Trajectories of glycaemia,insulin sensitivity and insulin secretion in South Asian and white individuals before diagnosis of type 2 diabetes: a longitudinal analysis from the Whitehall II cohort study

Aims/hypothesis

South Asian individuals have reduced insulin sensitivity and increased risk of type 2 diabetes compared with white individuals. Temporal changes in glycaemic traits during middle age suggest that impaired insulin secretion is a particular feature of diabetes development among South Asians. We therefore aimed to examine ethnic differences in early changes in glucose metabolism prior to incident type 2 diabetes.

Methods

In a prospective British occupational cohort, subject to 5 yearly clinical examinations, we examined ethnic differences in trajectories of fasting plasma glucose (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI_0,120) among 120 South Asian and 867 white participants who developed diabetes during follow-up (1991–2013). We fitted cubic mixed-effects models to longitudinal data with adjustment for a wide range of covariates.

Results

Compared with white individuals, South Asians had a faster increase in FPG before diagnosis (slope difference 0.22 mmol/l per decade; 95% CI 0.02, 0.42; p = 0.03) and a higher FPG level at diagnosis (0.27 mmol/l; 95% CI 0.06, 0.48; p = 0.01). They also had higher FSI and 2hSI levels before and at diabetes diagnosis. South Asians had a faster decline and lower HOMA2-S (log _e -transformed) at diagnosis compared with white individuals (0.33; 95% CI 0.21, 0.46; p < 0.001). HOMA2-B increased in both ethnic groups until 7 years before diagnosis and then declined; the initial increase was faster in white individuals. ISI_0,120 declined steeply in both groups before diagnosis; levels were lower among South Asians before and at diagnosis. There were no ethnic differences in 2hPG trajectories.

Conclusions/interpretation

We observed different trajectories of plasma glucose, insulin sensitivity and secretion prior to diabetes diagnosis in South Asian and white individuals. This might be due to ethnic differences in the natural history of diabetes. South Asian individuals experienced a more rapid decrease in insulin sensitivity and faster increases in FPG compared with white individuals. These findings suggest more marked disturbance in beta cell compensation prior to diabetes diagnosis in South Asian individuals.

     

Alterations of specific lipid groups in serum of obese humans: a review

Obesity is a major contributor to the dysfunction of liver, cardiac, pulmonary, endocrine and reproductive system, as well as a component of metabolic syndrome. Although development of obesity‐related disorders is associated with lipid abnormalities, most previous studies dealing with the problem in question were limited to routinely determined parameters, such as serum concentrations of triacylglycerols, total cholesterol, low‐density and high‐density lipoprotein cholesterol. Many authors postulated to extend the scope of analysed lipid compounds and to study obesity‐related alterations in other, previously non‐examined groups of lipids. Comprehensive quantitative, structural and functional analysis of specific lipid groups may result in identification of new obesity‐related alterations. The review summarizes available evidence of obesity‐related alterations in various groups of lipids and their impact on health status of obese subjects. Further, the role of diet and endogenous lipid synthesis in the development of serum lipid alterations is discussed, along with potential application of various lipid compounds as risk markers for obesity‐related comorbidities.     

High plasma fetuin-A levels are associated with metabolic syndrome among males but not females in a Japanese general population

Aims

Fetuin-A, a protein exclusively secreted from the liver, is associated with insulin resistance and/or metabolic syndrome (MetS). However, few studies have examined this association in Japan. We investigated this issue in a Japanese general population.

Methods

We performed an epidemiological survey in a small community in Japan. The participants consisted of 659 subjects (253 males and 406 females). Fetuin-A levels were measured by a sandwich ELISA method and the modified NCEP-ATP III criteria were adopted to diagnose MetS. The homeostasis model assessment index (HOMA-IR) was calculated as a marker of insulin resistance.

Results

Statistically significant characteristics of the 659 subjects stratified by fetuin-A quartiles were male gender (inversely), age (inversely), insulin, HOMA-IR, uric acid (inversely), alcohol intake (inversely) and the prevalence of MetS. Mean fetuin-A levels were 249.7 ± 45.1 μg/ml in males and 262.7 ± 55.8 μg/ml in females. In males, the prevalence of MetS was 43.1%, and their mean HOMA-IR level was 1.1. In females, the prevalence of MetS was 17.7%, and their mean HOMA-IR level was 0.9. Multiple stepwise regression analyses showed that fetuin-A levels in males but not females were independently associated with MetS and LDL-c. Multiple logistic regression analysis of fetuin-A (quartile 1 vs. quartile 4) in males showed significant odds ratios of 1.009 (95% C.I.: 1.003–1.015) for MetS and 1.376 (95% C.I.: 1.027–1.844) for 1-SD increment increase in LDL-c.

Conclusions

High plasma fetuin-A levels were associated with MetS in community-dwelling Japanese males but not females.     

Ezetimibe combined with standard diet and exercise therapy improves insulin resistance and atherosclerotic markers in patients with metabolic syndrome

Aims/Introduction

Ezetimibe lowers serum lipid levels by inhibiting intestinal absorption of dietary and biliary cholesterol. However, the effect of ezetimibe on insulin resistance remains unclear. The aim of the present study was to examine this issue in patients with metabolic syndrome in local-dwelling Japanese, who were not being treated with lipid-lowering drugs.

Materials and Methods

In 2009, 1,943 participants received a health examination in the Tanushimaru Study, a Japanese cohort of the Seven Countries Study, of whom 490 participants had metabolic syndrome. Among them, 61 participants (41 men and 20 women) were examined in the present study. They were treated with 10 mg of ezetimibe once a day for 24 weeks, combined with standard diet and exercise therapy.

Results

Bodyweight (P < 0.001), body mass index (P < 0.001), systolic blood pressure (P = 0.003), diastolic blood pressure (P < 0.001), triglycerides (P = 0.002), non-high-density lipoprotein cholesterol (P = 0.001), low-density lipoprotein cholesterol (P < 0.001) and homeostasis model assessment of insulin resistance (P = 0.011) significantly decreased after the observational period. There were no statistically significant differences in the effects of ezetimibe between men and women. Univariate analysis showed that the reduction of homeostasis model assessment of insulin resistance was not associated with the improvement of other metabolic components.

Conclusions

Ezetimibe combined with standard diet and exercise therapy improves not only bodyweight and atherogenic lipid profiles, but also insulin resistance, blood pressure and anthropometric factors in metabolic syndrome in local-dwelling Japanese. Interestingly, the improvement of insulin resistance had no correlation with other metabolic components.     

3D Printable Biophotopolymers for in Vivo Bone Regeneration

The present study investigated two novel biophotopolymer classes that are chemically based on non-toxic poly (vinyl alcohol). These vinylesters and vinylcarbonates were compared to standard acrylates in vitro on MC3T3-E1 cells and in vivo in a small animal model. In vitro, both vinylester and vinylcarbonate monomers showed about tenfold less cytotoxicity when compared to acrylates (IC₅₀: 2.922 mM and 2.392 mM vs. 0.201 mM) and at least threefold higher alkaline phosphatase activity (17.038 and 18.836 vs. 5.795, measured at [10 mM]). In vivo, polymerized 3D cellular structures were implanted into the distal femoral condyle of 16 New Zealand White Rabbits and were observed for periods from 4 to 12 weeks. New bone formation and bone to implant contact was evaluated by histomorphometry at end of observation. Vinylesters showed similar rates of new bone formation but significantly less (p = 0.002) bone to implant contact, when compared to acrylates. In contrast, the implantation of vinylcarbonate based biophotopolymers led to significantly higher rates of newly formed bone (p < 0.001) and bone to implant contact (p < 0.001). Additionally, distinct signs of polymer degradation could be observed in vinylesters and vinylcarbonates by histology. We conclude, that vinylesters and vinylcarbonates are promising new biophotopolymers, that outmatch available poly(lactic acid) and (meth)acrylate based materials.     

Erosion during extreme flood events dominates Holocene canyon evolution in northeast Iceland

Extreme flood events have the potential to cause catastrophic landscape change in short periods of time (10⁰ to 10³ h). However, their impacts are rarely considered in studies of long-term landscape evolution (>10³ y), because the mechanisms of erosion during such floods are poorly constrained. Here we use topographic analysis and cosmogenic ³He surface exposure dating of fluvially sculpted surfaces to determine the impact of extreme flood events within the Jökulsárgljúfur canyon (northeast Iceland) and to constrain the mechanisms of bedrock erosion during these events. Surface exposure ages allow identification of three periods of intense canyon cutting about 9 ka ago, 5 ka ago, and 2 ka ago during which multiple large knickpoints retreated large distances (>2 km). During these events, a threshold flow depth was exceeded, leading to the toppling and transportation of basalt lava columns. Despite continuing and comparatively large-scale (500 m³/s) discharge of sediment-rich glacial meltwater, there is no evidence for a transition to an abrasion-dominated erosion regime since the last erosive event because the vertical knickpoints have not diffused over time. We provide a model for the evolution of the Jökulsárgljúfur canyon through the reconstruction of the river profile and canyon morphology at different stages over the last 9 ka and highlight the dominant role played by extreme flood events in the shaping of this landscape during the Holocene.Extreme floods in both terrestrial and extraterrestrial environments can cause abrupt landscape change that can have long-term consequences (1–5), especially when a geomorphic threshold is exceeded (6). The timescale over which this change is visible is controlled by the ability and efficiency of background processes to reshape the landscape. As a result, progress in understanding both short-term and long-term landscape evolution requires better knowledge of bedrock channel erosion processes and thresholds over the different scales at which geomorphological processes operate (7–10).The majority of research into extreme flood events has focused on the interpretation of deposited sediments (e.g., refs. 11 and 12) and the reconstruction of the hydraulic conditions prevailing during such events (e.g., refs. 13–15). Further work has defined the geomorphic impact of extreme flood events in proglacial areas close to the source of the flood water (e.g., refs. 16 and 17). Studies that examine the processes of bedrock erosion, especially large canyon formation, during extreme flood events can help establish a diagnostic link between formation processes and morphology in canyons in both terrestrial and extraterrestrial settings, but they remain scarce (e.g., refs. 18–20). Here, evidence for bedrock landscape change during extreme floods along the course of the Jökulsá á Fjöllum River (northeast Iceland) is used to test whether the contemporary landscape morphology reflects erosion during rare extreme events, or longer-term “background” erosional processes.The Jökulsá á Fjöllum has experienced multiple glacial outburst floods (jökulhlaups) since the Last Glacial Maximum, with peak discharge for the largest flood estimated to be in the order of 0.9 × 10⁶ m³/s (14, 21). The landscape contains many characteristic landforms associated with extreme flood events, including boulder bars and terraces, dry cataracts such as Ásbyrgi, numerous flood overspill channels, and the Jökulsárgljúfur canyon (Fig. 1) (e.g., refs. 16 and 22–25). The canyon has been carved through a volcanic system that was active 8.5 ka B.P. (26) ∼4 km downstream of its head. As the canyon is cut directly through the fissure and associated lava flows and there is no evidence of lava from the fissure flowing into the canyon, the eruption age provides an independent constraint on the maximum age for the formation of the canyon upstream of the fissure (Fig. 1). The impact of the largest flood events has never been tied to the evolution of the bedrock landscape within the Jökulsárgljúfur canyon, as previous studies have focused on sedimentary deposits (e.g., refs. 24 and 25). This study uses topographic analysis and cosmogenic ³He surface exposure dating of fluvial surfaces to determine the erosive impact of extreme flood events and assess the importance, and legacy, of high-magnitude low-frequency events in landscape evolution over multimillennial timescales.Open in a separate windowFig. 1.(A) Location map of Iceland showing the Vatnajökull ice cap, the source of the floodwaters, and the course of the Jökulsá á Fjöllum. The locations of the two study sites—the upper 5 km of Jökulsárgljúfur canyon at Dettifoss and Ásbyrgi, 25 km further downstream—are shown with black stars. The location of the gauging station at Grimsstadir used for hydrological calculations is also shown. (B) Aerial photograph from 1998 of the 5-km study reach at the head of Jökulsárgljúfur canyon. Yellow dashed lines delineate the areas where clear evidence for fluvial erosion is present (landscape outside these areas is shaded to improve clarity). The three large knickpoints are highlighted: Selfoss, Dettifoss, and Hafragilsfoss (height in parentheses), as well as the Sanddalur overspill channel, which contains two cataracts. The volcanic fissure that erupted 8.5 ka ago (black circles show volcanoes) provides an independent constraint on the maximum age of the canyon. Orange stars indicate the locations of the samples collected for surface exposure dating. The upper, middle, and lower terraces are shown in red, green, and yellow, respectively; active fluvial surfaces associated with upper and middle terraces are shown in transparent red and green upstream of Dettifoss. A cross section of the gorge across the line from west to east is inset. (C) A zoomed in image of Dettifoss from 1998, with the yellow line showing the digitized position of the waterfall in 1955. Dettifoss has been mostly stable during the 43-y period between the images, with only a small retreat (maximum 5 m) evident on the western side of the channel. If the Jökulsárgljúfur canyon was formed by the progressive retreat of Dettifoss following the fissure eruption (2,500 m in 8.5 ka, equivalent to a rate of 0.3 m/y), we would expect to see a minimum of 13 m of retreat between 1955 and 1998, shown with the red line. (D) Ásbyrgi canyon and the Klappir scabland area immediately upstream. This landscape exhibits perfectly preserved landforms that were formed during an extreme flood event, with the Jökulsá á Fjöllum now flowing in a deeply incised canyon to the east.     

Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience

This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the “real-life” setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rituximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m² or 500 mg/m², and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associated with shorter progression-free survival (hazard ratio 3.6, P<0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the “real-life” setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome.     

Carvedilol decreases elevated oxidative stress in human failing myocardium

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating beta-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results- Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (P<0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9+/-4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22+/-8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (P<0.005) along with amelioration of heart failure. CONCLUSIONS: Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.