Body mass index, estimated glucose disposal rate and vascular complications in type 1 diabetes: Beyond glycated haemoglobin.

AIMS: To understand the relationship between insulin resistance (IR), assessed as estimated glucose disposal rate (eGDR), and microvascular/macrovascular complications in people with type 1 diabetes. MATERIALS AND METHODS: Individuals with a confirmed diagnosis of type 1 diabetes were included in this cross-sectional study. BMI was categorised into normal weight (18.0-24.9 kg m-2 ), overweight (25.0-29.9 kg m-2 ) and obese groups (≥30.0 kg m-2 ). We categorised eGDR into four groups: eGDR >8, 6-7.9, 4-5.9 and <4 mg kg-1  min-1 . Multiple logistic regression was used to identify associations with vascular complications, after adjusting for relevant confounders. RESULTS: A total of 2151 individuals with type 1 diabetes were studied. Median [interquartile range (IQR)] age was 41.0 [29.0, 55.0] with diabetes duration of 20.0 [11, 31] years. Odds ratio (OR) for retinopathy and nephropathy in obese compared with normal weight individuals was 1.64 (95% CI: 1.24-2.19; p = 0.001) and 1.62 (95% CI: 1.10-2.39; p = 0.015), while the association with cardiovascular disease just failed to reach statistical significance (OR 1.66 [95% CI: 0.97-2.86; p = 0.066]). Comparing individuals with eGDR ≥8 mg kg-1  min-1 and <4 mg kg-1  min-1 showed OR for retinopathy, nephropathy and macrovascular disease of 4.84 (95% CI: 3.36-6.97; p < 0.001), 8.35 (95% CI: 4.86-14.34; p < 0.001) and 13.22 (95% CI: 3.10-56.38; p < 0.001), respectively. Individuals with the highest eGDR category (≥8 mg kg-1  min-1 ) had the lowest complication rates irrespective of HbA1c levels. CONCLUSIONS: Obesity is prevalent in type 1 diabetes and diabetes complications are not only related to glucose control. IR, assessed as eGDR, is strongly associated with both microvascular and macrovascular complications, regardless of HbA1c levels.

Progressive Development of Aberrant Smooth Muscle Cell Phenotype in Abdominal Aortic Aneurysm Disease.

Abdominal aortic aneurysm (AAA) is a silent, progressive disease with a high mortality and an increasing prevalence with aging. Smooth muscle cell (SMC) dysfunction contributes to gradual dilatation and eventual rupture of the aorta. Here we studied phenotypic characteristics in SMC cultured from end-stage human AAA (≥5 cm) and cells cultured from a porcine carotid artery (PCA) model of early and end-stage aneurysm. Human AAA-SMC presented a secretory phenotype and expressed elevated levels of the differentiation marker miR-145 (2.2-fold, p < 0.001) and the senescence marker SIRT-1 (1.3-fold, p < 0.05), features not recapitulated in aneurysmal PCA-SMC. Human and end-stage porcine aneurysmal cells were frequently multi-nucleated (3.9-fold, p < 0.001, and 1.8-fold, p < 0.01, respectively, vs. control cells) and displayed an aberrant nuclear morphology. Human AAA-SMC exhibited higher levels of the DNA damage marker γH2AX (3.9-fold, p < 0.01, vs. control SMC). These features did not correlate with patients' chronological age and are therefore potential markers for pathological premature vascular aging. Early-stage PCA-SMC (control and aneurysmal) were indistinguishable from one another across all parameters. The principal limitation of human studies is tissue availability only at the end stage of the disease. Refinement of a porcine bioreactor model would facilitate the study of temporal modulation of SMC behaviour during aneurysm development and potentially identify therapeutic targets to limit AAA progression.

Preservation of Smooth Muscle Cell Integrity and Function: A Target for Limiting Abdominal Aortic Aneurysm Expansion?

(1) Abdominal aortic aneurysm (AAA) is a silent, progressive disease with significant mortality from rupture. Whilst screening programmes are now able to detect this pathology early in its development, no therapeutic intervention has yet been identified to halt or retard aortic expansion. The inability to obtain aortic tissue from humans at early stages has created a necessity for laboratory models, yet it is essential to create a timeline of events from EARLY to END stage AAA progression. (2) We used a previously validated ex vivo porcine bioreactor model pre-treated with protease enzyme to create "aneurysm" tissue. Mechanical properties, histological changes in the intact vessel wall, and phenotype/function of vascular smooth muscle cells (SMC) cultured from the same vessels were investigated. (3) The principal finding was significant hyperproliferation of SMC from EARLY stage vessels, but without obvious histological or SMC aberrancies. END stage tissue exhibited histological loss of α-smooth muscle actin and elastin; mechanical impairment; and, in SMC, multiple indications of senescence. (4) Aortic SMC may offer a therapeutic target for intervention, although detailed studies incorporating intervening time points between EARLY and END stage are required. Such investigations may reveal mechanisms of SMC dysfunction in AAA development and hence a therapeutic window during which SMC differentiation could be preserved or reinstated.

Metabolic Control in Type 1 Diabetes: Is Adjunctive Therapy the Way Forward?

Despite advances in insulin therapies, patients with type 1 diabetes (T1DM) have a shorter life span due to hyperglycaemia-induced vascular disease and hypoglycaemic complications secondary to insulin therapy. Restricting therapy for T1DM to insulin replacement is perhaps an over-simplistic approach, and we focus in this work on reviewing the role of adjuvant therapy in this population. Current data suggest that adding metformin to insulin therapy in T1DM temporarily lowers HbA1c and reduces weight and insulin requirements, but this treatment fails to show a longer-term glycaemic benefit. Agents in the sodium glucose co-transporter-2 inhibitor (SGLT-2) class demonstrate the greatest promise in correcting hyperglycaemia, but there are safety concerns in relation to the risk of diabetic ketoacidosis. Glucagon-like peptide-1 agonists (GLP-1) show a modest effect on glycaemia, if any, but significantly reduce weight, which may make them suitable for use in overweight T1DM patients. Treatment with pramlintide is not widely available worldwide, although there is evidence to indicate that this agent reduces both HbA1c and weight in T1DM. A criticism of adjuvant studies is the heavy reliance on HbA1c as the primary endpoint while generally ignoring other glycaemic parameters. Moreover, vascular risk markers and measures of insulin resistance-important considerations in individuals with a longer T1DM duration-are yet to be fully investigated following adjuvant therapies. Finally, studies to date have made the assumption that T1DM patients are a homogeneous group of individuals who respond similarly to adjuvant therapies, which is unlikely to be the case. Future longer-term adjuvant studies investigating different glycaemic parameters, surrogate vascular markers and harder clinical outcomes will refine our understanding of the roles of such therapies in various subgroups of T1DM patients.

Traumatic pseudoaneurysms of the superficial temporal artery.

Persistent scalp swelling following blunt head injury may be the presenting feature of a pseudoaneurysm of the temporal artery. This paper describes three patients who sustained injuries to the temporal region, which resulted in the formation of pseudoaneurysms. All patients had a delayed presentation to the Emergency Department. We describe their clinical presentations, subsequent management and pitfalls encountered when dealing with this condition.