Abstract P225: Nox1 or Nox4 Deletion Prevents Type-1 Diabetes-induced Endothelial Dysfunction

Objective: The prognosis of type-1 diabetes is in part related to the increased risk of vascular complications such as atherosclerosis. Overproduction of reactive oxygen species by NADPH oxidase (NOX) is believed to play an important role in diabetes-related vascular injury. NOX1 may play a role in the macrovascular disease, whereas NOX4 may have protective actions. Nevertheless, their role in diabetic vascular injury is less well understood. We hypothesized that deletion of Nox1 would prevent diabetes-induced endothelial dysfunction and vascular remodeling of small arteries whereas Nox4 would exaggerate vascular injury in atherosclerosis-prone apolipoprotein knockout ( Apoe -/- ) mice. Methods: Diabetes was induced by streptozotocin IP injections (STZ, 55 mg/kg/day) for 5 days in 6-week-old male Apoe -/- mice, Apoe -/- mice deficient in Nox1 ( Apoe -/- / Nox1 y/- ) and Nox4 ( Apoe -/- / Nox4 -/- ). Mice were studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Results: Apoe -/- mice presented a maximal endothelium-dependent vasodilatory response (E max ) to acetylcholine of 48±8%, which was further decreased by diabetes to 20±6%. In contrast, endothelium-dependent relaxations to acetylcholine were 1.5-fold higher in diabetic Apoe -/- / Nox1 y/- and Apoe -/- / Nox4 -/- mice compared to non-diabetic Apoe -/- mice (E max : 72±9 and 70±7 vs 48±8%). Diabetes decreased MA stiffness in Apoe -/- mice, as indicated by a rightward displacement of the stress-strain curves (strain at 140 mm Hg: 1.02±0.04 vs 0.75±0.04), which was blunted by Nox1 or Nox4 knockout (strain at 140 mm Hg: 0.77±0.02 and 0.81±0.02). MA media/lumen was unaltered by diabetes. Knockout of Nox4 but not Nox1 increased MA media/lumen 1.4-fold in diabetic Apoe -/- mice (4.1±0.4 and 3.5±0.2 vs 2.9±0.2%). Conclusions: These results suggest that NOX1 and NOX4 play a pathophysiological role in diabetes-induced endothelial dysfunction and contribute to potentially maladaptive changes in vascular stiffness. NOX4 seems to have dual actions on the vasculature, as it is also protective against vascular remodeling of small arteries in type 1 diabetes.

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Abstract 344: Endothelin-1 Overexpression Exaggerates Diabetes-induced Endothelial Dysfunction

Hypertension ◽

10.1161/hyp.64.suppl_1.344 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Noureddine IDRIS KHODJA ◽

Muhammad Oneeb Rehman Mian ◽

Tlili Barhoumi ◽

Sofiane Ouerd ◽

Jordan Gornitsky ◽

...

Keyword(s):

Type 1 Diabetes ◽

Endothelial Dysfunction ◽

Vascular Complications ◽

Fold Increase ◽

Wild Type ◽

No Donor ◽

Meclofenamic Acid ◽

Fibronectin Expression ◽

Endothelium Dependent Relaxation

Objective: Vascular disease associated with endothelial dysfunction is a major cause of morbidity in patients with type-1 diabetes. Endothelin (ET)-1 plays a role in diabetes-induced vascular complications, since ET-1 type A receptor blockade reduces diabetes-induced vascular injury. However, whether ET-1 contributes to diabetes-induced endothelial dysfunction remains unproven. We hypothesized that vascular ET-1 overexpression will exaggerate diabetes-induced endothelial dysfunction. Methods: Diabetes was induced by streptozotocin treatment (STZ, 55 mg/kg/day, ip) for 5 days in 6-week-old male wild-type (WT) mice and in mice overexpressing ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Blood was collected to determine glucose. Mesenteric artery reactivity and remodeling were evaluated using pressurized myography and aortic fibronectin expression by immnunofluorescence. Results: STZ-induced diabetes was confirmed by a 3-fold increase in glycemia in WT and eET-1 ( P <0.001). Diabetes impaired endothelium-dependent relaxation (EDR) reponses to acetylcholine in WT (60.9±6.4% vs 83.9±3.4%, P <0.05) and eET-1 (48.6±5.1% vs 81.5±5.2%, P <0.001). EDR impairment was exaggerated in eET-1 compared to WT ( P <0.05). Meclofenamic acid, an inhibitor of cyclooxygenase, increased EDR in eET-1 compared to WT (78.4±9.4% vs 66.7±3.2%, P <0.01), which was not observed in diabetic mice. L-NAME, an inhibitor of nitric oxide (NO) synthase, completely blocked EDR in WT, eET-1 and diabetic WT, but not in diabetic eET-1 (4.1±1.6%, 6.4±5.7%, 2.2±4.6% and 26.6±4.6%, P <0.05). Apamin plus Tram34, inhibitors of endothelium-dependent hyperpolarization inhibited EDR in the four groups. Endothelium-independent relaxation to sodium nitroprusside, a NO donor, was similar in the four groups. Diabetes reduced media/lumen in WT (2.7±0.3 vs 3.6±0.3, P <0.05) and eET-1 (2.9±0.2 vs 3.8±0.3, P <0.05). Diabetes decreased aortic fibronectin expression in WT (94.0±11.0 vs. 151.9±21.8 RFU/μm 2 , P <0.05) and eET-1 (66.3±8.7 vs. 146.6±20.7 RFU/μm 2 , P <0.05). Conclusion: ET-1 contributes to alterations in several pathways mediating endothelium-dependent relaxation in type-1 diabetes, leading to exaggerated endothelial dysfunction.

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Carotid intima media thickness and associations with serum osteoprotegerin and s-RANKL in children and adolescents with type 1 diabetes mellitus with increased risk for endothelial dysfunction

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0147 ◽

2018 ◽

Vol 0 (0) ◽

Cited By ~ 1

Author(s):

Kyriaki Karavanaki ◽

Emmanouil Tsouvalas ◽

Marina Vakaki ◽

Alexandra Soldatou ◽

Charalambos Tsentidis ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Endothelial Dysfunction ◽

Type 1 Diabetes Mellitus ◽

Children And Adolescents ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Negatively Associated ◽

Increased Risk

Abstract Background Although carotid intima media thickness (CIMT) is an established marker of endothelial dysfunction, limited data exist on relative laboratory biomarkers in youngsters with type 1 diabetes mellitus (T1DM). Our aim was to study CIMT and the biomarkers of the osteoprotegerin (OPG)/RANKL system in young T1DM patients and controls, and also in subgroups of patients with increased risk for endothelial dysfunction, such as those with overweight/obesity, poor metabolic control or the presence of microalbuminuria. Methods CIMT and OPG/RANKL of 56 T1DM children and adolescents were compared to 28 healthy controls. Results Anthropometric, laboratory, CIMT and OPG/RANKL measurements were similar between patients and controls. Overweight/obese patients had greater CIMT than the normal weight ones (0.50 vs. 0.44 mm, p=0.001). Microalbuminuric patients had greater CIMT (0.49 vs. 0.44 mm, p=0.035) than the normoalbuminuric ones, with no difference in terms of OPG/RANKL. In the microalbuminuric group, OPG (r=−0.90, p=0.036) and RANKL (r=−0.92, p=0.024) were significantly negatively associated with CIMT. Following linear regression analysis, in the total patients group, microalbuminuria was the only factor significantly associated with CIMT (beta±SE: 0.050±0.021, p=0.035), body mass index (BMI)-z-scores were negatively associated with OPG (beta±SE: −0.25±0.12, p=0.05), while in the microalbuminuric group, CIMT was negatively associated with OPG (beta±SE: −0.070±0.019, p=0.036). During the forward stepwise procedure, microalbuminuria and age were the only variables negatively associated with RANKL (b=−0.334, p=0.034, b=−35.95, p=0.013, respectively). Conclusions In T1DM pediatric patients, overweight/obesity and microalbuminuria were associated with greater CIMT and with impaired OPG/RANKL levels, as biochemical indices of calcification of the atherosclerotic plaque.

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Reduced expression of OXPHOS and DNA damage genes is linked to protection from microvascular complications in long-term type 1 diabetes: the PROLONG study

Scientific Reports ◽

10.1038/s41598-021-00183-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Türküler Özgümüş ◽

Oksana Sulaieva ◽

Leon Eyrich Jessen ◽

Ruchi Jain ◽

Henrik Falhammar ◽

...

Keyword(s):

Dna Repair ◽

Type 1 Diabetes ◽

Microvascular Complications ◽

Vascular Complications ◽

Diabetes Duration ◽

Chronic Hyperglycemia ◽

Increased Risk ◽

Term Type

AbstractType 1 diabetes is a chronic autoimmune disease requiring insulin treatment for survival. Prolonged duration of type 1 diabetes is associated with increased risk of microvascular complications. Although chronic hyperglycemia and diabetes duration have been considered as the major risk factors for vascular complications, this is not universally seen among all patients. Persons with long-term type 1 diabetes who have remained largely free from vascular complications constitute an ideal group for investigation of natural defense mechanisms against prolonged exposure of diabetes. Transcriptomic signatures obtained from RNA sequencing of the peripheral blood cells were analyzed in non-progressors with more than 30 years of diabetes duration and compared to the patients who progressed to microvascular complications within a shorter duration of diabetes. Analyses revealed that non-progressors demonstrated a reduction in expression of the oxidative phosphorylation (OXPHOS) genes, which were positively correlated with the expression of DNA repair enzymes, namely genes involved in base excision repair (BER) machinery. Reduced expression of OXPHOS and BER genes was linked to decrease in expression of inflammation-related genes, higher glucose disposal rate and reduced measures of hepatic fatty liver. Results from the present study indicate that at transcriptomic level reduction in OXPHOS, DNA repair and inflammation-related genes is linked to better insulin sensitivity and protection against microvascular complications in persons with long-term type 1 diabetes.

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Circulating endothelial progenitor cells, endothelial function, carotid intima–media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria

Diabetologia ◽

10.1007/s00125-009-1401-0 ◽

2009 ◽

Vol 52 (8) ◽

pp. 1464-1473 ◽

Cited By ~ 91

Author(s):

L. Sibal ◽

A. Aldibbiat ◽

S. C. Agarwal ◽

G. Mitchell ◽

C. Oates ◽

...

Keyword(s):

Type 1 Diabetes ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Progenitor Cells ◽

Macrovascular Disease ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Circulating Endothelial Progenitor Cells ◽

Circulating Markers

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Altered Kinetics of Interleukin-6 and Other Inflammatory Mediators During Exercise in Children With Type 1 Diabetes

Journal of Investigative Medicine ◽

10.2310/jim.0b013e31816c0fba ◽

2008 ◽

Vol 56 (4) ◽

pp. 701-713 ◽

Cited By ~ 12

Author(s):

Jaime S. Rosa ◽

Stacy R. Oliver ◽

Masato Mitsuhashi ◽

Rebecca L. Flores ◽

Andria M. Pontello ◽

...

Keyword(s):

Type 1 Diabetes ◽

Inflammatory Mediators ◽

Molecular Mechanisms ◽

Intermittent Exercise ◽

Vascular Complications ◽

Healthy Controls ◽

Measured Variable ◽

Monocyte Chemoattractant Protein 1 ◽

Increased Risk

BackgroundLeukocyte mobilization and secretions of cytokines, chemokines, and growth factors in children during exercise are necessary biochemical signals for physiological growth and long-term cardiovascular protection. Because of glycemic instability, altered exercise responses, particularly the proinflammatory cytokine interleukin (IL)-6, may occur in type 1 diabetes mellitus (T1DM) that could influence the onset/progression of diabetic vascular complications. Relatively little is known, however, on most molecular aspects of immunomodulatory adaptation to exercise in diabetic children.MethodsWe therefore studied 21 children (age, 13.4 ± 0.3 years; 13 boys/8 girls) with T1DM and 21 age-matched healthy controls during 30 minutes of intense and intermittent cycling exercise. Euglycemia was maintained during and for greater than 90 minutes before exercise; blood samples for IL-6 and other cytokines/chemokines were drawn before, during (every 6 minutes), and after (every 15 minutes) exercise.ResultsIn T1DM, exercise-induced IL-6 peak occurred earlier and with greater magnitude than that in controls; an exploratory analysis of additional inflammatory mediators displayed a similarly accelerated/exaggerated pattern in T1DM, including the kinetic profiles of tumor necrosis factor α, IL-4, IL-12p70, IL-17, granulocyte-monocyte colony-stimulating factor, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and eotaxin (interferon-inducible protein-10 was the only measured variable essentially indistinguishable between groups).ConclusionTherefore, during intense and intermittent exercise, significant alterations in the immunologic pattern of inflammatory regulation occurred in children with T1DM as compared with healthy controls. Our findings underscore how the understanding of all the underlying molecular mechanisms is a necessary prerequisite for achieving effective use of exercise and the full manifestation of its health benefits, particularly in understudied populations such as children with T1DM who are at increased risk for cardiovascular complications.

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Immune status is associated with the mode of delivery in infants at increased risk for Type 1 Diabetes

Diabetologie und Stoffwechsel ◽

10.1055/s-0034-1374887 ◽

2014 ◽

Vol 9 (S 01) ◽

Author(s):

O D'Orlando ◽

R Puff ◽

A Henniger ◽

S Krause ◽

F Haupt ◽

...

Keyword(s):

Type 1 Diabetes ◽

Immune Status ◽

Mode Of Delivery ◽

Increased Risk

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Metabolic Markers Associated with Increased Risk for Progression from Single to Multiple Autoantibodies in Type 1 Diabetes Relatives

Diabetes ◽

10.2337/db18-94-or ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 94-OR

Author(s):

EMANUELE BOSI ◽

SUSAN GEYER ◽

JAY SOSENKO ◽

DOROTHY J. BECKER ◽

MANUELA BATTAGLIA ◽

...

Keyword(s):

Type 1 Diabetes ◽

Metabolic Markers ◽

Increased Risk

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836-P: Cannabis Use in Adults with Type 1 Diabetes (T1D) Is Associated with Poor Glycemic Control and Increased Risk for Diabetic Ketoacidosis (DKA)

Diabetes ◽

10.2337/db19-836-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 836-P ◽

Cited By ~ 1

Author(s):

VIRAL N. SHAH ◽

DANIEL D. TAYLOR ◽

NICOLE C. FOSTER ◽

ROY BECK ◽

HALIS K. AKTURK ◽

...

Keyword(s):

Type 1 Diabetes ◽

Glycemic Control ◽

Diabetic Ketoacidosis ◽

Cannabis Use ◽

Poor Glycemic Control ◽

Increased Risk

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Coeliac disease is associated with depression in children and young adults with type 1 diabetes: results from a multicentre diabetes registry

Acta Diabetologica ◽

10.1007/s00592-020-01649-8 ◽

2021 ◽

Author(s):

Sascha René Tittel ◽

◽

Désirée Dunstheimer ◽

Dörte Hilgard ◽

Burkhild Knauth ◽

...

Keyword(s):

Type 1 Diabetes ◽

Young Adults ◽

Coeliac Disease ◽

Diabetes Patient ◽

Routine Care ◽

Diabetes Registry ◽

Increased Risk ◽

Treatment Data ◽

Children And Young Adults

Abstract Aims To analyse the association between coeliac disease (CD) and depression in children, adolescents, and young adults with type 1 diabetes (T1D). Methods We included 79,067 T1D patients aged 6–20 years, with at least six months of diabetes duration, and treatment data between 1995 and 2019 were documented in the diabetes patient follow-up registry. We categorized patients into four groups: T1D only (n = 73,699), T1 + CD (n = 3379), T1D + depression (n = 1877), or T1D + CD + depression (n = 112). Results CD and depression were significantly associated (adjusted OR: 1.25 [1.03–1.53]). Females were more frequent in both the depression and the CD group compared with the T1D only group. Insulin pumps were used more frequently in T1D + CD and T1D + depression compared with T1D only (both p < .001). HbA1c was higher in T1D + depression (9.0% [8.9–9.0]), T1D + CD + depression (8.9% [8.6–9.2]), both compared with T1D only (8.2% [8.2–8.2], all p < .001). We found comorbid autism, attention deficit hyperactivity disorder, anxiety, schizophrenia, and eating disorders more frequently in the T1D + CD + depression group compared with T1D only (all p < .001). Conclusions CD and depression are associated in young T1D patients. The double load of T1D and CD may lead to an increased risk for depression. Depression was associated with additional psychological and neurological comorbidities. Aside from imperative CD screening after T1D diagnosis and regular intervals, depression screening might be helpful in routine care, especially in patients with diagnosed CD.

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