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Stig Valdemarsson, Pavo Hedner and Peter Nilsson-Ehle

Abstract. We have studied the effects of l-thyroxine substitution on lipoprotein concentrations, on the activities of lipoprotein lipase (LPL) and hepatic lipase (HL), and on the elimination rate of exogenous triglyceride in a homogeneous group of patients with hypothyroidism of pituitary origin. All were deficient of sex hormones but not of corticosteroids during the observation period.

Before treatment total plasma cholesterol, LDL cholesterol, and triglyceride levels were significantly higher than in a euthyroid control group but not as high as in patients with overt primary hypothyroidism. The activities of LPL and HL were also intermediate between those of euthyroid and overt primary hypothyroid subjects, and there was a significant reduction of the elimination rate of exogenous triglyceride. No changes were found for HDL cholesterol levels.

When the patients with secondary hypothyroidism were compared to patients with primary hypothyroidism, matched for thyroid function levels, age, sex, and weight, there were no differences with regard to plasma lipoprotein concentrations or post-heparin lipase activities.

In 3 patients with secondary hypothyroidism the lipoprotein profiles were studied by zonal ultracentrifugation and found to agree well with changes observed in primary hypothyroidism.

l-thyroxine substitution produced a normalization of lipase activities and lipoprotein concentrations in patients with secondary hypothyroidism. We conclude that there are no fundamental differences in the disturbances of the lipoprotein metabolism in primary and secondary forms of hypothyroidism.

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Stig Valdemarsson, Per Hansson, Pavo Hedner and Peter Nilsson-Ehle

Abstract. Lipoprotein concentrations and activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were measured in 70 subjects with thyroid function ranging from overt hypothyroidism over subclinical hypothyroidism and euthyroidism to hyperthyroidism.

In parallel with serum T3 (S-T3) concentrations increasing from low in hypothyroidism to high in hyperthyroidism there were gradually higher HL activities over the full spectrum of thyroid function, accompanied by decreasing levels of total and low density lipoprotein (LDL) cholesterol. High density lipoprotein (HDL) cholesterol was lower (P < 0.05) in hyperthyroidism than in euthyroidism but not significantly changed in the hypothyroid groups. HL was correlated to S-T3 (r = 0.77, P< 0.001), LDL cholesterol to log S-T3 (r = -0.76, P < 0.001), and LDL cholesterol to log HL (r = -0.55, P <0.001).

The activity of LPL was decreased (P< 0.001) in overt hypothyroidism compared to euthyroidism but, in contrast to HL, the activity of LPL was not increased in hyperthyroidism. The plasma triglyceride (P-TG) concentration was elevated (P< 0.01) in overt hypothyroidism but not significantly changed in subclinical hypothyroidism or in hyperthyroidism. The LPL activity was correlated to log S-T3 (r = 0.45, P < 0.001), P-TG to log S-T3 (r = -0.37, P< 0.01) and P-TG to log LPL activity (r= -0.71, P<0.001).

Our results demonstrate that thyroid hormones influence HL and LPL activities in different ways, suggesting different mechanisms of action. Changes in HL activity seem to be an important mechanism for the disturbance of cholesterol metabolism in thyroid dysfunction while the thyroid hormone influence on LPL seems to be of importance mainly for the disturbance in triglyceride metabolism.

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Anna-Lena Berg, Lars-Erik Hammarström, Per Hansson, Torsten Holmin and Peter Nilsson-Ehle

Abstract.

Hepatic hilar denervation, hepatic vagotomy or sham operation were performed in hypothyroid rats. Activities of hepatic lipase were measured nine days after surgery. Sham operation in itself was associated with a decrease of hepatic lipase activity by about 40% compared with non-operated animals. Both hilar denervation and hepatic vagotomy were associated with increased hepatic lipase activity (40% and 35%, compared with sham-operated animals). Liver contents of norepinephrine were reduced by about 90% after hilar denervation, whereas hepatic vagotomy did not affect norepinephrine levels. No major changes in lipids and lipoproteins were noted.

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Stig Valdemarsson, Birger Fagher, Pavo Hedner, Mario Monti and Peter Nilsson-Ehle

Abstract. Direct microcalorimetry was used for measurements of heat production in cell suspensions of platelets and adipocytes, obtained from hypothyroid patients before and after 3 months on full l-thyroxine substitution.

Platelet heat production was significantly lower than normal before treatment and increased in all 10 patients studied; the mean value increased from 51.3 ± 1.6 fW/cell before to 57.1 ± 1.8 fW/cell after therapy (P< 0.001).

Similarily, adipocyte heat production was initially significantly lower than normal and increased during treatment in all 6 patients investigated. The mean value for heat production per adipocyte was 18.8 ± 1.7 pW/cell before and 32.4 ± 2.5 pW/cell after therapy (P < 0.025), which is still below the level recorded in lean healthy subjects. The adipocyte size did not change significantly. The increase in adipocyte heat production was correlated to the increase in S-triiodothyronine levels (r = 0.84, P <0.05).

In hypothyroidism, the total metabolic activity seems to be comparatively more reduced in adipocytes than in platelets. A difference may exist between these cells with regard to recovery of normal metabolic acitivity during treatment for hypothyroidism. Direct microcalorimetry appears to be an adequate method for monitoring net metabolic effects of thyroid hormones in these cells.

Open access

Sofia Enhörning, Marketa Sjögren, Bo Hedblad, Peter M Nilsson, Joachim Struck and Olle Melander

Objective

Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if the genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM.

Design

Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991–1996.

Methods

Four tag single nucleotide polymorphisms (SNPs: rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort).

Results

In MDC-CC, the major allele of rs35810727 was associated with elevated BMI (β-coefficient±s.e.m.; 0.30±0.14, P=0.03) and waist (0.78±0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21±0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00–1.20), P=0.04).

Conclusions

Genetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between the disturbance of the pharmacologically modifiable AVP system and the body weight regulation.

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Anders Ström, Agneta Mode, Peter Zaphiropoulos, Anne-Gerd Nilsson, Edward Morgan and Jan-Åke Gustafsson

Abstract. cDNA clones for P-45016α were isolated from a male liver λgt 11 expression library using antibodies against P-45016α. The clones encompassed 1633 and 1791 bp, respectively. The latter clone contained the whole coding sequence. The 20 deduced NH2-terminal amino acids were identical to those of P-450h and the cDNA sequence was in complete agreement with that of P-450 (M-1). Northern blots showed that P-45016α in the rat liver is pretranslationally regulated by the growth hormone secretory pattern. Southern blots indicated that few genes belong to the same P-450 gene family as P-45016α.

Free access

Mette L Nielsen, Manan Pareek, Margrét Leósdóttir, Karl-Fredrik Eriksson, Peter M Nilsson and Michael H Olsen

Objective

To examine the predictive capability of a 1-h vs 2-h postload glucose value for cardiovascular morbidity and mortality.

Design

Prospective, population-based cohort study (Malmö Preventive Project) with subject inclusion 1974–1992.

Methods

4934 men without known diabetes and cardiovascular disease, who had blood glucose (BG) measured at 0, 20, 40, 60, 90 and 120 min during an OGTT (30 g glucose per m2 body surface area), were followed for 27 years. Data on cardiovascular events and death were obtained through national and local registries. Predictive capabilities of fasting BG (FBG) and glucose values obtained during OGTT alone and added to a clinical prediction model comprising traditional cardiovascular risk factors were assessed using Harrell’s concordance index (C-index) and integrated discrimination improvement (IDI).

Results

Median age was 48 (25th–75th percentile: 48–49) years and mean FBG 4.6 ± 0.6 mmol/L. FBG and 2-h postload BG did not independently predict cardiovascular events or death. Conversely, 1-h postload BG predicted cardiovascular morbidity and mortality and remained an independent predictor of cardiovascular death (HR: 1.09, 95% CI: 1.01–1.17, P = 0.02) and all-cause mortality (HR: 1.10, 95% CI: 1.05–1.16, P < 0.0001) after adjusting for various traditional risk factors. Clinical risk factors with added 1-h postload BG performed better than clinical risk factors alone, in predicting cardiovascular death (likelihood-ratio test, P = 0.02) and all-cause mortality (likelihood-ratio test, P = 0.0001; significant IDI, P = 0.0003).

Conclusion

Among men without known diabetes, addition of 1-h BG, but not FBG or 2-h BG, to clinical risk factors provided incremental prognostic yield for prediction of cardiovascular death and all-cause mortality.

Free access

Mette Lundgren Nielsen, Manan Pareek, Margrét Leósdóttir, Kurt Højlund, Karl-Fredrik Eriksson, Peter M Nilsson and Michael Hecht Olsen

Abstract

Objective

To examine the impact of follow-up duration on the incremental prognostic yield of a baseline oral glucose tolerance test (OGTT) for predicting type 2 diabetes and to assess the discrimination ability of blood glucose (BG) obtained at different time points during OGTT.

Design

A prospective, population-based cohort study (Malmö Preventive Project) with inclusion of subjects from 1974 to 1992.

Methods

A total of 5256 men without diabetes, who had BG measured at 0, 20, 40, 60, 90, and 120 min during OGTT (30 g/m2 glucose), were followed for 30 years. Incident type 2 diabetes was recorded using registries. The performance of OGTT added to a clinical prediction model (age, body mass index (BMI), diastolic blood pressure, fasting BG, triglycerides, and family history of diabetes) was assessed using Harrell’s concordance index (C-index) and integrated discrimination improvement (IDI).

Results

Median age was 48 years, mean BMI 24.9 kg/m2, and mean fasting BG 4.7 mmol/L. Models with added post-load BG performed better than the clinical model (C-index: P = 0.08 for BG at 120 min at 5 years, otherwise P ≤ 0.045; IDI: P ≥ 0.06 for BG at 60 and 90 min at 5 years, otherwise P ≤ 0.01). With a longer follow-up duration, C-index decreased, and the C-index increase associated with OGTT was attenuated. Models including BG at 60 or 90 min performed significantly better than the model with BG at 120 min, evident beyond follow-up of 10 and 5 years, respectively.

Conclusions

OGTT provided incremental prognostic yield for type 2 diabetes prediction. BG measured at 60 or 90 min provided better discrimination than BG at 120 min.

Free access

Camilla A M Glad, Lena M S Carlsson, Olle Melander, Peter Almgren, Lars Sjöström, Staffan Nilsson, Ingrid Larsson, Per-Arne Svensson and Gudmundur Johannsson

Objective

To test the hypothesis that the GH receptor (GHR) exon 3 deleted (d3)/full-length (fl) polymorphism influences anthropometry and body composition in the general population.

Design and setting

The Swedish Obese Subjects (SOS) reference study is a cross-sectional population-based study, randomly selected from a population registry. A subgroup of the population-based Malmö Diet and Cancer study (MDC-CC) was used as a replication cohort.

Methods

The SOS reference study comprises 1135 subjects (46.2% men), with an average age of 49.5 years. The MDC-CC includes 5451 successfully genotyped subjects (41.5% men), with an average age of 57.5 years. GHR d3/fl genotypes were determined using TagSNP rs6873545. Linear regression analyses were used to test for genotype–phenotype associations.

Results

In the SOS reference study, subjects homozygous for the d3-GHR weighed ∼4 kg more (P=0.011), and had larger waist-to-hip ratio (WHR, P=0.036), larger waist circumference (P=0.016), and more fat-free mass estimated from total body potassium (P=0.026) than grouped fl/d3 and fl/fl subjects (d3-recessive genetic model). The association with WHR was replicated in the MDC-CC (P=0.002), but not those with other anthropometric traits.

Conclusions

In this population-based study, the GHR d3/fl polymorphism was found to be of functional relevance and associated with central adiposity, such that subjects homozygous for the d3-GHR showed an increased abdominal obesity.

Free access

Cecilia Laurell, David Velázquez-Fernández, Kristina Lindsten, Christofer Juhlin, Ulla Enberg, Janos Geli, Anders Höög, Magnus Kjellman, Joakim Lundeberg, Bertil Hamberger, Catharina Larsson, Peter Nilsson and Martin Bäckdahl

Objective

Tumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5–2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities.

Methods

Microarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis.

Results

Unsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples.

Conclusions

Adrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.