Diabetes & Vascular Disease Research

Diabetes mellitus appears to be negatively associated with abdominal aortic aneurysm; however, the mechanisms underlying this relationship remain poorly understood. The aim of this article is to provide a comprehensive review of the currently understood biological pathways underlying this relationship.

A review of the literature (‘diabetes’ OR ‘hyperglycaemia’ AND ‘aneurysm’) was performed and relevant studies grouped into biological pathways.

This review identified a number of biological pathways through which diabetes mellitus may limit the presence, growth and rupture of abdominal aortic aneurysms. These include those influencing extracellular matrix volume, extracellular matrix glycation, the formation of advanced glycation end-products, inflammation, oxidative stress and intraluminal thrombus biology. In addition, there is an increasing evidence to suggest that the medications used to treat diabetes can also limit the development and progression of abdominal aortic aneurysms.

The negative association between diabetes and abdominal aortic aneurysm is robust. Future studies should attempt to target the pathways identified in this review to develop novel therapeutic agents aimed at slowing or even halting aneurysm progression.

To investigate the long-term prognostic value of insulin-like growth factor-binding protein 1 in patients with acute myocardial infarction.

Patients (n = 180) with admission glucose < 11 mmol/L without previously known diabetes admitted for an acute myocardial infarction in 1998–2000 were followed for mortality and cardiovascular events (first of cardiovascular mortality/acute myocardial infarction/stroke/severe heart failure) until the end of 2011 (median 11.6 years). Fasting levels of insulin-like growth factor-binding protein 1 at day 2 were related to outcome in Cox proportional hazard regression analyses.

Median age was 64 years, 69% were male and median insulin-like growth factor-binding protein 1 was 20 µg/L. Total mortality was 34% (n = 61) and 44% (n = 80) experienced a cardiovascular event during a median follow-up time of 11.6 years. After age adjustment, insulin-like growth factor-binding protein 1 was associated with all-cause (1.40; 1.02–1.93, p = 0.039) and cancer mortality (2.09; 1.15–3.79, p = 0.015) but not with cardiovascular death (p = 0.29) or cardiovascular events (p = 0.57). After adjustments also for previous myocardial infarction, previous heart failure and body mass index, insulin-like growth factor-binding protein 1 was still associated with all-cause mortality (1.38; 1.01–1.89, p = 0.046).

In patients with acute myocardial infarction without previously known diabetes, high insulin-like growth factor-binding protein 1 was associated with long-term all-cause and cancer mortality but not with cardiovascular events.

Continuous-wave Doppler is frequently used for detecting peripheral arterial disease in patients with diabetes; however, there is limited evidence investigating diagnostic accuracy. This study aimed to determine sensitivity and specificity of continuous-wave Doppler for detecting peripheral arterial disease in populations with, and without, diabetes and to investigate the influence of disease severity on sensitivity of continuous-wave Doppler for detecting peripheral arterial disease.

Data from 396 participants were included. Using colour Duplex ultrasound as reference standard (N=66), printed continuous-wave Doppler waveform analysis sensitivity was 81.75% (95% confidence interval: 76.75 to 85.88) and specificity 89.34% (95% confidence interval: 82.62 to 93.67). Printed continuous-wave Doppler waveform analysis sensitivity for peripheral arterial disease was comparable to sensitivity calculated using angiography as the reference standard (81.67%; 95% confidence interval: 69.56 to 90.48). Sensitivity and specificity were unaffected by diabetes diagnosis (n = 176), sensitivity 82.76% (95% confidence interval: 74.86 to 88.55), and specificity 88.33% (95% confidence interval: 77.82 to 94.23).

Continuous-wave Doppler is a fair assessment tool for peripheral arterial disease in a community-based sample with suspected peripheral arterial disease. Diagnostic accuracy of continuous-wave Doppler for peripheral arterial disease is unaffected by the presence of diabetes.

To examine the association between haemoglobin A1c variability and macrovascular complication in type 2 diabetes.

We retrospectively enrolled 5278 diabetes patients with no history of cardiovascular disease and atherosclerosis by ultrasound at their first visit to the hospital from 1999 to 2010. Patients had a median of 4 haemoglobin A1c (range = 3–9) measurements during follow-up. Average haemoglobin A1c and haemoglobin A1c variability were calculated as intra-individual mean, standard deviation, coefficient of variation and adjusted standard deviation. Cardiovascular disease events and ultrasound results were re-evaluated from the medical history at the end of the study.

A total of 972 patients had macrovascular complication. Compared to those without atherosclerosis/cardiovascular disease (n = 4306), haemoglobin A1c intra-individual mean and haemoglobin A1c variability levels were significantly higher in patients with macrovascular complication (p < 0.001). Multivariable logistic regression analysis showed that haemoglobin A1c variability was associated with macrovascular complication. Moreover, 488 patients with only atherosclerosis had significantly higher haemoglobin A1c intra-individual mean and haemoglobin A1c variability values than those without atherosclerosis/cardiovascular disease (p < 0.001), but in 484 patients with cardiovascular disease incidents, only higher haemoglobin A1c intra-individual mean level was found (p = 0.004).

In Chinese type 2 diabetes, haemoglobin A1c variability was associated with macrovascular complication. Long-term stabilization of glucose is important in diabetes management, especially in the early stage of atherosclerosis.

Glomerular hyperfiltration usually occurs early in development of kidney complications in diabetes. To understand hyperfiltration as a marker of renal disease progression in type 2 diabetes mellitus, we aimed to examine association between glomerular hyperfiltration (estimated glomerular filtration rate ⩾ 120 mL/min/1.73 m²) and rapid renal decline (annual estimated glomerular filtration rate loss ⩾ 3 mL/min/1.73 m²).

This was a prospective cohort comprising 1014 patients with type 2 diabetes mellitus attending a Diabetes Centre of a regional hospital in 2002–2014. A separate prospective cohort, comprising 491 patients who attended Diabetes Centre or primary-care polyclinics, was used for validation. We performed binary mediation analysis to examine role of hyperfiltration on relationship between baseline haemoglobin A1c and rapid renal decline.

Among patients in discovery cohort, 5.2% had baseline hyperfiltration. Over mean follow-up of 6 years, 22.9% had rapid glomerular filtration rate decline. Baseline hyperfiltration was significantly associated with greater odds of rapid renal decline after adjusting for demographics, diabetes duration and clinical covariates (odds ratio: 2.57; 95% confidence interval: 1.21–5.46; p = 0.014). Similar finding was found in validation cohort (odds ratio: 2.98; 95% confidence interval: 1.06–8.42; p = 0.034). Hyperfiltration significantly accounted for 35.3% of association between increasing baseline haemoglobin A1c and rapid renal decline.

Glomerular hyperfiltration is an independent risk factor of rapid renal decline. It mediates the association between increasing haemoglobin A1c and rapid renal decline.

In type 2 diabetes, we aimed at clarifying the role of glycated haemoglobin variability and other risk factors in the development of the main micro-vascular complications: peripheral neuropathy, nephropathy and retinopathy.

In a single-centre cohort of 900 patients, glycated haemoglobin variability was evaluated as intra-individual standard deviation, adjusted standard deviation and coefficient of variation of serially measured glycated haemoglobin in the 2-year period before a randomly selected index visit. We devised four models considering different aspects of glycated haemoglobin evolution. Multivariate stepwise logistic regression analysis was performed including the following covariates at the index visit: age, disease duration, body mass index, total cholesterol, high-density lipoprotein cholesterol, triglycerides, sex, smoking habit, hypertension, dyslipidemia, treatment with anti-diabetic drugs, occurrence of macro-vascular events and the presence of another micro-vascular complication.

Males with high mean glycated haemoglobin, long duration of diabetes, presence of macro-vascular events and retinopathy emerged at higher risk for peripheral neuropathy. Development of nephropathy was independently associated with higher glycated haemoglobin variability, older age, male sex, current smoking status, presence of retinopathy, of peripheral neuropathy and of hypertension. Higher mean glycated haemoglobin, younger age, longer duration of diabetes, reduced estimated glomerular filtration rate and the presence of peripheral neuropathy were significantly associated with increased incidence of retinopathy.

Glycated haemoglobin variability was associated with increased incidence of nephropathy, while mean glycated haemoglobin emerged as independent risk factor for the development of retinopathy and peripheral neuropathy. The presence of macro-vascular events was positively correlated with peripheral neuropathy. Finally, the occurrence of another micro-vascular complication was found to be a stronger risk factor for developing another micro-vascular complication than the mean or variability of glycated haemoglobin.

Type 2 diabetes mellitus complicated with microvascular diseases can be used as a model to study the relationship between bone health and the microvascular situation.

A total of 2,170 patients with type 2 diabetes mellitus (1,188 postmenopausal females and 982 males aged ⩾50 years) were included in our cross-sectional study. These patients were grouped according to 24-hour urine protein level: Group I (<30 mg), Group II (30-299 mg) and Group III (≥300 mg). Bone mineral density of the lumbar spine, hip and femoral neck was evaluated by dual-energy X-ray absorptiometry. Fundus oculi photography for diabetic retinopathy and 24-h urine protein for diabetic nephropathy were used as markers of microangiopathy in type 2 diabetes mellitus. Characteristics of the patients and bone mineral density were compared. Multivariate analysis was used to study the association between bone mineral density and microangiopathy. Statistical analysis was performed using SPSS 20.0. p < 0.05 was considered statistically significant.

Group III had the lowest bone mineral density level in both genders. Multivariate analysis revealed that microangiopathy was negatively correlated with bone mineral density in females (lumbar: r = –0.522, p < 0.001; hip: r = –0.301, p = 0.010; femoral neck: r = –0.314, p = 0.009), but not in males, after adjustment for age, body mass index, hypertension, hyperlipidemia, diabetic status, hepatic function, kidney function, sex hormones and 25(OH) vitamin D.

These results demonstrate an independent negative correlation between microangiopathy and bone mineral density in postmenopausal female type 2 diabetes mellitus patients.

To compare the lamina cribrosa thickness and anterior lamina cribrosa depth between patients with and without diabetes mellitus and to investigate the effect of metabolic control and duration of diabetes mellitus on lamina cribrosa thickness and anterior lamina cribrosa depth using enhanced depth imaging spectral-domain optical coherence tomography.

A total of 70 patients were enrolled in this cross-sectional study and were divided into the diabetes and control groups. Intraocular pressure, circumpapillary retinal nerve fibre layer thickness, anterior lamina cribrosa depth and lamina cribrosa thickness were compared between the groups.

In the control group, the mean intraocular pressure was 14.6 ± 3.1 (mean ± standard deviation) mmHg, mean circumpapillary retinal nerve fibre layer thickness was 105.41 ± 5.86 μm, mean anterior lamina cribrosa depth was 420.3 ± 90.2 μm and mean lamina cribrosa thickness was 248.5 ± 5.4 μm. In the diabetes group, the mean intraocular pressure was 13.9 ± 2.2 mmHg, mean circumpapillary retinal nerve fibre layer thickness was 101.37 ± 10.97 μm, mean anterior lamina cribrosa depth was 351.4 ± 58.6 μm and mean lamina cribrosa thickness was 271.6 ± 33.9 μm. Lamina cribrosa thickness was significantly higher (p < 0.001) and anterior lamina cribrosa depth was significantly lower (p = 0.003) in the diabetes group. There was no statistical difference between the groups with regard to age, spherical equivalent, axial length, circumpapillary retinal nerve fibre layer thickness and intraocular pressure (p = 0.69, 0.26, 0.47, 0.06 and 0.46, respectively). Lamina cribrosa thickness and anterior lamina cribrosa depth were not significantly correlated with duration of diabetes mellitus (lamina cribrosa thickness: r = −0.078, p = 0.643; anterior lamina cribrosa depth: r = −0.062, p = 0.710) or HbA1c levels (lamina cribrosa thickness: r = −0.078, p = 0.596; anterior lamina cribrosa depth: r = −0.228, p = 0.169).

The results of this study showed that the optical coherence tomography measurement of lamina cribrosa revealed thicker and more anteriorly positioned lamina cribrosa for patients with diabetes mellitus compared with those for healthy controls.

Women with gestational diabetes mellitus and milder gestational impaired glucose intolerance have elevated future risks of type 2 diabetes and cardiovascular disease. However, it is unclear whether they show postpartum evidence of vascular injury/dysfunction, an early event in the natural history of cardiovascular disease.

In total, 337 women underwent a glucose challenge test and oral glucose tolerance test in pregnancy, yielding four gestational glucose tolerance groups: gestational diabetes mellitus, gestational impaired glucose intolerance, abnormal glucose challenge test with normal glucose tolerance on the oral glucose tolerance test and normal glucose challenge test with normal glucose tolerance. At 3 years postpartum, they underwent repeat oral glucose tolerance test (on which 69 women had pre-diabetes/diabetes) and measurement of the following serum markers of vascular injury/dysfunction: thrombomodulin, E-selectin, P-selectin, intercellular adhesion molecule-3 and vascular cell adhesion molecule-1.

At 3 years postpartum, mean adjusted vascular cell adhesion molecule-1 was the only vascular marker that differed across the previous gestational glucose tolerance groups. On multiple linear regression analysis, each strata of gestational dysglycaemia was an independent predictor of lower vascular cell adhesion molecule-1 at 3 years postpartum (gestational diabetes mellitus: p = 0.005; gestational impaired glucose intolerance: p = 0.003; abnormal glucose challenge test normal glucose tolerance: p = 0.0008), as was current pre-diabetes/diabetes (p = 0.01).

Dysregulation of vascular cell adhesion molecule-1 may be an early event in the natural history of cardiovascular disease in women with recent glucose intolerance in pregnancy.

Previous studies have indicated an association between interleukin-18 and glucose. Interleukin-18 becomes active when cleaved by caspase-1, activated by the NLR family pyrin domain containing-3 inflammasome.

To investigate associations between glucometabolic variables and serum levels of interleukin-18 and genetic expression of interleukin-18, caspase-1 and NLR family pyrin domain containing-3 in adipose tissue and circulating leukocytes, and whether these mediators are related to the amount of abdominal adipose tissue .

Fasting blood samples and subcutaneous adipose tissue were collected in a cohort of 103 middle-aged men. Serum levels of interleukin-18 were determined by enzyme-linked immunosorbent assay, gene expression by real-time polymerase chain reaction and insulin sensitivity by glucose clamp. The distribution of abdominal adipose tissue, separated into superficial- and deep subcutaneous, and visceral adipose tissue, was assessed by computed tomography scan.

Glucometabolic variables correlated significantly to serum levels of interleukin-18, and to the expression of interleukin-18 and NLR family pyrin domain containing-3 in subcutaneous adipose tissue (p < 0.05). Significant correlations were further observed between the amount of fat in the different compartments of abdominal adipose tissue and both serum levels of interleukin-18 and genetic expression of interleukin-18 and NLR family pyrin domain containing-3 in adipose tissue.

The results implicate that the glucometabolic state is of importance for the inflammasome-related inflammation expressed both circulatory and genetically in subcutaneous adipose tissue, the latter highly reflected in the amount of abdominal adipose tissue.

Animal studies demonstrated that glucagon-like peptide-1 receptor agonists reduce myocardial necrosis following regional ischaemia induction. This effect may improve cardiovascular outcomes after myocardial infarction. Risk of cardiovascular death or hospitalisation for heart failure after myocardial infarction was evaluated in patients with type 2 diabetes at high cardiovascular risk in the LEADER trial.

Data from patients randomised to liraglutide or placebo, in addition to standard of care, in Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) (NCT01179048) were analysed post hoc. Cox regression, with myocardial infarction as a time-dependent covariate, was used to analyse time from randomisation to a composite of cardiovascular death or hospitalisation for heart failure.

Patients who experienced myocardial infarction had a sevenfold higher risk of the composite endpoint (with myocardial infarction: n = 148, 25.0%; without myocardial infarction: n = 716, 8.2%; hazard ratio: 7.0; 95% confidence interval: 5.8, 8.4). The risk of the composite endpoint after myocardial infarction was not significantly lower in the liraglutide group (n = 63, 23.0%) compared with placebo (n = 85, 26.7%; hazard ratio: 0.91; 95% confidence interval: 0.66, 1.26).

The data demonstrated that having myocardial infarction significantly increased the risk of subsequent cardiovascular death or hospitalisation for heart failure. However, we did not find evidence for a reduced risk in these cardiovascular outcomes following myocardial infarction in patients treated with liraglutide versus placebo.

To evaluate the renoprotective effects of canagliflozin, we assessed the albuminuria-lowering effect in Japanese type 2 diabetes patients with chronic kidney disease (CKD).

In this prospective, open-label, parallel-group study, type 2 diabetes patients with CKD were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory parameters, and adverse events.

Both groups included 20 patients in the analysis. Mean changes in UACR was −83 (−266 to −31) mg/gCr and 27 (−11 to 131) mg/gCr, in the canagliflozin and control groups, respectively (p = 0.004). Urinary liver-type free acid binding protein, N-acetyl-β-d-glucosaminidase, and β₂-microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in estimated glomerular filtration rate at the end of the study was 0.7 and −3.4 mL/min/1.73 m² in the canagliflozin and control group, respectively (p = 0.024). Canagliflozin treatment led to improvement of glycaemic control and reduction in body weight, blood pressure, and liver transaminase. There were no adverse events associated with canagliflozin.

Canagliflozin was associated with slower progression of kidney disease and reduction in albuminuria and tubulointerstitial markers in diabetes patients with CKD.