PubMed Health⌕ Search

Biomedical subjects

L B Knudsen

Publications and source records attributed to L B Knudsen.

At least 19 recordsLinked to original sources
PubMed2003

Different domains of the glucagon and glucagon-like peptide-1 receptors provide the critical determinants of ligand selectivity.

(1) Glucagon and glucagon-like peptide-1 (GLP-1) are homologous peptide hormones with important functions in glucose metabolism. The receptors for glucagon and GLP-1 are homologous family B G-protein coupled receptors. The GLP-1 receptor amino-terminal extracellular domain is a major determinant of glucagon/GLP-1 selectivity of the GLP-1 receptor. However, the divergent residues in glucagon and GLP-1 that determine specificity for the GLP-1 receptor amino-terminal extracellular domain are not known. Less is known about how the glucagon receptor distinguishes between glucagon and GLP-1. (2) We analysed chimeric glucagon/GLP-1 peptides for their ability to bind and activate the glucagon receptor, the GLP-1 receptor and chimeric glucagon/GLP-1 receptors. The chimeric peptide GLP-1(7-20)/glucagon(15-29) was unable to bind and activate the glucagon receptor. Substituting the glucagon receptor core domain with the GLP-1 receptor core domain (chimera A) completely rescued the affinity and potency of GLP-1(7-20)/glucagon(15-29) without compromising the affinity and potency of glucagon. Substituting transmembrane segment 1 (TM1), TM6, TM7, the third extracellular loop and the intracellular carboxy-terminus of chimera A with the corresponding glucagon receptor segments re-established the ability to distinguish GLP-1(7-20)/glucagon(15-29) from glucagon. Corroborant results were obtained with the opposite chimeric peptide glucagon(1-14)/GLP-1(21-37). (3) The results suggest that the glucagon and GLP-1 receptor amino-terminal extracellular domains determine specificity for the divergent residues in the glucagon and GLP-1 carboxy-terminals respectively. The GLP-1 receptor core domain is not a critical determinant of glucagon/GLP-1 selectivity. Conversely, the glucagon receptor core domain contains two or more sub-segments which strongly determine specificity for divergent residues in the glucagon amino-terminus.

Amino Acid Sequence↗
PubMed2002

The intergenerational transmission of fertility in contemporary Denmark: the effects of number of siblings (full and half), birth order, and whether male or female.

Using the Danish Fertility Database, we investigate intergenerational fertility transmission, including the relationship between the number of children born to those aged 25 and 26 years in 1994 and the number of their full sibs and half-sibs. We find that the fertility behaviour of parents and their children is positively correlated, and that half-sibs and full sibs have broadly similar effects. We do not find, in this complete national population, the strong birth order effects reported in some earlier studies. Nor do we find evidence of a weakening of intergenerational fertility transmission over time, perhaps because the greater flexibility of lifestyles in this post-transitional phase provides the extended social space within which intergenerational continuities can manifest themselves. We show that members of large families are over-represented in subsequent generations - that they have far more kin than those from smaller families - and that intergenerational continuities in fertility behaviour play a substantial role in keeping fertility higher than it would be in the absence of such transmission.

Birth Rate↗
PubMed2001

Identification of alkylidene hydrazides as glucagon receptor antagonists.

High throughput screening of our small molecule combinatorial library identified a class of benzoylnaphthalenehydrazones with modest affinity for the human glucagon receptor. Optimization of this initial hit through a series of targeted libraries and traditional medicinal chemistry led to ligands with nanomolar affinities. Pharmacological evaluation demonstrated that these ligands were competitive glucagon receptor antagonists. Intravenous administration of a representative benzoylnaphthalenehydrazone into rats attenuated glucagon-stimulated glucose levels.

Animals↗
PubMed2001

Pregnancy planning and acceptance among Danish pregnant women.

OBJECTIVE: To study how living conditions influence pregnancy planning and acceptance among Danish women. METHOD: A cross-sectional questionnaire study performed among 3516 pregnant women attending Odense University Hospital, Denmark. The study population consisted of women with spontaneous abortion, women with ectopic pregnancies, women attending antenatal care and women with induced abortion. They were divided into four groups: women with planned and accepted pregnancies (accepting planners, n=2137), women who accepted an initially unplanned pregnancy (accepting non-planners, n=1006), women who rejected an initially planned pregnancy (rejecting planners, n=31), and women with unplanned and rejected pregnancies (rejecting non-planners, n=342). The association between socio-economic characteristics and pregnancy planning and acceptance was evaluated by comparing accepting non-planners with accepting planners and by comparing rejecting planners with rejecting non-planners. The variables studied comprise age, number of children, partner relationship, education, occupation, economic situation and contraceptives. RESULTS: The characteristics of accepting non-planners and accepting planners were in accordance and in contrast to those of rejecting planners and in particular of rejecting non-planners. The contraceptive prevalence rate among accepting non-planners was 15%. Among rejecting non-planners the same figure was 51%. CONCLUSION: Accepting non-planners seemed to be in a situation which could be considered appropriate for childbirth. The contraceptive prevalence rate among accepting non-planners was low and might reflect that these women were not entirely against the thought of having a child, although they did not actively plan to have one.

Adult↗
PubMed2001

Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats.

Postprandial release of the incretin glucagon-like peptide-1 (GLP-1) has been suggested to act as an endogenous satiety factor in humans. In rats, however, the evidence for this is equivocal probably because of very high endogenous activity of the GLP-1 degrading enzyme dipeptidyl peptidase-IV. In the present study, we show that intravenously administered GLP-1 (100 and 500 microg/kg) decreases food intake for 60 min in hungry rats. This effect is pharmacologically specific as it is inhibited by previous administration of 100 microg/kg exendin(9-39), and biologically inactive GLP-1(1-37) had no effect on food intake when administered alone (500 microg/kg). Acute intravenous administration of GLP-1 also caused dose-dependent inhibition of water intake, and this effect was equally well abolished by previous administration of exendin(9-39). A profound increase in diuresis was observed after intravenous administration of both 100 and 500 microg/kg GLP-1. Using a novel long-acting injectable GLP-1 derivative, NN2211, the acute and subchronic anorectic potentials of GLP-1 and derivatives were studied in both normal rats and rats made obese by neonatal monosodium glutamate treatment (MSG). We showed previously that MSG-treated animals are insensitive to the anorectic effects of centrally administered GLP-1(7-37). Both normal and MSG-lesioned rats were randomly assigned to groups to receive NN2211 or vehicle. A single bolus injection of NN2211 caused profound dose-dependent inhibition of overnight food and water intake and increased diuresis in both normal and MSG-treated rats. Subchronic multiple dosing of NN2211 (200 microg/kg) twice daily for 10 days to normal and MSG-treated rats caused profound inhibition of food intake. The marked decrease in food intake was accompanied by reduced body weight in both groups, which at its lowest stabilized at approximately 85% of initial body weight. Initial excursions in water intake and diuresis were transient as they were normalized within a few days of treatment. Lowered plasma levels of triglycerides and leptin were observed during NN2211 treatment in both normal and MSG-treated obese rats. In a subsequent study, a 7-day NN2211 treatment period of normal rats ended with measurement of energy expenditure (EE) and body composition determined by indirect calorimetry and dual energy X-ray absorptiometry, respectively. Compared with vehicle-treated rats, NN2211 and pair-fed rats decreased their total EE corresponding to the observed weight loss, such that EE per weight unit of lean body mass was unaffected. Despite its initial impact on body fluid balance, NN2211 had no debilitating effects on body water homeostasis as confirmed by analysis of body composition, plasma electrolytes, and hematocrit. This is in contrast to pair-fed animals, which displayed hemoconcentration and tendency toward increased percentage of fat mass. The present series of experiments show that GLP-1 is fully capable of inhibiting food intake in rats via a peripherally accessible site. The loss in body weight is accompanied by decreased levels of circulating leptin indicative of loss of body fat. The profound weight loss caused by NN2211 treatment was without detrimental effects on body water homeostasis. Thus, long-acting GLP-1 derivatives may prove efficient as weight-reducing therapeutic agents for overweight patients with type 2 diabetes.

Animals↗
PubMed2000

Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration.

A series of very potent derivatives of the 30-amino acid peptide hormone glucagon-like peptide-1 (GLP-1) is described. The compounds were all derivatized with fatty acids in order to protract their action by facilitating binding to serum albumin. GLP-1 had a potency (EC(50)) of 55 pM for the cloned human GLP-1 receptor. Many of the compounds had similar or even higher potencies, despite quite large substituents. All compounds derivatized with fatty acids equal to or longer than 12 carbon atoms were very protracted compared to GLP-1 and thus seem suitable for once daily administration to type 2 diabetic patients. A structure-activity relationship was obtained. GLP-1 could be derivatized with linear fatty acids up to the length of 16 carbon atoms, sometimes longer, almost anywhere in the C-terminal part without considerable loss of potency. Derivatization with two fatty acid substituents led to a considerable loss of potency. A structure-activity relationship on derivatization of specific amino acids generally was obtained. It was found that the longer the fatty acid, the more potency was lost. Simultaneous modification of the N-terminus (in order to obtain better metabolic stability) interfered with fatty acid derivatization and led to loss of potency.

Acylation↗
PubMed2000

[Differences when it comes to induced abortion in different Danish counties].

The paper describes actual regional differences in the rate of legally induced abortions as well as different trends observed since abortion on request was introduced in 1973. The analysis is primarily based on national population-based and published data from the Registry of Legally Induced Abortions in the National Board of Health, supplemented with data from a linking with the Fertility Database. The rate of abortion has shown regional differences, being at the highest level in counties with large cities. The observed differences are related to higher age at first birth and fewer children per woman in counties with a high frequency of abortion. A large part of the differences are observed among women below age 30-35. Over time developments have shown a parallelism between the counties, even though some differences have also been observed as regards both induced abortion and fertility. Various background factors do not seem to have the same impact on the choice of induced abortion in all counties.

Abortion, Legal↗
PubMed1998

Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists.

The first non-peptide competitive human glucagon receptor antagonist, 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethan one, NNC 92-1687 (2), is described. This antagonist has a binding affinity of 20 microM (IC50) and a functional Ki = 9.1 microM at the human glucagon receptor. A structure-activity relationship (SAR) was obtained on this compound, and the results show that only the benzimidazole part can be changed without complete loss of affinity. Analogues with tert-butyl or benzyloxy groups in the 5-position of the benzimidazole moiety were found to be equipotent or slightly more potent, all displaying binding affinities around 5-20 microM. Most of the changes to the catechol and the linker gave compounds without any affinity toward the human glucagon receptor. The 3-hydroxy group could, however, in the presence of a 4-hydroxy group be changed to a methoxy or a chloro group while retaining affinity.

Animals↗
PubMed1998

Glucagon-like peptide-1 receptor expression in Xenopus oocytes stimulates inositol trisphosphate-dependent intracellular Ca2+ mobilization.

The signal transduction pathway of the cloned human glucagon-like peptide-1 (GLP-1) receptor was studied in voltage-clamped Xenopus oocytes. Binding of GLP-1(7-36)amide was associated with cAMP production, increased [Ca2+]i and activation of Ca2+-dependent Cl- current. The effect of GLP-1(7-36)amide reflects intracellular Ca2+ mobilization and was suppressed by injection of the Ca2+ chelator BAPTA and the inositol trisphosphate receptor antagonist heparin. The responses were not mimicked by the adenylate cyclase activator forskolin and unaffected by the protein kinase A (PKA) inhibitor Rp-cAMPS. We conclude that GLP-1 receptor expression in Xenopus oocytes evokes inositol trisphosphate-dependent intracellular Ca2+ mobilization independent of the cAMP/PKA signaling pathway.

Adenylyl Cyclases↗
PubMed1998

Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity.

Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or alpha-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7-36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50% of each analogue remained undegraded compared to 22.7 % for GLP-1 (7-36) amide. In vivo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3-3.9 min) than GLP-1 (7-36) amide (0.9 min; p < 0.01), but these did not exceed the C-terminal t1/2 (intact plus metabolite: analogues, 3.5-4.4 min; GLP-1 (7-36) amide, 4.1 min). Analogues were assessed for receptor binding using a cell line expressing the cloned receptor, and for ability to stimulate insulin or inhibit glucagon secretion from the isolated perfused porcine pancreas. All bound to the receptor, but only the Aib8 and Gly8 analogues had similar affinities to GLP-1 (7-36) amide (IC50; Aib8=0.45 nmol/l; Gly8=2.8 nmol/l; GLP-1 (7-36) amide=0.78 nmol/l). All analogues were active in the isolated pancreas, with the potency order reflecting receptor affinities (Aib8 > Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically active and have prolonged metabolic stability in vivo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy.

Animals↗
PubMed1998

Low birth weight and preterm birth after short interpregnancy intervals.

OBJECTIVE: Our purpose was to study low birth weight and preterm birth after short interpregnancy intervals. STUDY DESIGN: Follow-up of a cohort of a register-based random sample of women who had at least two live births in Denmark between 1980 and 1992. Frequency of preterm birth (gestational age <37 weeks) and low birth weight (<2500 gm) were studied as a function of the interpregnancy interval in 10,187 women. RESULTS: Short interpregnancy intervals (< or =8 months) were associated with preterm birth but not with low birth weight. The adjusted odds ratios for preterm birth were 3.60 (95% confidence interval 2.04 to 6.35) for intervals up to 4.00 months and 2.28 (1.49 to 3.48) for intervals between 4.01 and 8.00 months compared with deliveries after 24 to 36 months, in which the risk of preterm birth was 3.5%. Risks were higher in women with a previous pregnancy at term. Social status, age, and parity were adjusted for. CONCLUSIONS: Short interpregnancy intervals were associated with an increased risk of premature delivery. This risk should be taken into account when planning a new pregnancy.

Cohort Studies↗
PubMed1998

Women in Denmark--why do they die so young? Risk factors for premature death.

"In Denmark the life expectancy of women has been declining since 1980, and is now the lowest of all OECD countries. Based upon analyses of the different trends in mortality of 35-64-year-old women in Denmark compared to women in Norway and Sweden, national differentials in external determinants of morbidity and premature mortality are described. The excess mortality of women in Denmark is linked to lifestyle factors: tobacco smoking, alcohol and drug consumption. We discuss the possible impact of other external factors...."

Alcohol Drinking↗
PubMed1998

Registration of congenital malformations in Denmark.

General registration of congenital malformations was established in Denmark in the early 1960s as a consequence of the thalidomide tragedy. The aims of the present paper are to describe the registration of congenital malformations in Denmark since the thalidomide tragedy, to discuss the limitations of these data and to point towards possibilities for improving the registration of congenital malformations in the future. Important components in a surveillance system are compulsory detailed reporting of malformations shortly after the diagnoses have been made and continuous expert evaluation of all reports. However, since 1995 the registration of congenital malformations in Denmark is based mainly on routine discharge diagnoses from hospitals. A high quality registration of congenital malformations in Denmark would be particularly valuable, because such a register together with existing health related registers and an ongoing large scale cohort study of pregnant women would provide a unique resource for etiological research in congenital malformations. Considering the consequences of congenital malformations for the affected children, their families and society, the establishment of a high quality registration of congenital malformations seems justifiable--and the Swedish experience shows that it is feasible.

Congenital Abnormalities↗
PubMed1998

The Danish Fertility Database.

BACKGROUND: The Fertility Database (FTDB) in Statistics Denmark is solely based on data from other registers, which comprise data on a different number of birth cohorts and different time spans. The FTDB was established during 1989-1992 in order to provide a better tool for socio-demographic research on the developments in fertility. The variables included also make the register a valuable tool in medical research regarding reproductive outcome and characterization of parents. RESULTS: Based on the Register of Population Statistics, the FTDB comprises at present annual information on any woman and man in the fertile age in Denmark for the period 1980-1993, approximately 1.2 and 1.4 million persons, respectively. Their children are identified through various registers and for all children born 1973-1993 specific information on the birth was available from the Medical Register of Vital Statistics. The adult populations are described annually as regards education, occupation, income, social benefit and housing conditions. CONCLUSION: The FTDB has been used in a number of research projects; in some cases data from the FTDB have been linked with data from other registers. The FTDB is a valuable tool in demographic as well as medical research.

Adolescent↗
PubMed1998

The Danish Medical Birth Registry.

BACKGROUND: The Danish Medical Birth Registry (MBR) was established in 1968 and has been computerized since 1973. The primary purpose of the registration is to monitor the health of the newborns and of the quality of the antenatal and delivery care services, but the registry is increasingly being used in research. Major changes in registration have taken place in 1978 and 1991. The paper describes the content and usage of the MBR over time and suggests research topics for the future. RESULTS: A broad scope of studies illustrates how the MBR has been used, either as single data source, linked with data from other registries or with data from interviews or self-completed questionnaires. Validations have shown variations in the quality of data, depending on source, and have underlined the need for constant quality control. Any access to data at the individual level is subjected to special provisions laid down by the Data Surveillance Authority and also requires a permission from the National Board of Health. CONCLUSIONS: The time from conception to early childhood is an important period concerning future health for the individual. The Danish Medical Birth Registry is a valuable tool in this respect, which has not yet been used to its full potential in research or monitoring. Experience indicates that the quality of the registry depends upon having a close link to the staff responsible for delivery services and thus having the necessary specialised skills and interest.

Data Interpretation, Statistical↗