Relation of plasma ceramides to visceral adiposity,insulin resistance and the development of type 2 diabetes mellitus: the Dallas Heart Study

Aims/hypothesis

Ceramides are sphingolipids that contribute to insulin resistance in preclinical studies. We hypothesised that plasma ceramides would be associated with body fat distribution, insulin resistance and incident type 2 diabetes in a multi-ethnic cohort.

Methods

A total of 1557 participants in the Dallas Heart Study without type 2 diabetes underwent measurements of metabolic biomarkers, fat depots by MRI and plasma ceramides by liquid chromatography-mass spectrometry. Diabetes outcomes were assessed after 7 years. Associations of body fat and insulin resistance with ceramides at baseline and of ceramides with incident diabetes outcomes were analysed.

Results

The cohort had a mean age of 43 years, with 58% women, 45% black participants and a mean BMI of 28 kg/m². Total cholesterol levels were associated with all ceramides, but higher triacylglycerols and lower HDL-cholesterol and adiponectin were associated only with saturated fatty acid chain ceramides (p?<?0.0003). After adjusting for clinical characteristics and total body fat, visceral adipose tissue was positively associated with saturated fatty acid ceramides (per SD, β?=?0.16 to 0.18) and inversely associated with polyunsaturated fatty acid ceramides (β?=??0.14 to ?0.16, p?<?0.001 for all). Lower-body subcutaneous fat showed an opposite pattern to that for visceral fat. HOMA-IR was positively associated with saturated (β?=?0.08 to 0.09, p?<?0.001) and inversely with polyunsaturated ceramides (β?=??0.06 to ?0.07, p?<?0.05). Ceramides were not associated with incident type 2 diabetes after adjustment for clinical factors.

Conclusions/interpretation

Plasma ceramides demonstrate a biologically complex relationship with metabolic and imaging indicators of dysfunctional adiposity. The role of ceramides in a shared pathway of metabolic dysfunction linking visceral adiposity and insulin resistance requires further investigation.

     

Autoantibodies to N-terminally truncated GAD improve clinical phenotyping of individuals with adult-onset diabetes: Action LADA 12

Aims/hypothesis

Adult-onset type 1 diabetes, in which the 65 kDa isoform of GAD (GAD65) is a major autoantigen, has a broad clinical phenotype encompassing variable need for insulin therapy. This study aimed to evaluate whether autoantibodies against N-terminally truncated GAD65 more closely defined a type 1 diabetes phenotype associated with insulin therapy.

Methods

Of 1114 participants with adult-onset diabetes from the Action LADA (latent autoimmune diabetes in adults) study with sufficient sera, we selected those designated type 1 (n?=?511) or type 2 diabetes (n?=?603) and retested the samples in radiobinding assays for human full-length GAD65 autoantibodies (f-GADA) and N-terminally truncated (amino acids 96–585) GAD65 autoantibodies (t-GADA). Individuals’ clinical phenotypes were analysed according to antibody binding patterns.

Results

Overall, 478 individuals were f-GADA-positive, 431 were t-GADA-positive and 628 were negative in both assays. Risk of insulin treatment was augmented in t-GADA-positive individuals (OR 4.69 [95% CI 3.57, 6.17]) compared with f-GADA-positive individuals (OR 3.86 [95% CI 2.95, 5.06]), irrespective of diabetes duration. Of 55 individuals who were f-GADA-positive but t-GADA-negative, i.e. with antibody binding restricted to the N-terminus of GAD65, the phenotype was similar to type 2 diabetes with low risk of progression to insulin treatment. Compared with these individuals with N-terminal GAD65-restricted GADA, t-GADA-positive individuals were younger at diagnosis (p?=?0.005), leaner (p?<?0.0001) and more often had multiple diabetes-associated autoantibodies (28.3% vs 7.3%; p?=?0.0005).

Conclusions/interpretation

In individuals with adult-onset diabetes, presence of N-terminally truncated GAD65 autoantibodies is associated with the clinical phenotype of autoimmune type 1 diabetes and predicts insulin therapy.

     

Genome-wide association study of coronary artery disease among individuals with diabetes: the UK Biobank

Aims/hypothesis

Coronary artery disease (CAD) is a common complication among individuals with diabetes. A better understanding of the genetic background of CAD in this population has the potential to suggest novel molecular targets for screening, risk assessment and drug development.

Methods

We performed a genome-wide association study of CAD in 15,666 unrelated individuals (3,968 CAD cases and 11,698 controls) of white British ancestry with diabetes at inclusion in the UK Biobank study. Our results were compared with results from participants without diabetes.

Results

We found genome-wide significant evidence for association with CAD at the previously well-established LPA locus (lead variant: rs74617384; OR 1.38 [95% CI 1.26, 1.51], p?=?3.2?×?10^?12) and at 9p21 (lead variant: rs10811652; OR 1.19 [95% CI 1.13, 1.26], p?=?6.0?×?10^?11). Moreover, other variants previously associated with CAD showed similar effects in the participants with and without diabetes, indicating that the genetic architecture of CAD is largely the same.

Conclusions/interpretation

Our results indicate large similarities between the genetic architecture of CAD in participants with and without diabetes. Larger studies are needed to establish whether there are important diabetes-specific CAD loci.

     

Very long-term outcomes after a single catheter ablation procedure for the treatment of atrial fibrillation—the protective role of antiarrhythmic drug therapy

Background

Pulmonary vein isolation (PVI) is the cornerstone of AF ablation, but its long-term clinical outcomes, predictors of relapse, and optimal pharmacological treatment remain controversial.

Objective

The objectives of this paper were to (1) assess very long-term AF recurrence, (2) identify predictors of relapse, and (3) evaluate the impact of continued antiarrhythmic drug (AAD) treatment after ablation.

Methods

Multicenter observational registry including all consecutive patients with drug-resistant AF who underwent a first PVI between 2006 and 2008 (n?=?253 (age 55 years (IQR 48–63)), 80% males, 64% with paroxysmal AF. Endpoint was AF/AT/AFL relapse after a 3-month blanking period. Predictors and protective factors of AF relapse were assessed with multivariate Cox regression.

Results

A total of 144 patients (57%) relapsed over a median 5-year (IQR 2–9) follow-up—annual relapse rate of 10%/year. Female sex (aHR 1.526, 95% CI 1.037–2.246, P?=?0.032), non-paroxysmal AF (aHR 1.410, 95% CI 1.000–1.987, P?=?0.050), and LA volume/BSA (aHR 1.012, 95% CI 1.003–1.021, P?=?0.008) were identified as independent predictors of relapse. A total of 139 patients (55%) continued AAD (55% on amiodarone) after blanking period. One-year overall PVI success rate of patients under AAD was 86 vs 76% with no AAD (P?<?0.001)—annual relapse rates were 8%/year vs 14%/year (P?<?0.001), respectively. AAD was associated with a long-term reduction in AF relapse (aHR 0.673, 95% CI 0.509–0.904 P?=?0.004).

Conclusion

Half the patients remained free from AF 5 years after a single procedure. Female sex, non-paroxysmal AF, and LA volume/BSA independently predicted recurrence, whereas continuing AAD after the 3-month blanking period reduced relapse.

Condensed abstract

In a multicenter registry of AF patients undergoing a first PVI, 57% relapsed over a median 5-year follow-up. Female sex, non-paroxysmal AF and LA volume/BSA were identified as independent predictors of relapse. Maintaining AAD therapy after the blanking period was associated with a long-term reduction in AF relapse.

     

BMI Trajectories as a Harbinger of Pre-Diabetes or Underdiagnosed Diabetes: an 18-Year Retrospective Cohort Study in Taiwan

Background

Although prior studies have examined BMI trajectories in Western populations, little is known regarding how BMI trajectories in Asian populations vary between adults with and without diabetes.

Objective

To examine how BMI trajectories vary between those developing and not developing diabetes over 18 years in an Asian cohort.

Design

Multilevel modeling was used to depict levels and rates of change in BMI for up to 18 years for participants with and without self-reported physician-diagnosed diabetes.

Participants

We used 14,490 data points available from repeated measurements of 3776 participants aged 50+ at baseline without diabetes from a nationally representative survey of the Taiwan Longitudinal Study on Aging (TLSA1989-2007).

Main Measures

We defined development of diabetes as participants who first reported diabetes diagnoses in 2007 but had no diabetes diagnoses at baseline. We defined the reference group as those participants who reported the absence of diabetes at baseline and during the entire follow-up period.

Key Results

When adjusted for time-varying comorbidities and behavioral factors, higher level and constant increases in BMI were present more than 6.5 years before self-reported diabetes diagnosis. The higher BMI level associating with the development of diabetes was especially evident in females. Within 6.5 years prior to self-reported diagnosis, however, a wider range of decreases in BMI occurred (β_diabetes?=?1.294, P?=?0.0064; β_{diabetes*time}?=?0.150, P?=?0.0327; β_{diabetes*time} ²?=??0.008, P?=?0.0065). The faster rate of increases in BMI followed by a greater decline was especially prominent in males and individuals with BMI ≧24.

Conclusions

An unintentional decrease in BMI in sharp contrast to the gradually rising BMI preceding that time may be an alarm for undiagnosed diabetes or a precursor to developing diabetes.

     

Brain changes in overweight/obese and normal-weight adults with type 2 diabetes mellitus

Aims/hypothesis

Overweight and obesity may significantly worsen glycaemic and metabolic control in type 2 diabetes. However, little is known about the effects of overweight and obesity on the brains of people with type 2 diabetes. Here, we investigate whether the presence of overweight or obesity influences the brain and cognitive functions during early stage type 2 diabetes.

Methods

This study attempted to uncouple the effects of overweight/obesity from those of type 2 diabetes on brain structures and cognition. Overweight/obese participants with type 2 diabetes had more severe and progressive abnormalities in their brain structures and cognition during early stage type 2 diabetes compared with participants with normal weight. Relationships between each of these measures and disease duration were also examined.

Results

Global mean cortical thickness was lower in the overweight/obese type 2 diabetes group than in the normal-weight type 2 diabetes group (z = ?2.96, p for group effect = 0.003). A negative correlation was observed between disease duration and global mean white matter integrity (z = 2.42, p for interaction = 0.02) in the overweight/obese type 2 diabetes group, but not in the normal-weight type 2 diabetes group. Overweight/obese individuals with type 2 diabetes showed a decrease in psychomotor speed performance related to disease duration (z = ?2.12, p for interaction = 0.03), while normal-weight participants did not.

Conclusions/interpretation

The current study attempted to uncouple the effects of overweight/obesity from those of type 2 diabetes on brain structures and cognition. Overweight/obese participants with type 2 diabetes had more severe and progressive abnormalities in brain structures and cognition during early stage type 2 diabetes compared with normal-weight participants.

     

Risk of Autoimmune Disease in Adults with Chronic Insomnia Requiring Sleep-Inducing Pills: A Population-Based Longitudinal Study

BACKGROUND

Recent studies indicate that chronic insomnia is associated with the development of certain somatic diseases. Whether it would be associated with the development of an autoimmune disease (AID) was unknown.

OBJECTIVE

We aimed to examine the association and quantify the magnitude of risk for AID in individuals suffering from chronic insomnia requiring sleep-inducing pills.

DESIGN

This was a population-based, nationwide longitudinal study.

PARTICIPANTS

Using a claims data set containing 1 million randomly sampled, insured subjects derived from the National Health Insurance Research Database, we assembled a chronic insomnia group and a 1:3 propensity score–matched comparison group (CP), which were balanced in terms of sex, age, insurance premium, urbanization, alcohol use disorder, smoking-related diagnoses, and morbid obesity.

MAIN MEASURES

Person-time data with incidence rate, adjusted hazard ratios (aHR) by the Cox model, AID-free survival functions compared with the log-rank test, and a sensitivity analysis on the time lag effect were presented. Incident AID within the first year of follow-up were excluded. The error rate was controlled using the Benjamini–Hochberg procedure.

KEY RESULTS

With 39,550 and 129,914 person-years’ follow-up for the chronic insomnia and CP groups (n?=?5,736 and 17,208), respectively, we found an increased risk for subsequent AID, representing a 70 % increase in the aHR (1.7; 95 % confidence interval [CI], 1.5–1.9, p?<?0.0001). A positive association between chronic insomnia and primary Sjögren’s syndrome (pSS) was observed (aHR, 1.3; 95 % CI, 1.1–1.6). Sensitivity analysis disclosed that AID risk was even stronger after 5 years of follow-up (aHR, 2.0; 95 % CI, 1.7–2.4).

CONCLUSION

Chronic insomnia requiring sleep-inducing pills may be associated with a 70 % increased risk for future AID, particularly pSS.

     

Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels

Aim/hypothesis

Neprilysin, a widely expressed peptidase, is upregulated in metabolically altered states such as obesity and type 2 diabetes. Like dipeptidyl peptidase-4 (DPP-4), neprilysin can degrade and inactivate the insulinotropic peptide glucagon-like peptide-1 (GLP-1). Thus, we investigated whether neprilysin deficiency enhances active GLP-1 levels and improves glycaemia in a mouse model of high fat feeding.

Methods

Nep ^+/+ and Nep ^?/? mice were fed a 60% fat diet for 16 weeks, after which active GLP-1 and DPP-4 activity levels were measured, as were glucose, insulin and C-peptide levels during an OGTT. Insulin sensitivity was assessed using an insulin tolerance test.

Results

High-fat-fed Nep ^?/? mice exhibited elevated active GLP-1 levels (5.8?±?1.1 vs 3.5?±?0.8 pmol/l, p?<?0.05) in association with improved glucose tolerance, insulin sensitivity and beta cell function compared with high-fat-fed Nep ^+/+ mice. In addition, plasma DPP-4 activity was lower in high-fat-fed Nep ^?/? mice (7.4?±?1.0 vs 10.7?±?1.3 nmol ml^?1 min^?1, p?<?0.05). No difference in insulin:C-peptide ratio was observed between Nep ^?/? and Nep ^+/+ mice, suggesting that improved glycaemia does not result from changes in insulin clearance.

Conclusions/interpretation

Under conditions of increased dietary fat, an improved glycaemic status in neprilysin-deficient mice is associated with elevated active GLP-1 levels, reduced plasma DPP-4 activity and improved beta cell function. Thus, neprilysin inhibition may be a novel treatment strategy for type 2 diabetes.

     

The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age

Aims/hypothesis

The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process.

Methods

Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD.

Results

Two regions were convincingly associated with AAD (p < 5 × 10^?8): the MHC on 6p21, and 6q22.33. Fine-mapping of 6q22.33 identified two AAD-associated haplotypes in the region nearest to the genes encoding protein tyrosine phosphatase receptor kappa (PTPRK) and thymocyte-expressed molecule involved in selection (THEMIS). We examined the susceptibility to type 1 diabetes at these SNPs by performing a meta-analysis including 19,510 control participants. Although these SNPs were not associated with type 1 diabetes overall (p > 0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (p = 2.3 × 10^?9).

Conclusion/interpretation

PTPRK and its neighbour THEMIS are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant.

     

Persistence of abnormalities in white matter in children with type 1 diabetes

Aims/hypothesis

Prior studies suggest white matter growth is reduced and white matter microstructure is altered in the brains of young children with type 1 diabetes when compared with brains of non-diabetic children, due in part to adverse effects of hyperglycaemia. This longitudinal observational study examines whether dysglycaemia alters the developmental trajectory of white matter microstructure over time in young children with type 1 diabetes.

Methods

One hundred and eighteen children, aged 4 to <10 years old with type 1 diabetes and 58 age-matched, non-diabetic children were studied at baseline and 18 months, at five Diabetes Research in Children Network clinical centres. We analysed longitudinal trajectories of white matter using diffusion tensor imaging. Continuous glucose monitoring profiles and HbA_1c levels were obtained every 3 months.

Results

Axial diffusivity was lower in children with diabetes at baseline (p?=?0.022) and at 18 months (p?=?0.015), indicating that differences in white matter microstructure persist over time in children with diabetes. Within the diabetes group, lower exposure to hyperglycaemia, averaged over the time since diagnosis, was associated with higher fractional anisotropy (p?=?0.037). Fractional anisotropy was positively correlated with performance (p?<?0.002) and full-scale IQ (p?<?0.02).

Conclusions/interpretation

These results suggest that hyperglycaemia is associated with altered white matter development, which may contribute to the mild cognitive deficits in this population.

     

Effect of Pharmacist Counseling Intervention on Health Care Utilization Following Hospital Discharge: A Randomized Control Trial

Background

Reduction in 30-day readmission rates following hospitalization for acute coronary syndrome (ACS) and acute decompensated heart failure (ADHF) is a national goal.

Objective

The aim of this study was to determine the effect of a tailored, pharmacist-delivered, health literacy intervention on unplanned health care utilization, including hospital readmission or emergency room (ER) visit, following discharge.

Design

Randomized, controlled trial with concealed allocation and blinded outcome assessors

Setting

Two tertiary care academic medical centers

Participants

Adults hospitalized with a diagnosis of ACS and/or ADHF

Intervention

Pharmacist-assisted medication reconciliation, inpatient pharmacist counseling, low-literacy adherence aids, and individualized telephone follow-up after discharge

Main Measures

The primary outcome was time to first unplanned health care event, defined as hospital readmission or an ER visit within 30 days of discharge. Pre-specified analyses were conducted to evaluate the effects of the intervention by academic site, health literacy status (inadequate versus adequate), and cognition (impaired versus not impaired). Adjusted hazard ratios (aHR) and 95 % confidence intervals (CI) are reported.

Key Results

A total of 851 participants enrolled in the study at Vanderbilt University Hospital (VUH) and Brigham and Women’s Hospital (BWH). The primary analysis showed no statistically significant effect on time to first unplanned hospital readmission or ER visit among patients who received interventions compared to controls (aHR?=?1.04, 95 % CI 0.78-1.39). There was an interaction of treatment effect by site (p?=?0.04 for interaction); VUH aHR?=?0.77, 95 % CI 0.51-1.15; BWH aHR?=?1.44 (95 % CI 0.95-2.12). The intervention reduced early unplanned health care utilization among patients with inadequate health literacy (aHR 0.41, 95 % CI 0.17-1.00). There was no difference in treatment effect by patient cognition.

Conclusion

A tailored, pharmacist-delivered health literacy-sensitive intervention did not reduce post-discharge unplanned health care utilization overall. The intervention was effective among patients with inadequate health literacy, suggesting that targeted practice of pharmacist intervention in this population may be advantageous.

     

Incident Type 2 Diabetes Risk is Influenced by Obesity and Diabetes in Social Contacts: a Social Network Analysis

BACKGROUND

Obesity and diabetes family history are the two strongest risk factors for type 2 diabetes (T2D). Prior work shows that an individual’s obesity risk is associated with obesity in social contacts, but whether T2D risk follows similar patterns is unknown.

OBJECTIVE

We aimed to estimate the relationship between obesity or diabetes in an individual’s social contacts and his/her T2D risk. We hypothesized that obesity and diabetes in social contacts would increase an individual’s T2D risk.

DESIGN

This was a retrospective analysis of the community-based Framingham Offspring Study (FOS).

PARTICIPANTS

FOS participants with T2D status, height and weight, and at least one social contact were eligible for this study (n?=?4797 at Exam 1). Participants’ interpersonal ties, cardiometabolic and demographic variables were available at eight exams from 1971 to 2008, and a T2D additive polygenic risk score was measured at the fifth exam.

MAIN MEASURES

Primary exposures were T2D (fasting glucose?≥?7 mmol/L or taking diabetes medications) and obesity status (BMI?≥?30 kg/m²) of social contacts at a prior exam. Primary outcome was incident T2D in participants.

KEY RESULTS

Incident T2D was associated with having a social contact with diabetes (OR 1.32, p?=?0.004) or with obesity (OR 1.21, p?=?0.004). In stratified analyses, incident T2D was associated with diabetes in siblings (OR 1.64, p?=?0.001) and obesity in spouses (OR 1.54, p =?0.0004). The associations between diabetes and obesity in social contacts and an individual’s incident diabetes risk were stronger in individuals with a high diabetes genetic risk score.

CONCLUSIONS

T2D and obesity in social contacts, particularly siblings and spouses, were associated with an individual’s risk of incident diabetes even after accounting for parental T2D history. Assessing risk factors in an individual’s siblings and spouses can inform T2D risk; furthermore, social network based lifestyle interventions involving spouses and siblings might be a novel T2D prevention approach.

     

Patient–Family Agenda Setting for Primary Care Patients with Cognitive Impairment: the SAME Page Trial

Background

Establishing priorities for discussion during time-limited primary care visits is challenging in the care of patients with cognitive impairment. These patients commonly attend primary care visits with a family companion.

Objective

To examine whether a patient–family agenda setting intervention improves primary care visit communication for patients with cognitive impairment

Design

Two-group pilot randomized controlled study

Participants

Patients aged 65?+ with cognitive impairment and family companions (n?=?93 dyads) and clinicians (n?=?14) from two general and one geriatrics primary care clinic

Intervention

A self-administered paper-pencil checklist to clarify the role of the companion and establish a shared visit agenda

Measurements

Patient-centered communication (primary); verbal activity, information disclosure including discussion of memory, and visit duration (secondary), from audio recordings of visit discussion

Results

Dyads were randomized to usual care (n?=?44) or intervention (n?=?49). Intervention participants endorsed an active communication role for companions to help patients understand what the clinician says or means (90% of dyads), remind patients to ask questions or ask clinicians questions directly (84% of dyads), or listen and take notes (82% of dyads). Intervention dyads identified 4.4 health issues for the agenda on average: patients more often identified memory (59.2 versus 38.8%; p?=?0.012) and mood (42.9 versus 24.5%; p?=?0.013) whereas companions more often identified safety (36.7 versus 18.4%; p?=?0.039) and personality/behavior change (32.7 versus 16.3%; p?=?0.011). Communication was significantly more patient-centered in intervention than in control visits at general clinics (p?<?0.001) and in pooled analyses (ratio of 0.86 versus 0.68; p?=?0.046). At general clinics, intervention (versus control) dyads contributed more lifestyle and psychosocial talk (p?<?0.001) and less biomedical talk (p?<?0.001) and companions were more verbally active (p?<?0.005). No intervention effects were found at the geriatrics clinic. No effect on memory discussions or visit duration was observed.

Conclusion

Patient–family agenda setting may improve primary care visit communication for patients with cognitive impairment.

Trial Registration

ClinicalTrials.gov: NCT02986958

     

Enhanced VEGF signalling mediates cerebral neovascularisation via downregulation of guidance protein ROBO4 in a rat model of diabetes

Aims/hypothesis

Diabetes promotes cerebral neovascularisation via increased vascular endothelial growth factor (VEGF) angiogenic signalling. Roundabout-4 (ROBO4) protein is an endogenous inhibitor of VEGF signalling that stabilises the vasculature. Yet, how diabetes affects ROBO4 function remains unknown. We hypothesised that increased VEGF signalling in diabetes decreases ROBO4 expression and function via binding of ROBO4 with VEGF-activated β3 integrin and that restoration of ROBO4 expression prevents/repairs cerebral neovascularisation in diabetes.

Methods

ROBO4 protein expression in a rat model of type 2 diabetes (Goto–Kakizaki [GK] rats) was examined by western blotting and immunohistochemistry. ROBO4 was locally overexpressed in the brain and in primary brain microvascular endothelial cells (BMVECs). GK rats were treated with SKLB1002, a selective VEGF receptor-2 (VEGFR-2) antagonist. Cerebrovascular neovascularisation indices were determined using a FITC vascular space-filling model. Immunoprecipitation was used to determine ROBO4–β3 integrin interaction.

Results

ROBO4 expression was significantly decreased in the cerebral vasculature as well as in BMVECs in diabetes (p?<?0.05). Silencing Robo4 increased the angiogenic properties of control BMVECs (p?<?0.05). In vivo and in vitro overexpression of ROBO4 inhibited VEGF-induced angiogenic signalling and increased vessel maturation. Inhibition of VEGF signalling using SKLB1002 increased ROBO4 expression (p?<?0.05) and reduced neovascularisation indices (p?<?0.05). Furthermore, SKLB1002 significantly decreased ROBO4–β3 integrin interaction in diabetes (p?<?0.05).

Conclusions/interpretation

Our study identifies the restoration of ROBO4 and inhibition of VEGF signalling as treatment strategies for diabetes-induced cerebral neovascularisation.

     

Serum metabolomic profile of incident diabetes

Aims/hypothesis

Metabolomic profiling offers the potential to reveal metabolic pathways relevant to the pathophysiology of diabetes and improve diabetes risk prediction.

Methods

We prospectively analysed known metabolites using an untargeted approach in serum specimens from baseline (1987–1989) and incident diabetes through to 31 December 2015 in a subset of 2939 Atherosclerosis Risk in Communities (ARIC) study participants with metabolomics data and without prevalent diabetes.

Results

Among the 245 named compounds identified, seven metabolites were significantly associated with incident diabetes after Bonferroni correction and covariate adjustment; these included a food additive (erythritol) and compounds involved in amino acid metabolism [isoleucine, leucine, valine, asparagine, 3-(4-hydoxyphenyl)lactate] and glucose metabolism (trehalose). Higher levels of metabolites were associated with increased risk of incident diabetes (HR per 1 SD increase in isoleucine 2.96, 95% CI 2.02, 4.35, p?=?3.18?×?10^?8; HR per 1 SD increase in trehalose 1.16, 95% CI 1.09, 1.25, p?=?1.87?×?10^?5), with the exception of asparagine, which was associated with a lower risk of diabetes (HR per 1 SD increase in asparagine 0.78, 95% CI 0.71, 0.85, p?=?4.19?×?10^?8). The seven metabolites modestly improved prediction of incident diabetes beyond fasting glucose and established risk factors (C statistics 0.744 vs 0.735, p?=?0.001 for the difference in C statistics).

Conclusions/interpretation

Branched chain amino acids may play a role in diabetes development. Our study is the first to report asparagine as a protective biomarker of diabetes risk. The serum metabolome reflects known and novel metabolic disturbances that improve prediction of diabetes.

     

Disseminated nocardiosis caused by <Emphasis Type="Italic">Nocardia elegans</Emphasis>: a case report and review of the literature

Background

Disseminated nocardiosis is a rare disease mostly occurring in immunocompromised patients.

Methods

We report a case of disseminated nocardiosis in a diabetic patient with both pulmonary and cutaneous involvement. Nocardia elegans was isolated and identified using the 16s ribosomal RNA gene sequence data.

Results

Clinical improvement was observed within 3 months after initiation of antimicrobial treatment with oral doxycycline, trimethoprim-sulfamethoxazole and intravenous penicillin, but the patient died 5 months later after arbitrary discontinuation of the treatment.

Conclusions

This is the first case report of disseminated nocardiosis caused by Nocardia elegans in China.

     

<Emphasis Type="Italic">LIPC</Emphasis> variants as genetic determinants of adiposity status,visceral adiposity indicators,and triglyceride-glucose (TyG) index-related parameters mediated by serum triglyceride levels

Background

Visceral adiposity indicators and the product of triglyceride and fasting plasma glucose (TyG) index-related parameters are effective surrogate markers for insulin resistance (IR) and are predictors of metabolic syndrome and diabetes mellitus. However, their genetic determinants have not been previously reported. Pleiotropic associations of LIPC variants have been observed in lipid profiles and atherosclerotic cardiovascular diseases. We aimed to investigate LIPC polymorphisms as the genetic determinants of adiposity status, visceral adiposity indicators and TyG index-related parameters.

Methods

A total of 592 participants from Taiwan were genotyped for three LIPC single nucleotide polymorphisms (SNPs).

Results

The LIPC SNPs rs2043085 and rs1532085 were significantly associated with body mass index (BMI), waist circumference (WC), lipid accumulation product, visceral adiposity index, and TyG index-related parameters [including the TyG index, TyG with adiposity status (TyG-BMI), and TyG-WC index], whereas the rs1800588 SNP was only significantly associated with the TyG index. The associations became nonsignificant after further adjustment for serum TG levels. No significant association was observed between any the studied LIPC SNPs and IR status.

Conclusion

Our data revealed a pleiotropic association between the LIPC variants and visceral adiposity indicators and TyG index-related parameters, which are mediated by serum TG levels.

     

Statin Use,Diabetes Incidence and Overall Mortality in Normoglycemic and Impaired Fasting Glucose Patients

BACKGROUND

The association between the use of statins and the risk of diabetes and increased mortality within the same population has been a source of controversy, and may underestimate the value of statins for patients at risk.

OBJECTIVE

We aimed to assess whether statin use increases the risk of developing diabetes or affects overall mortality among normoglycemic patients and patients with impaired fasting glucose (IFG).

DESIGN AND PARTICIPANTS

Observational cohort study of 13,508 normoglycemic patients (n?=?4460; 33 % taking statins) and 4563 IFG patients (n?=?1865; 41 % taking statin) among residents of Olmsted County, Minnesota, with clinical data in the Mayo Clinic electronic medical record and at least one outpatient fasting glucose test between 1999 and 2004. Demographics, vital signs, tobacco use, laboratory results, medications and comorbidities were obtained by electronic search for the period 1999–2004. Results were analyzed by Cox proportional hazards models, and the risk of incident diabetes and mortality were analyzed by survival curves using the Kaplan–Meier method.

MAIN MEASURES

The main endpoints were new clinical diagnosis of diabetes mellitus and total mortality.

KEY RESULTS

After a mean of 6 years of follow-up, statin use was found to be associated with an increased risk of incident diabetes in the normoglycemic (HR 1.19; 95 % CI, 1.05 to 1.35; p?=?0.007) and IFG groups (HR 1.24; 95%CI, 1.11 to 1.38; p?=?0.0001). At the same time, overall mortality decreased in both normoglycemic (HR 0.70; 95 % CI, 0.66 to 0.80; p?<?0.0001) and IFG patients (HR 0.77, 95 % CI, 0.64 to 0.91; p?=?0.0029) with statin use.

CONCLUSION

In general, recommendations for statin use should not be affected by concerns over an increased risk of developing diabetes, since the benefit of reduced mortality clearly outweighs this small (19–24 %) risk.

     

Suppression of glucagon secretion is lower after oral glucose administration than during intravenous glucose administration in human subjects

Aims/hypothesis

The incretin effect describes the augmentation of postprandial insulin secretion by gut hormones. It is not known whether glucagon secretion is also influenced by an incretin effect. A glucagon suppression deficiency has been reported in some patients with type 2 diabetes, but it is unclear whether this abnormality is present prior to diabetes onset. We therefore addressed the questions: (1) Is glucagon secretion different after oral and during intravenous glucose administration? (2) If so, is this related to the secretion of incretin hormones? (3) Is glucagon secretion abnormal in first-degree relatives of patients with type 2 diabetes?

Materials and methods

We examined 16 first-degree relatives of patients with type 2 diabetes and ten matched control subjects with an oral glucose load (75 g) and with an ‘isoglycaemic’ intravenous glucose infusion.

Results

Glucagon levels were significantly suppressed by both oral and intravenous glucose (p?p?r?=?0.60, p?=?0.001) and glucagon-like peptide (GLP)-1 (r?=?0.46, p?

Conclusions/interpretation

Despite the glucagonostatic actions of GLP-1, the suppression of glucagon secretion by glucose is diminished after oral glucose ingestion, possibly due to the glucagonotropic actions of GIP and GLP-2. Furthermore, in this group of first-degree relatives, abnormalities in glucagon secretion did not precede the development of other defects, such as impaired insulin secretion.

     

A Coaching by Telephone Intervention on Engaging Patients to Address Modifiable Cardiovascular Risk Factors: a Randomized Controlled Trial

Background

A large proportion of deaths and chronic illnesses can be attributed to three modifiable risk factors: tobacco use, overweight/obesity, and physical inactivity.

Objective

To test whether telephone-based health coaching after completion of a comprehensive health risk assessment (HRA) increases patient activation and enrollment in a prevention program compared to HRA completion alone.

Design

Two-arm randomized trial at three sites.

Setting

Primary care clinics at Veterans Affairs facilities.

Participants

Four hundred seventeen veterans with at least one modifiable risk factor (BMI?≥?30, <?150 min of at least moderate physically activity per week, or current smoker).

Intervention

Participants completed an online HRA. Intervention participants received two telephone-delivered health coaching calls at 1 and 4 weeks to collaboratively set goals to enroll in, and attend structured prevention programs designed to reduce modifiable risk factors.

Measurements

Primary outcome was enrollment in a structured prevention program by 6 months. Secondary outcomes were Patient Activation Measure (PAM) and Framingham Risk Score (FRS).

Results

Most participants were male (85%), white (50%), with a mean age of 56. Participants were eligible, because their BMI was ≥?30 (80%), they were physically inactive (50%), and/or they were current smokers (39%). When compared to HLA only at 6 months, health coaching intervention participants reported higher rates of enrollment in a prevention program, 51 vs 29% (OR?=?2.5; 95% CI: 1.7, 3.9; p?<?0.0001), higher rates of program participation, 40 vs 23% (OR?=?2.3; 95% CI: 1.5, 3.6; p?=?0.0004), and greater improvement in PAM scores, mean difference 2.5 (95% CI: 0.2, 4.7; p?=?0.03), but no change in FRS scores, mean difference 0.7 (95% CI ??0.7, 2.2; p?=?0.33).

Conclusions

Brief telephone health coaching after completing an online HRA increased patient activation and increased enrollment in structured prevention programs to improve health behaviors.

ClinicalTrials.gov Identifier

NCT01828567