South Asian than European men, indicating impaired whole-body insulin sensitivity. Energy restriction decreased abdominal fat mass and hepatic triacylglycerol content in both groups. However, the shift induced by energy restriction from glucose towards lipid oxidation observed in European men was impaired in South Asian men, indicating whole-body metabolic inflexibility. Remarkably, although energy restriction improved hepatic insulin sensitivity in both groups, Rd improved only in South Asian men owing to higher NOGD. At the molecular level, an increase in insulin-induced activation of the skeletal muscle mTOR pathway was found in South Asian men, showing that skeletal muscle energy/nutrient-sensing pathways were differentially affected by energy restriction. CONCLUSIONS/INTERPRETATION: We conclude that South Asian men exhibit a different metabolic adaptation to short-term energy restriction than European men. TRIAL REGISTRATION: Dutch trial registry ( www.trialregister.nl ), trial number NTR 2473.

Short-term high-fat diet increases macrophage markers in skeletal muscle accompanied by impaired insulin signalling in healthy male subjects.

Macrophage markers in skeletal muscle of obese subjects are elevated and inversely relate to insulin sensitivity. The present study aimed to investigate whether short-term high-fat high-calorie (HFHC) diet already increases macrophage markers and affects glucose metabolism in skeletal muscle of healthy lean subjects. Muscle biopsies were obtained from 24 healthy lean young men before and after a 5-day HFHC-diet. mRNA expression levels of relevant genes in muscle and glucose, insulin, C-peptide and cholesteryl ester transfer protein (CETP) levels in plasma were measured. In addition, we assessed hepatic triacylglycerol ('triglyceride') (HTG) content by magnetic resonance spectroscopy and subcutaneous white adipose tissue (sWAT) biopsies were analysed histologically from a subset of subjects (n=8). A 5-day HFHC-diet markedly increased skeletal muscle mRNA expression of the general macrophage markers CD68 (3.7-fold, P<0.01) and CD14 (3.2-fold, P<0.01), as well as the M1 macrophage markers MARCO (11.2-fold, P<0.05), CD11c (1.8-fold, P<0.05) and MRC1 (1.7-fold, P<0.05). This was accompanied by down-regulation of SLC2A4 and GYS1 mRNA expression, and elevated plasma glucose (+4%, P<0.001) and insulin (+55%, P<0.001) levels together with homoeostasis model assessment of insulin resistance (HOMA-IR) (+48%, P<0.001), suggesting development of insulin resistance (IR). Furthermore, the HFHC-diet markedly increased HTG (+118%, P<0.001) and plasma CETP levels (+21%, P<0.001), a marker of liver macrophage content, whereas sWAT macrophage content remained unchanged. In conclusion, short-term HFHC-diet increases expression of macrophage markers in skeletal muscle of healthy men accompanied by reduced markers of insulin signalling and development of IR. Therefore, recruitment of macrophages into muscle may be an early event in development of IR in response to short-term HFHC-feeding.

A 5-day high-fat, high-calorie diet impairs insulin sensitivity in healthy, young South Asian men but not in Caucasian men.

South Asians (SAs) develop type 2 diabetes at a younger age and lower BMI compared with Caucasians (Cs). The underlying cause is still poorly understood but might result from an innate inability to adapt to the Westernized diet. This study aimed to compare the metabolic adaptation to a high-fat, high-calorie (HFHC) diet between both ethnicities. Twelve healthy, young lean male SAs and 12 matched Cs underwent a two-step hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies and indirect calorimetry before and after a 5-day HFHC diet. Hepatic triglyceride content (HTG) and abdominal fat distribution were assessed using magnetic resonance imaging and spectroscopy. At baseline, SAs had higher insulin clamp levels than Cs, indicating reduced insulin clearance rate. Despite the higher insulin levels, endogenous glucose production was comparable between groups, suggesting lower hepatic insulin sensitivity in SAs. Furthermore, a 5-day HFHC diet decreased the insulin-stimulated (nonoxidative) glucose disposal rate only in SA. In skeletal muscle, no significant differences were found between groups in insulin/mammalian target of rapamycin signaling, metabolic gene expression, and mitochondrial respiratory chain content. Furthermore, no differences in (mobilization of) HTG and abdominal fat were detected. We conclude that HFHC feeding rapidly induces insulin resistance only in SAs. Thus, distinct adaptation to Western food may partly explain their propensity to develop type 2 diabetes.

Higher insulin and glucagon-like peptide-1 (GLP-1) levels in healthy, young South Asians as compared to Caucasians during an oral glucose tolerance test.

OBJECTIVE: Higher insulin levels during an oral glucose test (OGTT) have been shown in South Asians. We aimed to investigate if this increased insulin response causes reactive hypoglycemia later on, and if an increased glucagon-like-peptide-1 (GLP-1) response, which could contribute to the hyperinsulinemia, is present in this ethnic group. METHODS: A prolonged, 6-h, 75-g OGTT was performed in healthy, young Caucasian (n=10) and South Asian (n=8) men. The glucose, insulin and GLP-1 response was measured and indices of insulin sensitivity and beta-cell activity were calculated. RESULTS: Age (Caucasians (CAU) 21.5±0.7 years vs South Asians (SA) 21.4±0.7 years (mean±SEM)) and body mass index (CAU 22.7±0.7 kg/m(2) vs SA 22.1±0.8 kg/m(2)) were comparable between the two groups. South Asian men were more insulin resistant, as indicated by a comparable glucose but significantly higher insulin response, and a significantly lower Matsuda index (CAU 8.7(8.6) vs SA 3.2(19.2), median(IQR)). South Asians showed a higher GLP-1 response, as reflected by a higher area under the curve for GLP-1 (CAU 851±99.8 mmol/l vs SA 1235±155.0 mmol/L). During the whole 6-h period, no reactive hypoglycemia was observed. CONCLUSION: Healthy, young South Asian men have higher insulin levels during an OGTT as compared to Caucasians. This does not, however, lead to reactive hypoglycemia. The hyperinsulinemia is accompanied by increased levels of GLP-1. Whether this is an adaptive response to facilitate hyperinsulinemia to overcome insulin resistance or reflects a GLP-1 resistant state has yet to be elucidated.

Sustained cardiac remodeling after a short-term very low calorie diet in type 2 diabetes mellitus patients.

A very low calorie diet (VLCD) results in cardiac remodeling and improved diastolic function. It is unknown how long these effects sustain after reintroduction of a regular diet. We aimed to assess the long-term effects of initial weight loss by VLCD on cardiac dimensions and function in type 2 diabetes mellitus (T2DM) patients. Fourteen insulin-dependent T2DM patients (mean ± SEM: age 53 ± 2 years; BMI 35 ± 1 kg/m(2)) were treated by a VLCD (450 kcal/day) during 16 weeks. Cardiac function and myocardial triglyceride (TG) content were measured by magnetic resonance imaging and spectroscopy at baseline, after a 16-week VLCD and after 14 months of follow-up on a regular diet. BMI decreased from 35 ± 1 to 28 ± 1 kg/m(2) after VLCD and increased again to 32 ± 1 kg/m(2) at 18 months (both P < 0.05 vs. baseline). Left ventricular (LV) end-diastolic volume index increased after the 16-week VLCD (80 ± 3 to 89 ± 4 ml/m(2), P < 0.05) and remained increased after follow-up (90 ± 3 ml/m(2); P < 0.05 vs. baseline) at comparable filling pressures. The improvement in LV diastolic function after the 16-week VLCD, was sustained at 18 months [early (E)/atrial (A) diastolic filling phase ratio: 0.96 ± 0.07 (baseline); 1.12 ± 0.06 (after VLCD); 1.06 ± 0.07 (18 months, P < 0.05 vs. baseline)]. Myocardial TG content decreased after the 16-week VLCD [0.74 (0.41-1.10) to 0.45 (0.31-0.54) %, P < 0.05], but returned to baseline levels at 18 months [0.76 (0.65-1.32) %]. Weight reduction by a 16-week VLCD in T2DM patients results in sustained cardiac remodeling and improved diastolic function after 14 months of follow-up, despite weight regain on a regular diet.

Pathogenesis of type 2 diabetes in South Asians.

The risk of developing type 2 diabetes mellitus (T2DM) is exceptionally high among both native and migrant South Asians. T2DM occurs more often and at a younger age and lower BMI, and the risk of coronary artery and cerebrovascular disease, and renal complications is higher for South Asians compared with people of White Caucasian descent. The high prevalence of T2DM and its related complications in South Asians, which comprise one-fifth of the total world's population, poses a major health and socioeconomic burden. The underlying cause of this excess risk, however, is still not completely understood. Therefore, gaining insight into the pathogenesis of T2DM in South Asians is of great importance. The predominant mechanism, in this ethnicity seems to be insulin resistance (IR) rather than an impaired ß-cell function. In this systematic review, we describe several possible mechanisms that may underlie or contribute to the increased IR observed in South Asians.

[Brown adipose tissue: the body's own weapon against obesity?]. / Bruin vet: een lichaamseigen middel in de strijd tegen obesitas?

Brown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP1. It has recently been discovered that BAT is present and active in adults. BAT is situated predominantly around the aorta and in the supraclavicular area. BAT volume and activity are lower in individuals who are obese. This suggests that BAT significantly contributes to total energy expenditure. Several pathological conditions that are accompanied by activation of BAT, such as hyperthyroidism and phaeochromocytoma, result in the increased expenditure of energy and in weight loss. Various ways in which BAT can be manipulated to increase the expenditure of energy have been identified, e.g. exposure to cold, the use of so-called uncoupling agents or the administration of the hormone irisin. The activation of BAT could potentially be used to induce weight loss.

Effects of adding exercise to a 16-week very low-calorie diet in obese, insulin-dependent type 2 diabetes mellitus patients.

CONTEXT: Reduction of 50% excess body weight, using a very low-calorie diet (VLCD; 450 kcal/d) improves insulin sensitivity in obese type 2 diabetes mellitus patients. OBJECTIVE: The objective of the study was to evaluate whether adding exercise to the VLCD has additional benefits. DESIGN: This was a randomized intervention study. SETTING: The study was conducted at a clinical research center in an academic medical center. SUBJECTS: Twenty-seven obese [body mass index 37.2 ± 0.9 kg/m(2) (mean ± sem)] insulin-treated type 2 diabetes mellitus patients. INTERVENTION: Patients followed a 16-wk VLCD. Thirteen of them simultaneously participated in an exercise program (E) consisting of 1-h, in-hospital training and four 30-min training sessions on a cycloergometer weekly. OUTCOME MEASURES: Insulin resistance was measured by a hyperinsulinemic euglycemic clamp. Insulin signaling, mitochondrial DNA (mtDNA) content, and intramyocellular lipid content was measured in skeletal muscle biopsies. RESULTS: Baseline characteristics were identical in both groups. Substantial weight loss occurred (-23.7 ± 1.7 kg VLCD-only vs. -27.2 ± 1.9 kg VLCD+E, P = NS within groups). The exercise group lost more fat mass. Insulin-stimulated glucose disposal increased similarly in both study groups [15.0 ± 0.9 to 39.2 ± 4.7 µmol/min(-1) · kg lean body mass (LBM(-1)) VLCD-only vs. 17.0 ± 1.0 to 37.5 ± 3.5 µmol/min(-1) · kg LBM(-1) in VLCD+E], as did phosphorylation of the phosphatidylinositol 3-kinase-protein kinase B/AKT insulin signaling pathway. In contrast, skeletal muscle mtDNA content increased only in the VLCD+E group (1211 ± 185 to 2288 ± 358, arbitrary units, P = 0.016 vs. 1397 ± 240 to 1196 ± 179, P = NS, VLCD-only group). Maximum aerobic capacity also only increased significantly in the VLCD+E group (+6.6 ± 1.7 ml/min(-1) · kg LBM(-1) vs. +0.7 ± 1.5 ml/min(-1) · kg LBM(-1) VLCD-only, P = 0.017). CONCLUSION: Addition of exercise to a 16-wk VLCD induces more fat loss. Exercise augments maximum aerobic capacity and skeletal muscle mtDNA content. These changes are, however, not reflected in a higher insulin-stimulated glucose disposal rate.

Quality of life in type 2 diabetes mellitus after a very low calorie diet and exercise.

OBJECTIVE: To evaluate whether the addition of exercise to a very low calorie diet (VLCD) has beneficial short- and long-term effects on health-related quality of life (QoL) in obese patients with type 2 diabetes mellitus (T2DM). METHODS: We included 27 obese, insulin-dependent T2DM patients in a 16-week VLCD study, of whom 13 participated simultaneously in an exercise program (VLCD+E). Before, immediately after and 18 months after the intervention anthropometric measurements, glucoregulation and QoL (SF-36, HADS, NHP and MFI-20) were assessed. Patients were compared to healthy lean and obese (matched for body mass index) controls matched for gender and age. RESULTS: At baseline, T2DM patients had significantly worse QoL scores in 18 and 14 of the 22 subscales of the QoL questionnaires, compared to lean and obese controls, resp. The 16-week VLCD (n=27) decreased bodyweight (-25.4±1.3 kg, p<0.0001, p=0.179 between groups), and improved glucoregulation (HbA1c -1.3±0.3%, p<0.0001, p=0.488 between groups) and 9 (VLCD-only) and 11 (VLCD+E) of the 22 subscales of QoL. After 18 months, in the VLCD+E group the QoL subscales did not differ from those in obese controls and only 4 of the 22 subscales were significantly worse compared to lean controls. However, in the VLCD-only group 17 and 13 of the 22 QoL subscales were significantly worse compared to the lean and obese controls, resp. CONCLUSION: A 16-week VLCD induces considerable weight loss, metabolic amelioration, and major improvements in QoL in obese T2DM patients. The addition of exercise is of paramount importance for the maintenance of better QoL.

Long-term beneficial effect of a 16-week very low calorie diet on pericardial fat in obese type 2 diabetes mellitus patients.

Pericardial fat accumulation has been associated with an increased cardiovascular risk. A very low calorie diet (VLCD) improves the cardiovascular risk profile in patients with type 2 diabetes mellitus (T2DM), by improving the metabolic profile, heart function, and triglyceride (TG) stores in (non)adipose tissues. However, long-term effects of a VLCD on pericardial fat volume and tissue-specific TG accumulation have not been documented. The aim of this study was therefore to assess the effects of a 16-week VLCD and of subsequent 14 months follow-up on a regular diet on pericardial fat in relation to other TG stores in obese T2DM patients. We included 14 obese patients with insulin-treated T2DM (mean ± s.e.m.: age 53 ± 2 years; BMI 35 ± 1 kg/m(2)). Pericardial fat and other (non)adipose TG stores were measured using magnetic resonance (MR) imaging and proton spectroscopy before and after a 16-week VLCD and after a 14-month follow-up without dietary interventions. A 16-week VLCD reduced body weight, pericardial fat, hepatic TG content, visceral and subcutaneous abdominal fat volumes to 78, 83, 16, 40, and 53% of baseline values respectively, (all P < 0.05). After an additional 14 months of follow-up on a regular diet, the reduction in pericardial fat volume sustained, despite a substantial regain in body weight, visceral abdominal fat, and hepatic TG content (respectively 90, 83 and 73% of baseline values). In conclusion, VLCD-induced weight loss in obese T2DM patients is accompanied by a substantial decrease in pericardial fat volume, which is sustained even after subsequent weight regain.

Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases plasma CETP and increases apolipoprotein AI levels without improving the cholesterol efflux properties of HDL.

OBJECTIVE: Using a mouse model for human-like lipoprotein metabolism, we observed previously that reduction of the hepatic triglyceride (TG) content resulted in a decrease in plasma cholesteryl ester transfer protein (CETP) and an increase in HDL levels. The aim of the current study was to investigate the effects of prolonged caloric restriction in obese patients with type 2 diabetes mellitus, resulting in a major reduction in hepatic TG content, on plasma CETP and HDL levels. RESEARCH DESIGN AND METHODS: We studied 27 obese (BMI: 37.2 ± 0.9 kg/m(2)) insulin-dependent patients with type 2 diabetes mellitus (14 men and 13 women, aged 55 ± 2 years) who received a 16-week very low calorie diet (VLCD). At baseline and after a 16-week VLCD, plasma lipids, lipoproteins, and CETP were measured. Furthermore, functionality of HDL with respect to inducing cholesterol efflux from human monocyte cells (THP-1) was determined. RESULTS: A 16-week VLCD markedly decreased plasma CETP concentration (-18%; P < 0.01) and increased plasma apolipoprotein (apo)AI levels (+16%; P < 0.05), without significantly affecting plasma HDL-cholesterol and HDL-phospholipids. Although a VLCD results in HDL that is less lipidated, the functionality of HDL with respect to inducing cholesterol efflux in vitro was unchanged. CONCLUSIONS: The marked decrease in hepatic TG content induced by a 16-week VLCD is accompanied by a decrease in plasma CETP concentration and an increase in apoAI levels, without improving the cholesterol efflux properties of HDL in vitro.

[Rosiglitazone: no increase in cardiovascular mortality]. / Rosiglitazon: niet méér cardiovasculaire sterfte.

Several meta-analyses imply that rosiglitazone increases the risk of myocardial infarction. However, the studies included were small and not designed to study the effect on cardiovascular risk. The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes study (RECORD) was specifically designed to assess the effect of rosiglitazone on cardiovascular outcomes. After a mean follow-up of 5.5 years, the study showed no increase in cardiovascular hospitalisation or cardiovascular mortality with rosiglitazone and either metformin or sulphonylurea versus metformin/sulphonylurea combination therapy. There was a non-significant increase in myocardial infarction with rosiglitazone, but this did not result in increased mortality rates. Moreover, the Bypass Angioplasty revascularisation Investigation 2 Diabetes study (BARI 2D) showed no increase in myocardial infarction or cardiovascular death in type 2 diabetic patients with coronary disease who received insulin-sensitising therapy including rosiglitazone. Therefore, rosiglitazone can be prescribed as long as the indications are followed and the patients concerned do not have heart failure or an increased risk for this.

Bromocriptine reduces augmented thyrotropin secretion in obese premenopausal women.

CONTEXT: Diurnal TSH secretion is enhanced in obese premenopausal women. Dopamine inhibits TSH secretion through activation of dopamine D(2) receptors (D(2)R). Dopamine D(2)R availability in the brain is reduced in obese humans in proportion to body adiposity. We hypothesized that deficient dopamine D(2)R signaling is involved in the enhanced TSH secretion associated with obesity. OBJECTIVE: The effect of short-term bromocriptine treatment on spontaneous TSH secretion in obese women was studied while body weight and caloric intake remained constant. DESIGN AND SETTING: We conducted a prospective, fixed-order, crossover study in a Clinical Research Center. PARTICIPANTS: Seventeen obese women (body mass index, 33.2 +/- 0.6 kg/m(2)) were studied twice in the early follicular phase of their menstrual cycle. INTERVENTION: Subjects were treated for 8 d with placebo and bromocriptine. MAIN OUTCOME MEASURE(S): Blood was collected for 24 h at 10-min intervals, and TSH and leptin were analyzed with deconvolution and correlation techniques, approximate entropy, and cosine regression. RESULTS: Bromocriptine reduced 24-h TSH secretion (placebo, 29.8 +/- 4.6 mU/liter . 24 h, vs. bromocriptine, 22.4 +/- 3.7 mU/liter . 24 h; P = 0.001), whereas free T(4) and total T(3) concentrations did not change. Bromocriptine administration reduced the mesor and amplitude of the 24-h rhythm without resetting the phase. The regularity of the subordinate TSH pattern and synchrony between leptin and TSH were unaffected by bromocriptine. CONCLUSION: Activation of dopamine D(2)R by bromocriptine reverses enhanced diurnal TSH secretion in obese women. Thus, reduced dopaminergic neuronal signaling might be involved in the perturbation of the thyrotrope hormonal axis in obese premenopausal women.

Short-term treatment with bromocriptine improves impaired circadian growth hormone secretion in obese premenopausal women.

CONTEXT: A profound reduction of spontaneous as well as stimulated GH secretion has been consistently observed in obesity. Dopamine promotes GH release through activation of dopamine D2 receptors (D2Rs). Dopamine D2R availability in the brain is reduced in obese humans in proportion to body adiposity. We hypothesized that impaired dopamine D2R signaling is mechanistically involved in the deficient GH secretion associated with obesity. OBJECTIVE: To test this hypothesis, we studied the effect of short-term bromocriptine (B) (a D2R agonist) treatment on spontaneous 24-h GH secretion in obese women, while body weight and caloric intake remained constant. DESIGN: This was a prospective, fixed order, cross-over study. SETTING: The study was performed in the Clinical Research Center at Leiden University Medical Center. PARTICIPANTS: There were 18 healthy obese women (body mass index 33.2 +/- 0.6 kg/m2) studied twice in the early follicular phase of their menstrual cycle. INTERVENTION(S): Eight days of treatment with B and placebo (Pl) was performed. MAIN OUTCOME MEASURE(S): Blood was collected during 24 h at 10-min intervals for determination of GH concentrations. GH secretion parameters were calculated using deconvolution analysis. RESULTS: Short-term treatment with B significantly enhanced diurnal GH secretion (Pl 121.4 +/- 16.4 vs. B 155.4 +/- 15.2 microg/liter(volume of distribution).24 h; P = 0.01), whereas IGF-I concentrations remained constant (Pl 22.4 +/- 2.4 vs. B 21.8 +/- 1.6 nmol/liter; P = 0.928). CONCLUSIONS: Activation of dopamine D2Rs by B favorably affects impaired nyctohemeral GH secretion in obese women. Reduced dopaminergic neuronal signaling might be involved in the pathogenesis of obesity associated hyposomatotropism.

Sustained beneficial metabolic effects 18 months after a 30-day very low calorie diet in severely obese, insulin-treated patients with type 2 diabetes.

Eighteen insulin-treated obese type 2 diabetic patients were followed for 18 months after they followed a 30-day very low calorie diet (VLCD, 450kCal/day) with the cessation of all glucose-lowering medication. After the 30-day VLCD, caloric intake was slowly increased to eucaloric and glucose-lowering medication was restarted if necessary. On day 0 and 30 of the VLCD and after 18 months follow-up, bodyweight, blood-pressure, glycaemic control and lipid levels were measured. The 30-day VLCD significantly reduced bodyweight (-11.7+/-0.7kg, mean+/-S.E.M.) and improved dyslipidaemia, hypertension and glycaemia. As a group, this effect was sustained at 18 months follow-up despite the fact that patients used less lipid-, blood-pressure- and glucose-lowering medication. Especially, the use of insulin was significantly reduced: 18 out of 18 patients on day 0 (mean 137+/-22units/day); 5 out of 18 patients at 18 months (86+/-14units/day). Patients using insulin at 18 months had regained weight to prediet levels, but still had a better cardiovascular risk profile compared with before the dietary intervention. Thus, a once-only 30-day VLCD leads to a sustained improvement in glycaemia, dyslipidaemia and blood-pressure up to 18 months follow-up in obese type 2 diabetic patients, even, although to a lesser extent, in patients who regained body-weight.

Decrease in visceral fat following diet-induced weight loss in upper body compared to lower body obese premenopausal women.

BACKGROUND: Obesity is associated with numerous metabolic disturbances, such as insulin resistance, diabetes mellitus type 2, dyslipidemia, and hypertension. An excess of fat within the abdomen, so-called visceral adiposity, confers a greater and independent health risk of metabolic and cardiovascular complications than does adipose tissue accumulation elsewhere. The present study aimed to investigate a possible differential effect of diet-induced weight loss in visceral fat mass and metabolic parameters in obese individuals with the upper body (UBO) and lower body (LBO) obese phenotype. METHODS: The obese subjects were prescribed a liquid, very-low calorie diet to reduce 50% of their overweight (15% body weight loss). Specific body fat measurements (MRI, BIA), anthropometrics, and fasting metabolic parameters were obtained in control subjects and two groups of obese subjects (UBO and LBO) before and after weight loss. RESULTS: Weight loss was accompanied by significant decreases in total, subcutaneous, and visceral fat in both UBO and LBO women. The largest reduction in visceral fat mass was found in the UBO women (absolute decrease 223+/-32 cm(2) vs 122+/-91 cm(2) in LBO women; P=0.01), while the amount of visceral fat was reduced to normal levels in LBO women (155+/-25 cm(2) after weight loss vs 143+/-17 cm(2) in controls; P=NS). Furthermore, weight loss significantly lowered fasting glucose, total cholesterol, and LDL cholesterol concentrations in UBO women. CONCLUSION: The obese phenotype is preserved after body weight loss. UBO women have to lose a larger amount of overweight in order to bring the amount of fat in the visceral depot down to normal levels and to obtain normalization of their cardiovascular risk profile.

Insulin-mediated phosphorylation of the proline-rich Akt substrate PRAS40 is impaired in insulin target tissues of high-fat diet-fed rats.

Clinical insulin resistance is associated with decreased activation of phosphatidylinositol 3'-kinase (PI3K) and its downstream substrate protein kinase B (PKB)/Akt. However, its physiological protein substrates remain poorly characterized. In the present study, the effect of in vivo insulin action on phosphorylation of the PKB/Akt substrate 40 (PRAS40) was examined. In rat and mice, insulin stimulated PRAS40-Thr246 phosphorylation in skeletal and cardiac muscle, the liver, and adipose tissue in vivo. Physiological hyperinsulinemia increased PRAS40-Thr246 phosphorylation in human skeletal muscle biopsies. In cultured cell lines, insulin-mediated PRAS40 phosphorylation was prevented by the PI3K inhibitors wortmannin and LY294002. Immunohistochemical and immunofluorescence studies showed that phosphorylated PRAS40 is predominantly localized to the nucleus. Finally, in rats fed a high-fat diet (HFD), phosphorylation of PRAS40 was markedly reduced compared with low-fat diet-fed animals in all tissues examined. In conclusion, the current study identifies PRAS40 as a physiological target of in vivo insulin action. Phosphorylation of PRAS40 is increased by insulin in human, rat, and mouse insulin target tissues. In rats, this response is reduced under conditions of HFD-induced insulin resistance.