Biomedical subjects

J E Reseland

Publications and source records attributed to J E Reseland.

At least 19 recordsLinked to original sources

PubMed2007

Long-term fluoxetine administration does not result in major changes in bone architecture and strength in growing rats.

Many studies have indicated that serotonin and its transporter play a role in bone metabolism. In this study we investigated the effect of selective serotonin re-uptake inhibitor (SSRI), fluoxetine (Prozac) on bone architecture and quality in growing female rats. We therefore administrated rats with clinically relevant doses of fluoxetine for a period of 6 months. DXA scans were performed during the treatment period in order to follow parameters as body weight, fat percentage and BMD. After 6 months of treatment, femurs were used to analyze bone architecture and bone strength, by means of microCT scans and three-point bending assays, respectively. We found a slightly diminished bone quality, reflected in a lower bone tissue strength, which was compensated by changes in bone geometry. As leptin and adiponectin could be possible factors in the serotonergic regulation of bone metabolism, we also determined the levels of these factors in plasma samples of all animals. Leptin and adiponectin levels were not different between the control group and fluoxetine-treated group, indicating that these factors were not involved in the observed changes in bone geometry and quality.

Adiponectin↗

PubMed2006

Serotonin and fluoxetine modulate bone cell function in vitro.

Recent studies have proposed a role for serotonin and its transporter in regulation of bone cell function. In the present study, we examined the in vitro effects of serotonin and the serotonin transporter inhibitor fluoxetine "Prozac" on osteoblasts and osteoclasts. Human mononuclear cells were differentiated into osteoclasts in the presence of serotonin or fluoxetine. Both compounds affected the total number of differentiated osteoclasts as well as bone resorption in a bell-shaped manner. RT-PCR on the human osteoclasts demonstrated several serotonin receptors, the serotonin transporter, and the rate-limiting enzyme in serotonin synthesis, tryptophan hydroxylase 1 (Tph1). Tph1 expression was also found in murine osteoblasts and osteoclasts, indicating an ability to produce serotonin. In murine pre-osteoclasts (RAW264.7), serotonin as well as fluoxetine affected proliferation and NFkappaB activity in a biphasic manner. Proliferation of human mesenchymal stem cells (MSC) and primary osteoblasts (NHO), and 5-HT2A receptor expression was enhanced by serotonin. Fluoxetine stimulated proliferation of MSC and murine preosteoblasts (MC3T3-E1) in nM concentrations, microM concentrations were inhibitory. The effect of fluoxetine seemed direct, probably through 5-HT2 receptors. Serotonin-induced proliferation of MC3T3-E1 cells was inhibited by the PKC inhibitor (GF109203) and was also markedly reduced when antagonists of the serotonin receptors 5-HT2B/C or 5-HT2A/C were added. Serotonin increased osteoprotegerin (OPG) and decreased receptor activator of NF-kappaB ligand (RANKL) secretion from osteoblasts, suggesting a role in osteoblast-induced inhibition of osteoclast differentiation, whereas fluoxetine had the opposite effect. This study further describes possible mechanisms by which serotonin and the serotonin transporter can affect bone cell function.

3T3 Cells↗

PubMed2003

The hypotriglyceridemic effect of dietary n-3 FA is associated with increased beta-oxidation and reduced leptin expression.

To study the mechanisms responsible for the hypotriglyceridemic effect of marine oils, we monitored the effects of high dietary intake of n-3 PUFA on hepatic and muscular beta-oxidation, plasma leptin concentration, leptin receptor gene expression, and in vivo insulin action. Two groups of male Wistar rats were fed either a high-fat diet [28% (w/w) of saturated fat] or a high-fat diet containing 10% n-3 PUFA and 18% saturated fat for 3 wk. The hypotriglyceridemic effect of n-3 PUFA was accompanied by increased hepatic oxidation of palmitoyl-CoA (125%, P < 0.005) and palmitoyl-L-carnitine (480%, P < 0.005). These findings were corroborated by raised carnitine palmitoyltransferase-2 activity (154%, P < 0.001) and mRNA levels (91%, P < 0.01) as well as by simultaneous elevation of hepatic peroxisomal acyl-CoA oxidase activity (144%, P < 0.01) and mRNA content (82%, P < 0.05). In contrast, hepatic carnitine palmitoyltransferase-1 activity remained unchanged despite a twofold increased mRNA level after n-3 PUFA feeding. Skeletal muscle FA oxidation was less affected by dietary n-3 PUFA, and the stimulatory effect was found only in peroxisomes. Dietary intake of n-3 PUFA was followed by increased acyl-CoA oxidase activity (48%, P < 0.05) and mRNA level (83%, P < 0.05) in skeletal muscle. The increased FA oxidation after n-3 PUFA supplementation of the high-fat diet was accompanied by lower plasma leptin concentration (-38%, P < 0.05) and leptin mRNA expression (-66%, P < 0.05) in retroperitoneal adipose tissue, and elevated hepatic mRNA level for the leptin receptor Ob-Ra (140%, P < 0.05). Supplementation of the high-fat diet with n-3 PUFA enhanced in vivo insulin sensitivity, as shown by normalization of the glucose infusion rate during euglycemic hyperinsulinemic clamp. Our results indicate that the hypotriglyceridemic effect of dietary n-3 PUFA is associated with stimulation of FA oxidation in the liver and to a smaller extent in skeletal muscle. This may ameliorate dyslipidemia, tissue lipid accumulation, and insulin action, in spite of decreased plasma leptin level and leptin mRNA in adipose tissue.

Animals↗

PubMed2002

Altered plasma concentrations of leptin, transforming growth factor-beta(1) and plasminogen activator inhibitor type 2 at 18 weeks of gestation in women destined to develop pre-eclampsia. Circulating markers of disturbed placentation?

BACKGROUND: In many pre-eclamptic women the placentation process seems to be disturbed. Our objective was to investigate if disturbed placentation in pre-eclamptic women may be recognized in early second trimester as altered plasma levels of factors involved in the formation of the uteroplacental unit. METHODS: In a prospective study of 2190 pregnant women we compared plasma leptin, transforming growth factor-beta(1) (TGF-beta(1)) and plasminogen activator inhibitor type 2 (PAI-2) concentrations at 18 weeks' gestation in 71 women with subsequent pre-eclampsia and 71 controls matched for age, parity and first trimester body mass index. RESULTS: Leptin and TGF-beta(1) concentrations were lower and PAI-2 concentration higher in women destined to develop pre-eclampsia relative to controls (leptin: median (25-75 percentiles): 19.0 (14.5-29.0) vs 25.0 (16.0-35.0) ng/ml (p =0.03), TGF-beta(1): 3.2 (2.0-6.1) vs 5.3 (3.8-7.1) ng/ml (P=0.01) and PAI-2: 78.8 (65.1-118.1) vs 67.6 (61.6-79.6) ng/ml (P=0.002)). OR (95 per cent CI) for pre-eclampsia for women in the upper quartile compared to women in the lower quartile were: leptin: 0.2 (0.03-0.7), TGF-beta(1): 0.2 (0.08-0.7) and PAI-2: 3.1 (1.2-8.2). CONCLUSIONS: Altered plasma concentrations levels of factors involved in the process of placentation in women destined to develop pre-eclampsia, indicate that disturbed formation of the uteroplacental unit is reflected in the maternal circulation before 20 weeks' gestation.

Adult↗

PubMed2002

An increase in peroxisomal fatty acid oxidation is not sufficient to prevent tissue lipid accumulation in hHTg rats.

We observed earlier that increased skeletal muscle lipid content in the hereditary hypertriglyceridemic (hHTg) rat is accompanied by a decline in plasma leptin. Leptin has recently been shown to enhance peripheral insulin sensitivity by decreasing the tissue triglyceride accumulation, possibly through regulation of fatty acid oxidation and lipogenesis. Thus, to test the hypothesis that insulin resistance and increased skeletal muscle lipid accumulation in hHTg rats are due to a defect in lipid catabolism, we measured mitochondrial and peroxisomal fatty acid oxidation and malonyl-CoA and acetyl-CoA carboxylase-2 content in skeletal muscles of these animals. In addition, we investigated possible molecular mechanisms responsible for the lower leptin levels in hHTg rats by measuring leptin and leptin-receptor (Ob-Ra) mRNA levels. We found the following: (1) in spite of a higher skeletal muscle malonyl-CoA content and an increased sensitivity of carnitine palmitoyltransferase-1 to malonyl-CoA, carnitine palmitoyltransferase-1 activity in muscle of hHTg rats was normal; (2) increased peroxisomal fatty acid oxidation did not seem to be sufficient to prevent the tissue lipid accumulation in these animals; (3) both lower leptin production by white adipose tissue and increased leptin uptake seem to be responsible for lower circulating leptin levels and therefore lower fatty acid catabolism.

Animals↗

PubMed2001

Effect of long-term changes in diet and exercise on plasma leptin concentrations.

BACKGROUND: Although it is known that plasma leptin concentrations correlate with the amount of adipose tissue in the body, little information is available on the long-term effects on leptin concentrations of changes in diet and exercise. OBJECTIVE: We wanted to examine whether changes in dietary energy sources and exercise-mediated energy expenditure, alone or in combination, affect plasma leptin concentrations. DESIGN: In a randomized, 2 x 2 factorial trial, 186 men with metabolic syndrome were divided into 4 groups: diet, exercise, a combination of diet and exercise, and control. Data on dietary intake, physical fitness, and demographics were collected and plasma leptin concentrations were measured before and after a 1-y intervention period. RESULTS: Plasma leptin concentrations, body mass index, and fat mass decreased in association with long-term reductions in food intake as well as increased physical activity. By adjusting for either body mass index or fat mass, we observed a highly significant reduction in plasma leptin concentration after both the diet and the exercise interventions. There was no interaction between the interventions, suggesting a direct and additive effect of changes in diet and physical activity on plasma leptin concentrations. CONCLUSION: Long-term changes in lifestyle consisting of decreased intake of dietary fat and increased physical activity reduced plasma leptin concentrations in humans beyond the reduction expected as a result of changes in fat mass.

Adipose Tissue↗

PubMed2001

Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization.

The adipose hormone leptin and its receptor are important for regulation of food intake and energy metabolism. Leptin also is involved in the growth of different tissues. In this study, we show the expression of leptin in primary cultures of normal human osteoblasts (hOBs) as evidenced by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemistry. Release of leptin into the medium also was found. Leptin was not detected in commercially available hOBs (NHOst) or in three different human monoclonal osteosarcoma cell lines. Leptin expression was observed in OBs in the mineralization and/or the osteocyte transition period but not during the matrix maturation period. Furthermore, hOBs and osteosarcoma cell lines expressed the long signal-transducing form of the leptin receptor (OB-Rb) as shown by RT-PCR. We observed no significant changes in leptin or OB-Rb genes in hOBs after incubation with recombinant leptin, indicating no autoregulation of the leptin expression. Incubation of both hOBs entering the mineralization phase and osteosarcoma cell lines with recombinant leptin markedly increased the number of mineralized nodules as shown by alizarin S staining. These findings indicate that leptin may be of importance for osteoblastic cell growth and bone mineralization.

3T3 Cells↗

PubMed2001

Pharmacological interference with transcriptional control of osteoblasts: a possible role for leptin and fatty acids in maintaining bone strength and body lean mass.

Osteoblasts pass through a sequence of events controlled by hormones and transcriptional factors ensuring proper development of phenotype and functional properties until the osteoblast enter the osteocyte phenotype and/or undergo apoptosis. During its life cycle, the osteoblasts proliferate, deposit matrix proteins and mineralize it until they turn into osteocytes believed to constitute a mechanosensor mesh giving feed-back to the osteoblast to initiate bone modeling or remodeling necessary for the making or remaking of proper bone architecture and strength. It appears that several factors common to osteoblast and adipocyte differentiation determine their entry into different functional stages. Such factors are insulin, growth hormone (GH), insulin-like growth factor type I (IGF-I), transforming growth factor beta (TGFbeta), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), cytokines (e.g. interleukins, interferon and tumor necrosis factor alpha (TNF alpha), bone morphogenetic proteins (BMPs), glucocorticoids, retinoic acid (RA), prostaglandins and cAMP-elevating hormones. The focus of this article is to review the effects of leptin on bone cells and bone turnover, the peroxisome proliferator-activated receptors (PPARs) in the regulation of bone and fat cell differentiation, hormones and fatty acids on the orchestration of osteoblast and adipocyte derived regulatory signals, and mechanostimulation of bone on the mechanisms by which the above mentioned factors modulate osteoblast and adipocyte function. The hypothesis or concept is that prescription of a certain treatment regimen to correct bone turnover, without attempting to assess how hormonal homeostasis, nutritional factors and physical exercise may interact locally, will remain far from optimal, and may even prove detrimental to the patient's health condition.

Adipocytes↗

PubMed2001

Smoking related to plasma leptin concentration in pregnant women and their newborn infants.

UNLABELLED: Leptin, a hormone produced in adipose tissue and placenta, is potentially important in relation to energy metabolism and growth. We investigated the effect of cigarette smoking on maternal plasma leptin concentration during pregnancy, and on plasma leptin concentration and weight among infants up to 13 wk of age. Plasma leptin concentration was measured in women in week 18 (n = 203) and week 35 (n = 164) of pregnancy, while cotinine (nicotine metabolite) was measured in plasma sampled from mothers in week 35 of pregnancy (n = 159). Leptin concentration was also measured in plasma from the umbilical cord (n = 133) and from 4-wk-old (n = 129) and 13-wk-old (n = 130) infants. There was no difference in plasma leptin concentration between smoking and non-smoking mothers at 18 wk and at 35 wk of pregnancy. Plasma cotinine concentration was higher in smoking than in non-smoking mothers, and a negative correlation between plasma cotinine and leptin concentrations was found. The leptin concentrations in umbilical cord plasma were similar, although the birthweights of newborns from smoking mothers were significantly lower than those from non-smoking mothers. The plasma leptin concentrations were similar between the two groups also at 4 wk of age. At 13 wk of age, infants of smoking mothers had significantly higher plasma leptin concentrations than infants of non-smoking mothers. CONCLUSION: Our results indicate that a lower birthweight of neonates among smoking mothers is not due to altered plasma leptin concentration.

Adult↗

PubMed2001

Reduction of leptin gene expression by dietary polyunsaturated fatty acids.

Supplementation with n-3 polyunsaturated fatty acids (PUFA) for 6 weeks did not alter plasma leptin concentrations in male smokers. Changes in dietary intake of saturated fatty acids (FA) correlated positively, whereas changes in the intake of PUFA correlated negatively to changes in plasma leptin levels. A 3-week n-3 PUFA-enriched diet, as compared with a 3-week lard-enriched diet, induced lower plasma leptin concentration and reduced leptin mRNA expression in rat epididymal adipose tissue. In the human trophoblast cell line (BeWo), n-3 PUFA had a dose- and time-dependent effect on leptin expression. One mM of eicosapentaenoic acid or docosahexaenoic acid (DHA) reduced leptin expression by 71% and 78%, respectively, as compared with control, after 72 h. There was no effect on expression of the signal transducing form of the leptin receptor. In BeWo cells transfected with the human leptin promoter, we found that n-3 PUFA reduced leptin promoter activity; in contrast saturated and monounsaturated FA had no effect on leptin promoter activity. The transcription factors peroxysomal proliferator activated receptor gamma and sterol regulatory element binding protein-1 mRNAs were reduced after incubation with n-3 PUFA, whereas the expression of CCAAT/enhancer binding protein alpha was unchanged. DHA-reduced leptin expression was abolished in BeWo cells grown in cholesterol-free medium. In conclusion, n-3 FA decreased leptin gene expression both in vivo and in vitro. The direct effects of PUFA on leptin promoter activity indicate a specific regulatory action of FA on leptin expression.

Adipose Tissue↗

PubMed1999

[Leptin--a fatty tissue hormone with many functions].

The importance of genetic factors in obesity is under investigation. During the last few years, our understanding of the regulation of body weight in mammals has broadened to include several new proteins based on the cloning of genes from rodent mutants and characterization of their effects on energy stores and metabolism. Since its discovery in 1994, leptin has been acknowledged as an adipocyte-derived signal molecule, able to limit food intake and increase energy expenditure by interacting with specific leptin receptors located in the central nervous system and in peripheral tissues. Leptin is also important for growth, reproduction and neuroendocrine signalling. Although leptin is mainly synthesized in adipocytes, it is also expressed in the placenta, epithelium of the stomach and breast glands and, under certain conditions, in skeletal muscles. The importance of leptin is demonstrated by the discovery of mutations in the genes encoding leptin and its receptor among some subjects with morbid obesity and infertility. Plasma concentration of leptin should be measured in obese infertile adolescents since replacement could be curative among individuals with leptin deficiency.

Adipose Tissue↗

PubMed1999

Decreased CD4+ lymphocyte activation and increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation.

We investigated the effects of acute starvation on mitogen-induced T-cell activation and Th1/Th2 cytokine responses in rheumatoid arthritis (RA) patients. Ten RA patients with active disease underwent a 7-day fast followed by a 2-week refeeding period. Immunological, hormonal, laboratory and clinical evaluations were carried out on days 0, 7 and 21. Using flow cytometry, mitogen-stimulated T-cell activation was assessed in fresh heparinised blood via analysis of CD69 expression. Production of Th1 (interferon-gamma) and Th2 (interleukin-4, IL-4) cytokines was also assessed by ELISA. The 7-day fast significantly decreased the erythrocyte sedimentation rate, C-reactive protein level, joint count, morning stiffness, body weight, CD4+ and CD8+ counts and CD69+ expression on mitogen stimulated CD4+ lymphocytes. A significant increase in mitogen-induced IL-4 production after fasting was found. The fast markedly reduced serum leptin and insulin-like growth factor-1 concentrations. No significant differences occurred in serum cortisol or prolactin before and after fasting. Decreases in CD4+ lymphocyte activation during fasting correlated with decreases in body weight. Our results suggest that the clinical and laboratory improvements in fasting RA patients may be attributed to decreased CD4+ T-cell activation and an increase in the number and/or function of IL-4-producing Th2 cells. Factors associated with loss of body weight during acute starvation appear to have an inhibitory effect on CD4+ lymphocyte activation.

Adult↗

PubMed1998

Leptin levels in pregnant women and newborn infants: gender differences and reduction during the neonatal period.

OBJECTIVE: Leptin is a highly hydrophilic protein that circulates in plasma as a 16-kDa protein. It is produced in adipose tissue and also recently described to be synthesized by placental tissue. Plasma concentration of leptin is positively correlated to body fat mass, and administration of recombinant leptin to mice indicates that leptin participates in the regulation of food intake and energy expenditure. Leptin may have a role during initiation of human pubertal development. Gender differences have been reported among adults as well as among children, even after correction for body fat content. Little is known about variation in leptin levels during pregnancy or the level or function of leptin in the growing fetus and infants. The aim of the present study was to examine plasma concentration of leptin in pregnant women and their newborn infants during the first 3 months of life, and to relate plasma leptin concentration to body weight and gender during this period. MATERIALS AND METHODS: Among 609 women recruited to study the effect of very long-chain n-3 fatty acids during pregnancy, 180 women were selected to study leptin as well. The women were all healthy and nulli- or primiparas, and 16% were smokers. The study was randomized and double-blinded, and the participants received either 10 mL of cod liver oil (Peter Moller, avd.av Orkla ASA, Oslo, Norway) daily or the same amount of corn oil. Blood samples were taken from the mothers during pregnancy in weeks 18 and 35, and from the umbilical cord and from 4- and 14-week-old infants. The mothers' body mass index (BMI) at 18 and 35 weeks of pregnancy was calculated by using body weight recorded within 1 week or, if this was missing, by using means from weights at the closest time points before and after the sampling. The infants were weighed and measured at local health care centers. Plasma leptin concentration was measured by radio immunoassay (Linco Research, St Charles, MO) using recombinant 125I-leptin as tracer. RESULTS: We found no differences between the group receiving cod liver oil and the group receiving corn oil in any of the measured variables; thus, the groups are treated statistically as one. Leptin concentration in maternal plasma increased during pregnancy from 15.5 +/- 9.0 microg/L (n = 175) in week 18 to 17.7 +/- 10.7 microg/L (n = 166) in week 35. Mothers, pregnant with female fetuses (n = 77), had a significant increase in plasma leptin concentration, from 15.5 +/- 8.8 microg/L (n = 83) at 18 weeks to 18.5 +/- 10.9 microg/L (n = 80) at 35 weeks of pregnancy, whereas in mothers pregnant with male fetuses, the increase was insignificant (15.4 +/- 9.3 microg/L (n = 92) to 17.0 +/- 10.5 microg/L (n = 86). BMI increased during the same time period, from 24.2 +/- 3.3 kg/m to 27.8 +/- 3.8 kg/m (n = 174). There was a significant correlation between BMI and plasma leptin concentration at 18 weeks (r = 0.54, n = 169) and at 35 weeks (r = 0.45, n = 160), but we found no change in the relative leptin concentration (plasma leptin concentration/BMI) from week 18 to week 35. We found no significant difference between smokers and nonsmokers in plasma leptin concentration, neither at 18 nor 35 weeks of pregnancy. Gender differences in plasma leptin concentration was present already at birth in umbilical cord plasma (10.8 +/- 9.2 microg/L for girls [n = 65] vs 7.6 +/- 6.6 microg/L for boys [n = 74]). We also observed gender differences in plasma leptin concentration at 4 weeks (3.9 +/- 1.8 microg/L, n = 68 vs 3.2 +/- 1.8 microg/L, n = 71) and 14 weeks of age (4.9 +/- 2.1 microg/L, n = 61 vs 4.1 +/- 3.1 microg/L, n = 73). Plasma leptin levels at 4 and 14 weeks were lower than the level in umbilical cord plasma (n = 101). An increase in plasma leptin concentration was observed from 4 to 14 weeks of age, both for girls (n = 48) and for boys (n = 60). Leptin concentration in umbilical cord plasma correlated with birth weight (r = 0.44, n = 139), and there was significant corre

Adipose Tissue↗

PubMed1997

A novel human chymotrypsin-like digestive enzyme.

The gene of a novel chymotrypsin-like serine protease has been cloned from human pancreas. The chymotrypsin-like enzyme-1 gene is located on chromosome 16q22.1 in a tight cluster with four unrelated genes. The gene has seven exons with the signal and activation peptide and the three main catalytic residues forming the active site encoded by separate exons. Northern blots of pancreatic mRNA showed a major transcript of 1.0 kilobases and a minor transcript of 1.3 kilobases due to alternative polyadenylation. No transcript was found in other tissues. Its presence in pancreatic tissue, duodenal juice, and urine was demonstrated with antisera raised against synthetic peptides from the derived amino acid sequence of the gene. The peptide sequences were chosen for being most dissimilar to chymotrypsin, and the antisera obtained did not react with purified human chymotrypsin. The proteolytically active CTRL-1 has been identified in pancreatic homogenate, duodenal juice, and urine, and a recombinant CTRL-1 has been characterized. Increased pancreatic secretion of CTRL-1 was induced by protease inhibitors indicating that the enzyme is secreted from pancreas upon feedback stimulation. Both native and recombinant CTRL-1 displayed chymotrypsin- and elastase-2-like activities and hydrolyzed the amide bonds of substrates having tyrosine, phenylalanine, or leucine residues at the P1 position. The enzyme was active over a broad pH range (6.5-9. 0), with a maximum at pH 8.0-8.5. CTRL-1 was produced as a zymogen of 264 amino acids as deduced from the gene sequence, with a sequence identity of 54% with human chymotrypsin B. The number and location of intron/exon junctions as well as the sequence similarity to chymotrypsin both at the DNA and protein level and the presence in duodenal juice indicate that this is a novel digestive enzyme of the chymotrypsin superfamily, albeit one with distinct physiological and biochemical features.

Amino Acid Sequence↗

PubMed1996

Proteinase inhibitors induce selective stimulation of human trypsin and chymotrypsin secretion.

Among the variety of signals stimulating pancreatic secretion, cholecystokinin (CCK) and related hormones are assumed to be responsible for modulating proteinase output. In some species, intraduodenal tryptic activity has to be abolished to demonstrate feedback-induced CCK release. The aim of this study was to investigate in vivo effects of modest inhibition of intraduodenal proteolytic enzymes on the secretion patterns of pancreatic enzymes and plasma CCK concentrations. Two inhibitors (Kunitz trypsin inhibitor and Bowman-Birk inhibitor) were applied. Intermittent sampling of plasma nd duodenal juice was performed during intraduodenal saline and inhibitor instillations in six healthy volunteers. Enzyme activities and concentrations were determined in the duodenal samples and expressed as percentage of basal values. Instillation of Kunitz trypsin inhibitor caused an increase in trypsin and the pancreatic secretory trypsin inhibitor (PSTI), without changes in plasma CCK. This result demonstrates, for the first time, that pancreatic exocrine secretion of trypsin and chymotrypsin is regulated by different mechanisms. Bowman-Birk inhibitor additionally stimulated the secretion of chymotrypsin and carboxypeptidase A and B and increased plasma CCK. Elastase 1 and amylase secretions were not increased by either instillations. Although the inhibitors have similar in vitro inhibition patterns, their in vivo effects are different. The nonparallel secretion of proteinases (trypsin, chymotrypsin and elastase 1) supports the view of a complex system involved in feedback regulation of human pancreatic exocrine secretion, including signals other than CCK.

Adult↗

PubMed1995

Inhibitor-stimulated non-parallel pancreatic secretion in man: hormonal and neural regulation?

BACKGROUND: We wanted to study whether a total inhibition of tryptic activity in the duodenum would induce a cholecystokinin (CCK)-dependent increase in pancreatic exocrine proteinase secretion. METHODS: Concentrations of CCK and activities and concentrations of pancreatic enzymes were measured in human plasma and duodenal juices, respectively, collected during continuous intraduodenal instillations of proteinase inhibitors, with and without intravenous atropine administration. RESULTS: Inhibitor instillation totally abolished tryptic activity and reduced the chymotryptic and elastase (1 and 2) activities by 95-100%. The inhibitors caused a rapid increase in the concentrations of trypsin, chymotrypsin, and pancreatic secretory trypsin inhibitor (PSTI) but had only a slight or no effect on amylase and elastase 1 secretion. An enhanced secretion of PSTI lends support to a possible connection between PSTI (resembling the monitor peptide causing CCK release in rats) and the enzyme secretion in man. CCK increased from 7 to 12-13 pmol/l. Intravenous atropine almost completely blocked the inhibitor-stimulated enzyme and PSTI secretion and reduced amylase activity by 50%. A further significant (P = 0.002) increase in the inhibitor-induced CCK output was found during atropine administration, as compared with the test situation without atropine. CONCLUSION: The inhibitor-induced pancreatic secretion during total inhibition of tryptic activity shows a non-parallel secretion requiring different signals for different enzymes. The increase in plasma CCK levels indicates that CCK is feedback-regulated by both an inhibitor-mediated decrease in duodenal enzyme activity and a further decrease in pancreatic enzyme secretion by atropine.

Atropine↗

PubMed1992

Raw soybeans stimulate human pancreatic proteinase secretion.

Intraduodenal instillation of raw soybeans stimulated pancreatic proteinase secretion in humans. Raw soybeans almost abolished the activity of chymotrypsin and severely reduced (50%) the tryptic activity. Immunoreactive tryptic and chymotryptic material simultaneously appeared in amounts 2 to 4 times basal concentrations. This increase, demonstrated with rocket immunoelectrophoresis, was begun within the first 10 min of soybean instillation. The enhanced secretion also persisted throughout the succeeding saline instillation, and it is suggested that the presence of Kunitz trypsin inhibitor contributed to this postprandial stimulation. An amidase that hydrolyzes low-molecular-weight substrates (i.e., benzoyl-arginine p-nitroanilide) was found in raw soybeans. Its low activity was not assumed to substantially bias standard trypsin assays. The increased proteinase secretion was, as previously published, not preceded by an elevated plasma cholecystokinin concentration. The raw soybeans also caused a nonparallel secretion of amylase and proteinases. Nervous, perhaps cholinergic, regulation mediates the inhibitor-stimulated proteinase secretion in humans. This stimulation yields both a general increase of proteinases and also a specific inhibitor-resistant trypsin. This is consistent with the physiologic need for proenzyme-activation in the presence of inhibitors and for restoration of the proteolytic capacity of the duodenal juice.

Amylases↗

PubMed1991

Characterization of a human trypsin resistant to Kunitz soybean trypsin inhibitor. Studies of duodenal juices after tube instillation of raw soybean extract.

Human duodenal juices collected during tube instillation of raw soybean extract into the duodenum contained free trypsin and free Kuntiz soybean trypsin inhibitor (KTI) in the simultaneous presence of trypsin-KTI complexes. It has previously been suggested that this KTI-non-inhibitable trypsin has a general resistance to serine protease inhibitors. Four different trypsin forms have been found and partly characterized by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and isoelectric focusing followed by Western immunoblotting or enzyme staining. In addition, crossed immunoelectrophoresis and affinity chromatography with antibody-coupled gels have been used for identification of free and inhibitor-complexed trypsin.

Blotting, Western↗