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.

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.

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.

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.

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.

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.

Activation of dopamine D2 receptors lowers circadian leptin concentrations in obese women.

CONTEXT: Leptin release is regulated by factors other than fat mass alone. Previous observations provide indirect evidence for an inhibitory effect of dopaminergic neurotransmission on leptin secretion. This study was done to establish the effect of bromocriptine treatment on circadian plasma leptin concentrations in obese humans. OBJECTIVE: The objective of the study was to study the acute effects of bromocriptine (a D2R agonist) on circadian leptin levels in obese women, whereas body weight and caloric intake remained constant. DESIGN: This was a prospective, single-blind, crossover study (2004). SETTING: The study was conducted at a clinical research center. PARTICIPANTS: Eighteen healthy 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(S): Treatment consisted of bromocriptine or placebo for 8 d. MAIN OUTCOME MEASURE(S): Blood was collected during 24 h at 20-min intervals for determination of leptin concentrations at the last day of medical treatment (bromocriptine or placebo). Mean 24-h serum concentrations were determined for insulin, glucose, free fatty acids, and triglycerides. RESULTS: Short-term treatment with bromocriptine reduced leptin concentration (placebo 33.6 +/- 2.5 vs. bromocriptine 30.5 +/- 2.5 ng/liter, P = 0.03). Free fatty acid concentrations were increased by treatment with bromocriptine. The increase of free fatty acids was inversely related with the decline of leptin levels. The decline of glucose, insulin, or prolactin concentrations in response to bromocriptine was not correlated with the reduction of leptin. CONCLUSION: Activation of dopamine D2 receptors by bromocriptine lowers circulating leptin levels in obese women, which suggests that dopaminergic neurotransmission is involved in the control of leptin release in humans.

Infectious complications of central venous catheters increase the risk of catheter-related thrombosis in hematology patients: a prospective study.

PURPOSE: We studied whether the risk of central venous catheter (CVC) -related thrombosis increased after an episode of CVC-related infection in patients undergoing intensive chemotherapy. Secondly, we determined whether thrombosis can be predicted or excluded by CVC lock fluid surveillance cultures. PATIENTS AND METHODS: In a prospective setting, 105 consecutive patients were carefully examined for CVC-related infection and thrombosis. In all patients, microbial surveillance cultures of CVC lock fluid were taken every other day. All patients with clinical suspicion of CVC-related thrombosis underwent Doppler ultrasound or additional venography. RESULTS: The cumulative incidence of CVC-related infection was 24% (25 of 105 patients). Clinically manifest thrombosis occurred in 13 (12%) of 105 patients. In patients with CVC-related infection, the risk of thrombosis increased markedly in comparison to those without infection (relative risk, 17.6; 95% CI, 4.1 to 74.1). In patients having two or more positive subsequent CVC lock fluid cultures with identical micro-organisms, 71.4% developed thrombosis, as compared with 3.3% in patients with negative or a single positive culture. CONCLUSION: The risk of clinically manifest thrombosis is increased after an episode of CVC-related infection in patients undergoing intensive chemotherapy. Surveillance culturing of CVC lock fluid may be clinically useful in estimating the risk for thrombosis and the instigation of focused early intervention.

The relation between leptin and insulin remains when insulin secretion is disturbed.

BACKGROUND: Serum insulin and leptin levels correlate positively. It is not known whether this relation remains the same in cases of severely disturbed insulin secretion and after rapid weight loss. We therefore studied the relation between insulin and leptin in obese type 2 diabetic patients before and after considerable weight loss. METHODS: In 17 obese type 2 diabetic patients, blood glucose-lowering medication was discontinued (day-1) and a 30-day very low calorie diet (VLCD, 450 kcal/day) was started. On days 0, 2, and 30, body weight, body fat mass [with bioelectrical impedance analysis (BIA)], fasting serum glucose, insulin, and leptin were determined. Homeostatic model assessment was used to estimate insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta). On days 2 and 30, an intravenous glucose tolerance test (IVGTT) was performed. RESULTS: Fasting serum leptin levels correlated positively with fasting serum insulin levels (r=0.72, p=0.001 on day 2; r=0.78, p=0.001 on day 30) and area under the curve (AUC) of insulin (r=0.74, p=0.001 on day 2; r=0.84, p=0.0001 on day 30), as well as HOMA-beta, as a measure of insulin secretion, even after correction for body mass index (BMI) and body fat mass, with which leptin was also positively correlated. CONCLUSION: In a group of obese type 2 diabetic patients with a wide range of residual endogenous insulin secretion, we found a positive relation between fasting serum leptin and insulin levels, even after correction for BMI and body fat mass. This was true both before weight loss and during energy restriction with weight loss.

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.

The effect of statin therapy on endothelial function in type 2 diabetes without manifest cardiovascular disease.

OBJECTIVE: Cardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes and is preceded by endothelial dysfunction. Flow-mediated dilation (FMD) is a noninvasive technique for measuring endothelial dysfunction. We aimed to determine the effect of long-term statin therapy versus placebo on FMD in patients with type 2 diabetes without manifest CVD. RESEARCH DESIGN AND METHODS: A randomized, placebo-controlled, double-blind trial was performed with 250 type 2 diabetic patients. Patients were given 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, the 0.4 mg cerivastatin was replaced by 20 mg simvastatin, without deblinding the study. The primary end point was the change in FMD, measured by B-mode ultrasound, after 2 years. RESULTS: Determinants of baseline FMD were diabetes duration, common carotid intima-media thickness, and brachial artery diameter. FMD at baseline was 1.51% in the placebo group and 1.66% in the statin group and did not change significantly after 2 years. CONCLUSIONS: The 2-year statin therapy had no effect on FMD in type 2 diabetes. Statin-induced improvement of cardiovascular risk in patients with type 2 diabetes may be mediated through mechanisms other than increased nitric oxide availability.

No effect of statin therapy on silent myocardial ischemia in patients with type 2 diabetes without manifest cardiovascular disease.

OBJECTIVE: Coronary artery disease is the most important cause of mortality in patients with type 2 diabetes. We aimed to determine the prevalence of silent myocardial ischemia (SMI) and the effect of statin therapy on SMI in type 2 diabetic patients without manifest cardiovascular disease. RESEARCH DESIGN AND METHODS: A randomized, placebo-controlled, double-blind trial was performed in 250 patients with type 2 diabetes without manifest cardiovascular disease. Patients were given either 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, cerivastatin 0.4 mg was replaced by 20 mg simvastatin without deblinding the study. The primary end point was the change in ischemic episodes, duration, and burden as measured by 48-h ambulatory electrocardiography (AECG) over 2 years. RESULTS: At baseline, 47 of 233 (20%) evaluable ambulatory electrocardiograms showed evidence of ischemia. After 2 years, there was a trend toward more ischemia in both treatment groups, without significant differences between the changes in ischemic parameters (episodes P = 0.498; duration P = 0.697; burden P = 0.798) in the two treatment groups. Cardiovascular events occurred in 12 patients in the placebo group and in two patients in the statin group (P = 0.006). There was no relationship between these cardiovascular events and the presence of SMI at baseline. CONCLUSIONS: SMI occurred in 20% of type 2 diabetes patients without manifest cardiovascular disease. There was no effect from 2 years of statin therapy on SMI. In contrast, we observed a significantly lower cardiovascular event rate on statin therapy. AECG may not be a proper tool for risk stratification in patients with type 2 diabetes.

Spontaneous diurnal thyrotropin secretion is enhanced in proportion to circulating leptin in obese premenopausal women.

CONTEXT: Recent evidence implicates leptin as an important modulator of thyroid axis activity. OBJECTIVE: The objective of this study was to study spontaneous 24-h TSH secretion and 24-h circulating leptin concentrations in obese and lean women. DESIGN: This was a prospective parallel study (2004). SETTING: This study was conducted at the Clinical Research Center (Leiden University Medical Center, Leiden, The Netherlands). PARTICIPANTS: Twelve healthy obese premenopausal women (body mass index, 33.2 +/- 0.9 kg/m2) and 11 lean controls (body mass index, 21.4 +/- 0.5 kg/m2) were studied in the follicular phase of their menstrual cycle. INTERVENTION(S): There were no interventions in this study. MAIN OUTCOME MEASURE(S): Spontaneous 24-h TSH concentrations (10-min time intervals) and secretion were calculated using waveform-independent deconvolution technique (pulse). Twenty-four-hour circulating leptin concentrations (20-min time intervals) were measured. RESULTS: Mean TSH concentration (obese, 1.9 +/- 0.2 vs. lean, 1.1 +/- 0.1 mU/liter; P = 0.009) and secretion rate (obese, 43.4 +/- 5.5 vs. lean, 26.1 +/- 2.2 mU/liter distribution volume.24 h; P = 0.011) were substantially enhanced in obesity, whereas the fasting free T4 (fT4) concentrations were similar (fT4 in obese, 15.4 +/- 1.5 vs. in lean, 16.4 +/- 1.5 pmol/liter; P = 0.147). TSH secretion was positively related to 24-h leptin concentrations (r2= 0.31; P = 0.007). CONCLUSIONS: TSH release is enhanced in the face of normal plasma fT4 concentrations in obese premenopausal women, and hyperleptinemia may well be involved in this neuroendocrine alteration.

High circulating thyrotropin levels in obese women are reduced after body weight loss induced by caloric restriction.

CONTEXT: Previous clinical studies concerning the impact of body weight loss on single plasma TSH concentration measurements or the TSH response to TRH in obese humans have shown variable results. OBJECTIVE: The objective of this study was to investigate the effect of weight loss induced by caloric restriction on diurnal TSH concentrations and secretion in obese humans. DESIGN: This was a clinical, prospective, crossover study. SETTING: The study was conducted at the Clinical Research Center of Leiden University Medical Center. PARTICIPANTS: Eleven obese premenopausal women (body mass index, 33.3 +/- 0.7 kg/m2) were studied. INTERVENTION: The study intervention was weight loss (50% reduction overweight by caloric restriction). MAIN OUTCOME MEASURE(S): Twenty-four-hour plasma TSH concentrations (10-min intervals) and the 24-h TSH secretion rate, calculated by a waveform-independent deconvolution technique (Pulse), were determined. RESULTS: The 24-h TSH secretion rate was significantly higher in obese women than in normal weight controls, and weight loss was accompanied by diminished TSH release (before weight loss, 43.4 +/- 6.4 mU/liter.24 h; after weight loss, 34.4 +/- 5.9 mU/liter.24 h; P = 0.02). Circulating free T3 levels decreased after weight loss from 4.3 +/- 0.19 to 3.8 +/- 0.14 pmol/liter (P = 0.04). Differences in 24-h TSH release correlated positively with the decline of circulating leptin (r2 = 0.62; P < 0.01). CONCLUSIONS: Elevated TSH secretion in obese women is significantly reduced by diet-induced weight loss. Among various physiological cues, leptin may be involved in this phenomenon. The decreases in TSH and free T3 may blunt energy expenditure in response to long-term calorie restriction, thereby frustrating weight loss attempts of obese individuals.

Renal contribution to increased clearance of exogenous growth hormone in obese hypertensive patients.

To evaluate the possible role of the kidney in the enhanced metabolic clearance rate (MCR) of GH in obesity, we studied the kinetics of GH and renal fractional extraction of GH (RFEGH) in 12 male hypertensive patients over a wide range of body weights (71.7-129 kg) while undergoing contrast angiography on suspicion of renal artery stenosis. A continuous infusion of recombinant human GH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. After 2 h of GH infusion, when plasma GH had reached a steady state at concentrations that were still in the physiological range, blood was sampled from the left and right renal arteries and veins for determination of GH levels. Subsequently, the GH infusion was stopped, and GH kinetics were investigated with noncompartmental analysis. In none of the patients was hemodynamically significant renal artery stenosis present. Whole body MCR of GH averaged 375 +/- 142 ml/min. Average GH levels were significantly higher in arterial plasma than in simultaneously sampled renal venous plasma (P < 0.001). RFEGH was 8.6 +/- 6.8%. The MCRs of both GH and RFEGH correlated significantly with body weight, body fat mass, and endogenous creatinine clearance. Renal uptake of GH per 100 g kidney tissue correlated inversely with MCR. These results suggest that RFEGH rises with increasing adiposity, but per unit of renal mass, the capacity of the kidney to remove GH from the circulation falls at high MCR values.

Hypophosphatemia: an update on its etiology and treatment.

Phosphate plays a key role in several biological processes. In recent years, new insights have been obtained into the regulation of the phosphate metabolism, including a growing amount of evidence suggesting that factors other than parathyroid hormone (PTH) and vitamin D are involved in maintaining the phosphate balance. A new class of phosphate-regulating factors, the so-called "phosphatonins," have been shown to be important in phosphate-wasting diseases. However, the role of the phosphatonins in the normal human homeostasis remains to be established. The incidence of hypophosphatemia in selected patient series can be more than 20%, with clinical sequelae ranging from mild to life threatening. Only when combined with phosphate depletion does hypophosphatemia become clinically significant. The factors that are involved in the phosphate homeostasis, the pathophysiology, the relevance in patient care, the clinical manifestations, and an appropriate management of phosphate depletion are discussed in this review.

Two days of a very low calorie diet reduces endogenous glucose production in obese type 2 diabetic patients despite the withdrawal of blood glucose-lowering therapies including insulin.

The mechanism of the blood glucose-lowering effect of a 2-day very low calorie diet (VLCD; 1890 kJ/d) in combination with the cessation of all blood glucose-lowering agents was studied in 12 (7 women, 5 men) obese (body mass index, 36.3 +/- 1.0 kg/m 2 [mean +/- SEM]) type 2 diabetic patients (age, 55 +/- 4 years; HbA 1c , 7.3% +/- 0.4%) undergoing insulin therapy. Endogenous glucose production (EGP) and whole body glucose disposal (6,6 2 H 2 -glucose), lipolysis ( 2 H 5 -glycerol), and substrate oxidation (indirect calorimetry) rates were measured before and after the intervention in basal and hyperinsulinemic conditions. After 2 days of a VLCD and discontinuation of all blood glucose-lowering therapies, fasting plasma glucose levels did not increase (11.3 +/- 1.3 vs 10.3 +/- 1.0 mmol/L). Basal EGP significantly declined (14.2 +/- 1.0 to 11.9 +/- 0.7 mu mol/kg per minute; P = .009). Basal metabolic clearance rate of glucose and rate of basal lipolysis did not change. During hyperinsulinemia, EGP (5.5 +/- 0.8 to 5.2 +/- 0.5 mu mol/kg per minute), whole body glucose disposal (12.1 +/- 0.7 to 11.3 +/- 1.0 mu mol/kg per minute), the metabolic clearance rate of glucose, and the rate of lipolysis did not change after the 2-day intervention. Cessation of blood glucose-lowering therapy in combination with a 2-day VLCD does not lead to hyperglycemia and is associated with a reduction in basal EGP. Insulin-stimulated whole body glucose disposal did not improve, nor did insulin suppressibility of EGP and lipolysis.

Effect of a 2-day very low-energy diet on skeletal muscle insulin sensitivity in obese type 2 diabetic patients on insulin therapy.

This study investigates the molecular mechanisms underlying the blood glucose-lowering effect of a 2-day very low-energy diet (VLED, 1883 kJ/d) in 12 obese (body mass index, 36.3 +/- 1.0 kg/m2 [mean +/- SEM]) type 2 diabetic (HbA(1C) 7.3% +/- 0.4%) patients simultaneously taken off all glucose-lowering therapy, including insulin. Endogenous glucose production (EGP) and glucose disposal ([6,6-2H2]-glucose) were measured before and after the VLED in basal and hyperinsulinemic (40 mU/m2 per minute) euglycemic conditions. Insulin signaling and expression of GLUT-4, FAT/CD36, and triglycerides were assessed in muscle biopsies, obtained before the clamp and after 30 minutes of hyperinsulinemia. Fasting plasma glucose decreased from 11.3 +/- 1.3 to 10.3 +/- 1.0 mmol/L because of a decreased basal EGP (14.2 +/- 1.0 to 11.9 +/- 0.7 micromol/kg per minute, P = .009). Insulin-stimulated glucose disposal did not change. No diet effect was found on the expression of the insulin receptor and insulin receptor substrate-1 or on phosphatidylinositol 3'-kinase activity, or on FAT/CD36 expression pattern, GLUT-4 translocation, or triglyceride distribution in either the basal or insulin-stimulated situation. Unexpectedly, basal PKB/Akt phosphorylation on T308 and S473 increased after the diet, at equal protein expression. In conclusion, a 2-day VLED lowers fasting plasma glucose via a decreased basal EGP without an effect on glucose disposal. Accordingly, no changes in activation of phosphatidylinositol 3'-kinase, triglyceride distribution, FAT/CD36 expression, and GLUT-4 translocation were found in skeletal muscle biopsies.

Two-year statin therapy does not alter the progression of intima-media thickness in patients with type 2 diabetes without manifest cardiovascular disease.

OBJECTIVE: Cardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes. We aimed to determine the effect of statin therapy versus placebo on the progression of carotid intima-media thickness (IMT) in type 2 diabetic patients without manifest CVD. RESEARCH DESIGN AND METHODS: A randomized, placebo-controlled, double-blind clinical trial was performed in 250 patients with type 2 diabetes. Patients were given either 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, 0.4 mg cerivastatin was replaced by 20 mg simvastatin without deblinding the study. The primary end point was the change of mean common carotid IMT, as measured by B-mode ultrasound, over 2 years. RESULTS: Common carotid IMT at baseline was 0.780 mm in the placebo group and 0.763 mm in the statin group and did not change significantly after 2 years. There was no significant difference in IMT change in any carotid segment between the groups. LDL cholesterol was reduced by 25% in the statin group and increased by 8% in the placebo group (P <0.001). Cardiovascular events occurred in 12 patients in the placebo group and two patients in the statin group (P=0.006). CONCLUSIONS: There was no effect of 2 years' statin therapy on carotid IMT in type 2 diabetic subjects. The natural history of IMT in our patients was milder than anticipated. In contrast, we observed a significantly lower cardiovascular event rate on statin therapy. Prognostic tools other than IMT should be explored in this patient group.