The use of dietary supplements, and the association between supplemental vitamin D and glycaemic control in adult individuals with type 1 diabetes.

AIMS: To assess the dietary supplement use in adult individuals with type 1 diabetes, and to study the association between vitamin D supplementation and glycaemic control in an observational cross-sectional study. METHODS: The study subjects were participants of the Finnish Diabetic Nephropathy Study. Data were included from all individuals with type 1 diabetes with estimated glomerular filtration rate ≥60 mL/min/1.73 m2, who had completed a diet questionnaire. In the questionnaire, the participants reported dietary supplement use for the past 30 days. A thorough investigation with an assessment of the blood panel was conducted at the study visit. RESULTS: Data were available from 1181 individuals (43% men, mean ± SD age 45 ± 13 years). Altogether 62% of the sample reported supplement use; 56% reported some vitamin or mineral and 27% reported non-vitamin and non-mineral supplement use. Supplement use was more frequent among women and those supplementing had better overall health. In the study sample, of the vitamins and minerals, vitamin D (45%) and magnesium (31%), respectively, were the most frequently reported. In the multivariable models, vitamin D supplementation was associated with better glycaemic control. Starting from a daily dose of ≥30 µg, there was evidence of improving glycaemic control with higher doses of supplemental vitamin D (e.g., for 30 µg: B [Wald Confidence Internal], p-value, -2.76 [-5.03 to -0.49], 0.017). CONCLUSIONS: Supplement use was frequent in this sample of adult individuals with type 1 diabetes. Due to potential drug-supplement interactions, the attending physicians should be aware of their patients' supplement use. The causality between vitamin D supplementation and glycaemic control should be assessed in a randomized controlled trial.

Antibiotic treatment and supplemental hemin availability affect the volatile organic compounds produced by P. gingivalis in vitro.

We have measured the changes in the production of volatile organic compounds (VOCs) by the oral pathogen Porphyromonas gingivalis, when treated in vitro with the antibiotic amoxicillin. We have also measured the VOC production of P. gingivalis grown in the presence and absence of supplemental hemin. Planktonic bacterial cultures were treated with different amounts of amoxicillin in the lag phase of the bacterial growth. Planktonic bacteria were also cultured with and without supplemental hemin in the culture medium. Concentrations of VOCs were measured with proton-transfer-reaction time-of-flight mass spectrometry (PTR-ToF-MS) and further molecular identification was done with gas chromatography-mass spectrometry (GC-MS) using solid phase microextraction (SPME) for sampling. The cell growth of P. gingivalis in the cultures was estimated with optical density measurements at the wavelength of 600 nm (OD600). We found that the production of methanethiol, hydrogen sulfide and several short- to medium-chain fatty acids was decreased with antibiotic treatment using amoxicillin. Compounds found to increase with the antibiotic treatment were butyric acid and indole. In cultures without supplemental hemin, indole and short- to medium-chain fatty acid production was significantly reduced. Acetic acid production was found to increase when supplemental hemin was not available. Our results suggest that the metabolic effects of both antibiotic treatment and supplemental hemin availability are reflected in the VOCs produced by P. gingivalis and could be used as markers for bacterial cell growth and response to threat. Analysis of these volatiles from human samples, such as the exhaled breath, could be used in the future to rapidly monitor response to antibacterial treatment.

Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo.

AIMS/HYPOTHESIS: Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. METHODS: Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. RESULTS: In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p < 0.001), TNFα (48%, p < 0.01), IL-1ß (51%, p < 0.001) and TGFß (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-κB-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNFα (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1ß, IL-18, IL-6 and IL-10. CONCLUSIONS/INTERPRETATION: AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.

The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study.

OBJECTIVE: To explore the effects of baroreflex activation therapy (BAT) on hypertension in patients with treatment resistant or refractory hypertension. METHODS: This investigator-initiated randomized, double-blind, 1:1 parallel-design clinical trial will include 100 patients with refractory hypertension from 6 tertiary referral hypertension centers in the Nordic countries. A Barostim Neo System will be implanted and after 1 month patients will be randomized to either BAT for 16 months or continuous pharmacotherapy (BAT off) for 8 months followed by BAT for 8 months. A second randomization will take place after 16 months to BAT or BAT off for 3 months. Eligible patients have a daytime systolic ambulatory blood pressure (ABPM) of ≥145 mm Hg, and/or a daytime diastolic ABPM of ≥95 mm Hg after witnessed drug intake (including ≥3 antihypertensive drugs, preferably including a diuretic). RESULTS: The primary end point is the reduction in 24-hour systolic ABPM by BAT at 8 months, as compared to pharmacotherapy. Secondary and tertiary endpoints are effects of BAT on home and office blood pressures, measures of indices of cardiac and vascular structure and function during follow-up, and safety. CONCLUSIONS: This academic initiative will increase the understanding of mechanisms and role of BAT in the refractory hypertension.

Baroreflex activation therapy in the treatment of resistant hypertension.

Baroreceptors are sensory nerve endings in the carotid sinuses and the aortic arch. Notably, a dysfunction in the autonomic nervous system (sympathetic hyperactivity) has been shown to be part of the pathophysiology of chronic hypertension. Baroreflex activation therapy is an invasive treatment modality to decrease blood pressure by stimulating baroreceptors in the wall of the carotid sinus. Preliminary results of baroreflex activation therapy in resistant hypertension and systolic heart failure have been promising. If its effect can be proven in controlled studies, it may serve as an important new tool in the treatment of patients with resistant hypertension at a high risk of cardiovascular complications.

Trained breathing-induced oxygenation acutely reverses cardiovascular autonomic dysfunction in patients with type 2 diabetes and renal disease.

AIMS: Cardiovascular autonomic dysfunction, evaluated as baroreflex sensitivity (BRS), could be acutely corrected by slow breathing or oxygen administration in patients with type 1 diabetes, thus suggesting a functional component of the disorder. We tested this hypothesis in patients with the type 2 diabetes with or without renal impairment. METHODS: Twenty-six patients with type 2 diabetes (aged 61.0 ± 0.8 years, mean ± SEM; duration of diabetes 10.5 ± 2 years, BMI 29.9 ± 0.7 kg/m(2), GFR 68.1 ± 5.6 ml/min) and 24 healthy controls (aged 58.5 ± 1.0 years) were studied. BRS was obtained from recordings of RR interval and systolic blood pressure fluctuations during spontaneous and during slow, deep (6 breaths/min) controlled breathing in conditions of normoxia or hyperoxia (5 l/min oxygen). RESULTS: During spontaneous breathing, diabetic patients had lower RR interval and lower BRS compared with the control subjects (7.1 ± 1.2 vs. 12.6 ± 2.0 ms/mmHg, p < 0.025). Deep breathing and oxygen administration significantly increased arterial saturation, reduced RR interval and increased BRS in both groups (to 9.6 ± 1.8 and 15.4 ± 2.4 ms/mmHg, respectively, p < 0.05, hyperoxia vs. normoxia). Twelve diabetic patients affected by chronic diabetic kidney disease (DKD) presented a significant improvement in the BRS during slow breathing and hyperoxia (p < 0.025 vs. spontaneous breathing during normoxia). CONCLUSIONS: Autonomic dysfunction present in patients with type 2 diabetes can be partially reversed by slow breathing, suggesting a functional role of hypoxia, also in patients with DKD. Interventions known to relieve tissue hypoxia and improve autonomic function, like physical activity, may be useful in the prevention and management of complications in patients with diabetes.

Evidence for abnormal glucose uptake or metabolism in thalamus during acute hyperglycaemia in type 1 diabetes--a 1H MRS study.

Acute hyperglycaemia impairs cognitive function. It is however not known, whether different brain regions are equally exposed to glucose during acute hyperglycemia or whether the brain is able to adjust its glucose uptake or metabolism in response to blood glucose fluctuation. We studied the effect of acute hyperglycaemia on the brain glucose concentration in seven men with type 1 diabetes with daily glucose fluctuations of 11 +/- 3 mmol/l, and in eleven age-matched non-diabetic men. Glucose was quantified with proton magnetic resonance spectroscopy in three different brain regions at baseline (fasting glycaemia) and twice during a 2 h hyperglycaemic clamp with plasma glucose increase of 12 mmol/l. The increase in brain glucose during acute hyperglycaemia in the non-diabetic group was: cortex (2.7 +/- 0.9 mmol/l) > thalamus (2.3 +/- 0.7 mmol/l) > white matter (1.7 +/- 0.7 mmol/l, P = 0.021 vs. cortex) and in the diabetic group: cortex (2.0 +/- 0.7 mmol/l) > white matter (1.3 +/- 0.7 mmol/l) > thalamus (1.1 +/- 0.4 mmol/l, P = 0.010 vs. cortex). In the diabetic group, the glucose increase in the thalamus was attenuated compared to the non-diabetic participants (P = 0.011). In conclusion, the increase of glucose during acute hyperglycaemia seems to be dependent on the brain tissue type. The high exposure of cortex to excess glucose and the altered glucose uptake or metabolism in the thalamus may thus contribute to hyperglycaemia related cognitive dysfunction.

A multi-metabolite analysis of serum by 1H NMR spectroscopy: early systemic signs of Alzheimer's disease.

A three-molecular-window approach for (1)H NMR spectroscopy of serum is presented to obtain specific molecular data on lipoproteins, various low-molecular-weight metabolites, and individual lipid molecules together with their degree of (poly)(un)saturation. The multiple data were analysed with self-organising maps, illustrating the strength of the approach as a holistic metabonomics framework in solely data-driven metabolic phenotyping. We studied 180 serum samples of which 30% were related to mild cognitive impairment (MCI), a neuropsychological diagnosis with severely increased risk for Alzheimer's disease (AD). The results underline the association between MCI and the metabolic syndrome (MetS). Additionally, the low relativeamount of omega-3 fatty acids appears more indicative of MCI than low serum omega-3 or polyunsaturated fatty acid concentration as such. The analyses also feature the role of elevated glycoproteins in the risk for AD, supporting the view that coexistence of inflammation and the MetS forms a high risk condition for cognitive decline.

Risk for metabolic syndrome predisposes to alterations in the thalamic metabolism.

Risk factors for the metabolic syndrome (MetS) affect brain function and associate with asymptomatic brain infarctions in healthy individuals. We studied whether MetS risk factors alter cerebral metabolism. Eighteen non-smoking men (36 +/- 6years) were stratified into two groups according to their risk of developing the MetS. Individuals in the Risk group had a family history of type 2 diabetes, were pre-obese, had mild hypertension and higher fasting plasma glucose and serum insulin compared to the Control group with no risk factors. N-acetyl aspartate, choline, total creatine (tCr), myo-inositol, and glucose were studied in the thalamus, frontal cortex, and frontal white matter with proton magnetic resonance spectroscopy. The plasma glucose was 13% higher (p < 0.01) in the Risk group, but the brain glucose levels were comparable between the groups. In the Control group, the thalamic tCr correlated with the thalamic glucose level (r = 0.81, p = 0.015). In the Risk group, the tCr was 17% higher (p = 0.006) and correlated with the fasting plasma glucose concentration (r = 0.78, p = 0.013), but not with the thalamic glucose level. In conclusion, the increased tCr level in the Risk group suggests that a family history of type 2 diabetes together with MetS risk factors alters thalamic energy metabolism.

Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation.

OBJECTIVE: Equol, a gut bacterial metabolite of isoflavone daidzein, may improve health through changes in vascular function and in estrogen metabolism. Tibolone, a synthetic steroid alternative for the treatment of postmenopausal symptoms, causes a different estrogenic milieu than estrogen and may affect vascular health. We studied the effects of equol production and soy supplementation on vascular function in postmenopausal women under long-term tibolone use. METHODS: We screened 110 women using tibolone for 3-60 months for high equol production capacity with a one-week soy challenge. Twenty women with high equol production capacity (4-fold elevation in equol level) and 20 comparable control women without this capacity were treated in a randomized placebo-controlled cross-over trial with a soy drink (52 g of soy protein containing 112 mg of isoflavones) or placebo for 8 weeks. Arterial stiffness and endothelial function were assessed before and after soy and placebo supplementation with pulse-wave analysis. RESULTS: Prior to soy supplementation arterial stiffness, expressed as augmentation index, was lower (p=0.01) in equol producers (25.9+/-1.1%) than non-equol producers (29.6+/-0.9%). Similarly, endothelial function index was better at baseline (p=0.009) in these women (72.3+/-5.3%) compared to women lacking equol production capacity (55.2+/-3.8%). Soy supplementation had no effect on arterial stiffness or endothelial function in either group. CONCLUSION: In postmenopausal tibolone users, endogenous equol production capability is associated with favorable vascular function. This phenomenon was not affected by soy and thus, equol producing capacity may be an independent vascular health marker, at least in postmenopausal women using tibolone.