Kidney and vascular function in adult patients with hereditary fructose intolerance

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.</p

Retinal microvascular biomarker extraction on fundus images from the Maastricht study using supervised deep learning

Retinal fundus imaging enables detailed visualization of the microvascular structure in the retina of the human eye. Geometrical features, related to vessel caliber, tortuosity and bifurcations, have been identified as potential biomarkers for a variety of A.J, including (pre)diabetes and hypertension. A pipeline of automated unsupervised image analysis methods for extraction of such features from retinal fundus images has previously been developed and evaluated [1]. However, the current computationally expensive pipeline takes 24 minutes to process a single image, which impedes implementation in a screening setting. In the present work, we approximate the pipeline using a deep neural network that enables processing of a single image in a few seconds. We use a model that contains approximately 23 million trainable parameters and we train it with color fundus images from the Maastricht Study, a population-based cohort study with extensive phenotyping, that focuses on the etiology, complications and comorbidities of Type 2 Diabetes Mellitus. The set comprises 10668 images from 2872 subjects taken from both left and right eyes and are centered either on the fovea or on the optic disc. We design the model to simultaneously output four global biomarkers that represent key vessel geometries: Central Retinal Arteriolar Equivalent (CRAE), Central Retinal Venular Equivalent (CRVE), global tortuosity and asymmetry ratio of the bifurcations. The outputs from the original pipeline are used as training labels. Eighty percent of the data is used for training, while the remainder is used to evaluate the performance of the model. We obtain a substantial speed-up, requiring only 5 seconds to process an image. Intraclass correlation coefficient between the predictions of the model and the results of the pipeline showed strong correlation (0.86 - 0.91) for three of four biomarkers and moderate correlation (0.42) for one biomarker. To visualize what regions in the fundus images contribute to the model predictions, we create class activation maps. The maps show clearly that the local activations overlap with the vascular tree. It is able to differentiate between arterioles and venules around the optic disc when predicting CRAE and CRVE. Moreover, local high and low tortuous regions are clearly identified, verifying that the model is sensitive to key structures in the retina

Retinal microvascular biomarker extraction on fundus images from the Maastricht study using supervised deep learning

Retinal fundus imaging enables detailed visualization of the microvascular structure in the retina of the human eye. Geometrical features, related to vessel caliber, tortuosity and bifurcations, have been identified as potential biomarkers for a variety of A.J, including (pre)diabetes and hypertension. A pipeline of automated unsupervised image analysis methods for extraction of such features from retinal fundus images has previously been developed and evaluated [1]. However, the current computationally expensive pipeline takes 24 minutes to process a single image, which impedes implementation in a screening setting. In the present work, we approximate the pipeline using a deep neural network that enables processing of a single image in a few seconds. We use a model that contains approximately 23 million trainable parameters and we train it with color fundus images from the Maastricht Study, a population-based cohort study with extensive phenotyping, that focuses on the etiology, complications and comorbidities of Type 2 Diabetes Mellitus. The set comprises 10668 images from 2872 subjects taken from both left and right eyes and are centered either on the fovea or on the optic disc.We design the model to simultaneously output four global biomarkers that represent key vessel geometries: Central Retinal Arteriolar Equivalent (CRAE), Central Retinal Venular Equivalent (CRVE), global tortuosity and asymmetry ratio of the bifurcations. The outputs from the original pipeline are used as training labels. Eighty percent of the data is used for training, while the remainder is used to evaluate the performance of the model.We obtain a substantial speed-up, requiring only 5 seconds to process an image. Intraclass correlation coefficient between the predictions of the model and the results of the pipeline showed strong correlation (0.86 - 0.91) for three of four biomarkers and moderate correlation (0.42) for one biomarker. To visualize what regions in the fundus images contribute to the model predictions, we create class activation maps. The maps show clearly that the local activations overlap with the vascular tree. It is able to differentiate between arterioles and venules around the optic disc when predicting CRAE and CRVE. Moreover, local high and low tortuous regions are clearly identified, verifying that the model is sensitive to key structures in the retina

Microvascular dysfunction in obesity: A potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension

Obesity is an important risk factor for insulin resistance and hypertension and plays a central role in the metabolic syndrome. Insight into the pathophysiology of this syndrome may lead to new treatments. This paper has reviewed the evidence for an important role for the microcirculation as a possible link between obesity, insulin resistance and hypertension

Habitual intake of advanced glycation endproducts is not associated with worse insulin sensitivity, worse beta cell function, or presence of prediabetes or type 2 diabetes:The Maastricht Study

Background &amp; aims: A diet high in advanced glycation endproducts (AGEs) is a potential risk factor for insulin resistance, beta cell dysfunction, and ultimately type 2 diabetes. We investigated associations between habitual intake of dietary AGEs and glucose metabolism in a population-based setting. Methods: In 6275 participants of The Maastricht Study (mean ± SD age: 60 ± 9, 15.1% prediabetes and 23.2% type 2 diabetes), we estimated habitual intake of dietary AGEs Ne-(carboxymethyl)lysine (CML), Ne-(1-carboxyethyl)lysine (CEL), and Nd-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) by combining a validated food frequency questionnaire (FFQ) with our mass-spectrometry dietary AGE database. We determined insulin sensitivity (Matsuda- and HOMA-IR index), beta cell function (C-peptidogenic index, glucose sensitivity, potentiation factor, and rate sensitivity), glucose metabolism status, fasting glucose, HbA1c, post-OGTT glucose, and OGTT glucose incremental area under the curve. Cross–sectional associations between habitual AGE intake and these outcomes were investigated using a combination of multiple linear regression and multinomial logistic regression adjusting for several potential confounders (demographic, cardiovascular, and lifestyle factors). Results: Generally, higher habitual intake of AGEs was not associated with worse indices of glucose metabolism, nor with increased presence of prediabetes or type 2 diabetes. Higher dietary MG-H1 was associated with better beta cell glucose sensitivity. Conclusions: The present study does not support an association of dietary AGEs with impaired glucose metabolism. Whether higher intake of dietary AGEs translates to increased incidence of prediabetes or type 2 diabetes on the long term should be investigated in large prospective cohort studies

Serum phosphate and microvascular function in a population-based cohort

Background and objectives Higher serum phosphate is associated with cardiovascular events and all-cause mortality. Explanations of this association have focused on large vessel calcification and stiffness. Studies suggest that a higher serum phosphate induces microvascular dysfunction, but relationships in humans with direct measures of microvascular function are lacking. Design, setting, participants, & measurements We performed a cross-sectional analysis of 3189 community-living participants that underwent skin capillaroscopy, laser-Doppler flowmetry, and flicker light–induced retinal vessel responses. We used linear regression to assess the association between serum phosphate and each microvascular outcome. The primary outcome was skin capillary recruitment during postocclusive peak reactive hyperemia by capillaroscopy. Secondary outcomes included capillary recruitment during venous congestion, heat-induced skin hyperemic response, flicker light–induced retinal arteriolar, and venular dilation. Results The mean age of the cohort was 5968 years, 48% were women, 7% had an eGFR,60 ml/min per 1.73 m 2, and the mean serum phosphate concentration was 3.260.5 mg/dl. A 1 mg/dl higher serum phosphate was independently associated with a 5.0% lower postocclusive capillary recruitment (95% CI, 210.0% to 20.1%). Results were similar for capillary recruitment with venous congestion (24.5%; 95% CI, 29.8% to 0.7%). A 1 mg/dl higher serum phosphate was also independently associated with a 0.23% lower retinal venular dilation in response to flicker light (95% CI, 20.44% to 20.02%). A higher serum phosphate was not associated with change in flicker light–induced retinal arteriolar dilation or heat-induced skin hyperemic response, however a higher serum phosphate was associated with a lower heat-induced skin hyperemic response among men (2149% [95% CI, 2260 to 238] per 1 mg/dl higher serum phosphate) but not women (P interaction, 0.01). Conclusions Higher serum phosphate concentrations, even within the normal range, are associated with microvascular dysfunction in community-living individuals

Diet-induced weight loss reduces postprandial dicarbonyl stress in abdominally obese men : Secondary analysis of a randomized controlled trial

Aims: Dicarbonyl compounds contribute to the formation of advanced glycation endproducts (AGEs) and the development of insulin resistance and vascular complications. Dicarbonyl stress may already be detrimental in obesity. We evaluated whether diet-induced weight loss can effectively reverse dicarbonyl stress in abdominally obese men. Materials and methods: Plasma samples were collected from lean (n = 25) and abdominally obese men (n = 52) in the fasting state, and during a mixed meal test (MMT). Abdominally obese men were randomized to 8 weeks of dietary weight loss or habitual diet, followed by a second MMT. The α-dicarbonyls methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG) and AGEs were measured by UPLC-MS/MS. Skin autofluorescence (SAF) was measured using the AGE reader. T-tests were used for the cross-sectional analysis and ANCOVA to assess the treatment effect. Results: Postprandial glucose, MGO and 3-DG concentrations were higher in obese men as compared to lean men (p < 0.05 for all). Fasting dicarbonyls, AGEs, and SAF were not different between lean and obese men. After the weight loss intervention, fasting MGO levels tended to decrease by 25 nmol/L (95%-CI: -51-0.5; p = 0.054). Postprandial dicarbonyls were decreased after weight loss as compared to the control group: iAUC of MGO decreased by 57% (5280 nmol/L∙min; 95%-CI: 33–10526; p = 0.049), of GO by 66% (11,329 nmol/L∙min; 95%-CI: 495–22162; p = 0.041), and of 3-DG by 45% (20,175 nmol/L∙min; 95%-CI: 5351–35000; p = 0.009). AGEs and SAF did not change significantly after weight loss. Conclusion: Abdominal obesity is characterized by increased postprandial dicarbonyl stress, which can be reduced by a weight loss intervention. Registered under ClinicalTrials.gov Identifier no. NCT01675401.</p