Stimulation of cholesteryl ester synthesis in human monocyte-derived macrophages by low-density lipoproteins from type 1 (insulin-dependent) diabetic patients:the influence of non-enzymatic glycosylation of low-density lipoproteins

Diabetes mellitus is an independent risk factor in the development of atherosclerosis. In this study we aimed to demonstrate whether there is an abnormal interaction between low-density lipoproteins from diabetic patients and human macrophages. We measured cholesteryl ester synthesis and cholesteryl ester accumulation in human monocyte-derived macrophages (obtained from non-diabetic donors) incubated with low density lipoproteins from Type 1 (insulin-dependent) diabetic patients in good or fair glycaemic control. Low density lipoproteins from the diabetic patients stimulated more cholesteryl ester synthesis than low density lipoproteins from non-diabetic control subjects (7.19 +/- 1.19 vs 6.11 +/- 0.94 nmol/mg cell protein/20 h, mean +/- SEM, p less than 0.05). The stimulation of cholesteryl ester synthesis by low density lipoproteins isolated from diabetic patients was paralleled by a significant increase in intracellular cholesteryl ester accumulation (p less than 0.02). There were no significant differences in the lipid composition of low density lipoproteins between the diabetic and control groups. Non-enzymatic glycosylation of low density lipoproteins was higher in the diabetic group (p less than 0.01) and correlated significantly with cholesteryl ester synthesis (r = 0.58). Similarly, low-density lipoproteins obtained from non-diabetic subjects and glycosylated in vitro stimulated more cholesteryl ester synthesis in macrophages than control low density lipoproteins. The increase in cholesteryl ester synthesis and accumulation by cells exposed to low density lipoproteins from diabetic patients seems to be mediated by an increased uptake of these lipoproteins by macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycosylation of low density lipoprotein in patients with type 1 (insulin-dependent) diabetes:correlations with other parameters of glycaemic control

Glycosylation of low density lipoproteins obtained from 16 patients with Type 1 (insulin-dependent) diabetes and from 16 age-, sex-, and race-matched controls, was determined. The diabetic patients were normolipaemic and were in good or fair glycaemic control. Eleven patients performed home blood glucose monitoring. Glycosylation of low density lipoproteins in the diabetic patients was significantly higher (p less than 0.001) than in the control subjects, and was significantly correlated with haemoglobin A1c, (p less than 0.01), glycosylation of plasma proteins, (p less than 0.001), and mean home blood glucose, (p less than 0.01). This study confirms that, in diabetic patients, increased glycosylation of low density lipoprotein occurs to an extent which correlates closely with other commonly used indices of glycaemic control.

Non-enzymatic glycosylation of skin collagen in patients with type 1 (insulin-dependent) diabetes mellitus and limited joint mobility

Forearm skin biopsies were obtained from diabetic subjects with and without limited joint mobility, and from non-diabetic control subjects. Collagen purified from these samples was assayed for non-enzymatic glycosylation. The level in all diabetic patients was significantly greater than that in control subjects (p less than 0.001), but those diabetic patients with limited joint mobility had a level of collagen glycosylation similar to that in those with normal joints (15.3 +/- 1.3 and 16.5 +/- 1.3 nmol fructose/10 mg protein, respectively; mean +/- SEM). Glycosylation of collagen in the diabetic patients correlated with glycosylated haemoglobin measured at the time of skin biopsy (r = 0.60). These results do not support the hypothesis that non-enzymatic glycosylation of collagen, as reflected by the ketoamine link, plays an important role in the development of limited joint mobility in diabetes.

Increased serum pigment epithelium derived factor levels in Type 2 diabetes patients

Serum PEDF levels (mean (S.D.)) were increased in 96 Type 2 diabetic vs. 54 non-diabetic subjects; 5.3 (2.8) vs. 3.2 (2.0)mug/ml, p

Immune complexes containing modified lipoproteins are related to the progression of internal carotid intima-media thickness in patients with type 1 diabetes

Modified lipoproteins induce autoimmune responses including the synthesis of autoantibodies with pro-inflammatory characteristics. Circulating modified lipoprotein autoantibodies combine with circulating antigens and form immune complexes (IC). We now report the results of a study investigating the role of circulating IC containing modified lipoproteins in the progression of carotid intima-media thickness (IMT) in patients enrolled in the Epidemiology of Diabetes Interventions and Complications (EDIC) Trial, a follow-up study of the Diabetes Control and Complications Trial (DCCT). This cohort includes 1229 patients with type 1 diabetes in whom B-mode ultrasonography of internal and common carotid arteries was performed in 1994-1996 and in 1998-2000. Conventional CHD risk factors, antibodies against modified forms of LDL and modified lipoprotein IC were determined in 1050 of these patients from blood collected in 1996-1998. Cholesterol and apolipoprotein B content of IC (surrogate markers of modified ApoB-rich lipoproteins) were significantly higher in patients who showed progression of the internal carotid IMT than in those showing no progression, regression or mild progression. Multivariate linear and logistic regression modeling using conventional and non-conventional risk factors showed that the cholesterol content of IC was a significant positive predictor of internal carotid IMT progression. In conclusion these data demonstrate that increased levels of modified ApoB-rich IC are associated with increased progression of internal carotid IMT in the DCCT/EDIC cohort of type 1 diabetes.

Super-luminous Type Ic Supernovae: Catching a Magnetar by the Tail

We report extensive observational data for five of the lowest redshift Super-Luminous Type Ic Supernovae (SL-SNe Ic) discovered to date, namely, PTF10hgi, SN2011ke, PTF11rks, SN2011kf, and SN2012il. Photometric imaging of the transients at +50 to +230 days after peak combined with host galaxy subtraction reveals a luminous tail phase for four of these SL-SNe. A high-resolution, optical, and near-infrared spectrum from xshooter provides detection of a broad He I ?10830 emission line in the spectrum (+50 days) of SN2012il, revealing that at least some SL-SNe Ic are not completely helium-free. At first sight, the tail luminosity decline rates that we measure are consistent with the radioactive decay of 56Co, and would require 1-4 M ? of 56Ni to produce the luminosity. These 56Ni masses cannot be made consistent with the short diffusion times at peak, and indeed are insufficient to power the peak luminosity. We instead favor energy deposition by newborn magnetars as the power source for these objects. A semi-analytical diffusion model with energy input from the spin-down of a magnetar reproduces the extensive light curve data well. The model predictions of ejecta velocities and temperatures which are required are in reasonable agreement with those determined from our observations. We derive magnetar energies of 0.4 <~ E(1051 erg) lsim 6.9 and ejecta masses of 2.3 <~ M ej(M ?) lsim 8.6. The sample of five SL-SNe Ic presented here, combined with SN 2010gx—the best sampled SL-SNe Ic so far—points toward an explosion driven by a magnetar as a viable explanation for all SL-SNe Ic.

Nerve pathology in the type 1 diabetic dog: effects of treatment with sulindac

The purpose of this study was to define pathological abnormalities in the peripheral nerve of a large animal model of long-duration type 1 diabetes and also to determine the effects of treatment with sulindac. Detailed morphometric studies were performed to define nerve fiber and endoneurial capillary pathology in 6 control dogs, 6 type 1 diabetic dogs treated with insulin, and 6 type 1 diabetic dogs treated with insulin and sulindac for 4 years. Myelinated fiber and regenerative cluster density showed a non-significant trend toward a reduction in diabetic compared to control animals, which was prevented by treatment with sulindac. Unmyelinated fiber density did not differ among groups. However, diabetic animals showed a non-significant trend toward an increase in axon diameter (p <0.07), with a shift of the size frequency distribution towards larger axons, which was not prevented by treatment with sulindac. Endoneurial capillary density and luminal area showed a non-significant trend toward an increase in diabetic animals, which was prevented with sulindac treatment. Endoneurial capillary basement membrane area was significantly increased (p <0.05) in diabetic animals, but was not prevented with sulindac treatment. We conclude that the type 1 diabetic dog demonstrates minor structural abnormalities in the nerve fibers and endoneurial capillaries of the sciatic nerve, and treatment with sulindac ameliorates some but not all of these abnormalities.

Evaluation of an algorithm to guide patients with type 1 diabetes treated with continuous subcutaneous insulin infusion on how to respond to real-time continuous glucose levels:A randomized controlled trial

OBJECTIVE - To evaluate an algorithm guiding responses of continuous subcutaneous insulin infusion (CSII)-treated type 1 diabetic patients using real-time continuous glucose monitoring (RT-CGM). RESEARCH DESIGN AND METHODS - Sixty CSII-treated type 1 diabetic participants (aged 13-70 years, including adult and adolescent subgroups, with A1C =9.5%) were randomized in age-, sex-, and A1C-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial. Group A was treated with CSII/RT-CGM with the algorithm, and group B was treated with CSII/RT-CGM without the algorithm. The primary outcome was the difference in time in target (4-10 mmol/l) glucose range on 6-day masked CGM. Secondary outcomes were differences in A1C, low (=3.9 mmol/l) glucose CGM time, and glycemic variability. Phase 2 was the week 16-32 follow-up. Group A was returned to usual care, and group B was provided with the algorithm. Glycemia parameters were as above. Comparisons were made between baseline and 16 weeks and 32 weeks. RESULTS - In phase 1, after withdrawals 29 of 30 subjects were left in group A and 28 of 30 subjects were left in group B. The change in target glucose time did not differ between groups. A1C fell (mean 7.9% [95% CI 7.7-8.2to 7.6% [7.2-8.0]; P <0.03) in group A but not in group B (7.8% [7.5-8.1] to 7.7 [7.3-8.0]; NS) with no difference between groups. More subjects in group A achieved A1C =7% than those in group B (2 of 29 to 14 of 29 vs. 4 of 28 to 7 of 28; P = 0.015). In phase 2, one participant was lost from each group. In group A, A1C returned to baseline with RT-CGM discontinuation but did not change in group B, who continued RT-CGM with addition of the algorithm. CONCLUSIONS - Early but not late algorithm provision to type 1 diabetic patients using CSII/RT-CGM did not increase the target glucose time but increased achievement of A1C =7%. Upon RT-CGM cessation, A1C returned to baseline. © 2010 by the American Diabetes Association.

Retinal vascular geometry predicts incident renal dysfunction in young people with type 1 diabetes

OBJECTIVE - To examine the relationship between retinal vascular geometry parameters and development of incident renal dysfunction in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS - This was a prospective cohort study of 511 adolescents with type 1 diabetes of at least 2 years duration, with normal albumin excretion rate (AER) and no retinopathy at baseline while attending an Australian tertiary-care hospital. AER was quantified using three overnight, timed urine specimen collections and early renal dysfunction was defined as AER >7.5 µg/min. Retinal vascular geometry (including length-to-diameter ratio [LDR] and simple tortuosity [ST]) was quantified from baseline retinal photographs. Generalized estimating equations were used to examine the relationship between incident renal dysfunction and baseline venular LDR and ST, adjusting for age, diabetes duration, glycated hemoglobin (A1C), blood pressure (BP), BMI, and cholesterol. RESULTS - Diabetes duration at baseline was 4.8 (IQR 3.3-7.5) years. After amedian 3.7 (2.3-5.7) years follow-up, 34% of participants developed incident renal dysfunction. In multivariate analysis, higher retinal venular LDR (odds ratio 1.7, 95% CI 1.2-2.4; quartile 4 vs. 1-3) and lower venular ST (1.6, 1.1-2.2; quartile 1 vs. 2-4) predicted incident renal dysfunction. CONCLUSIONS - Retinal venular geometry independently predicted incident renal dysfunction in young people with type 1 diabetes. These noninvasive retinal measures may help to elucidate early mechanistic pathways for microvascular complications. Retinal venular geometry may be a useful tool to identify individuals at high risk of renal disease early in the course of diabetes. © 2012 by the American Diabetes Association.

A spectroscopically normal type Ic supernova from a very massive progenitor

We present observations of the Type Ic supernova (SN Ic) 2011bm spanning a period of about one year. The data establish that SN 2011bm is a spectroscopically normal SN Ic with moderately low ejecta velocities and with a very slow spectroscopic and photometric evolution (more than twice as slow as SN 1998bw). The Pan-STARRS1 retrospective detection shows that the rise time from explosion to peak was 40 days in the R band. Through an analysis of the light curve and the spectral sequence, we estimate a kinetic energy of 7-17 foe and a total ejected mass of 7-17 Mo, 5-10 Mo of which is oxygen and 0.6-0.7 Mo is 56Ni. The physical parameters obtained for SN 2011bm suggest that its progenitor was a massive star of initial mass 30-50 Mo. The profile of the forbidden oxygen lines in the nebular spectra show no evidence of a bi-polar geometry in the ejected material.

The Type IIb Supernova 2011dh from a Supergiant Progenitor

A set of hydrodynamical models based on stellar evolutionary progenitors is used to study the nature of SN 2011dh. Our modeling suggests that a large progenitor star ---with R ~200 Rsun---, is needed to reproduce the early light curve of SN 2011dh. This is consistent with the suggestion that the yellow super-giant star detected at the location of the SN in deep pre-explosion images is the progenitor star. From the main peak of the bolometric light curve and expansion velocities we constrain the mass of the ejecta to be ~2 Msun, the explosion energy to be E= 6-10 x 10^50 erg, and the 56Ni mass to be approximately 0.06 Msun. The progenitor star was composed of a helium core of 3 to 4 Msun and a thin hydrogen-rich envelope of ~0.1 M_sun with a main sequence mass estimated to be in the range of 12--15 Msun. Our models rule out progenitors with helium-core masses larger than 8 Msun, which correspond to M_ZAMS > 25 Msun. This suggests that a single star evolutionary scenario for SN 2011dh is unlikely.

Comparison of progenitor mass estimates for the type IIP SN 2012A

We present the one-year long observing campaign of SN 2012A which exploded in the nearby (9.8 Mpc) irregular galaxy NGC 3239. The photometric evolution is that of a normal type IIP supernova. The absolute maximum magnitude, with MB = -16.23 +- 0.16 mag. SN2012A reached a peak luminosity of about 2X10**42 erg/s, which is brighter than those of other SNe with a similar 56Ni mass. The latter was estimated from the luminosity in the exponential tail of the light curve and found to be M(56Ni) = 0.011 +-0.004 Msun. The spectral evolution of SN 2012A is also typical of SN IIP, from the early spectra dominated by a blue continuum and very broad (~10**4 km/s) Balmer lines, to the late-photospheric spectra characterized by prominent P-Cygni features of metal lines (Fe II, Sc II, Ba II, Ti II, Ca II, Na ID). The photospheric velocity is moderately low, ~3X10**3 km/s at 50 days, for the low optical depth metal lines. The nebular spectrum obtained 394 days after the shock breakout shows the typical features of SNe IIP and the strength of the [O I] doublet suggests a progenitor of intermediate mass, similar to SN 2004et (~15 Msun). A candidate progenitor for SN 2012A has been identified in deep, pre-explosion K'-band Gemini North (NIRI) images, and found to be consistent with a star with a bolometric magnitude -7.08+-0.36 (log L/Lsun = 4.73 +- 0.14$ dex). The magnitude of the recovered progenitor in archival images points toward a moderate-mass 10.5 (-2/+4.5) Msun star as the precursor of SN 2012A. The explosion parameters and progenitor mass were also estimated by means of a hydrodynamical model, fitting the bolometric light curve, the velocity and the temperature evolution. We found a best fit for a kinetic energy of 0.48 foe, an initial radius of 1.8X10**13 cm and ejecta mass of 12.5 Msun.

On the progenitor of the type IIP SN 2013ej in M74

We use natural seeing imaging of SN 2013ej in M74 to identify a progenitor candidate in archival Hubble Space Telescope (HST) + Advanced Camera for Survey images. We find a source coincident with the supernova (SN) in the F814W filter within the total 75 mas (~3 pc astrometric uncertainty; however, the position of the progenitor candidate in contemporaneous F435W and F555W filters is significantly offset. We conclude that the 'progenitor candidate' is in fact two physically unrelated sources; a blue source which is likely unrelated to the SN, and a red source which we suggest exploded as SN 2013ej. Deep images with the same instrument on board HST taken when the SN has faded (in approximately two year's time) will allow us to accurately characterize the unrelated neighbouring source and hence determine the intrinsic flux of the progenitor in three filters.We suggest that the F814W flux is dominated by the progenitor of SN 2013ej, and assuming a bolometric correction appropriate to an M-type supergiant, we estimate that the mass of the progenitor of SN 2013ej was between 8 and 15.5M⊙.