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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 (approximately 2710 kJ/day for 2 days/week) or CER (approximately 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) micromoll-1 and for insulin resistance was -1.2 (-1.5 to -1.0) micromol-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.

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 beta (TGF-beta), 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.

Aims/hypothesis Obesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults. Methods Leptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic-euglycaemic clamp studies in 1,226 EGIR RISC participants. Results The LAR was highly correlated with HOMA-S in men (r = −0.58, p = 4.5 × 10⁻³³ and r = −0.65, p = 1.1 × 10⁻⁶⁶ within the Ely and EGIR RISC study cohorts, respectively) and in women (r = −0.51, p = 2.8 × 10⁻³⁶ and r = −0.61, p = 2.5 × 10⁻⁷³). The LAR was also strongly correlated with the clamp M/I value (r = −0.52, p = 4.5 × 10⁻³⁸ and r = −0.47, p = 6.6 × 10⁻⁴⁰ in men and women, respectively), similar to correlations between HOMA-S and the M/I value. Conclusions/interpretation The leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.

Aims/hypothesis Diabetic nephropathy has been associated with low-grade inflammation and activation of the complement system in cross-sectional studies. Data from prospective studies are sparse. We investigated the associations of the complement activator mannose-binding lectin (MBL) and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) with the development of nephropathy in a large prospective study of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. Methods Baseline MBL and hsCRP were measured in 1,564 type 1 diabetes patients from the FinnDiane study, of whom 1,010 had a normal albumin excretion rate, 236 had microalbuminuria and 318 had macroalbuminuria. The main outcome was progression in renal disease during follow-up. Results Both baseline MBL (p = 0.038) and hsCRP (p < 0.001) increased with increasing level of albuminuria. During 5.8 ± 2.2 years of follow-up, progression to a higher albuminuria level or end-stage renal disease (ESRD) occurred in 201 patients. MBL levels were higher in progressors compared with non-progressors at all steps of progression, and in a covariate adjusted multivariate Cox-regression analysis MBL levels above the median were significantly associated with progression from macroalbuminuria to ESRD (hazard ratio 1.88, 95% CI 1.06-3.32, p = 0.030). In a univariate analysis, hsCRP levels above the median were significantly associated with progression from normal albumin excretion rate to microalbuminuria, but the association was only borderline significant after adjustment for covariates (hazard ratio 1.56, 95% CI 0.97-2.51, p = 0.068). Conclusions/interpretation This study demonstrates that concentrations of both MBL and hsCRP are associated with the progression of renal disease in type 1 diabetes.

Summary 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 (E 2 ), prolactin and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) 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, E 2 was low ( p  < 0.05); prolactin decreased according to lactation status ( p  < 0.05). 1,25(OH) 2 D 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) 2 D 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 E 2 levels and perhaps increased parathyroid hormone-related protein levels.

Low 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. We 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. Serum 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%). Patients 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.

Aims/hypothesis An increasing amount of evidence indicates that mannose-binding lectin (MBL) plays a role in the development of diabetic nephropathy. The main objective of the study was to analyse whether MBL influences the effects of diabetes on the kidneys. Materials and methods In one group of wild-type mice and in one group of MBL double knockout mice we induced diabetes by the use of streptozotocin as a model of type 1 diabetes. Two groups of non-diabetic mice, wild-type and MBL knockout, were also included. By two-way ANOVA we evaluated if MBL modulated the effects of diabetes by testing the interaction between diabetes and MBL. Results MBL interacted with the effects of diabetes on three outcome measures: kidney weight (p < 0.001), urinary albumin excretion (p = 0.001) and the expression of collagen IVα1 (Col4a1) mRNA (p = 0.002). This means that the effects that diabetes normally has on these parameters were significantly modified by MBL. MBL showed a tendency to interact with the effects of diabetes on glomerular basement membrane thickness and total mesangial volume (p = 0.065 and p = 0.063, respectively). Glomerular volume and total mesangial volume were significantly smaller in animals lacking MBL than in wild-type animals (p = 0.006 and p = 0.047, respectively). Conclusions/interpretation These findings, for the first time, show that the degree of kidney alteration as a consequence of diabetes is modified by MBL. These findings support a pivotal role of MBL in the development of diabetic kidney disease.

Aim: Type 2 diabetes is associated with stroke and cardiac dysfunction. We therefore investigated isolated middle cerebral arteries and coronary septal arteries from the diabetic Goto-Kakizaki (GK) rat model of nonobese type 2 diabetes. Methods: Myogenic tone and agonist-induced responses were investigated under isobaric conditions with simultaneous recording of [Ca 2+ ] i . Rho-kinase and NO pathways were investigated using specific pharmacological tools. Results: Arteries from GK rats developed less tone at pressures from 20 to 100 mm Hg than arteries from control Wistar (CW) rats while [Ca 2+ ] i was similar. Blocking the Rho-kinase pathway decreased the pressure-induced development of tone and after blockade no difference in myogenic tone between arteries from GK and CW rats was seen. Cerebral arteries had similar tone to a maximal concentration of U46619 (GK: 35.5 ± 2% vs. CW: 31.6 ± 5%), while coronary arteries from GK rats developed less tone than arteries from CW rats (12 ± 3 vs. 26.1 ± 3%). Endothelium-dependent vasodilation to A23187 (cerebral) and to acetylcholine (coronary) was not different between arteries from GK and CW rats. Conclusion: Our data suggest that in resistance arteries from the brain and the heart of GK rats the myogenic tone is decreased due to impaired calcium sensitivity likely due to a defective Rho-kinase pathway.

Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals. We measured IR [by a euglycaemic-hyperinsulinaemic (240 pmol min(-1) m(-2)) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m(2) (range 18-44 kg/m(2))] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was approximately 2 for both glucagon (p = 0.05) and proinsulin (p = 0.02) and 0.36 for adiponectin (p < 0.0001). Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets.

Aims/hypothesis The bone-related peptide osteoprotegerin is produced by vascular cells and is involved in the process of vascular calcification. The aim of this study was to investigate the predictive value of plasma levels of osteoprotegerin in relation to mortality, cardiovascular events and deterioration in kidney function in patients with type 1 diabetes. Methods This prospective observational follow-up study included 397 type 1 diabetic patients with overt diabetic nephropathy (243 men; age [mean±SD] 42.1 ± 10.6 years, duration of diabetes 28.3 ± 9.9 years, GFR 67 ± 28 ml min −1 1.73 m 2 ) and a group of 176 patients with longstanding type 1 diabetes and persistent normoalbuminuria (105 men; age 42.6 ± 9.7 years, duration of diabetes 27.6 ± 8.3 years). Results The median (range) follow-up period was 11.3 (0.0–12.9) years. Among patients with diabetic nephropathy, individuals with high osteoprotegerin levels (fourth quartile) had significantly higher all-cause mortality than patients with low levels (first quartile) (covariate-adjusted hazard ratio [HR] 3.00 [1.24–7.27]). High osteoprotegerin levels also predicted cardiovascular mortality (covariate-adjusted HR 4.88 [1.57–15.14]). Furthermore, patients with high osteoprotegerin levels had significantly higher risk of progression to end-stage renal disease than patients with low levels (covariate-adjusted HR 4.32 [1.45–12.87]). In addition, patients with high levels of plasma osteoprotegerin had an elevated rate of decline in GFR. Conclusions/interpretation High levels of osteoprotegerin predict all-cause and cardiovascular mortality in patients with diabetic nephropathy. Furthermore, high levels of osteoprotegerin predict deterioration of kidney function towards end-stage renal disease.