Allan Flyvbjerg

Plasma Adiponectin, Body Mass Index, and Mortality in Patients With Chronic Heart Failure

Background—Recent studies have suggested that higher body mass index (BMI) is associated with improved prognosis in chronic heart failure (CHF). The adipocytokine adiponectin is inversely associated with BMI, and in healthy subjects, low adiponectin is a predictor of mortality. In a prospective study, we therefore evaluated the association between plasma adiponectin levels and mortality among patients with CHF. Methods and Results—In 195 CHF patients (age 69.3±10.2 years, BMI 27.3±5.2 kg/m2, left ventricular ejection fraction 30±8.9%, mean±SD), plasma adiponectin and N-terminal pro brain natriuretic peptide (NT-proBNP) were measured at baseline. Adiponectin was positively associated with NT-proBNP (&bgr;=0.47, P<0.001), and both biomarkers were negatively associated with BMI (&bgr;=−0.43, P<0.001 for adiponectin and &bgr;=−0.38, P<0.001 for NT-proBNP, respectively) During a median follow-up of 2.6 years, 46 (23.5%) of the patients died. After adjustment for clinical variables associated with CHF severity (age, systolic blood pressure, left ventricular ejection fraction <25%, duration of CHF, and creatinine clearance) and for NT-proBNP, the hazard ratio of mortality for values in the 2 upper tertiles relative to the lowest tertile of adiponectin was 3.23 (P=0.032). BMI predicted mortality independently of clinical parameters of CHF severity (hazard ratio=0.63, P=0.012), but this association became insignificant after additional adjustment for NT-proBNP (hazard ratio=0.74, P=0.13). Conclusions—A high adiponectin level was a predictor of mortality, independent of risk markers of CHF severity, presumably because of its role as a marker for wasting. BMI was also associated with mortality, but a part of this relation may be mediated by adiponectin and NT-proBNP levels.

Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise

We hypothesized that an acute bout of strenuous, non‐damaging exercise would increase rates of protein synthesis of collagen in tendon and skeletal muscle but these would be less than those of muscle myofibrillar and sarcoplasmic proteins. Two groups (n= 8 and 6) of healthy young men were studied over 72 h after 1 h of one‐legged kicking exercise at 67% of maximum workload (Wmax). To label tissue proteins in muscle and tendon primed, constant infusions of [1‐13C]leucine or [1‐13C]valine and flooding doses of [15N] or [13C]proline were given intravenously, with estimation of labelling in target proteins by gas chromatography–mass spectrometry. Patellar tendon and quadriceps biopsies were taken in exercised and rested legs at 6, 24, 42 or 48 and 72 h after exercise. The fractional synthetic rates of all proteins were elevated at 6 h and rose rapidly to peak at 24 h post exercise (tendon collagen (0.077% h−1), muscle collagen (0.054% h−1), myofibrillar protein (0.121% h−1), and sarcoplasmic protein (0.134% h−1)). The rates decreased toward basal values by 72 h although rates of tendon collagen and myofibrillar protein synthesis remained elevated. There was no tissue damage of muscle visible on histological evaluation. Neither tissue microdialysate nor serum concentrations of IGF‐I and IGF binding proteins (IGFBP‐3 and IGFBP‐4) or procollagen type I N‐terminal propeptide changed from resting values. Thus, there is a rapid increase in collagen synthesis after strenuous exercise in human tendon and muscle. The similar time course of changes of protein synthetic rates in different cell types supports the idea of coordinated musculotendinous adaptation.

Obesity and cancer risk: the role of the insulin–IGF axis

Accumulating epidemiological evidence shows that being either overweight or obese, in other words having excess body weight (EBW), is associated with an increased risk of several, common, adult cancers. The molecular mechanisms that underlie these associations are not understood fully, but insulin resistance is likely to be important. The insulin-cancer hypothesis postulates that chronic hyperinsulinemia is associated with decreased concentrations of insulin-like growth factor binding protein1 (IGFBP-1) and IGFBP-2, leading to increased availability of IGF-I and concomitant changes in the cellular environment that favor tumor formation. However, the situation is likely to be more complex because hyperinsulinemia is also associated with alterations in related molecular systems (e.g. sex steroids and adipocytokines). As the prevalence of EBW increases to epidemic proportions, untangling the links between EBW and the insulin-IGF axis and its wider molecular interactions will become increasingly important in the development of preventive strategies.

Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population.

Patients with fatty liver (FL) disease have a high risk of developing diabetes and cardiovascular diseases. The aim was to evaluate the association between FL, insulin resistance (IR), coronary heart disease (CHD) risk, and early atherosclerosis in a large European population (RISC Study). In 1,307 nondiabetic subjects (age 30‐60 years) recruited at 19 centers, we evaluated liver enzymes, lipids, insulin sensitivity (by euglycemic‐hyperinsulinemic clamp), glucose tolerance (by 75 g oral glucose tolerance test), carotid atherosclerosis as intima media thickness (IMT), CHD risk by the Framingham Heart study prediction score, and physical activity (by accelerometer). The presence of FL was estimated using the fatty liver index (FLI; >60, likelihood >78% presence FL; FLI <20 likelihood >91% absence of FL). Subjects were divided into three groups: G1: FLI <20 (n = 608); G3: FLI >60 (n = 234), G2: intermediate group (n = 465). Compared to G1, G3 included more men (70% versus 24%) and people with impaired glucose tolerance (23% versus 5%). IMT increased with FLI (G3 = 0.64 ± 0.08 versus G1 = 0.58 ± 0.08 mm, P < 0.0001). FLI was associated with increased CHD risk (r = 0.48), low‐density lipoprotein cholesterol (r = 0.33), alanine aminotransferase (r = 0.48), aspartate aminotransferase (r = 0.25), systolic blood pressure (r = 0.39) and IMT (r = 0.30), and reduced insulin sensitivity (r = −0.43), high‐density lipoprotein cholesterol (r = −0.50), adiponectin (r = −0.42), and physical activity (r = −0.16, all P < 0.0001). The correlations hold also in multivariate analysis after adjusting for age, gender, and recruiting center. Conclusion: In middle‐age nondiabetic subjects, increased IMT, CHD risk, and reduced insulin sensitivity are associated with high values of FLI. (HEPATOLOGY 2009.)

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.

Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications

Aims/hypothesisLow serum adiponectin (ADPN) has been associated with increased risk of cardiovascular disease (CVD) and retinopathy in patients with type 2 diabetes mellitus. In type 1 diabetic patients, the relationship between ADPN and the presence of vascular complications is largely unknown.MethodsWe investigated the relationship between serum ADPN and the presence of retinopathy, nephropathy and CVD in patients with type 1 diabetes, divided into matched groups with normoalbuminuria and no retinopathy (n=67), simplex retinopathy (n=106) or proliferative retinopathy (n=19), and nephropathy with simplex (n=62) or proliferative retinopathy (n=137). Healthy control subjects (n=25) were included.ResultsSerum ADPN was increased in subjects with type 1 diabetes compared with control subjects (p<0.0001). Further, serum ADPN was higher in patients with than in those without nephropathy (p<0.0001). It was also higher in normoalbuminuric patients with than in those without proliferative retinopathy (p<0.0001). These differences remained significant after adjustment for known risk factors (p<0.03). CVD was also associated with elevated ADPN levels (p<0.05), but this difference became insignificant after risk factor adjustment. The most important predictor of serum ADPN was sex (r2=19%) in normoalbuminuric patients and GFR in patients with nephropathy (r2=18%).Conclusion/interpretationPatients with type 1 diabetes and microvascular complications have higher serum levels of ADPN than patients without complications. It remains to be clarified whether elevated levels of ADPN are pathogenically related to the development of microvascular complications or represent a beneficial counter-regulatory response.

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease.

The development of diabetic nephropathy in patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus is still a huge clinical problem associated with increased morbidity and mortality. The mechanisms underlying the development of diabetic kidney disease are extremely complex and yet not completely understood. Among many potential pathogenic mechanisms responsible for the development of diabetic kidney disease, various growth factors have been suggested to be important players. In particular, growth hormone (GH)/insulin-like growth factors (IGFs), transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) have measurable effects on the development of experimental diabetic kidney disease through complex intra-renal systems. Recent findings that these growth factors might initiate the early diabetic renal changes have provided insight into processes that might be relevant for future development of new drugs useful in the treatment of diabetic kidney disease. As will appear from the present review, enhanced understanding of the cellular mechanisms responsible for the development of diabetic kidney disease has already allowed the design of specific antagonists of pathophysiologically increased growth factors. Recent studies have shown that treating experimental diabetic models with such antagonists is followed by renoprotection. [Diabetologia (2000) 43: 1205–1223]

Prevention and early detection of vascular complications of diabetes

Diabetes reduces life expectancy by five to 10 years. Premature cardiovascular disease is the most common cause of morbidity and mortality, but the microvascular complications specific to diabetes (box 1) are also contributory factors. Diabetes is the most common reason for renal replacement therapy worldwide, the most common cause of blindness in the under 65s, and the most common cause of non-traumatic amputation. With our current knowledge, most of these devastating events could be prevented or delayed, or their impact minimised. This review focuses on the prevention, early detection, and initial management of the vascular complications of diabetes in adults. Complications are common and the cost to the individual and society is enormous. The onset of complications reduces quality of life, particularly when both microvascular and macrovascular disease are present.w1 The CODE-2 study gathered data on 7000 people with type 2 diabetes from eight European studies—72% had at least one complication and 24% had both (microvascular and macrovascular) complications.w2 Over six months, 13% of the patients were admitted to hospital for a mean of 23 days. The estimated average yearly cost per patient was €2834 (£1934,

Local application of growth factors (insulin-like growth factor-1 and transforming growth factor-β1) from a biodegradable poly(d,l-lactide) coating of osteosynthetic implants accelerates fracture healing in rats

3585); 55% of this cost was attributable to hospital admissions and only 7% to the cost of insulin and oral drugs for lowering glucose.1 The risk of developing complications is variable (table 1). For nephropathy, in particular, a strong but unknown genetic influence exists. The duration of diabetes, glycaemic control, and hypertension are the strongest risk factors for microvascular disease; smoking, blood pressure, lipids, and albuminuria are the strongest risk factors for macrovascular disease. View this table: Table 1 Risk factors and markers for the development of complications of diabetes ### Macrovascular disease Excess mortality from cardiovascular disease is seen in all age groups, particularly in young people with type 1 diabetes (box 2), and is exacerbated by social …

Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity

In vitro and in vivo studies have demonstrated an osteoinductive effect of growth factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1). However, for therapeutic use in fracture treatment, questions remain with regard to the local application of these proteins. A controlled, local release of growth factors from a biodegradable polylactide coating of osteosynthetic implants may have a stimulating effect on fracture healing. Such implants could stabilize the fracture and their bioactive surface could function simultaneously as a local drug-delivery system. Previous studies have demonstrated the high mechanical stability of an approximately 10-14-microm-thick poly(D,L-lactide) (PDLLA) coating on metallic implants, which can even withstand the process of intramedullary insertion. Following an initial peak, 80% of incorporated growth factors IGF-1 and TGF-beta1 were continuously released within 42 days. The effect of locally applied IGF-1 and TGF-beta1 from a biodegradable PDLLA coating of intramedullary implants on fracture healing was investigated in a rat model. Midshaft fractures of the right tibia of 5-month-old female Sprague-Dawley rats (n = 127) were stabilized with coated vs. uncoated titanium Kirschner wires. X-ray examinations and blood analyses were performed, and body weight and body temperature measurements were taken throughout the experimental period. After 28 and 42 days, respectively, tibiae were dissected for mechanical torsional testing and histomorphometrical analyses. X-rays demonstrated an almost completely consolidated fracture, biomechanical testing showed a significantly higher maximum load and torsional stiffness, and histological and histomorphometric analyses demonstrated progressed remodeling after 28 and 42 days in the group treated with growth factors as compared with controls. Interestingly, the PDLLA coating itself revealed a positive effect on fracture healing even without incorporated growth factors. No systemic changes of serum parameters, including IGF-1 and IGF binding proteins, and no differences in body weight and body temperature were observed within and between groups. These findings suggest that the local application of growth factors from a biodegradable PDLLA coating of osteosynthetic implants accelerates fracture healing significantly without systemic side effects.