Although over a hundred thermal indices can be used for assessing thermal health hazards, many ignore the human heat budget, physiology and clothing. The Universal Thermal Climate Index (UTCI) ...addresses these shortcomings by using an advanced thermo-physiological model. This paper assesses the potential of using the UTCI for forecasting thermal health hazards. Traditionally, such hazard forecasting has had two further limitations: it has been narrowly focused on a particular region or nation and has relied on the use of single ‘deterministic’ forecasts. Here, the UTCI is computed on a global scale, which is essential for international health-hazard warnings and disaster preparedness, and it is provided as a probabilistic forecast. It is shown that probabilistic UTCI forecasts are superior in skill to deterministic forecasts and that despite global variations, the UTCI forecast is skilful for lead times up to 10 days. The paper also demonstrates the utility of probabilistic UTCI forecasts on the example of the 2010 heat wave in Russia.
Aims/hypothesis
Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated ...whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved.
Methods
Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup (
n
= 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity.
Results
Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray.
Conclusions/interpretation
Central insulin action in specific brain areas, including the hypothalamus, may time-dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism.
Aims/hypothesis Variation within six novel genetic loci has been reported to confer risk of type 2 diabetes and may be associated with beta cell dysfunction. We investigated whether these ...polymorphisms are also associated with impaired proinsulin to insulin conversion. Methods We genotyped 1,065 German participants for single nucleotide polymorphisms rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 and rs1111875 in HHEX, rs13266634 in SLC30A8, rs10811661 in CDKN2A/B and rs4402960 in IGF2BP2. All participants underwent an OGTT. Insulin, proinsulin and C-peptide concentrations were measured at 0, 30, 60, 90 and 120 min during the OGTT. Insulin secretion was estimated from C-peptide or insulin levels during the OGTT using validated indices. We used the ratio proinsulin/insulin during the OGTT as indicator of proinsulin conversion. Results In our cohort, we confirmed the significant association of variants in TCF7L2, CDKAL1 and HHEX with reduced insulin secretion during the OGTT (p < 0.05 for all). Variation in SLC30A8, CDKN2A/B and IGF2BP2 was not associated with insulin secretion. The risk alleles of the variants in TCF7L2, CDKAL1 and SLC30A8 reduced proinsulin to insulin conversion (p < 0.05 for all), whereas the risk alleles in HHEX, CDKN2A/B and IGF2BP2 were not associated with reduced proinsulin to insulin conversion (p > 0.6). Conclusions/interpretation Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. However, both aspects of beta cell function are not necessarily linked, as impaired insulin secretion is specifically present in variants of HHEX and impaired proinsulin conversion is specifically present in a variant of SLC30A8.
Aims/hypothesis
WFS1
type 2 diabetes risk variants appear to be associated with impaired beta cell function, although it is unclear whether insulin secretion is affected directly or secondarily via ...alteration of insulin sensitivity. We aimed to investigate the effect of a common
WFS1
single-nucleotide polymorphism on several aspects of insulin secretion.
Methods
A total of 1,578 non-diabetic individuals (534 men and 1,044 women, aged 40 ± 13 years, BMI 28.9 ± 8.2 kg/m
2
mean ± SD) at increased risk of type 2 diabetes were genotyped for rs10010131 within the
WFS1
gene. All participants underwent an OGTT (and a subset additionally an IVGTT
n
= 319) and a hyperglycaemic clamp combined with glucagon-like peptide-1 (GLP-1) and arginine stimuli (
n
= 102).
Results
rs10010131 was associated with reduced OGTT-derived insulin secretion (
p
= 0.03). In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 infusion combined with a hyperglycaemic clamp showed a significant reduction of the insulin secretion rate during the first and second phases of GLP-1-induced insulin secretion in carriers of the risk allele (reduction of 36% and 26%, respectively;
p
= 0.007 and
p
= 0.04, respectively).
Conclusions/interpretation
A common genetic variant in
WFS1
specifically impairs GLP-1-induced insulin secretion independently of insulin sensitivity. This defect might explain the impaired insulin secretion in carriers of the risk allele and confer the increased risk of type 2 diabetes.
Aims/hypothesis
We have previously found that the mass of perivascular adipose tissue (PVAT) correlates negatively with insulin sensitivity and post-ischaemic increase in blood flow. To understand ...how PVAT communicates with vascular vessels, interactions between perivascular, subcutaneous and visceral fat cells with endothelial cells (ECs) were examined with regard to inflammatory, metabolic and angiogenic proteins. To test for possible in vivo relevance of these findings, circulating levels of the predominant secretion product, hepatocyte growth factor (HGF), was measured in individuals carefully phenotyped for fat distribution patterns.
Methods
Mono- and co-cultures of human primary fat cells with ECs were performed. mRNA expression and protein production were studied using Luminex, cytokine array, RealTime Ready and ELISA systems. Effects of HGF on vascular cells were determined by WST assays. In patients, HGF levels were measured by ELISA, and the mass of different fat compartments was determined by whole-body MRI.
Results
In contrast with other fat cell types, PVAT cells released higher amounts of angiogenic factors, e.g. HGF, acidic fibroblast growth factor, thrombospondin-1, serpin-E1, monocyte chemotactic protein-1 and insulin-like growth factor-binding protein −3. Cocultures showed different expression profiles from monocultures, and mature adipocytes differed from pre-adipocytes. HGF was preferentially released by PVAT cells and stimulated EC growth and smooth muscle cell cytokine release. Finally, in 95 patients, only PVAT, not visceral or subcutaneous mass, correlated independently with serum HGF levels (
p
= 0.03;
r
= 0.225).
Conclusions
Perivascular (pre-)adipocytes differ substantially from other fat cells with regard to mRNA expression and protein production of angiogenic factors. This may contribute to fat tissue growth and atherosclerotic plaque complications. Higher levels of angiogenic factors, such as HGF, in patients with increased perivascular fat mass may have pathological relevance.
Plants and animals perceive diverse microbe-associated molecular patterns (MAMPs) via pattern recognition receptors and activate innate immune signalling. The actin cytoskeleton has been suggested as ...a target for innate immune signalling and a key transducer of cellular responses. However, the molecular mechanisms underlying actin remodelling and the precise functions of these rearrangements during innate immunity remain largely unknown. Here we demonstrate rapid actin remodelling in response to several distinct MAMP signalling pathways in plant epidermal cells. The regulation of actin dynamics is a convergence point for basal defence machinery, such as cell wall fortification and transcriptional reprogramming. Our quantitative analyses of actin dynamics and genetic studies reveal that MAMP-stimulated actin remodelling is due to the inhibition of capping protein (CP) by the signalling lipid, phosphatidic acid. In addition, CP promotes resistance against bacterial and fungal phytopathogens. These findings demonstrate that CP is a central target for the plant innate immune response.
Polymorphisms in the FTO (fat mass- and obesity-associated) gene are associated with obesity. The mechanisms how genetic variation in this gene influences body weight are unknown. Body weight is ...determined by energy intake/storage and energy expenditure. In this study, we investigated whether genetic variation in FTO influences energy expenditure or food intake in carefully phenotyped subjects. In 380 German subjects, insulin sensitivity was measured by a hyperinsulinemic euglycemic clamp. Lean body mass and body fat were quantified using the bioimpedance method. Indirect calorimetry was used to estimate the metabolic rate. Food intake was assessed using food diaries (mean 11+/-1 d) in 151 subjects participating in a lifestyle intervention program to prevent diabetes. All subjects were genotyped for the FTO single nucleotide polymorphism (SNP) rs8050136. The risk allele of SNP rs8050136 was associated with higher body fat-related parameters (all p< or =0.04, additive inheritance model). Energy expenditure was not affected by the SNP. However, the risk allele of rs8050136 was significantly associated with higher energy intake (p=0.01, dominant inheritance model) during dietary restriction. Our data suggest that the increased body weight in carriers of the risk allele of FTO SNP rs8050136 is a consequence of increased food intake, but not of impaired energy expenditure.
Although debated, metabolic health characterizes 10–25% of obese individuals and reduces risk of developing life-threatening co-morbidities. Adipose tissue is a recognized endocrine organ important ...for the maintenance of whole-body metabolic health. Adipocyte transcriptional signatures of healthy and unhealthy obesity are largely unknown.
Here, we used a small cohort of highly characterized obese individuals discordant for metabolic health, characterized their adipocytes transcriptional signatures, and cross-referenced them to mouse phenotypic and human GWAs databases.
Our study showed that glucose intolerance and insulin resistance co-operate to remodel adipocyte transcriptome. We also identified the Nuclear Export Mediator Factor (NEMF) and the Ectoderm-Neural Cortex 1 (ENC1) as novel potential targets in the management of metabolic health in human obesity.
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•Healthy obese individuals maintain glucose tolerance and insulin sensitivity.•Glucose intolerance primarily remodels adipocyte transcriptome in human obesity.•Insulin resistance co-operates with glucose tolerance to remodel adipocyte transcriptome.•NEMF and ENC1 are potential targets to manage metabolic health in human obesity.
The adipokine adiponectin has insulin-sensitising, anti-atherogenic and anti-inflammatory properties. Recently, the genes for mouse and human adiponectin receptor-1 (ADIPOR1) and -2 (ADIPOR2) have ...been cloned. The aim of this study was to investigate whether genetic variants of the genes encoding ADIPOR1 and ADIPOR2 play a role in human metabolism.
We screened ADIPOR1 and ADIPOR2 for polymorphisms and determined their association with glucose metabolism, lipid metabolism, an atherogenic lipid profile and inflammatory markers in 502 non-diabetic subjects. A subgroup participated in a longitudinal study; these subjects received diet counselling and increased their physical activity.
We identified six variants of ADIPOR1 and seven variants of ADIPOR2. A single-nucleotide polymorphism (SNP) in the putative promoter region 8503 bp upstream of the translational start codon (-8503 G/A) of ADIPOR1 (frequency of allele A=0.31) was in almost complete linkage disequilibrium with another SNP (-1927 T/C) in intron 1. Subjects carrying the -8503 A and -1927 C alleles had lower insulin sensitivity, as estimated from a 75 g OGTT (p=0.04) and determined during a euglycaemic clamp (n=295, p=0.04); they also had higher HbA(1)c levels (p=0.02) and, although the difference was not statistically significant, higher liver fat (n=85, determined by proton magnetic resonance spectroscopy, p=0.056) (all p values are adjusted for age, sex and percentage of body fat). In the longitudinal study (n=45), the -8503 A and -1927 C alleles were associated with lower insulin sensitivity (p=0.03) and higher liver fat (p=0.02) at follow-up compared with the -8503 G and -1927 T alleles, independently of basal measurements, sex and baseline and follow-up percentage of body fat.
The present findings suggest that the -8503 G/A SNP in the promoter or the -1927 T/C SNP in intron 1 of ADIPOR1 may affect insulin sensitivity and liver fat in humans.
Abstract Background In clinical practice, there is a strong interest in non-invasive markers of non-alcoholic fatty liver disease (NAFLD). Our hypothesis was that the fold-change in plasma ...triglycerides (TG) during a 2-h oral glucose tolerance test (fold-change TGOGTT ) in concert with blood glucose and lipid parameters, and the rs738409 C>G single nucleotide polymorphism (SNP) in PNPLA3 might improve the power of the widely used fatty liver index (FLI) to predict NAFLD. Methods The liver fat content of 330 subjects was quantified by1 H-magnetic resonance spectroscopy. Blood parameters were measured during fasting and after a 2-h OGTT. A subgroup of 213 subjects underwent these measurements before and after 9 months of a lifestyle intervention. Results The fold-change TGOGTT was closely associated with liver fat content ( r = 0.51, P < 0.0001), but had less power to predict NAFLD (AUROC = 0.75) than the FLI (AUROC = 0.79). Not only was the fold-change TGOGTT independently associated with liver fat content and NAFLD, but so also were the 2-h blood glucose level and rs738409 C>G SNP in PNPLA3 . In fact, a novel index (extended FLI) generated from these and the usual FLI parameters considerably increased its power to predict NAFLD (AUROC = 0.79–0.86). The extended FLI also increased the power to predict changes in liver fat content with a lifestyle intervention ( n = 213; standardized beta coefficient: 0.23–0.29). Conclusion This study has provided novel data confirming that the OGTT-derived fold-change TGOGTT and 2-h glucose level, together with the rs738409 C>G SNP in PNPLA3 , allow calculation of an extended FLI that considerably improves its power to predict NAFLD.
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