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Biomedical subjects

Markku Koulu

Publications and source records attributed to Markku Koulu.

11 recordsLinked to original sources
PubMed2006

Nutrient intake, weight, and Leu7Pro polymorphism in prepro-neuropeptide Y in children.

CONTEXT: The important role of neuropeptide Y (NPY) in the regulation of food intake and energy balance has been firmly documented in rodents, but human data are sparse. The recently identified functional Leu7Pro polymorphism in the signal peptide region of the prepro-NPY is a useful tool for the investigation of the role of NPY in men. Pro7 substitution has been associated with the following: plasma NPY concentration, the risk factors of cardiovascular disease, birth weight of children, serum triglyceride concentration, and the function of vascular endothelium. OBJECTIVE: The objective of this study was to analyze the connection between Leu7Pro polymorphism and relative weight, nutrient intakes, and serum lipids in early childhood. We closely followed 647 healthy Finnish children participating in the Special Turku Risk Factor Intervention Project through their first 9 yr of life. RESULTS: Leu7Pro polymorphism showed no relation to intakes of energy, macronutrients, or the relative weight in either gender. However, Pro7 substitution was associated with serum triglyceride concentration in boys at the ages of 5, 7, and 9 yr. CONCLUSION: The functional Leu7Pro polymorphism is not likely to be involved in the regulation of adiposity or major nutrient preferences in childhood. In boys, the Pro7 variant may have impact on serum triglyceride concentration.

Amino Acid Substitution↗
PubMed2006

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Journal Article↗
PubMed2005

The Leu7Pro polymorphism of preproNPY is associated with decreased insulin secretion, delayed ghrelin suppression, and increased cardiovascular responsiveness to norepinephrine during oral glucose tolerance test.

CONTEXT: Neuropeptide Y (NPY) plays a role in angiogenesis, cardiovascular regulation, and hormone secretion. The leucine7 to proline7 (Leu7Pro) polymorphism of preproNPY is associated with vascular diseases and has an impact on hormone levels in healthy subjects. OBJECTIVE: The current study investigated the role of the Leu7Pro polymorphism in metabolic and cardiovascular autonomic regulation. DESIGN AND SUBJECTS: A 5-h oral glucose tolerance test was performed on 27 healthy volunteers representing two preproNPY genotypes (Leu7/Pro7 and Leu7/Leu7) matched for age, sex, body mass index and physical activity. MAIN OUTCOME MEASURES: Simultaneously we performed cardiovascular autonomic function tests and plasma measurements of sympathetic transmitters, glucose, insulin, and ghrelin. RESULTS: The subjects with Leu7/Pro7 genotype had decreased plasma NPY, norepinephrine (NE), and insulin concentrations and insulin to glucose ratios. The suppression of ghrelin concentrations after glucose ingestion was delayed in these subjects. They also had increased heart rate variability indices and baroreflex sensitivity. However, they displayed significant negative association of NE concentration with variability of low-frequency R-R-intervals and with baroreflex sensitivity. CONCLUSIONS: The Leu7Pro polymorphism of preproNPY is related to decreased level of basal sympathetic activity, decreased insulin secretion, and delayed ghrelin suppression during oral glucose tolerance test. The increased responsiveness of autonomic functions to NE associated with the polymorphism may be connected to increased cardiovascular vulnerability.

Adult↗
PubMed2004

Leucine7 to proline7 polymorphism in prepro-NPY gene and femoral neck bone mineral density in postmenopausal women.

Neuropeptide Y (NPY) is a versatile neurotransmitter that has recently been shown to regulate bone metabolism in animal and in vitro studies. We studied the influence of leucine7-to-proline7 (Leu7/Pro7) polymorphism of the NPY signal peptide gene on bone mineral density (BMD) before and after a 5-year hormone replacement therapy (HRT) in 316 early postmenopausal women participating in a randomized controlled trial nested in the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The participants were randomized into two treatment groups: the HRT group (n = 146) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate and calcium lactate, 500 mg/day (equal to 93 mg Ca2+) alone or in combination with vitamin D3, 100-300 IU/day. The non-HRT group (n = 170) received calcium lactate, 500 mg alone or in combination with vitamin D3, 100-300 IU/day. BMDs of the lumbar spine (L2-4) and proximal femur were measured by using dual X-ray absorptiometry (DXA). The frequency of Leu7/Pro7 polymorphism was 15.2%. At baseline, there were no significant differences in the lumbar or femoral neck BMD between the subjects who had Leu7Pro7 polymorphism and the normal subjects. After 5 years, the BMD of the femoral neck remained unaltered and that of the lumbar spine increased by 1.7% in the HRT group, whereas both BMDs were decreased by 4-5% in the non-HRT group. After 5 years, the femoral neck BMD was significantly lower in those with the wild-type NPY polymorphism than in those with Leu7/Pro7 polymorphism (P = 0.040) in the non-HRT group. In the HRT group, the changes in BMD were quite modest and not significantly modified by Leu7/Pro7 genotype. We conclude that the Leu7/Pro7 polymorphism in NPY signal gene may favorably affect femoral neck BMD in postmenopausal women.

Bone Density↗
PubMed2004

Neuropeptide Y and Y2-receptor are involved in development of diabetic retinopathy and retinal neovascularization.

BACKGROUND: Neuropeptide Y is a sympathetic neurotransmitter, a potent endothelium-derived angiogenic factor and a vascular mitogen. We have studied the role of the functional leucine7 to proline7 polymorphism of the signal peptide region of preproneuropeptide Y (prepro-NPY) as a genetic susceptibility factor for diabetic retinopathy. In addition, we investigated the role of the NPY Y2-receptor as a putative mediator of angiogenic NPY signaling in the retina. METHODS: Frequencies of proline7 (Pro7) carriers in the prepro-NPY were determined in type 1 and type 2 diabetes patients having retinopathy, in type 2 diabetes patients without retinopathy and in healthy control subjects. The role of Y2-receptor in hyperoxemia-induced retinal neovascularization was investigated in Y2-receptor knockout mice (Y2-/-) and in rats administered Y2-receptor mRNA antisense oligonucleotide. RESULTS: The carriers having Pro7 in the preproNPY are markedly over-represented among type 2 diabetes patients with retinopathy compared to type 2 diabetes patients without retinopathy and to the population control. Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide. CONCLUSIONS: NPY and Y2-receptor play important roles in diabetic retinopathy and retinal neovascularization and are thus potential new targets for drug molecules for treatment of retinopathy.

Adult↗
PubMed2004

Serum leptin concentration poorly reflects growth and energy and nutrient intake in young children.

OBJECTIVE: We studied whether the serum leptin concentration at age 2 years predicts changes in relative body weight by age 8 and whether the serum leptin concentration is associated with intake of energy and nutrients at age 5. METHODS: A total of 156 8-year-old participants of the Special Turku Coronary Risk Factor Intervention Project were chosen to represent children whose relative weight decreased, was stable, or increased during the preceding 6 years. Their serum leptin concentrations were measured in samples collected when they were 2 years. Serum leptin was also measured in 100 5-year-old children in the Special Turku Coronary Risk Factor Intervention Project whose energy and nutrient intakes were analyzed using 4-day food records. RESULTS: The boys whose relative weight decreased (n = 25), was stable (n = 28), or increased (n = 26) between 2 and 8 years of age had similar serum leptin concentrations at the age of 2 years. The girls whose relative weight decreased (n = 27) had higher serum leptin concentrations at 2 years than the girls whose relative weight remained stable (n = 26) but only when the leptin values were not adjusted for body mass index. The serum leptin concentration was higher in 5-year-old girls than in 5-year-old boys even when adjusted for body mass index. Serum leptin correlated with relative weight in girls and boys (r = 0.65 and r = 0.45, respectively). Serum leptin concentration adjusted for relative weight correlated poorly with intakes of energy, fat, saturated fat, carbohydrates, sucrose, and protein. CONCLUSIONS: Serum leptin concentrations at age 2 poorly predicted changes in relative body weight during the following 6 years and poorly reflected the intake of energy or major nutrients at age 5.

Body Weight↗
PubMed2004

Leucine 7 to proline 7 polymorphism in the preproneuropeptide Y is associated with proteinuria, coronary heart disease, and glycemic control in type 1 diabetic patients.

OBJECTIVE: Neuropeptide Y is a potent vasoconstrictor thought to enhance the development of atherosclerosis. The leucine 7 to proline 7 (Leu7Pro) polymorphism, located in the signal peptide part of the human preproneuropeptide Y, has been associated with serum lipid levels, intima-media thickness of the common carotid arteries, and diabetic retinopathy in type 2 diabetic patients. Therefore, we investigated the impact of the Leu7Pro polymorphism on diabetic nephropathy, cardiovascular risk factors, and cardiovascular disease in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 996 patients from the Finnish Diabetic Nephropathy study were studied in a case-control, cross-sectional study. The carrier frequency of the Pro7 substitution was 13% in the entire study population. RESULTS: The Pro7 substitution was more common in patients with proteinuria than in those with a normal albumin excretion rate (16 vs. 11%, P < 0.05). Patients with the Pro7 allele had worse glycemic control (HbA(1c) 8.8 vs. 8.5%, P < 0.005), more coronary heart disease (CHD) (14 vs. 8%, P < 0.05), and higher serum triglycerides (1.65 vs. 1.35 mmol/l, P < 0.005) than patients with the wild-type genotype. There were no differences in the plasma neuropeptide Y levels between the patients with Pro7 compared with those with the wild-type genotype. The Leu7Pro polymorphism was independently associated with HbA(1c) (P < 0.001), proteinuria (P < 0.01), and CHD (P < 0.01) in multiple regression analyses. CONCLUSIONS: We conclude that the Leu7Pro polymorphism may contribute to the genetic susceptibility to diabetic nephropathy and CHD in type 1 diabetic patients, possibly by influencing glycemic control and triglycerides.

Adult↗
PubMed2003

Obesity in transgenic female mice with constitutively elevated luteinizing hormone secretion.

Transgenic (TG) female mice, expressing a chimeric bovine luteinizing hormone (LH) beta-subunit/human chorionic gonadotropin beta-subunit COOH-terminal extension (bLHbeta-CTP) gene, produce high levels of circulating LH and serve as a model for functional ovarian hyperandrogenism and follicular cysts. We report here that obesity is a typical feature of these female mice. The mean body weight of the bLHbeta-CTP females was significantly higher than in controls at, and beyond 5 wk of age, and at 5 mo, it was 32% increased. At this age, the amount of white adipose tissue in the bLHbeta-CTP females was significantly increased, as reflected by the weight difference of the retroperitoneal fat pad. In addition, the expression of leptin mRNA in white adipose tissue of the TG females was elevated about twofold. Serum leptin and insulin levels, and food intake, were also increased significantly in the TG females. Brown adipose tissue (BAT) thermogenic activity, as measured by GDP binding to BAT mitochondria, was reduced (P < 0.05). Ovariectomy at the age of 3 wk totally prevented the development of obesity. In summary, the present results show that intact female bLHbeta-CTP mice are obese, have increased food consumption, and reduced BAT thermogenic activity. The weight gain can be explained partly by elevated androgens but is probably also contributed to the increased adrenal steroidogenesis. Hence, the bLHbeta-CTP mice provide a useful model for studying obesity related to elevated LH secretion, with consequent alterations in ovarian and adrenal function.

Animals↗
PubMed2003

Enhanced endothelium-dependent vasodilation in subjects with Proline7 substitution in the signal peptide of neuropeptide Y.

Neuropeptide Y (NPY) is a molecule that may have both vasoconstrictive and vasodilatory actions. A common polymorphism in the human NPY gene that results in the Leucine7 to Proline7 substitution (Leu7Pro) in the signal peptide part of the NPY was recently identified. This substitution has been associated with elevated serum cholesterol levels and with slightly accelerated progression rate of carotid intima-media thickness, thus suggesting increased risk of atherosclerosis in carriers of Pro7 substitution. Recent data also indicate that subjects with Pro7 substitution may have increased endothelial release of NPY. This study was undertaken to elucidate the effects of Leu7Pro polymorphism on arterial endothelial function. We measured flow-mediated endothelial-dependent dilatation (FMD) of the brachial artery in two separate populations: in 152 middle-aged men and in 95 prepubertal children. In both study populations, subjects with Pro7 substitution had 48-52% higher FMD compared with subjects having the wildtype (Leu7/Leu7) signal peptide sequence. We conclude that Pro7 substitution in signal peptide of the NPY is associated with enhanced endothelial-dependent vasodilation. Prospective studies are needed to determine whether Pro7 substitution is associated with increased or decreased risk of cardiovascular morbidity and mortality.

Adult↗
PubMed2003

Changes in diurnal sympathoadrenal balance and pituitary hormone secretion in subjects with Leu7Pro polymorphism in the prepro-neuropeptide Y.

Neuropeptide Y (NPY) is an important neurotransmitter in the central and peripheral nervous systems. It has a regulatory role in cardiovascular and metabolic functions and control of hormone release. The leucine 7 to proline 7 (Leu7Pro) polymorphism in the signal peptide of prepro-NPY is associated with increased blood lipid levels, accelerated atherosclerosis, and diabetic retinopathy. This study elucidated the role of this polymorphism in diurnal cardiovascular, metabolic, and hormonal functions of healthy subjects during rest. The two study groups comprised individuals with different genotype, but they were matched for age and body mass index. Subjects with the Leu7Pro polymorphism had significantly lower plasma NPY and norepinephrine concentrations, lower insulin concentrations, higher glucose concentrations, and lower insulin-glucose ratio in plasma than the controls. Heart rate was significantly higher during daytime in the subjects with Leu7Pro polymorphism. Furthermore, these subjects had significantly lower prolactin concentrations in plasma. Systolic and diastolic blood pressure, serum free fatty acid and plasma leptin, ACTH, cortisol, LH, FSH, TSH, free thyroxin, and melatonin concentrations were similar during the 24-h period, compared with controls. These results show that genetically determined changes in NPY levels lead to widespread consequences in the control of sympathoadrenal, metabolic, and hormonal balance in healthy subjects.

Adult↗