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AIMS/HYPOTHESIS: Trials have not demonstrated benefits to the population of screening for type 2 diabetes. However, there may be cost savings for those found to have diabetes. We therefore aimed to compare healthcare costs among individuals with incident type 2 diabetes in a screened group with those in an unscreened group. METHODS: In this register-based, non-randomised controlled trial, eligible individuals were men and women aged 40-69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk-score questionnaire. Individuals with a moderate-to-high risk were invited to visit their family doctor for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other practices in Denmark constituted the retrospectively constructed no-screening (control) group. In this post hoc analysis, we identified individuals from the screening and no-screening groups who were diagnosed with diabetes between 2001 and 2009 (n = 139,075). Using national registry data, we quantified the cost of healthcare services in these two groups between 2001 and 2012. From a healthcare sector perspective, we estimated the potential healthcare cost savings for individuals with diabetes that were attributable to the screening programme. RESULTS: In the screening group, 27,177 of 153,107 individuals (18% of those sent a risk-score questionnaire) attended for screening, 1533 of whom were diagnosed with diabetes. Between 2001 and 2009, 13,992 people were newly diagnosed with diabetes in the screening group (including those diagnosed by screening) and 125,083 in the no-screening group. Healthcare costs were significantly lower in the screening group compared with the no-screening group (difference in mean total annual healthcare costs -€889 per individual with incident diabetes; 95% CI -€1196, -€581). The screening programme was associated with a cost saving per person with incident diabetes over a 5-year period of €2688 (95% CI €1421, €3995). CONCLUSIONS/INTERPRETATION: Healthcare costs were lower among individuals with incident type 2 diabetes in the screened group compared with the unscreened group. The relatively modest cost of screening per person discovered to have developed diabetes was offset within 2 years by savings in the healthcare system.

OBJECTIVE: To determine the benefit of multifactorial treatment on microvascular complications among people with type 2 diabetes detected by screening.RESEARCH DESIGN AND METHODS: This study was a multicenter cluster randomized controlled trial in primary care with randomization at the practice level. In four centers in Denmark; Cambridge, U.K.; the Netherlands; and Leicester, U.K., 343 general practices participated in the trial. Eligible for follow-up were 2,861 of the 3,057 people with diabetes detected by screening included in the original trial. Biomedical data on nephropathy were collected in 2,710 (94.7%) participants, retinal photos in 2,190 (76.6%), and questionnaire data on peripheral neuropathy in 2,312 (80.9%). The prespecified microvascular end points were analyzed by intention to treat. Results from the four centers were pooled using fixed-effects meta-analysis.RESULTS: Five years after diagnosis, any kind of albuminuria was present in 22.7% of participants in the intensive treatment (IT) group and in 24.4% in the routine care (RC) group (odds ratio 0.87 [95% CI 0.72-1.07]). Retinopathy was present in 10.2% of the IT group and 12.1% of the RC group (0.84 [0.64-1.10]), and severe retinopathy was present in one patient in the IT group and seven in the RC group. Neuropathy was present in 4.9% and 5.9% (0.95 [0.68-1.34]), respectively. Estimated glomerular filtration rate increased between baseline and follow-up in both groups (4.31 and 6.44 mL/min, respectively).CONCLUSIONS: Compared with RC, an intervention to promote target-driven, intensive management of patients with type 2 diabetes detected by screening was not associated with significant reductions in the frequency of microvascular events at 5 years.

In Denmark the co-operation between the primary and secondary health care system is organized through referrals. Recommendations for improving interaction between the diabetes team (diabetologists, diabetes nurses, dietitians, chiropodists etc.) at the diabetes clinic, and general practice have been prepared by a working party for the Danish National Board of Health. General recommendations: (a) Appointment of a liaison committee in each county consisting of general practitioners (GPs), diabetologists, administrators, etc. (b) Employment of a GP at the diabetes clinic to take care of improving communication, teaching, research, quality assessment, etc. (c) Referral of all newly diagnosed patients with Type 1 diabetes and younger or complicated patients with Type 2 diabetes to the diabetes clinic. More far-reaching forms of co-operation to be discussed in the liaison committees include: (a) Based upon his own knowledge of where to look for help to solve a specific health problem, the diabetic patient may on his own initiative consult either the diabetes clinic or general practice. (b) Provision of access to consult the diabetes nurse/dietitian at the diabetes clinic for instruction without a formal referral. (c) Patients treated solely in general practice and thus unknown to the diabetes clinic may be referred or reported systematically to the diabetes clinic.

Udgivelsesdato: 2008-Aug BACKGROUND: Few randomized controlled trials (RCT) have evaluated health tests and health consultations in primary care with a long follow-up period. The Ebeltoft Health Promotion Project (EHPP) evaluated health tests and health consultations over a period of 5 years in the frame of a health technology assessment. OBJECTIVE: To review the results of EHPP. DESIGN: RCT with a control group answering questionnaires and two intervention groups having questionnaires, a comprehensive health test with written advice followed by either a normal consultation on demand or a planned 45 minutes patient-centred consultation. SETTING: Primary care. PARTICIPANTS: The target population was all 30-49 year old persons in the municipality of Ebeltoft, Denmark. Invitations were received by 2000 randomly selected persons. INTERVENTION: A comprehensive biomedical health test including a cardiovascular risk score (CVRS) followed by written advice and health consultations. MAIN OUTCOME MEASURES: Biomedical measures, psychological measures, healthcare contacts, life years gained, direct and total health costs. RESULTS: At baseline 75% participated. During the 5 years 85% participated at least once. Elevated CVRS was found in 19% in the control group compared to 10% in the intervention groups (p

Udgivelsesdato: 2008-null BACKGROUND: The development of consultations towards more patient centredness and shared decision making has greatly influenced general practice. Several patient-based studies have been published on shared decision making in screening and health checks. However, few studies have explored the process in-depth to understand perspectives of patients at high cardiovascular risk and their experiences of preventive consultations. AIM: To explore and analyse experiences of preventive consultations in patients at high cardiovascular risk. METHOD: Individual, semi-structured interviews with 12 patients at increased risk of cardiovascular disease (CVD) conducted within two weeks of a dedicated preventive consultation. Grounded theory was used in the analysis. RESULTS: The patients' experienced benefits from the consultation included changed emotions, thoughts, readiness to change lifestyle and perceived knowledge related to health and risk. Patients reported that their experienced benefits were related to the general practitioner's (GP's) professional competence, communication in the consultation and especially the doctor-patient relationship. Patients also expressed a number of unfulfilled expectations concerning their opportunities to contribute their personal perspectives to the consultation, short consultation duration, problems with appropriate timing and personal relevance of content and insufficient tailoring to their personal situation. GPs' communication skills and scheduling of follow-up consultations were reported by the patients as essential for these specific aspects to be addressed successfully. CONCLUSION: Patients reported a number of benefits from preventive consultations. However, their unfulfilled expectations suggest the benefits could be even greater, both with enhanced communication skills from doctors, and attention to appropriate timing of the consultations at stages of life when patients are more able to make changes.

Udgivelsesdato: 2007-Dec OBJECTIVE: In the present study, we aimed to validate the type 2 diabetes susceptibility alleles identified in six recent genome-wide association studies in the HHEX/KIF11/IDE (rs1111875), CDKN2A/B (rs10811661), and IGF2BP2 (rs4402960) loci, as well as the intergenic rs9300039 variant. Furthermore, we aimed to characterize quantitative metabolic risk phenotypes of the four variants. RESEARCH DESIGN AND METHODS: The variants were genotyped in the population-based Inter99 cohort (n = 5,970), the ADDITION Study (n = 1,626), a population-based sample of young healthy subjects (n = 377), and in additional type 2 diabetic case (n = 2,111) and glucose-tolerant (n = 521) subjects. The case-control studies involved a total of 4,089 type 2 diabetic patients and 5,043 glucose-tolerant control subjects. RESULTS: We validated association of variants near HHEX/KIF11/IDE, CDKN2A/B, and IGF2BP2 with type 2 diabetes. Interestingly, in middle-aged people, the rs1111875 C-allele of HHEX/KIF11/IDE strongly associated with lower acute insulin response during an oral glucose tolerance test (P = 6 x 10(-7)). In addition, decreased insulin release following intravenous tolbutamide injection was observed in young healthy subjects (P = 0.02). Also, a reduced insulin release was observed for the CDKN2A/B rs10811661 T-allele after both oral and intravenous glucose challenges (P = 0.001 and P = 0.009, respectively). CONCLUSIONS: We validate that variants in the proximity of the HHEX/KIF11/IDE, CDKN2A/B, and IFG2BP2 loci associate with type 2 diabetes. Importantly, variations within the HHEX/KIF11/IDE and CDKN2A/B loci confer impaired glucose- and tolbutamide-induced insulin release in middle-aged and young healthy subjects, suggesting a role for these variants in the pathogenesis of pancreatic beta-cell dysfunction.

Udgivelsesdato: 2006-Jun BACKGROUND: Motivational interviewing has been shown to be broadly usable in a scientific setting in the management of behavioural problems and diseases. However, data concerning implementation and aspects regarding the use of motivational interviewing in general practice is missing. AIM:To evaluate GPs' conception of motivational interviewing in terms of methods, adherence to and aspects of its use in general practice after a course. STUDY DESIGN: In a randomised controlled trial concerning intensive treatment of newly diagnosed patients with type 2 diabetes detected by screening, the GPs were randomised to a course in motivational interviewing or not. The study also included a third group of GPs outside the randomised controlled trial, who had 2 years previously received a similar course in motivational interviewing. SETTING: General practice in Denmark. METHOD: The intervention consisted of a 1.5-day residential course in motivational interviewing with 0.5-day follow-ups, twice during the first year. Questionnaire data from GPs were obtained. RESULTS: We obtained a 100% response-rate from the GPs in all three groups. The GPs trained in motivational interviewing adhered statistically significantly more to the methods than did the control group. More than 95% of the GPs receiving the course stated that they had used the specific methods in general practice. CONCLUSION: A course in motivational interviewing seems to influence GPs professional behaviour. Based on self-reported questionnaires, this study shows that the GPs after a course in motivational interviewing seemed to change their professional behaviour in daily practice using motivational interviewing compared with the control group. GPs evaluated motivational interviewing to be more effective than 'traditional advice giving'. Furthermore, GPs stated that the method was not more time consuming than 'traditional advice giving'.

Udgivelsesdato: 2007-Feb AIM: To answer: (1) Do we have effective treatments to improve prognosis for those identified at risk of Type-2 diabetes? (2) Will prevention be cost-effective? METHODS: A systematic search was done in PubMed using the following search strategy: "diabetes AND prevention AND (IFG OR IGT)". Restrictions were: "English, Meta-Analysis, Randomized Controlled Trial, Review, Humans". RESULTS: Few randomised controlled preventive trials were found. Almost all were done in research settings in people with high risk of developing Type-2 diabetes. It seems possible to either delay or prevent Type-2 diabetes through lifestyle interventions and medication. Cost-utility analyses are few in number and come to very different conclusions as to whether health policy should promote prevention of Type-2 diabetes. CONCLUSION: Intervention studies using lifestyle counselling and drug therapy in research settings illustrate promising results with lowering of the incidence of Type-2 diabetes, meaning that Type-2 diabetes can be delayed or prevented. It is, however, questionable whether these interventions are cost-effective. We need studies in routine clinical settings evaluating morbidity, mortality and cost-effectiveness as primary outcomes. While waiting for these studies to prove cost-effective, patients with pre-diabetes should be treated according to their 10-year risk of cardiovascular disease following present guidelines.

OBJECTIVE - To examine the correlates of patient and provider attitudes toward insulin therapy. RESEARCH DESIGN AND METHODS - Data are from surveys of patients with type 2 diabetes not taking insulin (n = 2,061) and diabetes care providers (nurses = 1,109; physicians = 2,681) in 13 countries in Asia, Australia, Europe, and North America. Multiple regression analysis is used to identify correlates of attitudes toward insulin therapy among patients, physicians, and nurses. RESULTS - Patient and provider attitudes differ significantly across countries, controlling for individual characteristics. Patients rate the clinical efficacy of insulin as low and would blame themselves if they had to start insulin therapy. Self-blame is significantly lower among those who have better diet and exercise adherence and less diabetes-related distress. Patients who are not managing their diabetes well (poor perceived control, more complications, and diabetes-related distress) are significantly more likely to see insulin therapy as potentially beneficial. Most nurses and general practitioners (50-55%) delay insulin therapy until absolutely necessary, but specialists and opinion leaders are less likely to do so. Delay of insulin therapy is significantly less likely when physicians and nurses see their patients as more adherent to medication or appointment regimens, view insulin as more efficacious, and when they are less likely to delay oral diabetes medications. CONCLUSIONS - Patient and provider resistance to insulin therapy is substantial, and for providers it is part of a larger pattern of reluctance to prescribe blood glucose-lowering medication. Interventions to facilitate timely initiation of insulin therapy will need to address factors associated with this resistance.

To develop a simple self-administered questionnaire identifying individuals with undiagnosed diabetes with a sensitivity of 75% and minimizing the high-risk group needing subsequent testing.

INTRODUCTION: Both physical and psychosocial workplace factors are considered risk factors for low back pain (LBP). However, today, no consensus has been reached regarding the exact role of these factors in the genesis of LBP. MATERIAL AND METHODS: Questionnaire data were collected at baseline for 1,397 (and after five years for 1,163) men and women aged 31-50 years at baseline. LBP (any LBP within the past year; LBP < or = 30 days in total during the past year; LBP > 30 days in total during tha past year) was analysed in relation to physical workload (sedentary, light physical, and heavy physical work) using logistic regression and controlling for age, gender, and social group. The proportions af workers changing between the workload groups over the five-year period were analysed in relation to LBP status. RESULTS: A baseline no statistically significant differences in LBP outcomes were found for workers exposed to sedentary, light physical, or heavy physical work. This was true for both genders and all age and social groups. At follow-up these was a statistically significant dose-response association between any LBP and long-standing LBP during the past year and increasing physical workload at baseline, also after controlling for age, gender and social group. Subjects with a heavy physical workload at baseline changed significantly more often to sedentary work, if they had experienced LBP for more than 30 days out of the past year. DISCUSSION: Having a sedentary job might have a protective or neutral effect in relation to LBP, whereas having a heavy physical job constitutes a significant risk factor. Because og migration between exposure groups (the "healthy worker" effect), longitudinal studies are necessary for investigating the associations between physical workload and LBP. Udgivelsesdato: 2002-May-20

Udgivelsesdato: 2002-Jan-7

INTRODUCTION: We investigated the impact of general health screenings and discussions with general practitioners on the cardiovascular risk profile of the population. MATERIAL AND METHODS: A population-based, randomised, controlled, 5-year follow-up trial conducted in a primary care setting. In total 2000 randomly selected men and women, aged 30-50 years, from family practices in the district of Ebeltoft, Denmark. Of these persons, 1507 (75.4%) agreed to participate, and were randomised into: (1) a control group who did not receive health screenings; (2) an intervention group that received two health screenings; or (3) an intervention group that received both the two screenings and a 45-minute follow-up consultation annually with their general practitioner. All were followed up after 5 years by questionnaires and health screenings. The outcome measures were: cardiovascular risk score (CRS), body mass index (BMI), blood pressure, serum cholesterol, carbon monoxide in expiratory air, and use of tobacco. RESULTS: After 5 years, the CRS, BMI, and serum cholesterol levels were lower in the intervention groups, as compared with the control group. The improved outcome was greater in the baseline risk groups. The number of persons with elevated CRS in the intervention groups was about half the number of persons with elevated CRS in the control group. The difference was not a result of medication use. There was no difference between the group that received consultations after the screenings and the group that had health screenings alone. DISCUSSION: Systematic health screenings reduce the cardiovascular risk score in a middle-aged population. After 5 years of follow-up, the number of persons at elevated cardiovascular risk was about half the expected. The impact of intervention is higher in at-risk individuals. Planned consultations about health did not appear to improve the cardiovascular profile of the study population. Udgivelsesdato: 2002-Jun-17

In a representative population sample of 905 persons we examined the prevalence of raised levels of liver-derived enzymes and its possible association with self-reported alcohol consumption adjusted for smoking and BMI applying logistic regression analyses. A large proportion of 12% (women 8%; men 16%) presented raised liver-derived enzymes. Below 21 units per week (one unit equals 12 grams of alcohol) there was no association with self-reported alcohol consumption. However, the risk of abnormal liver enzymes increased with higher consumption for both sexes; if the intake was above 28 units per week, the odds ratio for raised liver enzymes increased dramatically. Whether this subclinical biochemical liver condition is an early marker of alcohol-related liver damage remains to be seen, but the long-term consequences of the reported alcohol consumption and the frequency of raised liver enzymes require follow-up.

A study was carried out to investigate people's interest in participating in health check-up and in discussions about health with their own general practitioner, participants' health status, the proportion who received health advice following health check-up, and the lifestyle goals they set following discussion with their general practitioner. This study reports the baseline data from a five-year randomized, controlled, prospective, population-based study in general practices in Ebeltoft, Denmark. All general practitioners from the four practices in Ebeltoft and a random sample of 2,000 people aged between 30 and 50 years were invited to participate. Participants were randomly divided into three groups-one control group and two intervention groups. One intervention group was given a health check-up which included a range og tests (Table 2 and 3); this group received written feedback from the general practitioner. The other intervention group was also given a health check-up and written feedback, in addition, they were given the opportunity to attend their general practitioner to discuss health-promoting measures. A total of 1370 people participated in the study (69% response rate). Health advice was given to 76% of 905 participants following health check-up. Almost all of the 456 participants (96%) who were offered the opportunity of discussing their health with their general practitioner took up the offer: 64% of the 456 participants reported that they had decided to undertake lifestyle changes. Eleven of those who discussed their health with the doctor were referred to a specialist (2%). There was considerable interest in participating in health promotion. Three out of four of those who had a health check-up were given health advice. Two out of three of those who were offered a health talk with the general practitioner appeared willing to make relevant lifestyle changes. Longterm follow up is needed to determine effects and side effects of health check-up and health talks.

To investigate (a) whether there is a causal link between smoking and low back pain (LBP), (b) whether smoking is uniquely associated with symptoms in the lumbar spine and (c) the role of respiratory problems in the possible link between smoking and LBP.

There is increasing political pressure on the medical profession to approach welfare diseases, such as coronary heart disease and diabetes, through prevention. General practitioners are required to offer regular health checks to healthy people, in spite of the lack of scientific evidence for the universal need, usefulness and side effects of such an intervention. Randomized controlled trials are needed.

Albumin-creatinine ration (ACR) has been correlated to increased morbidity and mortality in diabetic as well as in nondiabetic populations. We investigated the albumin-creatinine ratio in 898 randomly selected persons aged 30-50 years, 471 women and 424 men (year 0). ACR was remeasured 1 year later in 811 (90%) of these persons (year 1). This was done in the framework of a prospective, randomized, population-based intervention trial evaluating the effect of health test and health conversations in general practice. The mean age of the study population was 39.8 (range, 30-51) years with a mean body mass index of 24.3 (15.9-44.3) kg/m2. The 50th, 95th, and 99th percentiles of ACR were 0.6, 2.0, and 5.0 mg/mmol at year 0 and 0.5, 2.0, and 5.3 mg/mmol at year 1. There was no significant difference between ACR values at year 0 and year 1. ARC values were slightly higher in women than in men, 0.6, (0.2-20.4) mg/mmol versus 0.5 (0.2-16.3) mg/mmol (p 2.5 mg/mmol) were 0.33 expressed by Cohen's kappa.(ABSTRACT TRUNCATED AT 250 WORDS)

A total of 35 experiments in which insulin-dependent diabetics were connected to an artificial beta cell (Biostator) for feedback control of blood glucose during at least 24 h, were evaluated. Only 14 experiments, however, were available for analysis, since interruptions of more than 45 min/24 h in feedback control due to clots in analyser tubing occurred in those remaining. In these 14 experiments the 24-h insulin-infusion pattern was analysed. Basal insulin requirements (BIR), (between 01.00 and 04.00 hours) was found to be 0.178 +/- 0.044 (SD) mU/kg X min. Insulin requirements increased in the early morning (04.00-07.00 hours) to 0.231 +/- 0.084 mU/kg X min (P less than 0.01). A significant correlation between BIR and 24-h insulin requirement was found (r = 0.53, P less than 0.05). Insulin requirements per kJ following breakfast were higher than after lunch, 0.57 +/- 0.20 muU/kg X min X kJ versus 0.41 +/- 0.29 muU/kg X min X kJ (P less than 0.05).

Long-term near-normal blood glucose regulation is possible with portable insulin pumps, and this treatment is acceptable to patients, but is also expensive. The pharmacokinetic difference between continuous subcutaneous insulin infusion and conventional injection therapy is discussed and can explain the difference between the obtained levels of blood glucose control. One-year near-normal blood glucose regulation cannot prevent the development of proliferative retinopathy in patients with established diabetic background retinopathy. Long-term large-scale prospective clinical trials are needed to evaluate whether strict metabolic control can prevent, delay, arrest, or even reverse microvascular complications. Furthermore, the side effects of the pump treatment need to be clarified before routine use of continuous subcutaneous insulin infusion. While awaiting these studies, the only indication for pump therapy in routine clinic is considerable glycaemic instability which is incompatible with leading a normal life.

In a retrospective survey of 202 patients with acute cholecystitis 40 patients (19,8%) were found to have common duct stones. No close correlation between common duct stones and either serum bilirubin or serum alkaline phosphatase could be demonstrated. Therefore it was concluded that peroperative cholangiography is necessary in operations for acute cholecystitis.

Seven insulin-dependent diabetic patients (mean age 36 years and mean duration of diabetes 19 years) underwent intensified treatment with continuous subcutaneous insulin infusion (CSII) for one week. The patients were selected for the study due to long-standing hypergycemia in an endeavour to determine possible influence on retinal neurosensory function by even short-term near-normalization of blood glucose concentrations. During CSII treatment, near-normalization of the blood glucose levels was obtained (mean blood glucose concentration before treatment; 13.7 +/- 1.6 mmol/l-during treatment; 6.3 +/- 0.4 mmol/l. Recording of the oscillatory potentials by electroretinography and the macular recovery by nyctometry remained about the same in the course of this short-term treatment. Our study suggests that short-term strict metabolic control does not reverse the retinal neural abnormalities in long-standing insulin-dependent diabetes. Consequently; this regimen does not enable prediction of possible beneficial effect of sustained near-normoglycemic treatment.

30 insulin-dependent diabetic patients with background retinopathy were randomised to conventional treatment (UCT) or treatment with continuous subcutaneous insulin infusion (CSII). They were followed prospectively for 1 year with fortnightly seven-sample home blood glucose measurements and retinal examinations every 6 months. Mean blood glucose and stable haemoglobin A1c during months 3-12 were significantly lower in the CSII than the UCT group. Retinal morphology deteriorated during the year with no significant differences between UCT and CSII groups. The frequency of deterioration was highest in the CSII group, especially among the 10 patients with best glycaemic control. Proliferative retinopathy developed in 3 patients--2 of these were CSII treated. Retinal function (oscillatory potential, macular recovery time, and posterior vitreous fluorophotometry) improved significantly with CSII treatment and deteriorated significantly with UCT. Changes in retinal function were most pronounced in patients with the best and the poorest regulated glycaemic control.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

Since serum GH in normal subjects displays a circadian variation with a major and consistent surge after the onset of sleep we examined whether the time of GH administration in GH-deficient patients had any impact on its action. Eight GH-deficient patients all underwent 3 4-week study schedules in random order: 1) evening (2000 h) sc GH injections, 2) morning (0800 h) sc GH injections, and 3) no GH administration. At the end of each period the patients were admitted to hospital for 24-h measurements of hormones and metabolites. For comparison, 10 age- and sex-matched healthy untreated subjects were hospitalized once under identical conditions. Mean (+/- SE) GH availability, i.e. the area under the curve (AUC; micrograms per L/12 h) for 12 h after injection was significantly greater after evening injection than after morning injections [83.3 +/- 25.4 (evening) vs. 46.0 +/- 10.6 (morning); P less than 0.01]. This might be due to higher skin and sc temperatures when in bed. The 2000-0800 h AUC after evening injection was similar to the corresponding AUC in the reference group. Mean 24-h serum insulin-like growth factor-I levels (micrograms per L) were similar after evening (189.8 +/- 2) and morning (179.5 +/- 5.3) injections (P = 0.8), but the latter displayed a circadian variation suggesting that a steady state had not been reached. Both were significantly lower than the stable reference value (248.4 +/- 3.6 micrograms/L). Blood glucose profiles after morning and evening GH did not differ from that of the reference group, whereas blood glucose decreased when the patients received no GH (P less than 0.01). Daytime (0800-2400 h) insulin levels were increased after morning injections (P less than 0.05). Nighttime levels of lipid intermediates were below normal in the untreated state and after morning injection (P less than 0.05), whereas nighttime blood alanine tended to be above normal after morning GH injection (P = 0.08). Highly significant inverse relationships between circadian lipid intermediates and both blood alanine and lactate concentrations were observed in the reference group and in the patients after evening injections. These relationships disappeared after morning injections. We conclude that the metabolic effects of sc GH injections are clearly influenced by the time of administration and that the closest similarity to normal hormone and metabolite patterns and relationships is reached by GH injection in the evening in GH-deficient patients.

We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes.We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n = 6,070), the Danish ADDITION study (n = 8,662), and in additional type 2 diabetic patients (n = 1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects.The minor alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per allele, P = 0.001). The diabetes-associated alleles also associated strongly with a higher plasma glucose at 30 and 120 min and serum insulin at 120 min during an oral glucose tolerance test (all P0.006) and the minor allele of rs1889018 with a surrogate measure of insulin sensitivity (P = 0.03). Furthermore, the diabetes-associated alleles associated with a modestly increased A1C level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P = 0.006 and P = 0.008, respectively).We associate sequence variation in SREBF1 with a modestly increased predisposition to type 2 diabetes. In the general population, the diabetes-associated alleles are discreetly associated with hyperglycemia presumably due to decreased insulin sensitivity. Because sterol regulatory element-binding protein-1c is a mediator of insulin action, the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant.

BACKGROUND: Ambiguity exists in relation to the role of physical activity (PA) for cardiovascular disease (CVD) risk reduction. We examined the interplay between PA dimensions and more conventional CVD risk factors to assess which PA dimensions were associated with the first CVD event and whether subgroup differences exist. METHODS: A total of 1449 individuals [median age 65.8 (IQR: 61.2, 70.7) years] with low to high risk of type 2 diabetes and free from CVD from the Danish ADDITION-PRO study were included for survival analysis. PA was measured by individually calibrated heart rate and movement sensing for 7 consecutive days. The associations of different PA dimensions (PA energy expenditure, time spent in light-, moderate- and vigorous intensity PA), sedentary time and other conventional CVD risk factors with the first CVD event were examined by tree-structured survival analysis. Baseline information was linked to data on the first CVD event (ischemic heart disease, ischemic stroke, heart failure, atrial flutter/fibrillation and atherosclerotic disease) and mortality obtained from Danish registers. RESULTS: During a median follow-up time of 5.5 (IQR: 5.1-6.1) years, a total of 201 individuals (13.9%) developed CVD. Overall CVD incidence rate was 2.6/100 person-years. PA energy expenditure above 43 kJ/kg/day was associated with lower rates of CVD events among participants ≤ 70 years and with HbA1c ≤ 5.7% (39 mmol/mol), systolic blood pressure ≤ 156 mmHg and albumin creatinine ratio ≤ 70 (incidence rates 0.0-0.8/100 person-years). CONCLUSIONS: Any type of PA resulting in increased PA energy expenditure may over time be the best prevention strategy to uphold reduced risk of CVD.

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1