Janus Laust Thomsen

Endothelin-1 stimulates insulin secretion by direct action on the islets of Langerhans in mice

SummaryEndothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, is secreted in response to insulin. Elevated circulating ET-1 levels have been found in patients with diabetes mellitus and vascular dysfunction. The question arises whether ET-1 acts as a direct modulator of insulin secretion. To test this, we studied the effects of ET-1 on isolated mouse islets of Langerhans. ET-1 (1 nmol/l-1 Μmol/l) dose-dependently stimulated insulin secretion from islets incubated in the presence of 16.7 mmol/l glucose (p<0.05). The effect of ET-1 is glucose-dependent since no potentiation was found at 3.3 mmol/l glucose. Furthermore, ET-1 induced a large, transient increase in glucose-stimulated insulin secretion during islet perifusion in the presence (p<0.001), but not in the absence, of extracellular Ca2+. The rate of 45Ca2+-efflux from 45Ca2+-prelabelled islets was transiently stimulated by ET-1 during perifusion at 16.7 mmol/l glucose in the presence of extracellular Ca2+ (p<0.001). A short-lived increase in 45Ca2+-efflux was also observed in the absence of extracellular Ca2+ (p<0.05). It is suggested that the effects of ET-1 on insulin secretion are critically dependent on influx via Ca2+-channels. In addition, ET-1 transiently enhanced 86Rb+-efflux from 86Rb+-prelabelled islets both in the presence (p<0.001) and in the absence (p<0.001) of extracellular Ca2+ suggesting that ET-1 does not elicit insulin secretion by inhibition of the potassium permeability. Our study provides evidence that ET-1 stimulates insulin secretion via a direct effect on the islets of Langerhans.

A systematic review of the effect of tympanostomy tubes in children with recurrent acute otitis media.

OBJECTIVE Documentation of the effect of tympanostomy tubes in children with recurrent acute otitis media (RAOM) is limited. A recently published Cochrane review on the effect of tympanostomy tubes in children with RAOM was based on only two studies. Could the documentation be increased by including other randomized studies? METHODS A MEDLINE and EMBASE search for randomized controlled trials was performed and 143 eligible papers were found. Only five studies could be included. All five were randomized studies with a total of 519 children, four randomized by children and one by ears. All five studies had different designs and control groups, making a proper meta-analysis impossible. Three studies had an antibiotic treated group, two studies a placebo group, and two studies a no treatment group as comparison group. Outcome measures were rates of AOM or fraction free of AOM in six or 12 months. RESULTS Between two and five children have to be treated with tympanostomy tubes to prevent one child from attacks of acute otitis media (AOM) in six months. Tube treatment could reduce AOM with about one attack in six months after operation. Six months treatment with antibiotics was not different from treatment with tubes. No study reported quality of life for child and family or parental absence from day care or work. CONCLUSION Insertion of tympanostomy tubes or long-term treatment with antibiotics seems to prevent one attack of AOM or keep one child out of three free from AOM in six months.

Health tests and health consultations reduced cardiovascular risk without psychological strain, increased healthcare utilization or increased costs: An overview of the results from a 5-year randomized trial in primary care. The Ebeltoft Health Promotion Project (EHPP)

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<0.01) after 5 years. There were no measurable long term psychological reactions. Numbers of contacts to the healthcare system were not increased. Significantly better life expectancy was found without extra direct and total costs. Conclusions: An offer of health tests and patient-centred health consultations to the middle-aged population can be cost-effective and may be considered in the fight against the increasing burden of lifestyle diseases.

Associations between generic substitution and patients' attitudes, beliefs and experiences

BackgroundGeneric substitution has been implemented in many countries, but knowledge about patients’ attitudes, beliefs and experiences is still sparse.AimTo assess associations between generic switching and patients’ attitudes, beliefs and experiences with previous generic switching.Design and settingA cross-sectional study comprising questionnaire responses from 2,476 randomly selected patients aged 20 years or older and living in the Region of Southern Denmark, who had redeemed substitutable drugs.MethodsThe questionnaire included items on beliefs about medicine, views on generic medicine and confidence in the healthcare system. Only prescriptions issued by the general practitioners were included. For each patient, we focused on one purchase of a generically substitutable drug (index drug). Patients were identified by means of a dispensing database.ResultsEarlier generic switches within the index ATC code were statistically significantly associated with experience of a generic switch (adjusted OR 5.93; 95 % CI 4.70–7.49). Having had more than five earlier switches within other ATC codes and having negative views on generic medicines reduced the odds of experiencing a generic switch. No associations were found between generic substitution and gender, drug group, number of different drugs used by the patient, confidence in the health care system and beliefs about medicine in general.ConclusionPatients who had once experienced a generic switch were more likely to accept a future generic switch within the same ATC code. Negative views on generic medicines were negatively associated with switching, while beliefs about medicine and confidence in the healthcare system had no influence.

Hearing loss diagnosis followed by meningitis in Danish children, 1995-2004

Objective A higher risk of meningitis associated with cochlear implants may be explained in part by a generally higher risk of meningitis in children with severe to profound hearing loss. We investigated whether children with hearing loss have an increased risk of meningitis. Study Design and Setting A historical cohort study of all children born in Denmark between January 1, 1995, and December 31, 2004, was conducted. The cohort was selected through the Danish Medical Birth Registry, and information on hearing loss and meningitis was obtained from the National Hospital Registry. Results We identified 39 children with both hearing loss and meningitis. Of these children, five were diagnosed first with hearing loss and later with meningitis. The relative risk of meningitis in the group of children with a hearing loss diagnosis, as compared with the non-hearing loss group, was 5.0 (95% CI, 2.0 to 12.0). Conclusions The study provides evidence for an association between hearing loss and the development of meningitis. Parents and health care providers of children with hearing loss should be more alert for possible signs and symptoms of meningitis, and vaccination should be considered.

The insulinotropic effect of endothelin-1 is mediated by glucagon release from the islet alpha cells.

Aims/hypothesis. The circulating concentrations of endothelin-1 (ET-1), a peptide derived from endothelium, are increased in hypertension and diabetes. Endothelin-1 has recently been shown to be an insulinotropic agent. The mechanism of action of endothelin-1 on the endocrine pancreas has not yet been clarified. Methods. We investigated the action of endothelin-1 on the insulin secretion, the binding of 125I-ET-1 to beta cells as well as its effects on purified beta and non-beta cells from normal rats. The expression of endothelin receptors in alpha- and beta-cell lines and in normal rat islets was also studied. Results. First, we studied the effects of endothelin-1 on insulin secretion from beta-cell lines (INS-1, βTC3 and MIN6). At all endothelin-1 concentrations applied (1 pmol/l to 1 μmol/l) no change in insulin secretion was found. Ligand-binding experiments on βTC3 cells showed no specific binding of 125I-ET-1. A prominent expression of ETA-receptor mRNA in an alpha-cell line (αTC1.9) and in normal rat islets was found whereas no expression was found in INS-1 cells. No influence of endothelin-1(1 μmol/l) on insulin secretion stimulated by glucose was detected from purified beta cells. Endothelin-1-(100 nmol/l) increased, however, both insulin and glucagon secretion from a mixture of purified beta and non-beta cells indicating that alpha cells seem to have a key role for the action of ET-1 on insulin secretion. Conclusion/interpretation. The insulinotropic impact of endothelin-1 is not caused by a direct action on the beta cells but seems to be mediated by a paracrine action, probably secondary to enhanced release of glucagon from the endothelin receptor positive alpha cells. [Diabetologia (1999) 42: 1302–1307]

Multimorbidity and Blood Pressure Control in 37 651 Hypertensive Patients From Danish General Practice

Background Patients with hypertension are primarily treated in general practice. However, major studies of patients with hypertension are rarely based on populations from primary care. Knowledge of blood pressure (BP) control rates in patients with diabetes and/or cardiovascular diseases (CVDs), who have additional comorbidities, is lacking. We aimed to investigate the association of comorbidities with BP control using a large cohort of hypertensive patients from primary care practices. Methods and Results Using the Danish General Practice Database, we included 37 651 patients with hypertension from 231 general practices in Denmark. Recommended BP control was defined as BP <140/90 mm Hg in general and <130/80 mm Hg in patients with diabetes. The overall control rate was 33.2% (95% CI: 32.7 to 33.7). Only 16.5% (95% CI: 15.8 to 17.3) of patients with diabetes achieved BP control, whereas control rates ranged from 42.9% to 51.4% for patients with ischemic heart diseases or cerebrovascular or peripheral vascular diseases. A diagnosis of cardiac heart failure in addition to diabetes and/or CVD was associated with higher BP control rates, compared with men and women having only diabetes and/or CVD. A diagnosis of asthma in addition to diabetes and CVD was associated with higher BP control rates in men. Conclusion In Danish general practice, only 1 of 3 patients diagnosed with hypertension had a BP below target. BP control rates differ substantially within comorbidities. Other serious comorbidities in addition to diabetes and/or CVD were not associated with lower BP control rates; on the contrary, in some cases the BP control rates were higher when the patient was diagnosed with other serious comorbidities in addition to diabetes and/or CVD.

Endothelin-1 (ET-1)-potentiated insulin secretion : Involvement of protein kinase C and the ETA receptor subtype

Endothelin-1 (ET-1), a potent vasoconstrictor peptide of endothelial origin, is capable of influencing hormone secretion from endocrine tissues, eg, pancreatic islet cells. We have shown a direct stimulatory effect of ET-1 on insulin secretion from isolated mouse islets of Langerhans. However, it is unknown as to whether the peptide acts through specific receptors on the islet cells and which mechanisms are involved in this insulinotropic action. We have therefore used the specific ET(A) receptor antagonist BQ123, the ET(B) receptor agonist BQ3020, and classic alpha- and beta-adrenergic and cholinergic antagonists. ET-1 (100 nmol/L) stimulated insulin secretion from islets incubated at 8.3, 11.1, 16.7, and 25 mmol/L glucose (P < .05). At 3.3 mmol/L glucose, no alteration in insulin secretion was found. The cholinergic receptor antagonist atropine (5 micromol/L) or the adrenergic receptor antagonists propranolol (5 micromol/L) or phentolamine (5 micromol/L) did not affect ET-1 (100 nmol/L)-stimulated insulin secretion. BQ123 (10 pmol/L to 10 nmol/L) and BQ3020 (1 nmol/L to 1 micromol/L) had no effect on glucose (16.7 mmol/L)-stimulated insulin secretion, but BQ123 counteracted the stimulatory effect of ET-1 (100 nmol/L) at concentrations of 1 nmol/L to 10 micromol/L (P < .01). We also studied the relative role of protein kinase C (PKC) and a Wortmannin-sensitive pathway for ET-1-induced insulin secretion using 12-O-tetradecanoyl phorbol-13-acetate (TPA), Calphostin C, and Wortmannin, respectively. At 5.6 mmol/L glucose, ET-1 (100 nmol/L) had no effect per se, whereas in the presence of 1 micromol/L TPA, which acutely stimulates PKC, the peptide did potentiate insulin secretion (P < .05). Furthermore, the insulinotropic effect of ET-1 at 16.7 mmol/L glucose was counteracted by the PKC inhibitor Calphostin C (P < .05) and by downregulation of PKC by 24 hours of exposure of islets to TPA (0.5 micromol/L, P < .05). Wortmannin (1 micromol/L) did not alter ET-1-potentiated insulin secretion. In conclusion, our results suggest that ET-1 acts through specific ET-1 receptors, most likely the ETA subtype. Furthermore, PKC plays an essential role in the insulinotropic action of ET-1 in mouse islets.

Markers of fetal growth and serum levels of insulin-like growth factor (IGF) I, -II and IGF binding protein 3 in adults

Fetal growth has been linked with increased risk of cancer and cardiovascular disease later in life. The insulin-like growth factor (IGF) axis has recently been proposed as a predictor of risk of subsequent cancer and cardiovascular disease. However, only few data are available on the possible association between fetal growth and levels of IGFs later in life. We examined the association between markers of fetal growth, i.e. birth weight, birth length and Ponderal Index, from birth records and serum IGF-I, IGF-II, and IGF binding protein 3 (IGFBP-3) levels in 545 middle-aged Danish men and women. We fitted separate multivariate models including birth weight, birth length, Ponderal Index and serum IGF-I, IGF-II, and IGFBP-3, respectively. After adjustment for age, alcohol intake, smoking, diabetes mellitus, systolic and diastolic blood pressure, serum total cholesterol and current height and weight, we found negative associations between birth weight and Ponderal Index, respectively, and serum IGF-II in men, i.e. the mean regression coefficients were −49.41 (95% CI: −87.06–11.77) (μg/l)/kg and −3.49 (95% CI: −6.73–0.25) (μg/l)/(kg/m3), respectively. Furthermore, in men birth weight was negatively associated with the (IGF-I + IGF-II)/IGFBP-3 and IGF-II/IGFBP-3 ratios, which are believed to be indicators of bioavailable IGF and IGF-II, respectively. However, no other associations were found in any of the models. Between 1 and 16% of the variance in serum IGF-I, IGF-II, and IGFBP-3, respectively, could be explained by the statistical models used in the analyses. We found very little support to the hypothesis of an association between fetal growth and the IGF axis throughout life.

Danish General Practitioners' Use of Prostate-Specific Antigen in Opportunistic Screening for Prostate Cancer: A Survey Comprising 174 GPs

Background. The use of prostate-specific antigen test has markedly increased in Danish general practice in the last decade. Despite the national guidelines advice against PSA screening, opportunistic screening is supposed to be the primary reason for this increased number of PSA tests performed. Aims. Based on the increase in the amount of PSA conducted, we aimed to analyse how GPs in Denmark use the PSA test. Methods. A self-administrated questionnaire concerning symptomatic and asymptomatic patient cases was developed based on the national and international guidelines and the extensive literature review, and an in-depth interview conducted with a GP was performed. Results. None of the GPs would do a PSA measurement for an asymptomatic 76-year-old man. For asymptomatic 55- and 42-year-old men, respectively, 21.9% and 18.6% of GPs would measure PSA. Patient request and concern could be potential reasons for measuring PSA for asymptomatic patients. Almost all GPs stated that a PSA measurement is indicated for symptomatic 49- and 78-year-old men, respectively, 98.9% and 93.8%. Conclusion. Opportunistic PC screening is being performed in general practice to a high degree. Hence, current guidelines are not followed, and intense focus should be on more effective implementation strategies in order to avoid overuse of PSA.