Hypoglycaemic and Antioxidant Properties of Acrocomia aculeata (Jacq.) Lodd Ex Mart. Extract Are Associated with Better Vascular Function of Type 2 Diabetic Rats.

Oxidative stress is involved in the metabolic dysregulation of type 2 diabetes (DM2). Acrocomia aculeata (Aa) fruit pulp has been described for the treatment of several diseases, and recently we have proved that its leaves have phenolic compounds with a marked antioxidant effect. We aimed to assess whether they can improve metabolic, redox and vascular functions in DM2. Control Wistar (W-Ctrl) and non-obese type 2 diabetic Goto-Kakizaki (GK-Ctrl) rats were treated for 30 days with 200 mg.kg-1 aqueous extract of Aa (EA-Aa) (Wistar, W-EA-Aa/GK, GK-EA-Aa). EA-Aa was able to reduce fasting glycaemia and triglycerides of GK-EA-Aa by improving proteins related to glucose and lipid metabolism, such as GLUT-4, PPARγ, AMPK, and IR, when compared to GK-Ctrl. It also improved viability of 3T3-L1 pre-adipocytes exposed by H2O2. EA-Aa also increased the levels of catalase in the aorta and kidney, reduced oxidative stress and increased relaxation of the aorta in GK-treated rats in relation to GK-Ctrl, in addition to the protective effect against oxidative stress in HMVec-D cells. We proved the direct antioxidant potential of the chemical compounds of EA-Aa, the increase in antioxidant defences in a tissue-specific manner and hypoglycaemic properties, improving vascular function in type 2 diabetes. EA-Aa and its constituents may have a therapeutic potential for the treatment of DM2 complications.

Interdisciplinary assessment and diagnostic algorithm: The role of the cardiologist.

Patients with diabetes have an increased risk of developing heart failure and those with heart failure are at higher risk of developing diabetes. In patients with diabetes antidiabetic medications and the metabolic alterations of diabetes increase the risk of developing heart failure. In diabetic patients with heart failure and in those with an increased likelihood of developing the disease a stepwise approach based on the use of natriuretic peptides and echocardiography to rule out the presence of heart failure should be used. Once the diagnosis of heart failure is established it will be important to define the phenotype according to the left ventricular function and, where appropriate, use additional tests to identify possible additional underlying causes of heart failure like coronary artery disease. A multidisciplinary heart failure management programs is recommended in all patients with diabetes mellitus and heart failure to enable appropriate investigations, accurate diagnosis, and appropriate agreed evidence-based therapy and care plan. The implementation of a multidisciplinary heart failure management program requires a multidisciplinary team that will have to follow the patients throughout the whole heart failure trajectory and that should consider a holistic approach to the diabetic patient with heart failure rather than focussing merely on either heart failure or diabetes.

Effect of an aqueous extract of Terminalia chebula on endothelial dysfunction, systemic inflammation, and lipid profile in type 2 diabetes mellitus: A randomized double-blind, placebo-controlled clinical study.

Endothelial dysfunction is a crucial complication in type 2 diabetic patients, related to cardiovascular risk. Terminalia chebula (TC), a traditional ayurvedic herb, is known for its antioxidant and antihyperlipidemic activity. A prospective, randomized, double-blind, placebo-controlled clinical study was undertaken to evaluate the effects of an aqueous extract of T. chebula 250 and 500 mg versus placebo on endothelial dysfunction and biomarkers of oxidative stress in type 2 diabetic patients. A total of 60 eligible patients were randomized to receive either T. chebula 250 mg, T. chebula 500 mg, or placebo twice daily for 12 weeks. The subjects were assessed based on the endothelial function, the levels of nitric oxide, malondialdehyde, glutathione, high sensitivity C-reactive protein, glycosylated hemoglobin, and lipid profile at baseline and after 12 weeks of treatment. Treatment with T. chebula 250 mg and T. chebula 500 mg for 12 weeks significantly improved the endothelial function (reflection index) compared to placebo (absolute changes: - T. chebula 250: -2.55 ± 1.82% vs. T. chebula 500: -5.21 ± 2.41% vs. placebo: 1.40 ± 2.11%). Other cardiovascular risk indicators were also significantly ameliorated in the treatment groups compared to placebo. In conclusion, T. chebula (especially, 500 mg BID dose) significantly minimized the cardiovascular risk factors in patients with type 2 diabetes compared to placebo.

Traditional Chinese medicine Shenqi compound to improve lower extremity atherosclerosis of patients with type 2 diabetes by affecting blood glucose fluctuation: Study protocol for a randomized controlled multicenter trial.

BACKGROUND: Clinical and basic research supports that blood glucose fluctuation is an important predictor of diabetic vascular disease and an etiology of lower extremity atherosclerosis, which is an important pathological basis for lower extremity vascular diseases. Previous Chinese National Natural Science Foundation trials (No. 81503566) have reported that the traditional Chinese medicine Shenqi compound can reduce blood glucose fluctuation and low-grade inflammation, and protect blood vessels; however, there are no high-quality clinical evidences available to support the same. This multicenter randomized controlled trial aims to obtain more clinical evidence to confirm the efficacy and safety of Shenqi compound in type 2 diabetes with lower extremity atherosclerosis. METHODS: A multicenter RCT will be implemented in this study for a 32-week study period (8 weeks for intervention and 24 weeks for follow-up). Participants will be recruited from the Teaching Hospital of Chengdu University of TCM, Mianyang Hospital of TCM, and Shuangliu Hospital of TCM. Sixty participants will be randomly divided into a treatment group (basic treatment combined with traditional Chinese medicine Shenqi Compound) or a control group (basic treatment combined with Chinese medicine placebo) with 30 participants in each group. Patients will be selected considering the following inclusion criteria: age between 35 and 65 years, and a positive diagnosis for type 2 diabetes with lower extremity atherosclerosis and TCM syndromes. Primary outcome indicator is an arterial color Doppler ultrasound. Secondary outcome indicators include: blood glucose fluctuation indicators (MBG, SDBG, LAGE), islet ß-cell function evaluation indicators (Homa-IR, Homa-islet, SG, SCP), inflammation indicators (NLR, CRP, IL-6), blood lipids, and HbA1c. Safety index includes vital signs (T, P, R, BP), blood, urine, stool routine, liver and renal function, electrocardiogram, and adverse event records. The endpoint event is defined as the presence of gangrene in the lower limbs. DISCUSSION: Explore the clinical effect of traditional Chinese medicine "Shenqi Compound" to reduce blood glucose fluctuation and use HOMA-IR, the area under the glucose curve, and the area under the C-peptide curve to evaluate the effect of protecting islet ß cell function. TRIAL REGISTRATION: Chinese clinical trial registry (ChiCTR-1900027693). Registered on November 23, 2019. http://www.chictr.org.cn.

Chronic Diabetes Complications: The Need to Move beyond Classical Concepts.

Chronic-diabetes-related complications simultaneously compromise both the micro- and macrovascular trees, with target organs considered as the paradigm of large vessel injury also entailing microangiopathic changes. However, complications independent or partially independent from vascular damage are often overlooked. This includes neuronal dysfunction (e.g., retinal neurodegeneration), interstitial injury (e.g., tubulointerstitial disease), metabolic damage (e.g., in the heart and liver), and nonclassical conditions such as cognitive decline, impaired pulmonary function, or increased risk of cancer. In this scenario, researchers, endocrinologists and primary care physicians should have a holistic view of the disease and pay further attention to all organs and all potential clinical repercussions, which would certainly contribute to a more rational and integrated patient health care.

BuZangTongLuo decoction improved hindlimb ischemia by activating angiogenesis and regulating gut microbiota in diabetic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Seven traditional medicinal plants (including Astragalus membranaceus, Dioscorea hemsleyi, Salvia miltiorrhiza, Scrophularia ningpoensis, Ophiopogon japonicus, Panax ginseng and Fritillariae cirrhosae) and one insect leech (Whitmania pigra Whitman) were combined into BuZangTongLuo formula (BZTLF) under the guidance of traditional Chinese medicine. BZTLF is potentially effective against diabetic vascular complications. AIM OF THE STUDY: Previous studies failed to clarify the molecular mechanism through which BZTLF suppressed diabetic ischemia. In this study, we aimed to explore whether BZTLF treatment could prevent the occurrence of type 2 diabetic (T2D) hindlimb ischemia in mice. Further, we investigated the regulatory effect of BZTLF on angiogenesis-related VEGF signaling pathway and gut microbiota dysfunction in diabetic ischemia mice. MATERIALS AND METHODS: C57BL/6J mice fed with high-fat diet (HFD) received STZ injection and femoral artery ligation to build T2D diabetic hindlimb ischemia model. Mice were gavaged with BZTLF (5 g [raw materials]/kg/d) or with metformin plus atorvastatin for three weeks. Laser doppler imaging system was utilized for the visualization of blood flow. Histochemistry analysis was performed for microvascular vessel staining. Western blot was applied to detect the protein changes of signaling molecules responsible for VEGF pathway. Finally, 16S rDNA gene sequencing was conducted for analysis of gut microbiota structure. RESULTS: BZTLF treatment remarkably restored blood flow and capillary density of diabetic hindlimb ischemia. And the protein changes of VEGF signaling molecules were reversed in BZTLF-treated diabetic ischemia mice, including the decreased VEGF and HIF-1α, and the increased NO, eNOS and p-ERK1/2. The gut microbiota analysis suggests that BZTLF treatment increased the abundances of several beneficial bacteria (Akkermansia, Bifidobacterium and Bacteroides), while decreased the populations of some harmful bacteria(Blautia, Weissella, Escherichia Shigella and Kurthia). By using Spearman's correlation analysis, these changed gut flora were positively/negatively correlated with VEGF signaling pathway or glycometabolic parameters. CONCLUSION: BZTLF displayed beneficial effects on diabetic hindlimb ischemia by reshaping the gut microbiota structure and stunning the VEGF/HIF-1α pathway.

Effectiveness of the Combined Treatment of Functional Electrical Stimulation and Deambulation in Diabetic Arteriopathy.

OBJECTIVE: To determine whether functional electrical stimulation (FES) is able to improve ischemic pain and quality of life of patients with diabetic arteriopathy (DA) in grade-IIa Leriche-Le Fontaine. MATERIAL AND METHODS: This is a single-blinded, randomized, prospective cohort study. We included patients diagnosed with grade-IIa Leriche-Le Fontaine peripheral arterial disease in both lower extremities with and without diabetes mellitus (DM). The ankle-brachial index was 0.4-0.9. Patients were randomized into two experimental groups: nondiabetic (non-DM) (n = 71) and diabetic (DM) (n = 71). The patients received FES while walking for 1 hr on a supervised treadmill. Three months of follow-up were conducted after treatment. RESULTS: A total of 168 patients were randomized; 142 completed the study, with 71 in each group. Both groups reported an improvement after the treatment, but the improvement was statistically significant in the DM group, in which all the parameters studied improved. Greater benefits were observed in all the parameters in the DM group after the follow-up, except for the test of the meters walked in 6 min. CONCLUSIONS: The use of FES during daily walking is effective in patients with DA, reducing intermittent claudication and improving the quality of life of these patients.

Chronic consumption of a high-fat diet rich in corn oil activates intrinsic cell death pathway and induces several ultrastructural changes in the atria of healthy and type 1 diabetic rat.

This study investigates the effect of chronic consumption of a high-fat diet rich in corn oil (CO-HFD) on atrial cells ultrastructure, antioxidant levels and markers of intrinsic cell death of both control and type 1 diabetes mellitus (T1DM)-induced rats. Adult male rats (10 rats/group) were divided into four groups: control fed standard diet (STD) (3.82 kcal/g, 9.4% fat), CO-HFD (5.4 kcal/g, 40% fat), T1DM fed STD, and T1DM + CO-HFD. CO-HFD and T1DM alone or in combination impaired systolic and diastolic functions of rats and significantly reduced levels of GSH and the activity of SOD, enhanced lipid peroxidation, increased protein levels of P53, Bax, cleaved caspase-3, and ANF and decreased levels of Bcl-2 in their atria. Concomitantly, atrial cells exhibited fragmentation of the myofibrils, disorganized mitochondria, decreased number of atrionatriuretic factor (ANF) granules, and loss of gap junctions accompanied by changes in capillary walls. Among all treatments, the severity of all these findings was more severe in T1DM and most profound in the atria of T1DM + CO-HFD. In conclusion, chronic consumption of CO-HFD by T1DM-induced rats elicits significant biochemical and ultrastructural damage to rat atrial cells accompanied by elevated oxidative stress and mitochondria-mediated cell death.

Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients.

BACKGROUND: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes. METHODS AND RESULTS: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating. CONCLUSIONS: These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.

Lower extremity arterial disease in patients with diabetes: a contemporary narrative review.

Lower-extremity arterial disease (LEAD) is a major endemic disease with an alarming increased prevalence worldwide. It is a common and severe condition with excess risk of major cardiovascular events and death. It also leads to a high rate of lower-limb adverse events and non-traumatic amputation. The American Diabetes Association recommends a widespread medical history and clinical examination to screen for LEAD. The ankle brachial index (ABI) is the first non-invasive tool recommended to diagnose LEAD although its variable performance in patients with diabetes. The performance of ABI is particularly affected by the presence of peripheral neuropathy, medial arterial calcification, and incompressible arteries. There is no strong evidence today to support an alternative test for LEAD diagnosis in these conditions. The management of LEAD requires a strict control of cardiovascular risk factors including diabetes, hypertension, and dyslipidaemia. The benefit of intensive versus standard glucose control on the risk of LEAD has not been clearly established. Antihypertensive, lipid-lowering, and antiplatelet agents are obviously worthfull to reduce major cardiovascular adverse events, but few randomised controlled trials (RCTs) have evaluated the benefits of these treatments in terms of LEAD and its related adverse events. Smoking cessation, physical activity, supervised walking rehabilitation and healthy diet are also crucial in LEAD management. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in LEAD management. The revascularization strategy should take into account several factors including anatomical localizations of lesions, medical history of each patients and operator experience. Further studies, especially RCTs, are needed to evaluate the interest of different therapeutic strategies on the occurrence and progression of LEAD and its related adverse events in patients with diabetes.

l-Citrulline Supplementation: Impact on Cardiometabolic Health.

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.

Differences in laser-Doppler indices between skin-surface measurement sites in subjects with diabetes.

This study performed laser-Doppler flowmetry (LDF) measurements with the aim of identifying differences in diabetes-induced microcirculatory-blood-flow (MBF) responses between the following skin surface measurement sites: an acupoint around the wrist, an acupoint around the ankle, and a nearby nonacupoint around the ankle. The 67 study subjects were assigned to diabetic, prediabetic, and healthy groups according to the results of oral glucose tolerance tests. Beat-to-beat and spectral analyses were applied to the LDF waveform to obtain the foot delay time (FDT), the flow rise time (FRT), and the relative energy contributions (RECs) in five frequency bands. FRT and FDT were significantly shorter and the RECs of the endothelial-, neural-, and myogenic-related frequency bands were significantly smaller in the diabetic group than in the control group at the acupoint around the ankle, but there were no such prominent differences at the other sites. The acupoint around the ankle was better than the nearby nonacupoint and the acupoint around the wrist for distinguishing the age-matched diabetic, prediabetic, and healthy subjects. These findings imply that when monitoring diabetes-induced MBF responses, the measurement locations should be chosen carefully in order to minimize interference effects and to improve the ability to distinguish subjects with different conditions.

[Cerebral microangiopathy of diabetes].

Diabetes mellitus, a kind of chronic metabolic disease, has become one of major threats to human health with an increasing incidence. As a basic pathology of chronic complications related to diabetes mellitus, cerebral microangiopathy is mainly found in patients with Alzheimer's disease and lacunar infarction, and becomes one of the main reasons of death and disability in diabetic patients. The pathogenesis of cerebral microangiopathy is complicated, involving such signal pathways as metabolic abnormalities of polyol, saccharification hyperactivity, oxidative stress, abnormal transport of amyloid-ß across blood-brain barrier and protein kinase C activation. Treatment targeting at related pathogenesis may bring a new hope to prevention and delay of the occurrence and development of cerebral microangiopathy of diabetes mellitus. Currently, pathogenesis, diagnosis and therapies for cerebral microangiopathy of diabetes mellitus have become hot topics in medical studies. This article reviews pathogenesis, clinical diagnosis and treatment for cerebral microangiopathy of diabetes mellitus, in order to provide new ideas for the prevention and treatment of cerebral microangiopathy of diabetes mellitus.

High and low vitamin D level is associated with cardiovascular autonomic neuropathy in people with Type 1 and Type 2 diabetes.

AIM: To investigate the possible association between vitamin D deficiency and cardiovascular autonomic neuropathy in people with diabetes. METHODS: A total of 113 people with Type 1 or Type 2 diabetes [mean (interquartile range) diabetes duration 22.0 (12-31) years, mean (sd) age 56.2 (13.0) years, 58% men] underwent vitamin D (D2 and D3) assessment, and were screened for cardiovascular autonomic neuropathy using three cardiovascular reflex tests [heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva manoeuvre] and assessment of 5-min resting heart rate and heart rate variability indices. RESULTS: We found an inverse U-shaped association between serum vitamin D level and E/I ratio, 30/15 ratio and three heart rate variability indices (P < 0.05). Vitamin D level was non-linearly associated with cardiovascular autonomic neuropathy diagnosis (P < 0.05 adjusted for age and sex). Linear regression models showed that an increase in vitamin D level from 25 to 50 nmol/l was associated with an increase of 3.9% (95% CI 0.1;7.9) in E/I ratio and 4.8% (95% CI 4.7;9.3) in 30/15 ratio. Conversely, an increase from 125 to 150 nmol/l in vitamin D level was associated with a decrease of 2.6% (95% CI -5.8;0.1) and 4.1% (95% CI -5.8;-0.5) in the respective outcome measures. CONCLUSIONS: High and low vitamin D levels were associated with cardiovascular autonomic neuropathy in people with diabetes. Future studies should explore this association and the efficacy of treating dysvitaminosis D to prevent cardiovascular autonomic neuropathy.

Low molecular weight fucoidan ameliorates streptozotocin-induced hyper-responsiveness of aortic smooth muscles in type 1 diabetes rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Low molecular weight fucoidan (LMWF) was prepared from Laminaria japonica Areschoug, a popular seafood and medicinal plant consumed in Asia. Chinese have long been using it as a traditional medicine for curing hypertension and edema. AIM OF THE STUDY: This study was intent to investigate the possible beneficial effect of LMWF on hyper-responsiveness of aortic smooth muscles instreptozotocin (STZ)-induced type 1 diabetic rats. MATERIALS AND METHODS: Sprague-Dawley rats were made diabetic by injection of STZ, followed by the administration of LMWF (50 or 100mg/kg/day) or probucol (100mg/kg/day) for 12 weeks. Body weight, blood glucose level, basal blood pressure, serum lipid profiles, oxidative stress, prostanoids production, and vasoconstriction response of endothelium-denuded aorta rings to phenylephrine were measured by Real time-PCR, Western blots, ELISA assay, and force myograph, respectively. RESULTS: LMWF (100mg/kg/day)-treated group showed robust improvements on STZ-induced body weight-loss, hypertension, and hyperlipidaemia as indicated by decreased serum level of total cholesterol, triglyceride, and low density lipoprotein cholesterol; while probucol, a lipid-modifying drug with antioxidant properties, displayed mild effects. In addition, LMWF appreciably ameliorated STZ-elicited hyper-responsiveness and oxidative stress in aortic smooth muscles as indicated by decreased superoxide level, increased glutathione content and higher superoxide dismutase activity. Furthermore, administration with LMWF dramatically prevented cyclooxygenase-2 stimulation and restored the up-regulation of thromboxane synthase and down-regulation of 6-keto-PGF1α (a stable metabolic product of prostaglandin I2) in the STZ-administered rats. CONCLUSION: This study demonstrates for the first time that LMWF can protect against hyperlipidaemia, hypertension, and hyper-responsiveness of aortic smooth muscles in type 1 diabetic rat via, at least in part, amelioration of oxidative stress and restoration of prostanoids levels in aortic smooth muscles. Therefore, LMWF can be a potential adjuvant treatment against cardiovascular complications in type 1 diabetes.

Effect of Vitamins C and E on Endothelial Function in Type 1 Diabetes Mellitus.

BACKGROUND/OBJECTIVES: Endothelial dysfunction due to hyperglycemia-induced oxidative damage is an important predictor of future cardiovascular risk in patients with type 1 diabetes mellitus (T1DM) and is present in adolescent T1DM. We hypothesized that combined treatment with the antioxidant vitamins C and E might improve endothelial function (EF) and other biochemical risk factors in adolescents with T1DM. SUBJECTS/METHODS: Open-label antioxidant supplementation was given for six weeks with endpoint measurements collected at baseline and study completion. Endpoints measured included EF and plasma measurements of biochemical endothelial risk. RESULTS: Two males and 7 females were studied. Mean age was 12.9 ± 0.9 yrs; mean T1DM duration was 5.5 ± 2.5 yrs; mean BMI was 22.1 ± 3.8 kg/m(2); and mean hemoglobin A1c was 9.3 ± 1.1%. No differences were found for EF, high sensitivity CRP, total antioxidant capacity, adiponectin, or endothelial progenitor cells (EPCs) between before and after combined vitamin C and E therapy. CONCLUSIONS: Our negative study results do not support previous findings of decreased oxidative damage, improved endothelial function, and increased vascular repair capacity with antioxidant therapy. Longer term studies may be needed to determine the effects, if any, of combined antioxidant therapy on EPCs, EF, and markers of micro- and macrovascular complications in T1DM.

A randomised controlled trial evaluating the impact of targeted vitamin D supplementation on endothelial function in type 2 diabetes mellitus: The DIMENSION trial.

We sought to determine if vitamin D supplementation, to target 25(OH)D concentrations of 30-40 ng/mL, improves endothelial function in Singapore's multi-ethnic type 2 diabetes mellitus population. We randomised 64 type 2 diabetes mellitus patients with hypovitaminosis D to cholecalciferol 4000 International Unit/matching placebo [baseline 25(OH)D < 20 ng/mL] or cholecalciferol 2000 International Unit/matching placebo [baseline 25(OH)D: 20-30 ng/mL] daily for 16 weeks with a down titration at 8 weeks if 25(OH)D > 30 ng/mL. Endothelial function was assessed by peripheral tonometry (reactive hyperaemia index-endothelial peripheral arterial tonometry) and vascular biomarkers: E-selectin, von-Willebrand factor and high-sensitivity C-reactive protein. We compared the change from baseline parameters in the two groups using Student's t-test or Kruskal-Wallis test. A log-normal multivariate regression analysis was used to adjust for relevant baseline variables. The median reactive hyperaemia index in the vitamin D group increased from 0.65 (interquartile range: 0.42) to 0.73 (interquartile range: 0.36), whereas it decreased from 0.73 (interquartile range: 0.65) to 0.65 (interquartile range: 0.38) (p = 0.02) in the placebo group. After adjustment for baseline variables, the change was not statistically significant for reactive hyperaemia index (p = 0.07) and for other vascular biomarkers (p > 0.05). Targeted vitamin D supplementation for 16 weeks resulted in a small but non-significant improvement in endothelial function in a type 2 diabetes mellitus cohort.

Prevention and management of foot problems in diabetes: a Summary Guidance for Daily Practice 2015, based on the IWGDF Guidance Documents.

In this 'Summary Guidance for Daily Practice', we describe the basic principles of prevention and management of foot problems in persons with diabetes. This summary is based on the International Working Group on the Diabetic Foot (IWGDF) Guidance 2015. There are five key elements that underpin prevention of foot problems: (1) identification of the at-risk foot; (2) regular inspection and examination of the at-risk foot; (3) education of patient, family and healthcare providers; (4) routine wearing of appropriate footwear; and (5) treatment of pre-ulcerative signs. Healthcare providers should follow a standardized and consistent strategy for evaluating a foot wound, as this will guide further evaluation and therapy. The following items must be addressed: type, cause, site and depth, and signs of infection. There are seven key elements that underpin ulcer treatment: (1) relief of pressure and protection of the ulcer; (2) restoration of skin perfusion; (3) treatment of infection; (4) metabolic control and treatment of co-morbidity; (5) local wound care; (6) education for patient and relatives; and (7) prevention of recurrence. Finally, successful efforts to prevent and manage foot problems in diabetes depend upon a well-organized team, using a holistic approach in which the ulcer is seen as a sign of multi-organ disease, and integrating the various disciplines involved.

Microvascular oxygen partial pressure during hyperbaric oxygen in diabetic rat skeletal muscle.

Hyperbaric oxygen (HBO) is a major therapeutic treatment for ischemic ulcerations that perforate skin and underlying muscle in diabetic patients. These lesions do not heal effectively, in part, because of the hypoxic microvascular O2 partial pressures (PmvO2 ) resulting from diabetes-induced cardiovascular dysfunction, which alters the dynamic balance between O2 delivery (Q̇o2) and utilization (V̇o2) rates. We tested the hypothesis that HBO in diabetic muscle would exacerbate the hyperoxic PmvO2 dynamics due, in part, to a reduction or slowing of the cardiovascular, sympathetic nervous, and respiratory system responses to acute HBO exposure. Adult male Wistar rats were divided randomly into diabetic (DIA: streptozotocin ip) and healthy (control) groups. A small animal hyperbaric chamber was pressurized with oxygen (100% O2) to 3.0 atmospheres absolute (ATA) at 0.2 ATA/min. Phosphorescence quenching techniques were used to measure PmvO2 in tibialis anterior muscle of anesthetized rats during HBO. Lumbar sympathetic nerve activity (LSNA), heart rate (HR), and respiratory rate (RR) were measured electrophysiologically. During the normobaric hyperoxia and HBO, DIA tibialis anterior PmvO2 increased faster (mean response time, CONT 78 ± 8, DIA 55 ± 8 s, P < 0.05) than CONT. Subsequently, PmvO2 remained elevated at similar levels in CONT and DIA muscles until normobaric normoxic recovery where the DIA PmvO2 retained its hyperoxic level longer than CONT. Sympathetic nervous system and cardiac and respiratory responses to HBO were slower in DIA vs. CONT. Specifically the mean response times for RR (CONT: 6 ± 1 s, DIA: 29 ± 4 s, P < 0.05), HR (CONT: 16 ± 1 s, DIA: 45 ± 5 s, P < 0.05), and LSNA (CONT: 140 ± 16 s, DIA: 247 ± 34 s, P < 0.05) were greater following HBO onset in DIA than CONT. HBO treatment increases tibialis anterior muscle PmvO2 more rapidly and for a longer duration in DIA than CONT, but not to a greater level. Whereas respiratory, cardiovascular, and LSNA responses to HBO are profoundly slowed in DIA, only the cardiovascular arm (via HR) may contribute to the muscle vascular incompetence and these faster PmvO2 kinetics.

Alpha-Lipoic Acid and Antioxidant Diet Help to Improve Endothelial Dysfunction in Adolescents with Type 1 Diabetes: A Pilot Trial.

After evaluating the prevalence of early endothelial dysfunction, as measured by means of reactive hyperemia in adolescents with type 1 diabetes, we started a 6-month, double-blind, randomized trial to test the efficacy of an antioxidant diet (± alpha-lipoic acid supplementation) to improve endothelial dysfunction. Seventy-one children and adolescents, ages 17 ± 3.9 yrs, with type 1 diabetes since 9.5 ± 5.3 yrs, using intensified insulin therapy, were randomized into 3 arms: (a) antioxidant diet 10.000 ORAC + alpha-lipoic acid; (b) antioxidant diet 10.000 ORAC + placebo; (c) controls. BMI, blood pressure, fasting lipid profile, HbA1c, insulin requirement, dietary habits, and body composition were determined in each patient. An antioxidant diet significantly improved endothelial dysfunction when supplemented with alpha-lipoic acid, unlike diet with placebo or controls. A significant reduction in bolus insulin was also observed. We speculate that alpha-lipoic acid might have an antioxidant effect in pediatric diabetes patients by reducing insulin.