The objective of this study is to evaluate whether exogenously induced hyperinsulinemia may increase the development of atherosclerosis.
Hyperinsulinemia, induced by exogenous insulin implantation in ...high-fat fed (60% fat HFD) apolipoprotein E-deficient mice (ApoE
) mice, exhibited insulin resistance, hyperglycemia, and hyperinsulinemia. Atherosclerosis was measured by the accumulation of fat, macrophage, and extracellular matrix in the aorta. After 8 weeks on HFD, ApoE
mice were subcutaneously implanted with control (sham) or insulin pellet, and phlorizin, a sodium glucose cotransporters inhibitor (1/2)inhibitor, for additional 8 weeks. Intraperitoneal glucose tolerance test showed that plasma glucose levels were lower and insulin and IGF-1 (insulin-like growth factor-1) levels were 5.3- and 3.3-fold higher, respectively, in insulin-implanted compared with sham-treated ApoE
mice. Plasma triglyceride, cholesterol, and lipoprotein levels were decreased in mice with insulin implant, in parallel with increased lipoprotein lipase activities. Atherosclerotic plaque by en face and complexity staining showed significant reductions of fat deposits and expressions of vascular adhesion molecule-1, tumor necrosis factor-α, interleukin 6, and macrophages in arterial wall while exhibiting increased activation of pAKT and endothelial nitric oxide synthase (
<0.05) comparing insulin-implanted versus sham HFD ApoE
mice. No differences were observed in atherosclerotic plaques between phlorizin-treated and sham HFD ApoE
mice, except phlorizin significantly lowered plasma glucose and glycated hemoglobin levels while increased glucosuria. Endothelial function was improved only by insulin treatment through endothelial nitric oxide synthase/nitric oxide activations and reduced proinflammatory (M1) and increased anti-inflammatory (M2) macrophages, which were inhibited by endothelial nitric oxide synthase inhibitor.
Exogenous insulin decreased atherosclerosis by lowering inflammatory cytokines, macrophages, and plasma lipids in HFD-induced hyperlipidemia, insulin resistant and mildly diabetic ApoE
mice.
Abstract
Background
Both long-term glycaemic variability and arterial stiffness have been recognized as cardiovascular risk factors. This study aims to investigate whether an association between ...these phenomena exists in individuals with type 1 diabetes.
Methods
This cross-sectional study included 673 adults (305 men, 368 women) with type 1 diabetes and combined available retrospective laboratory data on HbA
1c
from the preceding 10 years with outcome data on arterial stiffness and clinical variables from a comprehensive study visit. HbA
1c
variability was calculated as adjusted standard deviation (adj-HbA
1c
-SD), coefficient of variation (HbA
1c
-CV) and average real variability (HbA
1c
-ARV). As measures of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV; n = 335) and augmentation index (AIx; n = 653) were assessed using applanation tonometry.
Results
The study population had a mean age of 47.1 (± 12.0) years and a median duration of diabetes of 31.2 (21.2–41.3) years. The median number of HbA
1c
assessments per individual was 17 (12–26). All three indices of HbA
1c
variability were significantly correlated with both cfPWV and AIx after adjustment for sex and age (
p
< 0.001). In separate multivariable linear regression models, adj-HbA
1c
-SD and HbA
1c
-CV were significantly associated with cfPWV (
p
= 0.032 and
p
= 0.046, respectively) and AIx (
p
= 0.028 and
p
= 0.049, respectively), even after adjustment for HbA
1c
-mean. HbA
1c
-ARV was not associated with cfPWV or AIx in the fully adjusted models.
Conclusions
An association independent of HbA
1c
-mean was found between HbA
1c
variability and arterial stiffness, suggesting a need to consider multiple HbA
1c
metrics in studies assessing cardiovascular risk in type 1 diabetes. Longitudinal and interventional studies are needed to confirm any causal relationship and to find strategies for reducing long-term glycaemic variability.
Novel biomarkers are needed in diagnosing reliably acute kidney injury (AKI) in dogs and in predicting morbidity and mortality after AKI. Our hypothesis was that two novel tubular biomarkers, urinary ...clusterin (uClust) and cystatin B (uCysB), are elevated in dogs with AKI of different etiologies. In a prospective, longitudinal observational study, we collected serum and urine samples from 18 dogs with AKI of different severity and of various etiology and from 10 healthy control dogs. Urinary clusterin and uCysB were compared at inclusion between dogs with AKI and healthy controls and remeasured one and three months later. Dogs with AKI had higher initial levels of uClust (median 3593 ng/mL; interquartile range IQR; 1489-10,483) and uCysB (554 ng/mL; 29-821) compared to healthy dogs (70 ng/mL; 70-70 and 15 ng/mL; 15-15;
< 0.001, respectively). Initial uCysB were higher in dogs that died during the one-month follow-up period (n = 10) (731 ng/mL; 517-940), compared to survivors (n = 8) (25 ng/mL; 15-417 (
= 0.009). Based on these results, uClust and especially uCysB are promising biomarkers of AKI. Further, they might reflect the severity of tubular injury, which is known to be central to the pathology of AKI.
Abstract Background Despite improved glycemic treatment, the impact of glycation on pathological consequences may persist and contribute to adverse clinical outcomes in diabetes. In the present study ...we investigated the association between serum protein glycation products and progression of kidney disease as well as incident major adverse cardiovascular events (MACE) in type 1 diabetes. Methods Fructosamine, advanced glycation end products (AGEs), and methylglyoxal-modified hydro-imidazolone (MG-H1) were measured from baseline serum samples in the FinnDiane study ( n = 575). Kidney disease progression was defined as steep eGFR decline (> 3 mL/min/1.73 m 2 /year) or progression of albuminuria (from lower to higher stage of albuminuria). MACE was defined as acute myocardial infarction, coronary revascularization, cerebrovascular event (stroke), and cardiovascular death. Results Fructosamine was independently associated with steep eGFR decline (OR 2.15 95% CI 1.16–4.01, p = 0.016) in the fully adjusted model (age, sex, baseline eGFR). AGEs were associated with steep eGFR decline (OR 1.58 per 1 unit of SD 95% CI 1.07–2.32, p = 0.02), progression to end-stage kidney disease (ESKD) (HR 2.09 per 1 unit of SD 95% CI 1.43–3.05, p < 0.001), and pooled progression (to any stage of albuminuria) (HR 2.72 per 1 unit of SD 95% CI 2.04–3.62, p < 0.001). AGEs (HR 1.57 per 1 unit of SD 95% CI 1.23–2.00, p < 0.001) and MG-H1 (HR 4.99 95% CI 0.98–25.55, p = 0.054) were associated with incident MACE. MG-H1 was also associated with pooled progression (HR 4.19 95% CI 1.11–15.89, p = 0.035). Most AGEs and MG-H1 associations were no more significant after adjusting for baseline eGFR. Conclusions Overall, these findings suggest that protein glycation products are an important risk factor for target organ damage in type 1 diabetes. The data provide further support to investigate a potential causal role of serum protein glycation in the progression of diabetes complications.
Background Recent studies have shown an increasing prevalence of vascular risk factors in young adults with ischemic stroke ( IS ). However, the strength of the association between all vascular risk ...factors and early-onset IS has not been fully established. Methods and Results We compared 961 patients with a first-ever IS at 25 to 49 years to 1403 frequency-matched stroke-free controls from a population-based cohort study ( FINRISK ). Assessed risk factors included an active malignancy, atrial fibrillation, cardiovascular disease, current smoking status, a family history of stroke, high low-density lipoprotein cholesterol, high triglycerides, low high-density lipoprotein cholesterol, hypertension, and type 1 and type 2 diabetes mellitus. We performed subgroup analyses based on age, sex, and IS etiology. In a fully adjusted multivariable logistic regression analysis, significant risk factors for IS consisted of atrial fibrillation (odds ratio OR, 10.43; 95% confidence interval CI , 2.33-46.77, cardiovascular disease (OR, 8.01; 95% CI , 3.09-20.78), type 1 diabetes mellitus (OR, 6.72; 95% CI , 3.15-14.33), type 2 diabetes mellitus (OR, 2.31; 95% CI , 1.35-3.95), low high-density lipoprotein cholesterol (OR, 1.81; 95% CI , 1.37-2.40), current smoking status (OR, 1.81; 95% CI , 1.50-2.17), hypertension (OR, 1.43; 95% CI , 1.17-1.75), and a family history of stroke (OR, 1.37; 95% CI , 1.04-1.82). High low-density lipoprotein cholesterol exhibited an inverse association with IS . In the subgroup analyses, the most consistent associations appeared for current smoking status and type 1 diabetes mellitus. Conclusions Our study establishes the associations between 11 vascular risk factors and early-onset IS , among which atrial fibrillation, cardiovascular disease, and both type 1 and 2 diabetes mellitus in particular showed strong associations.
Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, their effects on arterial function may reveal different mechanisms, perhaps potentially useful. To test ...the effects of oxygen and slow breathing we measured arterial function (augmentation index, pulse wave velocity), baroreflex sensitivity (BRS) and oxygen saturation (SAT), during spontaneous and slow breathing (6 breaths/min), in normoxia and hyperoxia (5 L/min oxygen) in 91 type-1 diabetic and 40 age-matched control participants. During normoxic spontaneous breathing diabetic subjects had lower BRS and SAT, and worse arterial function. Hyperoxia and slow breathing increased BRS and SAT. Hyperoxia increased blood pressure and worsened arterial function. Slow breathing improved arterial function and diastolic blood pressure. Combined administration prevented the hyperoxia-induced arterial pressure and function worsening. Control subjects showed a similar pattern, but with lesser or no statistical significance. Oxygen-driven autonomic improvement could depend on transient arterial stiffening and hypertension (well-known irritative effect of free-radicals on endothelium), inducing reflex increase in BRS. Slow breathing-induced improvement in BRS may result from improved SAT, reduced sympathetic activity and improved vascular function, and/or parasympathetic-driven antioxidant effect. Lower oxidative stress could explain blunted effects in controls. Slow breathing could be a simple beneficial intervention in diabetes.
Aims/hypothesis
The aim of this study was to assess how physical activity predicts the development and progression of diabetic nephropathy in patients with type 1 diabetes.
Methods
This prospective ...study (follow-up time 6.4 ± 3.1 years) included 1,390 patients (48.5% men, mean age 37.0 ± 12.4 years, duration of diabetes 20.4 ± 12.3 years) participating in the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Leisure-time physical activity (LTPA) was assessed using a validated self-report questionnaire. Renal status was defined according to standard clinical cut-off values for urinary AER.
Results
The total amount of LTPA was not associated with progression in renal status. For the intensity of LTPA, however, the 10 year cumulative progression rate was 24.0% (95% CI 18.8, 28.8), 13.5% (95% CI 10.3, 16.6) or 13.1% (95% CI 10.3%, 16.6%;
p
= 0.01) of the patients with low, moderate or high intensity LTPA. This pattern was similar to that for the development of de novo microalbuminuria. Corresponding progression rates for LTPA frequency of <1, 1–2 or >2 sessions/week was 24.7% (95% CI 18.3, 30.7), 14.7% (95% CI 10.2, 19.0) or 12.6% (95% CI 9.4, 15.7), respectively (
p
= 0.003).
Conclusions/interpretation
This study demonstrates for the first time in a prospective setting the relationship between physical activity and the risk of diabetic nephropathy in patients with type 1 diabetes. The data suggest that physical activity, and in particular its intensity, may have an impact on the initiation and progression of diabetic nephropathy in type 1 diabetes.
Diabetic neuropathy and diabetic eye disease are well known complications of type 1 diabetes. We hypothesized that chronic hyperglycemia also damages the optic tract, which can be measured using ...routine magnetic resonance imaging. Our aim was to compare morphological differences in the optic tract between individuals with type 1 diabetes and healthy control subjects. Associations between optic tract atrophy and metabolic measures, cerebrovascular and microvascular diabetic complications were further studied among individuals with type 1 diabetes.
We included 188 subjects with type 1 diabetes and 30 healthy controls, all recruited as part of the Finnish Diabetic Nephropathy Study. All participants underwent a clinical examination, biochemical work-up, and brain magnetic resonance imaging (MRI). Two different raters manually measured the optic tract.
The coronal area of the optic chiasm was smaller among those with type 1 diabetes compared to non-diabetic controls (median area 24.7 21.0-28.5 vs 30.0 26.7-33.3 mm
, p<0.001). In participants with type 1 diabetes, a smaller chiasmatic area was associated with duration of diabetes, glycated hemoglobin, and body mass index. Diabetic eye disease, kidney disease, neuropathy and the presence of cerebral microbleeds (CMBs) in brain MRI were associated with smaller chiasmatic size (p<0.05 for all).
Individuals with type 1 diabetes had smaller optic chiasms than healthy controls, suggesting that diabetic neurodegenerative changes extend to the optic nerve tract. This hypothesis was further supported by the association of smaller chiasm with chronic hyperglycemia, duration of diabetes, diabetic microvascular complications, as well as and CMBs in individuals with type 1 diabetes.
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