A model describing the multiphasic dynamics of mixed meal glucose responses in healthy subjects

Modelling of the glucose metabolism for the purpose of improving the diagnosis and therapy of diabetes mellitus has been the subject of research for decades. Despite this effort, conventional models describing postprandial glucose profiles of healthy subjects fail to include the phenomenon of biphasic glucose responses. Continuous glucose monitoring data recorded from five healthy subjects show that mono- and biphasic glucose responses from regular meals are equally common. We therefore developed a suitable parametric model, capable of producing mono- as well as biphasic meal responses. It is expressed by linear second order differential equation with a dual Gaussian input function. Additionally, a simple method for classifying meal responses into mono- or biphasic profiles was developed. Model inversion was performed using a fully Bayesian method. R2 values of model output compared to CGM data was 91.6 ± 8.3%, indicating the models ability of accurately describing a wide range of mixed meal glucose responses. Parameters were found to be associated with characteristics of individual meals. We suggest that the model could be used to objectively assess postprandial hyperglycemia, one of the main measures for glycemic control

Skin microvascular vasodilatory capacity in offspring of two parents with Type 2 diabetes

Aims<br/> Microvascular dysfunction occurs in Type 2 diabetes and in subjects with fasting hyperglycaemia. It is unclear whether this dysfunction relates to dysglycaemia. This study investigated in normogylcaemic individuals whether a genetic predisposition to diabetes, or indices of insulin resistance including endothelial markers, were associated with impaired microvascular function.<br/> Methods<br/> Maximum microvascular hyperaemia to local heating of the skin was measured using laser Doppler flowmetry in 21 normoglycaemic subjects with no family history of diabetes (Group 1) and 21 normoglycaemic age, sex and body mass index-matched offspring of two parents with Type 2 diabetes (Group 2). <br/>Results<br/> Although Group 2 had normal fasting plasma glucose and glucose tolerance tests, the 120-min glucose values were significantly higher at 6.4 (5.3-6.6) mmol/l (median (25th-75th centile)) than the control group at 4.9 (4.6-5.9) mmol/l (P=0.005) and the insulinogenic index was lower at 97.1 (60.9-130.8) vs. 124.0 (97.2-177.7) (P=0.027). Skin maximum microvascular hyperaemia (Group 1: 1.56 (1.39- 1.80) vs. Group 2: 1.53 (1.30-1.98) V, P=0.99) and minimum microvascular resistance which normalizes the hyperaemia data for blood pressure (Group 1: 52.0 (43.2-67.4) vs. Group 2: 56.0 (43.7-69.6) mmHgN, P=0.70) did not differ in the two groups. Significant positive associations occurred between minimum microvascular resistance and indices of the insulin resistance syndrome; plasminogen activator inhibitor type 1 (R-s=0.46, P=0.003), t-PA (R-s=0.36, P=0.03), total cholesterol (R-s=0.35, P=0.02), and triglyceride concentration (R-s=0.35, P=0.02), and an inverse association with insulin sensitivity (R-s=-0.33, P=0.03).<br/> Conclusions<br/> In normoglycaemic adults cutaneous microvascular vasodilatory capacity is associated with features of insulin resistance syndrome, particularly with plasminogen activator inhibitor type 1. A strong family history of Type 2 diabetes alone does not result in impairment in the maximum hyperaemic response

Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth

OBJECTIVE: Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS: We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS: Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype

Adolescent-parent interactions and communication preferences regarding body weight and weight management: a qualitative study

<p>Abstract</p> <p>Background</p> <p>This study aimed to canvass the nature of adolescent-parent interactions about weight, particularly overweight, and to explore ideas of how to foster supportive discussions regarding weight, both in the home and with family doctors.</p> <p>Methods</p> <p>A market research company was contracted to recruit and conduct a series of separate focus groups with adolescents and unrelated parents of adolescents from low-middle socio-economic areas in Sydney and a regional centre, Australia. Group discussions were audio recorded, transcribed, and then a qualitative content analysis of the data was performed.</p> <p>Results</p> <p>Nine focus groups were conducted; two were held with girls (n = 13), three with boys (n = 18), and four with parents (20 mothers, 12 fathers). Adolescent and parent descriptions of weight-related interactions could be classified into three distinct approaches: indirect/cautious (i.e. focus on eating or physical activity behaviors without discussing weight specifically); direct/open (i.e. body weight was discussed); and never/rarely discussing the subject. Indirect approaches were described most frequently by both adolescents and parents and were generally preferred over direct approaches. Parents and adolescents were circumspect but generally supportive of the potential role for family doctors to monitor and discuss adolescent weight status.</p> <p>Conclusions</p> <p>These findings have implications for developing acceptable messages for adolescent and family overweight prevention and treatment interventions.</p

Analysis of radiation-induced cell death in head and neck squamous cell carcinoma and rat liver maintained in microfluidic devices

Objective The aim of this study was to investigate how head and neck squamous cell carcinoma (HNSCC) tissue biopsies maintained in a pseudo in vivo environment within a bespoke microfluidic device respond to radiation treatment. Study Design Feasibility study. Setting Tertiary referral center. Subjects and Methods Thirty-five patients with HNSCC were recruited, and liver tissue from 5 Wistar rats was obtained. A microfluidic device was used to maintain the tissue biopsy samples in a viable state. Rat liver was used to optimize the methodology. HNSCC was obtained from patients with T1-T3 laryngeal or oropharyngeal SCC; N1-N2 metastatic cervical lymph nodes were also obtained. Irradiation consisted of single doses of between 2 Gy and 40 Gy and a fractionated course of 5×2 Gy. Cell death was assessed in the tissue effluent using the soluble markers lactate dehydrogenase (LDH) and cytochrome c and in the tissue by immunohistochemical detection of cleaved cytokeratin18 (M30 antibody). Results A significant surge in LDH release was demonstrated in the rat liver after a single dose of 20 Gy; in HNSCC, it was seen after 40 Gy compared with the control. There was no significant difference in cytochrome c release after 5 Gy or 10 Gy. M30 demonstrated a dose-dependent increase in apoptotic index for a given increase in single-dose radiotherapy. There was a significant increase in apoptotic index between 1×2 Gy and 5×2 Gy. Conclusion M30 is a superior method compared with soluble markers in detecting low-dose radiation-induced cell death. This microfluidic technique can be used to assess radiation-induced cell death in HNSCC and therefore has the potential to be used to predict radiation response

Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Heterozygous glucokinase (GCK) mutations cause mild, fasting hyperglycaemia from birth. Although patients are usually asymptomatic and have glycaemia within target ranges, some are put on pharmacological treatment. We aimed to investigate how many patients are on pharmacological treatment and the impact of treatment on glycaemic control.European Community’s Seventh Framework ProgrammeNIHR Exeter Clinical Research FacilityWellcome Trus

Associations between low HDL, sex and cardiovascular risk markers are substantially different in sub-Saharan Africa and the UK: analysis of four population studies

Introduction: Low high-density lipoprotein (HDL) is widely used as a marker of cardiovascular disease risk, although this relationship is not causal and is likely mediated through associations with other risk factors. Low HDL is extremely common in sub-Saharan African populations, and this has often been interpreted to indicate that these populations will have increased cardiovascular risk. We aimed to determine whether the association between HDL and other cardiovascular risk factors differed between populations in sub-Saharan Africa and the UK. // Methods: We compared data from adults living in Uganda and Malawi (n=26 216) and in the UK (n=8747). We examined unadjusted and adjusted levels of HDL and applied the WHO recommended cut-offs for prevalence estimates. We used spline and linear regression to assess the relationship between HDL and other cardiovascular risk factors. // Results: HDL was substantially lower in the African than in the European studies (geometric mean 0.9–1.2 mmol/L vs 1.3–1.8 mmol/L), with African prevalence of low HDL as high as 77%. Total cholesterol was also substantially lower (geometric mean 3.3–3.9 mmol/L vs 4.6–5.4 mmol/L). In comparison with European studies the relationship between HDL and adiposity (body mass index, waist to hip ratio) was greatly attenuated in African studies and the relationship with non-HDL cholesterol reversed: in African studies low HDL was associated with lower non-HDL cholesterol. The association between sex and HDL was also different; using the WHO sex-specific definitions, low HDL was substantially more common among women (69%–77%) than men (41%–59%) in Uganda/Malawi. // Conclusion: The relationship between HDL and sex, adiposity and non-HDL cholesterol in sub-Saharan Africa is different from European populations. In sub-Saharan Africans low HDL is a marker of low overall cholesterol and sex differences are markedly attenuated. Therefore low HDL in isolation is unlikely to indicate raised cardiovascular risk and the WHO sex-based cut-offs are inappropriate

The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes

Aims/hypothesis Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual’s probability of having MODY, as a crucial tool for rational genetic testing. Methods We developed prediction models using logistic regression on data from 1,191 patients with MODY (n0594), type 1 diabetes (n0278) and type 2 diabetes (n0319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. Results The models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA1c, parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA1c, parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic0 0.95 and 0.98, respectively), low rates of cross-validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic00.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis <25 years and an affected parent. The models are now available online at www.diabetesgenes.org. Conclusions/interpretation We have developed clinical prediction models that calculate an individual’s probability of having MODY. This allows an improved and more rational approac

Investigation of paediatric PKU breath malodour, comparing glycomacropeptide with phenylalanine free L-amino acid supplements

In clinical practice, caregivers of children with phenylketonuria (PKU) report that their children have breath malodour. This might be linked to the regular consumption of low phenylalanine (Phe)/Phe-free protein substitutes (PS), which are an essential component of a low-Phe diet. Oral malodour can negatively affect interpersonal communication, lead to bullying, low self-esteem and social isolation. In this longitudinal cross-over study, exhaled volatile organic compounds (VOCs) were measured using gas chromatography - ion mobility spectrometry (GC-IMS). 40 children (20 PKU, 20 controls) were recruited. Subjects with PKU took either L-Amino Acid (L-AA) or Casein Glycomacropeptide (CGMP-AA) exclusively for 1 week, in a randomised order. On the 7th day, 7 exhaled breath samples were collected over a 10-hr period. Subjects then transferred to the other PS for a week and on day 7, provided 7 further breath samples. All subjects had a standardised menu using low-Phe food alternatives and all food intake was measured and recorded. In the PKU group, the aim was to collect samples 30-min after consuming PS. In 3 subjects, breath was collected 5-min post-PS consumption. Fasted L-AA and CGMP-AA breath samples contained a similar number of VOC peaks (10-12) as controls. Longitudinal breath testing results demonstrate that there was no significant difference in the number of exhaled VOCs, comparing L-AA or CGMP-AA with controls, or between PS (12-18 VOC peaks). Breath analysed immediately after consumption of PS (n=3) showed an immediate increase in the number of VOC peaks (25-30), but these were no longer detectable at 30-min post-consumption. This suggests PS have a transient effect on exhaled breath. Measurements taken 30-min after consuming L-AA or CGMP-AA were not significantly different to controls. This indicates that timing food and drinks with PS consumption may be a potential solution for carers to reduce or eliminate unpleasant PS-related breath odours. [Abstract copyright: © 2019 IOP Publishing Ltd.