PAPP-A activity is increased in cerebrospinal fluid from patients with diabetic polyneuropathy and correlates with peripheral nerve impairment.

OBJECTIVE: Insulin-like growth factors (IGFs) have neuroprotective effects. IGF activity is partly controlled by pregnancy-associated plasma protein-A (PAPP-A), an enzyme which enhances IGF-action by cleavage of IGF-binding protein-4 (IGFBP-4). To study the role of PAPP-A and the IGF system in diabetic polyneuropathy (DPN), we measured immunoreactive (total) concentrations of IGF-I and IGF-II, bioactive IGF by cell-based bioassay, PAPP-A, as well as intact and PAPP-A-cleaved IGFBP-4 in cerebrospinal fluid (CSF) and serum from patients with type 2 diabetes (T2D) with and without DPN. DESIGN: Twenty-three patients with T2D were included. Based on clinical examination, vibratory perception thresholds and nerve conduction studies, patients were diagnosed with (n = 9) or without (n = 14) DPN. RESULTS: In CSF, PAPP-A activity, as estimated by IGFBP-4 fragment levels, was higher in patients with than without DPN (34.57 vs 13.79 µg/L, p = .003) and concentrations correlated with peripheral nerve impairment measures (r = 0.73, p < .01). Furthermore, serum bioactive IGF was lower in patients with than without DPN (0.8 vs 1.3 µg/L, p = .006) and correlated inversely to the severity of DPN (r = -0.67, p < .01). CONCLUSIONS: In both CSF and serum, members of the IGF system correlated with measures of peripheral nerve impairment in patients with T2D. This supports a relationship between the IGF system and the development of DPN. Further studies are needed to clarify if these changes are causally linked to the pathogenesis of DPN.

First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

OBJECTIVE: This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. DESIGN: The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50µg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. RESULTS: PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. CONCLUSIONS: PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases.

Low adiponectin levels at baseline and decreasing adiponectin levels over 10 years of follow-up predict risk of the metabolic syndrome.

AIM: Adiponectin is the most abundant adipokine and may play a key role in the interplay between obesity, inflammation, insulin resistance and the metabolic syndrome (MetS). Thus, this large population-based cohort investigated whether adiponectin at baseline and/or a decrease in adiponectin during follow-up is associated prospectively with the risk of incident MetS. METHODS: Using a prospective study design, the development of MetS was examined in 1134 healthy participants from the community. Plasma adiponectin was measured at study entry and again after a median follow-up of 9.4 years (IQR: 9.2-9.7). During follow-up, 187 participants developed MetS, and 439 presented with at least two components of MetS. RESULTS: During follow-up, adiponectin decreased in participants who developed MetS, whereas adiponectin was increased in those who did not develop MetS (P<0.001). Those with low adiponectin levels (quartile 1) at baseline had an increased risk of developing MetS (OR: 2.92, 2.08-6.97; P<0.001) compared with those with high levels (quartile 4). After adjusting for confounding variables, low adiponectin levels at baseline remained independently associated with MetS (OR: 2.24, 1.11-4.52; P=0.017). Similarly, participants with a decrease in adiponectin during follow-up also had an increased risk of MetS (OR: 2.96, 2.09-4.18; P<0.001). This association persisted after multivariable adjustments, including for baseline adiponectin (OR: 4.37, 2.77-6.97; P<0.001). Finally, adiponectin levels at follow-up were inversely associated with an increase in the number of components of MetS (P<0.001); geometric mean adiponectin levels were 9.5mg/L (95% CI: 9.0-10.0) for participants with no components vs 7.0mg/L (95% CI: 6.3-7.9) for those with four to five components. CONCLUSIONS/INTERPRETATION: Low plasma adiponectin levels at baseline and decreasing adiponectin levels during follow-up are both associated with an increased risk of MetS.

Digital histology quantification of intra-hepatic fat in patients undergoing liver resection.

BACKGROUND: High intra-hepatic fat (IHF) content is associated with insulin resistance, visceral adiposity, and increased morbidity and mortality following liver resection. However, in clinical practice, IHF is assessed indirectly by pre-operative imaging [for example, chemical-shift magnetic resonance (CS-MR)]. We used the opportunity in patients undergoing liver resection to quantify IHF by digital histology (D-IHF) and relate this to CT-derived anthropometrics, insulin-related serum biomarkers, and IHF estimated by CS-MR. METHODS: A reproducible method for quantification of D-IHF using 7 histology slides (inter- and intra-rater concordance: 0.97 and 0.98) was developed. In 35 patients undergoing resection for colorectal cancer metastases, we measured: CT-derived subcutaneous and visceral adipose tissue volumes, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), fasting serum adiponectin, leptin and fetuin-A. We estimated relative IHF using CS-MR and developed prediction models for IHF using a factor-clustered approach. RESULTS: The multivariate linear regression models showed that D-IHF was best predicted by HOMA-IR (Beta coefficient(per doubling): 2.410, 95% CI: 1.093, 5.313) and adiponectin (ß(per doubling): 0.197, 95% CI: 0.058, 0.667), but not by anthropometrics. MR-derived IHF correlated with D-IHF (rho: 0.626; p = 0.0001), but levels of agreement deviated in upper range values (CS-MR over-estimated IHF: regression versus zero, p = 0.009); this could be adjusted for by a correction factor (CF: 0.7816). CONCLUSIONS: Our findings show IHF is associated with measures of insulin resistance, but not measures of visceral adiposity. CS-MR over-estimated IHF in the upper range. Larger studies are indicated to test whether a correction of imaging-derived IHF estimates is valid.

Impact of moderate interval exercise versus supine rest on the pharmacokinetics and pharmacodynamic profiles of subcutaneously administered growth hormone in adult growth hormone deficient patients.

BACKGROUND: Diurnal variation in serum growth hormone (s-GH) levels after exogenous GH delivery has previously been reported in patients with no endogenous GH secretion. Changes in postural position or physical activity, leading to changes in blood flow and/or lymphatic drainage may be underlying explanations. PRIMARY OBJECTIVES: The primary aim of this study is to study a possible impact of exercise and supine rest on pharmacokinetics (PK) and day-to-day variation of subcutaneously (s.c.) administered GH in adult GH deficient (AGHD) patients. SECONDARY OBJECTIVE: The secondary aim of this study is to compare s-IGF-I, s-insulin, and plasma (p)-glucose profiles after a carbohydrate rich breakfast following s.c. GH injection vs. continuous infusion. DESIGN AND METHODS: During supine rest eight AGHD males (59.8±8 years, BMI 29.7±4.9 kg/m(2)) were treated with one daily s.c. GH injections of 3 mg/24 h for 48 h (treatment sessions A, B) or a continuous s.c. GH infusion of 3 mg/24 h for 60 h (treatment sessions C, D). Exercise comprised 1 h bicycling with 50 W load on two consecutive days during treatment sessions B and D. RESULTS: Administration of GH as a bolus injection, but not as a continuous GH infusion, resulted in about 32% higher s-GH levels during exercise (60 min) as well as 30 min after (s-GH logAUC(B-A) difference was 0.28; 95% CI: 0.14-0.4; p<0.001). However, the total s-GH(AUC 0-24 h) (p=0.75) and s-IGF-I(AUC0-48 h) levels (p=0.51) remained unchanged between the two occasions. P-glucose and insulin profiles were significantly higher after carbohydrate rich breakfast before first and second dosing both following s.c. GH injection and continuous infusion (p<0.05). CONCLUSIONS: Moderate exercise intermittently increased s-GH levels. These changes seem to have no clinical short-term relevance, since total s-GH(24 h) and s-IGF-I(48 h) levels were unaffected.

Plasma adiponectin in heart failure with and without cachexia: catabolic signal linking catabolism, symptomatic status, and prognosis.

BACKGROUND AND AIMS: Adiponectin (ADPN) as an adipose tissue hormone contributes to regulation of energy metabolism and body composition and is associated with cardiovascular risk profile parameters. Cardiac cachexia may develop as a result of severe catabolic derangement in chronic heart failure (CHF). We aimed to determinate an abnormal ADPN regulation as a link between catabolic signalling, symptomatic deterioration and poor prognosis. METHODS AND RESULTS: We measured plasma ADPN in 111 CHF patients (age 65 ± 11, 90% male, left ventricular ejection fraction (LVEF) 36 ± 11%, peak oxygen consumption (peakVO2) 18.1 ± 5.7 l/kg*min, body mass index (BMI) 27 ± 4 kg/m(2), all mean ± standard deviation) and 36 healthy controls of similar age and BMI. Body composition was assessed by dual energy X-ray absorptiometry, insulin sensitivity was evaluated by homoeostasis model assessment, exercise capacity by spiroergometry. Plasma ADPN did not differ between CHF vs. controls (13.5 ± 11.0 vs. 10.5 ± 5.3 mg/l, p > 0.4), but increased stepwise with NYHA functional class (I/II/III: 5.7 ± 1.4/10.7 ± 8.3/19.2 ± 14.0 mg/l, ANOVA p < 0.01). Furthermore, ADPN correlated with VO2 at anaerobic threshold (r = -0.34, p < 0.05). ADPN was highest in cachectic patients (cCHF, 16%) vs. non-cachectic (ncCHF) (18.7 ± 15.0 vs. 12.5 ± 9.9 mg/l; p < 0.05). ADPN indicated mortality risk independently of established prognosticators (HR: 1.04 95% CI: 1.02-1.07; p < 0.0001). ADPN above the mean (13.5 mg/l) was associated with a 3.4 times higher mortality risk in CHF vs. patients with ADPN levels below the mean. CONCLUSION: Circulating ADPN is abnormally regulated in CHF. ADPN may be involved in impaired metabolic signalling linking disease progression, tissue wasting, and poor outcome in CHF.

Growth hormone (GH) activity is associated with increased serum oestradiol and reduced anti-Müllerian hormone in healthy male volunteers treated with GH and a GH antagonist.

Growth hormone (GH) and insulin-like growth factor I (IGF-I) receptors are present on pituitary gonadotrophs and on testicular Leydig and Sertoli cells. Thus, the GH/IGF-I system may modulate the pituitary-gonadal axis in males. This is a randomized cross-over study. Eight healthy male volunteers (mean age 35, range 29-46 years) were treated with GH for 3 weeks (1st week 0.01, 2nd week 0.02, 3rd week 0.03 mg/day/kg) or a GH receptor antagonist (Pegvisomant) (1st week 10, last 2 weeks 15 mg/day), separated by 8 weeks of washout. Before and after the two treatment periods, concentrations of luteinizing hormone (LH), follicle-stimulating hormone, testosterone, oestradiol, sex hormone-binding globulin, inhibin B and Anti-Müllerian Hormone (AMH) were measured. During GH treatment, IGF-I increased [(median (IQR)] 166 (162-235) vs. 702 (572-875) µg/L, p < 0.001) together with oestradiol [(mean ± SD) 78 ± 23 vs. 111 ± 30 pm, p = 0.019], and the oestradiol/testosterone ratio (p = 0.003). By contrast, AMH (42 ± 14 vs. 32 ± 7 pm, p = 0.018), Inhibin B (211 (146-226) vs. 176 (129-204) ng/L, p = 0.059) and LH (3.8 ± 1.5 vs. 3.2 ± 1.2 U/L, p = 0.096) decreased. During pegvisomant treatment IGF-I (204 (160-290) vs. 106 (97-157) µg/L, p = 0.001) and oestradiol (86 ± 28 vs. 79 ± 25 pm, p = 0.060) decreased. No significant changes or trends in the other reproductive hormones occurred during the two treatment regimens. GH/IGF-I activity was positively associated with serum oestradiol, suggesting that GH/IGF-I stimulates aromatase activity in vivo. As a novel observation, we found that high GH activity was associated with reduced levels of the Sertoli cell marker AMH. Further studies are needed to evaluate possible effects of GH on Sertoli cell function and/or spermatogenesis.

Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study.

UNLABELLED: Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation INTRODUCTION: We describe physiological changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. METHODS: We studied 153 women planning pregnancy (n=92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36 weeks postpartum. The controls were followed in parallel. RESULTS: P-estradiol (E2), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)2D) increased (p<0.001) during pregnancy, whereas plasma levels of parathyroid hormone (P-PTH) and calcitonin decreased (p<0.01). Insulin-like growth factor I (IGF-I) was suppressed (p<0.05) in early pregnancy but peaked in the third trimester. Postpartum, E2 was low (p<0.05); prolactin decreased according to lactation status (p<0.05). 1,25(OH)2D was normal and IGF-I was again reduced (p<0.05). P-PTH and calcitonin increased postpartum. From early pregnancy, markers of bone resorption and formation rose and fall, respectively (p<0.001). From the third trimester, bone formation markers increased in association with IGF-I changes (p<0.01). Postpartum increases in bone turnover markers were associated with lactation status (p<0.001). During lactation, plasma phosphate was increased, whereas calcium levels tended to be decreased which may stimulate PTH levels during and after prolonged lactation. CONCLUSION: The increased calcium requirements in early pregnancy are not completely offset by increased intestinal calcium absorption caused by high 1,25(OH)2D since changes in bone markers indicated a negative bone balance. The rise in bone formation in late pregnancy may be initiated by a spike in IGF-I levels. The high bone turnover in lactating women may be related to high prolactin and PTH levels, low E2 levels and perhaps increased parathyroid hormone-related protein levels.

Effects of transdermal estrogen on collagen turnover at rest and in response to exercise in postmenopausal women.

Menopause is associated with loss of collagen content in the skin and tendon as well as accumulation of noncontractile tissue in skeletal muscle. The relative role of hormones and physical activity on these changes is not known. Accordingly, in a randomized, controlled, crossover study we investigated effects of transdermal estrogen replacement therapy (ERT) on type I collagen synthesis in tendon and skeletal muscle in 11 postmenopausal women. Patches with estrogen (Evorel) were placed on the skin above the patellar tendons and compared with no patch (control period). On day 2 all subjects performed one-legged exercise, and thereafter the exercised leg (EX leg) was compared with the nonexercised leg (Rest leg). Microdialysis catheters were placed in front of the patellar tendons and in the vastus lateralis muscle of both legs at days 3 and 5. The collected dialysate was analyzed for procollagen type I NH(2)-terminal propeptide (PINP), insulin-like growth factor I (IGF-I), and interleukin-6 (IL-6). Neither loading (Rest leg vs. EX leg) nor treatment (control vs. ERT) influenced peritendinous PINP, whereas combined exercise and ERT enhanced muscle PINP after 72 h (interaction between loading and treatment P = 0.008). In neither skeletal muscle nor peritendinous fluid were IGF-I and IL-6 influenced by treatment or exercise. In conclusion, ERT was associated with enhanced synthesis of type I collagen in the skeletal muscle in response to acute exercise. In perspective, this indicates that the availability of estrogen in postmenopausal women is important for repair of muscle damage or remodeling of the connective tissue within the skeletal muscle after exercise.

Positive associations between serum levels of IGF-I and subcutaneous fat depots in young men. The Odense Androgen Study.

INTRODUCTION: Serum levels of IGF-I are of growing interest due to the associations with morbidity and mortality. Despite markedly suppressed GH secretion, total IGF-I levels are often within normal range in obese adults. AIM: To study associations between IGF-I and estimated muscle mass in the Odense Androgen Study population and secondly to investigate associations between serum IGF-I and regional fat depots. METHOD: The Odense Androgen Study is a population-based, cross-sectional study of 776 randomly selected men aged 20-29 years. Regional lean and fat mass were measured by dual-energy X-ray absorptiometry, whereas regional muscle and fat areas were assessed by magnetic resonance imaging. RESULTS: Age-adjusted IGF-I levels correlated significantly with different estimates of muscle mass (r-values between 0.15 and 0.19; p<0.001). Using multiple linear regression, serum IGF-I correlated positively with subcutaneous adipose tissue on the abdomen (SAT) after controlling for visceral adipose tissue (VAT) in the whole group and in the subgroup of men with normal waist circumference (r-values between 0.13 and 0.15; p<0.03). In addition, IGF-I correlated positively with subcutaneous thigh fat area (TFA) after controlling for intramyocellular lipid (imcl) r=0.18; p<0.004) and IGF-I correlated negatively with TFAimcl in the whole group and in the subgroup of men with normal waist circumference. CONCLUSION: SAT and subcutaneous TFAs were positively associated with IGF-I in regression analyses. Conversely, imcl of the thigh was inversely associated with IGF-I levels. These findings emphasize the differential associations between IGF-I and regional fat deposits. Future studies may provide further insight regarding the interplay between circulating IGF-I levels and regional muscle and fat mass.

The effect of prolonged fasting on levels of growth hormone-binding protein and free growth hormone.

OBJECTIVE: There are limited data on growth hormone-binding protein (GHBP) and free GH levels during the physiological challenge of a prolonged fast. Our aim was to explore the relationships between GHBP, free GH, total GH and non-esterified fatty acid (NEFA) levels during overnight and 24-hour fasts in healthy young adults. DESIGN: We measured nocturnal levels of GHBP at three time-points (22:00, 03:00, 08:00), NEFA every 60 min and ultra-filtered free GH and total GH at 15-minute intervals for 10 h (22:00-08:00) during an overnight and a 24-hour fast in 7 female and 4 male normal-weight subjects aged 24.8 years (range: 22.8-26.9) with BMI 22.5 kg/m² (range: 18-27). RESULTS: Spontaneous free and total GH levels were closely related during the overnight and 24-hour fasts (r=0.99, p<0.0001 and r=0.99, p<0.0001 respectively). 24 h of fasting led to an increase in levels of basal free GH (p=0.03), mean free GH (p=0.04), mean total GH (p=0.04) and NEFA (p<0.0001) whilst GHBP levels remained similar (p=0.8). Percentage free (over total) GH was similar during the overnight and prolonged fasts (p=0.3). There were no associations between levels of NEFA and free (r=0.24, p=0.5) or total GH (r=0.20, p=0.6). CONCLUSIONS: A 24-hour fast led to parallel increases in free and total GH levels whilst there was no discernable change in GHBP levels or the fraction of free GH. This suggests that GHBP plays a role in limiting variations of circulating free GH levels. NEFA levels increased during the prolonged fast but they were not correlated with free or total GH levels.

Testosterone therapy decreases subcutaneous fat and adiponectin in aging men.

OBJECTIVE: Testosterone therapy increases lean body mass and decreases total fat mass in aging men with low normal testosterone levels. The major challenge is, however, to determine whether the metabolic consequences of testosterone therapy are overall positive. We have previously reported that 6-month testosterone therapy did not improve insulin sensitivity. We investigated the effect of testosterone therapy on regional body fat distribution and on the levels of the insulin-sensitizing adipokine, adiponectin, in aging men with low normal bioavailable testosterone levels. DESIGN: A randomized, double-blinded, placebo-controlled study on 6-month testosterone treatment (gel) in 38 men, aged 60-78 years, with bioavailable testosterone <7.3 nmol/l, and a waist circumference >94 cm. METHODS: Central fat mass (CFM) and lower extremity fat mass (LEFM) were measured by dual X-ray absorptiometry. Subcutaneous abdominal adipose tissue (SAT), visceral adipose tissue (VAT), and thigh subcutaneous fat area (TFA) were measured by magnetic resonance imaging. Adiponectin levels were measured using an in-house immunofluorometric assay. Coefficients (b) represent the placebo-controlled mean effect of intervention. RESULTS: LEFM was decreased (b = -0.47 kg, P = 0.07) while CFM did not change significantly (b = -0.66 kg, P = 0.10) during testosterone therapy. SAT (b = -3.0%, P = 0.018) and TFA (b = -3.0%, P < 0.001) decreased, while VAT (b = 1.0%, P = 0.54) remained unchanged. Adiponectin levels decreased during testosterone therapy (b = -1.3 mg/l, P = 0.001). CONCLUSION: Testosterone therapy decreased subcutaneous fat on the abdomen and lower extremities, but visceral fat was unchanged. Moreover, adiponectin levels were significantly decreased during testosterone therapy.

Quantification of the GH/IGF-axis components: lessons from human studies.

Originally, the circulating bioactivity of IGF-I was estimated by bioassays measuring the ability of serum to stimulate uptake of labeled sulfate or thymidine in cultures of costal cartilage or by the ability of serum to stimulate the uptake of glucose in fat tissue cultures. However, because of their laborious and unspecific nature, the original bioassays were quickly abandoned with the development of the first RIA for IGF-I in 1977. Consequently, for the past three decades the endogenous IGF-I bioactivity has been almost exclusively estimated by the use of immunoassays. Beyond any doubt, the immunoassays have provided an extensive insight into IGF-I physiology and pathophysiology. However, immunoassays ignore the presence of the IGFBPs, which are important regulators of IGF-I action in vivo. In addition, immunoassays do not consider the presence of IGF-II, which also interacts with the IGF-I receptor (IGF-IR). This aroused our interest to reintroduce the bioassay; therefore, we established a cell-based kinase receptor activation (KIRA) assay based on cells transfected with the human IGF-IR. The output signal of the KIRA assay is IGF-IR phosphorylation, and, as such, it is highly specific. Further, because detection of phosphorylated IGF-IRs is based on modern immunoassay techniques, the overall performance of the assay is close to that of a traditional IGF-I immunoassay. The first part of this review comprises a short description of the bioassay, and a more in-depth presentation of the data that have been obtained so far. It will be demonstrated that the bioassay is indeed able to yield novel information on the IGF system, most likely because it is able to integrate the different components of the IGF system into one signal: IGF-IR activation. As IGF-I, circulating GH is bound to larger proteins, the far most important GH-binding protein (GHBP) is identical to the extracellular domain of the GH receptor (GHR). Because of its origin, GHBP binds GH with the same affinity as GHR and, consequently, GHBP may affect GH bioactivity as well as pharmacokinetics. To improve our knowledge on the complex interaction between GH and GHBP in vivo, we found it of interest to develop a method for determination of free GH. To this end, we developed an ultrafiltration assay that enabled isolation of free GH in undiluted serum during approached in vivo-like conditions. The last part of this review presents our current data on free GH and its interaction with GHBP.

Insulin-like growth factor I - a novel biomarker of abdominal aortic aneurysms.

OBJECTIVE: The study aimed to test the potential role of insulin-like growth factor I (IGF-I) and IGF-II as biomarkers for abdominal aortic aneurysm (AAA). METHODS AND RESULTS: IGF-I and II levels were analysed in 115 patients with screening diagnosed AAA kept under annual surveillance for 10 years. Serum IGF-I correlated positively with AAA size and growth rate (r = 0.23, P = 0.016 and r = 0.27, P = 0.004), persisting after adjustment for potential confounders. Serum IGF-I level predicted cases needing later surgery (AOC: 0.63; 95% confidence interval: 0.52-0.73). CONCLUSIONS: In this prospective, long-term study, baseline serum IGF-I correlated positively with AAA size and growth rate and predicted future need for preventive surgery.

Serum adiponectin concentration is a positive predictor of all-cause and cardiovascular mortality in type 1 diabetes.

BACKGROUND: Adiponectin is widely regarded as an anti-atherogenic, antioxidant and anti-inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. OBJECTIVE: To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. DESIGN: Multicentre prospective cohort study. SETTING: Primary and tertiary care. SUBJECTS: Finnish adults with type 1 diabetes (n= 2034). Main outcome measures. All-cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. RESULTS: During a median of 11 years of follow-up, there were 173 deaths (8.5%, 1.0 per hundred person-years). Adiponectin was linearly associated with all-cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.03, P<0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00-1.04, P=0.035); patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre-existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease. CONCLUSIONS: Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all-cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes.

Counter-regulatory hormone responses to spontaneous hypoglycaemia during treatment with insulin Aspart or human soluble insulin: a double-blinded randomized cross-over study.

AIMS: To compare insulin Aspart and human insulin with respect to glycaemic control, hypoglycaemic frequency and counter-regulatory responses to spontaneous hypoglycaemia. METHODS: Glycaemic control, hypoglycaemic frequency, p-insulin concentrations, insulin dosages and patients' satisfaction were examined in a randomized, double-blinded cross-over study for two periods of 8 weeks. Sixteen patients with type 1 diabetes were subjected to three daily injections of human soluble insulin or Aspart in addition to Neutral Protamine Hagedorn (NPH) insulin twice daily. Each intervention period was followed by hospitalization where episodes of spontaneous hypoglycaemia and counter-regulatory hormone responses were evaluated from frequently obtained blood samples. RESULTS: No difference between soluble insulin and insulin Aspart was found regarding HbA1c (7.0 ± 0.2 vs. 7.0 ± 0.2%, ns), hypoglycaemic frequency (1.1 ± 0.2 vs. 0.9 ± 0.1 events per patient per week, ns), nocturnal hypoglycaemia, severe hypoglycaemic events, dosages of bolus insulin (31.8 ± 0.4 vs. 30.0 ± 0.6 IU day(-1), ns), or NPH insulin (26.7 ± 1.8 vs. 26.0 ± 1.7 IU day(-1) , ns) or in patients satisfaction (ns). Modest differences existed in the counter-regulatory responses regarding growth hormone, glucagon and ghrelin whereas no differences were found in relation to free fatty acid, cortisol, insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins 1 and 2. Treatment with insulin Aspart resulted in well-defined peaks in serum insulin concentrations as compared with more blunted insulin peaks using human soluble insulin. CONCLUSION: Although insulin Aspart treatment was associated with clear postprandial insulin peaks, no improvement in glycaemic control was obtained and no difference in the hypoglycaemic frequency was observed. However, insulin Aspart elicited a slightly different physiological response to spontaneous hypoglycaemia compared with human insulin.

The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women.

BACKGROUND: The problems of adherence to energy restriction in humans are well known. OBJECTIVE: To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers. DESIGN: Randomized comparison of a 25% energy restriction as IER (∼ 2710 kJ/day for 2 days/week) or CER (∼ 6276 kJ/day for 7 days/week) in 107 overweight or obese (mean (± s.d.) body mass index 30.6 (± 5.1) kg m(-2)) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months. RESULTS: Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was -6.4 (-7.9 to -4.8) kg vs -5.6 (-6.9 to -4.4) kg for CER (P-value for difference between groups = 0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER; difference between groups for fasting insulin was -1.2 (-1.4 to -1.0) µU ml(-1) and for insulin resistance was -1.2 (-1.5 to -1.0) µU mmol(-1) l(-1) (both P = 0.04). CONCLUSION: IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.

Adiponectin and peak bone mass in men: a cross-sectional, population-based study.

Adiponectin, a protein classically known to be secreted by adipocytes, is also secreted by bone-forming cells. Results of previous studies have been contradictory as to whether serum adiponectin and bone mineral density (BMD) are associated. The aim of this study was to investigate a possible association between serum adiponectin and BMD in young, healthy men at a time of peak bone mass. BMD in the femoral neck, total hip, and lumbar spine were measured in this population-based cross-sectional study of 700 men aged 20-29 years participating in the Odense Androgen Study. Magnetic resonance imaging of femoral cortical thickness and bone marrow size was performed in a subsample of 363 participants. The associations between serum adiponectin and various bone measures were investigated by means of regression analyses with adjustment for potential confounding variables. An inverse association was found between serum adiponectin and total hip BMD and a direct between adiponectin and femoral bone marrow size (r = -0.092; P = 0.036 and r = 0.164; P = 0.003, respectively). Femoral muscle size may, at least in part, explain the association between adiponectin and total hip BMD. Serum adiponectin was inversely associated with total hip BMD in men at the time of peak bone mass, but this association may be explained by factors related to muscle size and function. The observed association between adiponectin and femoral bone marrow size was retained even after adjustment for potential covariates.