Thomas Alexander Sick Nielsen

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l−1, P = 2.5 × 10−35) and serum insulin (β = 165 pmol l−1, P = 1.5 × 10−20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = −0.18 mmol l−1, P = 1.1 × 10−6) and fasting serum insulin (β = −8.3 pmol l−1, P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10−24). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l−1, P = 5.3 × 10−5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

Peri-urbanisation and multifunctional adaptation of agriculture around Copenhagen

Abstract Geografisk Tidsskrift Danish Journal of Geography 111(1):59–72, 2011 Peri-urbanisation, as a process of the physical expansion of settlement areas but also socio-economic transformation, has been recognised as a major spatial development beyond the urban fringes. Agriculture, the main land use actor in the hinterlands of many urban areas is increasingly affected by urban encroachment, responds with adaptation strategies and farming activities to cope with the peri-urban framework conditions. Adaptation pathways encompass specialisation into horticulture as well as enhanced environmental and lifestyle orientation offarming—typical elements of multifunctional agriculture. However, due to the heterogeneity of the peri- urbanisation processes also differences in farming transition are expected. Based on a differentiation into displaced-urbanisation, ex-urbanisation, anti-urbanisation and hidden-urbanisation as main types of peri-urbanisation, variances of farming responses are elaborated for municipal entities in the Copenhagen region in Denmark using statistical census data. Under consideration of location determinants, regression models have been applied to analyse the inter-relationship between different peri-urbanisation processes and multifunctional farming activities. Findings confirm that the differentiation of peri-urban processes is meaningful for the explanation of spatial distribution of farm adaptation strategies, particularly in the case of leisure and environmental oriented farm practices.

Children, Mobility, and Space: Using GPS and Mobile Phone Technologies in Ethnographic Research

This article discusses the potentials of a mixed methods approach to the study of children’s mobility patterns. The methodology presented here combined ethnographic fieldwork with global positioning system technology and an interactive questionnaire that children completed via mobile phone. This innovative methodology allowed the researchers to generate a rich understanding of children’s everyday movements. The study combined documentation of children’s subjective experiences with systematic observations, mapping, and survey data. The article sets out lessons learned for future mixed methods research into children’s everyday mobility. One such lesson was that it required the interdisciplinary research team to cooperate closely through dialogue, support, and coordination of activities and perspectives. The approach also promoted the children’s commitment to the study.

The Dynamics of Peri-Urbanization

The peri-urban (sometimes also called the urban fringe) may be the dominant urban form and spatial planning challenge of the twenty-first century. In older industrial or post-industrial countries the peri-urban is a zone of social and economic change and spatial restructuring, while in newer industrializing countries, and most of the developing world, the peri-urban is often a zone of chaotic urbanization leading to sprawl. In both cases the peri-urban can be seen as not just a fringe in-between city and countryside, a zone of transition, rather it is a new kind of multi-functional territory. While it resists simple definitions, there are common features wherever such areas are found, such as a relatively low population density by urban standards, scattered settlements, high dependence on transport for commuting, fragmented communities and lack of spatial governance. Many global challenges arise from the ways that cities grow and change, especially the emerging mega-cities in developing countries where massive social and environmental problems can be found in their peri-urban hinterlands.

Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle

During fasting, human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated eight healthy subjects after a 72-h fast compared with a 10-h overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was reduced profoundly in response to a 72-h fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160 but not TBC1D1, both key regulators of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK or insulin regulation of Akt, both of which are established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160, without Akt or AMPK being affected. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast.

Peri-urban futures : scenarios and models for land use change in Europe

Presently, peri-urbanisation is one of the most pervasive processes of land use change in Europe with strong impacts on both the environment and quality of life. It is a matter of great urgency to determine strategies and tools in support of sustainable development. The book synthesizes the results of PLUREL, a large European Commission funded research project (2007-2010). Tools and strategies of PLUREL address main challenges of managing land use in peri-urban areas. These results are presented and illustrated by means of 7 case studies which are at the core of the book. This volume presents a novel, future oriented approach to the planning and management of peri-urban areas with a main focus on scenarios and sustainability impact analysis. The research is unique in that it focuses on the future by linking quantitative scenario modeling and sustainability impact analysis with qualitative and in-depth analysis of regional strategies, as well as including a study at European level with case study work also involving a Chinese case study.

Reduced mRNA and Protein Expression of Perilipin A and G0/G1 Switch Gene 2 (G0S2) in Human Adipose Tissue in Poorly Controlled Type 2 Diabetes

CONTEXT Increased lipolysis and free fatty acid (FFA) levels contribute significantly to the pathogenesis of chronic and acute insulin resistance in type 2 diabetes, but the underlying mechanisms are uncertain. OBJECTIVE Our objective was to test whether increased lipolysis and FFA levels induced by insulin withdrawal are accompanied by increased adipose tissue (AT) contents of adipose triglyceride lipase (ATGL) and/or altered intracellular ATGL regulation. DESIGN AND PARTICIPANTS Nine patients with type 2 diabetes were examined twice in a randomized crossover design after 16 h of 1) hyperglycemia/insulin withdrawal and 2) euglycemia/insulin infusion. Blood samples were drawn and a sc abdominal AT biopsy was obtained. SETTING The study was conducted at a university hospital research unit. RESULTS Circulating glucose (7.2 ± 0.3 vs. 11.2 ± 0.8 mmol/liter) and FFA (0.51 ± 0.05 vs. 0.65 ± 0.04 mmol/liter) were increased and insulin levels decreased after insulin withdrawal. AT ATGL protein tended to be increased (P = 0.075) after insulin withdrawal; by contrast, AT protein and mRNA content of perilipin A (Plin) and G(0)/G(1) switch gene 2 (G0S2), known negative regulators of ATGL activity, were decreased by 20-30% (all P values <0.03). All measured parameters related to hormone-sensitive lipase remained unaffected. CONCLUSIONS We found reduced mRNA and protein content of Plin and G0S2 and borderline increased ATGL protein in sc AT from poorly controlled type 2 diabetic subjects. This suggests that increased ATGL activity may contribute to the elevated lipolysis and circulating FFA levels in acute insulin withdrawal and metabolic dysregulation in type 2 diabetic patients and that this mechanism may be modifiable.

Urban planning practices for bikeable cities – the case of Copenhagen

Cities are increasingly looking to cycling as a means to promote sustainability, liveability, and public health. Denmark is one of the European countries where cycling has remained significant – even in the motor age, and national strategies now aim to support and further increase cycling. The article presents the state of cycling in Denmark and Copenhagen – as well as the cycling promoting efforts of the city of Copenhagen which is one of the forerunners in the field.

Developing Suitable Buffers to Capture Transport Cycling Behavior

The association between neighborhood built environment and cycling has received considerable attention in health literature over the last two decades, but different neighborhood definitions have been used and it is unclear which one is most appropriate. Administrative or fixed residential spatial units (e.g., home-buffer-based neighborhoods) are not necessarily representative for environmental exposure. An increased understanding of appropriate neighborhoods is needed. GPS cycling tracks from 78 participants for 7 days form the basis for the development and testing of different neighborhood buffers for transport cycling. The percentage of GPS points per square meter was used as indicator of the effectiveness of a series of different buffer types, including home-based network buffers, shortest route to city center buffers, and city center-directed ellipse-shaped buffers. The results show that GPS tracks can help us understand where people go and stay during the day, which can help us link built environment with cycling. Analysis showed that the further people live from the city center, the more elongated are their GPS tracks, and the better an ellipse-shaped directional buffer captured transport cycling behavior. In conclusion, we argue that in order to be able to link built environment factors with different forms of physical activity, we must study the most likely area people use. In this particular study, to capture transport cycling, with its relatively large radius of action, city center-directed ellipse-shaped buffers yielded better results than traditional home-based network buffer types. The ellipse-shaped buffer types could therefore be considered an alternative to more traditional buffers or administrative units in future studies of transport cycling behavior.

Dietary fat drives whole-body insulin resistance and promotes intestinal inflammation independent of body weight gain

BACKGROUND The obesogenic potential of high-fat diets (HFD) in rodents is attenuated when the protein:carbohydrate ratio is increased. However, it is not known if intake of an HFD irrespective of the protein:carbohydrate ratio and in the absence of weight gain, affects glucose homeostasis and the gut microbiota. METHODS We fed C57BL6/J mice 3 different HFDs with decreasing protein:carbohydrate ratios for 8weeks and compared the results to a LFD reference group. We analyzed the gut microbiota composition by 16S rDNA amplicon sequencing and the intestinal gene expression by real-time PCR. Whole body glucose homeostasis was evaluated by insulin and glucose tolerance tests as well as by a hyperinsulinemic euglycemic clamp experiment. RESULTS Compared with LFD-fed reference mice, HFD-fed mice, irrespective of protein:carbohydrate ratio, exhibited impaired glucose tolerance, whereas no differences were observed during insulin tolerance tests. The hyperinsulinemic euglycemic clamp revealed tissue-specific effects on glucose homeostasis in all HFD-fed groups. HFD-fed mice exhibited decreased insulin-stimulated glucose uptake in white but not in brown adipose tissue, and sustained endogenous glucose production under insulin-stimulated conditions. We observed no impairment of insulin-stimulated glucose uptake in skeletal muscles of different fiber type composition. HFD-feeding altered the gut microbiota composition paralleled by increased expression of pro-inflammatory cytokines and genes involved in gluconeogenesis in intestinal epithelial cells of the jejunum. CONCLUSIONS Intake of a HFD profoundly affected glucose homeostasis, gut inflammatory responses, and gut microbiota composition in the absence of fat mass accretion.