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Biomedical subjects

J Wahren

Publications and source records attributed to J Wahren.

At least 37 records · Page 2Linked to original sources
PubMed2000

Site of nicotine absorption from a vapour inhaler--comparison with cigarette smoking.

OBJECTIVE: The aim of the study was to assess the site of nicotine absorption during and after use of a nicotine-vapour inhaler compared with that after cigarette smoking. METHODS: Using a catheterisation technique, the nicotine plasma concentration-time profiles in arterial and jugular venous blood after using a nicotine inhaler were compared with those achieved after cigarette smoking a in seven healthy habitual smokers. RESULTS: After use of the inhaler, arterial nicotine concentrations rose slowly to a maximum level of 5. 9 +/- 1.5 ng/ml at a mean time to reach peak concentration (t(max)) of 9.0 +/- 1.1 min, whereas jugular venous nicotine levels peaked at 25.4 +/- 5.4 ng/ml at 6.7 +/- 0.3 min. The concentration-time curves indicate that the absorption occurs mainly via the mucosa of the oral cavity and the pharynx, and that there is minimal absorption via the lungs. In contrast, after smoking a cigarette, arterial nicotine plasma concentrations rose quickly to a maximum level of 49. 2 +/- 9.7 ng/ml after 4.0 +/- 0.6 min, while the maximum concentration of nicotine in the jugular vein was 22.4 +/- 3.9 ng/ml after 6.4 +/- 0.4 min, indicating primarily pulmonary absorption of nicotine. CONCLUSION: Nicotine absorption after use of the vapour inhaler occurs primarily via the mucosa of the oral cavity; the absorption occurs slowly and the arterial nicotine concentration spike, typical of cigarette smoking, is avoided. Thus, the likelihood for abuse of the nicotine inhaler is probably small.

Absorption↗
PubMed2000

Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus.

AIMS: Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy. METHODS: Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months. RESULTS: Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 microg/min (basal) to 34 microg/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 +/- 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05). CONCLUSION: These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

Adult↗
PubMed2000

Role of C-peptide in human physiology.

The C-peptide of proinsulin is important for the biosynthesis of insulin but has for a long time been considered to be biologically inert. Data now indicate that C-peptide in the nanomolar concentration range binds specifically to cell surfaces, probably to a G protein-coupled surface receptor, with subsequent activation of Ca(2+)-dependent intracellular signaling pathways. The association rate constant, K(ass), for C-peptide binding to endothelial cells, renal tubular cells, and fibroblasts is approximately 3. 10(9) M(-1). The binding is stereospecific, and no cross-reaction is seen with insulin, proinsulin, insulin growth factors I and II, or neuropeptide Y. C-peptide stimulates Na(+)-K(+)-ATPase and endothelial nitric oxide synthase activities. Data also indicate that C-peptide administration is accompanied by augmented blood flow in skeletal muscle and skin, diminished glomerular hyperfiltration, reduced urinary albumin excretion, and improved nerve function, all in patients with type 1 diabetes who lack C-peptide, but not in healthy subjects. The possibility exists that C-peptide replacement, together with insulin administration, may prevent the development or retard the progression of long-term complications in type 1 diabetes.

Amino Acid Sequence↗
PubMed2000

Effects of proinsulin C-peptide on nitric oxide, microvascular blood flow and erythrocyte Na+,K+-ATPase activity in diabetes mellitus type I.

This study was conducted to evaluate the influence of proinsulin C-peptide on erythrocyte Na(+),K(+)-ATPase and endothelial nitric oxide synthase activities in patients with type I diabetes. In a randomized double-blind study design, ten patients with type I diabetes received intravenous infusions of either human C-peptide or physiological saline on two different occasions. C-peptide was infused at a rate of 3 pmol.min(-1).kg(-1) for 60 min, and thereafter at 10 pmol.min(-1).kg(-1) for 60 min. At baseline and after 60 and 120 min, laser Doppler flow (LDF) was measured following acetylcholine iontophoresis or mild thermal stimulation (44 degrees C), and venous blood samples were collected to determine plasma cGMP levels and erythrocyte membrane Na(+),K(+)-ATPase activity. The LDF response to acetylcholine increased during C-peptide infusion and decreased during saline infusion [18.6+/-19.2 and -13.2+/-9.4 arbitrary units respectively; mean+/-S.E.M.; P<0.05). No significant change in LDF was observed after thermal stimulation. The baseline plasma concentration of cGMP was 5.5+/-0.6 nmol.l(-1); this rose to 6.8+/-0.9 nmol.l(-1) during C-peptide infusion (P<0.05). Erythrocyte Na(+),K(+)-ATPase activity increased from 140+/-29 nmol of P(i).h(-1).mg(-1) in the basal state to 287+/-5 nmol of P(i). h(-1).mg(-1) during C-peptide infusion (P<0.01). There was a significant linear relationship between plasma C-peptide levels and erythrocyte Na(+),K(+)-ATPase activity during the C-peptide infusion (r=0.46, P<0.01). No significant changes in plasma cGMP levels or Na(+),K(+)-ATPase activity were observed during saline infusion. This study demonstrates an effect of human proinsulin C-peptide on microvascular function, which might be mediated by an increase in NO production and an activation of the erythrocyte Na(+),K(+)-ATPase. These mechanisms are compatible with the previous observed microvascular effects of C-peptide in patients with type I diabetes.

Acetylcholine↗
PubMed1999

Specific binding of proinsulin C-peptide to human cell membranes.

Recent reports have demonstrated beneficial effects of proinsulin C-peptide in the diabetic state, including improvements of kidney and nerve function. To examine the background to these effects, C-peptide binding to cell membranes has been studied by using fluorescence correlation spectroscopy. Measurements of ligand-membrane interactions at single-molecule detection sensitivity in 0.2-fl confocal volume elements show specific binding of fluorescently labeled C-peptide to several human cell types. Full saturation of the C-peptide binding to the cell surface is obtained at low nanomolar concentrations. Scatchard analysis of binding to renal tubular cells indicates the existence of a high-affinity binding process with K(ass) > 3.3 x 10(9) M(-1). Addition of excess unlabeled C-peptide is accompanied by competitive displacement, yielding a dissociation rate constant of 4.5 x 10(-4) s(-1). The C-terminal pentapeptide also displaces C-peptide bound to cell membranes, indicating that the binding occurs at this segment of the ligand. Nonnative D-C-peptide and a randomly scrambled C-peptide do not compete for binding with the labeled C-peptide, nor were crossreactions observed with insulin, insulin-like growth factor (IGF)-I, IGF-II, or proinsulin. Pretreatment of cells with pertussis toxin, known to modify receptor-coupled G proteins, abolishes the binding. It is concluded that C-peptide binds to specific G protein-coupled receptors on human cell membranes, thus providing a molecular basis for its biological effects.

Binding, Competitive↗
PubMed1999

Rat C peptide I and II stimulate glucose utilization in STZ-induced diabetic rats.

AIMS: To study the effects of physiological concentrations of rat proinsulin C peptide I and II, respectively, on whole body glucose utilization in streptozotocin diabetic and healthy rats. METHODS: A sequential insulin clamp procedure was used (insulin infusion rates 3.0 and 30.0 mU.kg-1.min-1) in awake animals. C-peptide infusion rates were 0.05 and 0.5 nmol.kg-1.min-1. Blood glucose was clamped at 7.7 +/- 0.3 mmol/l in the diabetic rats and at 3.9 +/- 0.1 mmol/l in the healthy rats. RESULTS: In diabetic rats infused at lower rates of C peptide and insulin, glucose utilization increased by 79-90% (p < 0.001) compared with diabetic animals infused with saline and insulin. Increasing the rate of C-peptide infusion tenfold did not elicit a statistically significant further increase in glucose utilization. C peptide I and II exerted similar effects. The metabolic clearance rate for glucose in the diabetic animals infused with C peptide was not different from that of the healthy rats. During high-dose insulin infusion (30.0 mU.kg-1.min-1) glucose utilization increased considerably and no statistically significant C-peptide effects were observed. About 85% of the increase in glucose utilization induced by C peptide could be blocked by treatment with N-monomethyl-L-arginine. CONCLUSIONS/INTERPRETATION: Physiological concentrations of homologous C peptide stimulate whole body glucose utilization in diabetic but not in healthy rats. C peptide I and II elicit similar effects. The influence of C peptide on glucose utilization may be mediated by nitric oxide.

Animals↗
PubMed1999

Arterial KIC as marker of liver and muscle intracellular leucine pools in healthy and type 1 diabetic humans.

In human protein turnover studies with isotopically labeled leucine (Leu) as a tracer, plasma ketoisocaproate (KIC) enrichment is extensively used as a surrogate measure of intracellular leucine enrichment. To test how accurately arterial ketoisocaproate (A-KIC) represents leucine isotopic enrichment in the hepatic (HV) and femoral veins (FV), which drain liver and muscle beds, we measured Leu and KIC enrichments in samples collected from HV, FV, and femoral artery (A) in 24 control and 6 type I diabetic subjects after a primed, continuous infusion of L-[1-(13)C,(15)N]-Leu. Studies were performed during insulin deprivation or insulin replacement in the diabetic group, whereas the effect of normal saline or three different doses of insulin infusion (0.25, 0.50, and 1 mU. kg(-1). min(-1)) were assessed in healthy controls. The ratios of baseline isotopic enrichments of A-KIC to HV Leu and FV Leu were 0.93 +/- 0.01 and 0.94 +/- 0.02, respectively, in normal subjects and 1.07 +/- 0.04 and 1.05 +/- 0.03, respectively, in diabetic subjects (P < 0.01, diabetic vs. normal subjects). Insulin did not change A-KIC-to-HV Leu ratios in either group, but the A-KIC-to-FV Leu ratio decreased during insulin infusion in normal subjects (P < 0.05). In conclusion, A-KIC represents a reliable surrogate measure of HV Leu enrichment at different levels of circulating insulin in humans. The present data support the use of A-KIC as a surrogate precursor pool for hepatic protein synthesis.

Adult↗
PubMed1999

Origins of the hydrogen bound to carbon 1 of glucose in fasting: significance in gluconeogenesis quantitation.

Healthy subjects ingested (2)H(2)O. (2)H enriched the hydrogen bound to carbon 1 of blood glucose 1.3 to 1.8 times more than the hydrogens bound to carbon 6. Enrichment at carbon 1 was more than at carbon 5 after 14 h, but not after 42 h, of fasting. After overnight fasting, when [2,3-(3)H]succinate was infused, 34 times as much (3)H was bound to carbon 6 as to carbon 1. On [1-(2)H,1-(3)H, 1-(14)C]galactose infusion, the ratios of (2)H to (14)C and of (3)H to (14)C in blood glucose were 30% less than in the galactose. (3)H at carbon 6 was 1% of that at carbon 1 of the glucose. Thus, although the two hydrogens bound to carbon 1 and the two bound to carbon 6 of fructose 6-phosphate (p) during gluconeogenesis are equally enriched in (2)H via pyruvate's equilibration with alanine, one of each is further enriched via hydration of fumarate that is converted to glucose. That hydrogen at carbon 1 of fructose 6-phosphate (P) is also enriched in fructose 6-P's equilibration with mannose 6-P. (2)H from (2)H(2)O at carbon 1 to carbon 2 of blood glucose cannot then quantitate gluconeogenesis because of [1-(2)H]glucose formation during glycogenolysis. Triose-P cycling has a minimal effect on quantitation. (2)H recovery in glucose from [1-(2)H]galactose does not quantitate galactose conversion via UDP-glucose to glycogen.

Adult↗
PubMed1999

Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting.

Contributions of renal glucose production to whole-body glucose turnover were determined in healthy individuals by using the arteriovenous balance technique across the kidneys and the splanchnic area combined with intravenous infusion of [U-13C6]glucose, [3-(3)H]glucose, or [6-(3)H]glucose. In the postabsorptive state, the rate of glucose appearance was 11.5 +/- 0.6 micromol x kg(-1) x min(-1). Hepatic glucose production, calculated as the sum of net glucose output (9.8 +/- 0.8 micromol x kg(-1) x min(-1)) and splanchnic glucose uptake (2.2 +/- 0.3 micromol x kg(-1) x min(-1)) accounted for the entire rate of glucose appearance. There was no net exchange of glucose across the kidney and no significant renal extraction of labeled glucose. The renal contribution to total glucose production calculated from the arterial, hepatic, and renal venous 13C-enrichments (glucose M+6) was 5 +/- 2%. In the 60-h fasted state, the rate of glucose appearance was 8.2 +/- 0.3 micromol x kg(-1) x min(-1). Hepatic glucose production, estimated as net splanchnic output (5.8 +/- 0.7 micromol x kg(-1) x min(-1)) plus splanchnic uptake (0.6 +/- 0.3 micromol x kg(-1) x min(-1)) accounted for 79% of the rate of glucose appearance. There was a significant net renal output of glucose (0.9 +/- 0.3 micromol x kg(-1) x min(-1)), but no significant extraction of labeled glucose across the kidney. The renal contribution to whole-body glucose turnover calculated from the 13C-enrichments was 24 +/- 3%. We concluded that 1) glucose production by the human kidney in the postabsorptive state, in contrast to recent reports, makes at most only a minor contribution (approximately 5%) to blood glucose homeostasis, but that 2) after 60-h of fasting, renal glucose production may account for 20-25% of whole-body glucose turnover.

Adult↗
PubMed1998

Gene fragment polymerization gives increased yields of recombinant human proinsulin C-peptide.

A multimerization strategy to improve yields upon recombinant production of the 31-aa human proinsulin C-peptide is presented. Gene fragments encoding the C-peptide were assembled using specific head-to-tail multimerization. DNA constructs encoding one, three or seven copies of the C-peptide gene, fused to a serum albumin binding affinity tag, were expressed intracellularly in Escherichia coli. The three fusion proteins were produced at similar levels (approximately 50 mg/l) and were proteolytically stable during production. Enzymatic digestion by trypsin-carboxypeptidase B treatment of the fusion proteins was shown to efficiently release native C-peptide, as determined by mass spectrometry, reverse-phase chromatography and a radioimmunoassay. The quantitative yields of C-peptide obtained from the three different fusion proteins suggest that this multimerization strategy could provide a cost-efficient production scheme for the C-peptide, and that this strategy could be useful also for production of other recombinant peptides.

Amino Acid Sequence↗
PubMed1998

Differential effects of proinsulin C-peptide fragments on Na+, K+-ATPase activity of renal tubule segments.

Proinsulin C-peptide has been shown to stimulate the activity of Na+ K+ ATPase of rat renal tubule segments. Thirty-six peptides and amino acids, corresponding to parts of the intact rat C-peptide and suitable controls were screened for capacity to stimulate Na+, K+-ATPase in an attempt to determine potential active sites in the C-peptide molecule. The carboxy-terminal tetra and penta peptides were found to elicit 92-103% of the intact molecule's activity, and the remaining segment, des-(27-31) C-peptide, did not possess stimulatory activity. Peptides from the middle C-peptide segment, however, centering around a GGPEAG sequence, stimulated Na+, K+-ATPase activity (36-80% of the intact molecule's effect) but this effect was not balanced by corresponding inactivity of other parts. Furthermore, it was paralleled by activity of a non-native dipeptide D-form. It is concluded that the latter effect and that of the middle segment may represent complex interactions other than the apparently specific effects of the C-terminal segment.

Amino Acid Sequence↗
PubMed1998

Cerebral effects of nicotine during cognition in smokers and non-smokers.

For the smoker, nicotine has a positive effect on attention, cognition and mood. Conversely, nicotine abstinence is characterized by uncomfortable psychological effects such as impaired attention, but also irritability. We postulated that nicotine exerts an effect on cerebral areas important for attention and mood. Regional cerebral blood flow (rCBF), as an index for cerebral activity, was measured in both smokers and non-smokers. They were scanned during performance of a psychometric task with and without i.v. infusion of nicotine (1-methyl-2-[3-pyridyll] pyrrolidine). Nicotine induced rCBF decreases in the anterior cingulate cortex and the cerebellum, and concomitant increases in the occipital cortex. The changes were similar in nature and magnitude in smokers and non-smokers. Thus, specific changes were induced in areas pertaining to the anterior attention system and to higher order visual cortex. We conclude that these effects on cerebral activity provide insights into the desired positive effects of nicotine on cognition as well as the negative effects experienced during nicotine abstinence.

Adult↗
PubMed1998

New aspects on biological activity of C-peptide in IDDM patients.

C-peptide, which is released from the pancreatic beta cells into the circulation in amounts equimolar with insulin, fulfills an important function in the assembly of the two-chain insulin structure, but has otherwise been considered to be biologically inactive. However, during the last few years several experimental and clinical studies have demonstrated that replacement of C-peptide in patients with insulin-dependent diabetes mellitus elicits several physiological effects. Thus, during short-term substitution of C-peptide (1-3 h) decreased glomerular hyperfiltration, augmented whole body and skeletal muscle glucose utilisation, improved autonomic nerve function and a redistribution of microvascular skin blood flow could be observed. In addition, replacement of C-peptide during a period of 1-3 months has been shown to improve renal function as well as autonomic and sensory nerve function in IDDM patients. The mechanisms behind these effects remain unclear, but recent investigations have indicated that an increase in Na+K+ATPase activity and a stimulation of the endothelial nitric oxide synthase may contribute to the observed physiological effects of C-peptide. Not only the intact C-peptide molecule, but also fragments from the C-terminal and mid-portion of the molecule have been shown to exert biological effects. Further research will be necessary to evaluate the underlying mechanism and the clinical impact of C-peptide replacement in IDDM patients.

C-Peptide↗
PubMed1998

Ernst-Friedrich-Pfeiffer Memorial Lecture. New aspects of C-peptide physiology.

C-peptide is co-secreted with insulin and has generally been considered not to possess biological activity. However, several recent studies during the last five years have demonstrated that administration of C-peptide in physiological amounts to type 1 diabetes (IDDM) patients on a short term basis (1-3h) results in decreased glomerular hyperfiltration, augmented glucose utilization and improved autonomic nerve function. More prolonged administration (1-3 months) of C-peptide to IDDM patients is accompanied by improvements in both renal function (diminished microalbuminuria) and autonomic and sensory nerve function. Both in vitro and in vivo data indicate that C-peptide may have a role in the regulation of insulin secretion. C-peptide's mechanism of action is not known but it may be related to its ability to stimulate Na+, K(+)-ATPase, activity, probably by activating a receptor coupled to a pertussis toxin-sensitive G-protein with subsequent activation of Ca2(+)-dependent intracellular signaling pathways. In conclusion, the combined findings indicate that C-peptide is a biologically active hormone. The possibility that C-peptide therapy in IDDM patients may be beneficial should be considered.

Albuminuria↗
PubMed1998

Limitations in estimating gluconeogenesis and Cori cycling from mass isotopomer distributions using [U-13C6]glucose.

Tayek and Katz proposed calculating gluconeogenesis's contributions to glucose production and Cori cycling from mass isotopomer distributions in blood glucose and lactate during [U-13C6]glucose infusion [Tayek, J. A., and J. Katz. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E476-E484, 1997]. However, isotopic exchange was not adequately differentiated from dilution, nor was condensation of labeled with unlabeled triose phosphates properly equated. We introduce and apply corrected equations to data from subjects fasted for 12 and 60 h. Impossibly low contributions of gluconeogenesis to glucose production at 60 h are obtained (23-41%). Distributions in overnight-fasted normal subjects calculate to only approximately 18%. Cori cycling estimates are approximately 10-15% after overnight fasting and 20% after 60 h of fasting. There are several possible reasons for the underestimates. The contribution of gluconeogenesis is underestimated because glucose production from glycerol and amino acids not metabolized via pyruvate is ascribed to glycogenolysis. Labeled oxaloacetate and alpha-ketoglutarate can exchange during equilibrium with circulating unlabeled aspartate, glutamate, and glutamine. Also, the assumption that isotopomer distributions in arterial lactate and hepatic pyruvate are the same may not be fulfilled.

Adult↗
PubMed1998

Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation.

We have previously demonstrated that the brain contains about 80% of the 24S-hydroxycholesterol in the human body and that there is a net flux of this steroid from the brain into the circulation (Lütjohann, D. et al. 1996. Proc. Natl. Acad. Sci. USA. 93: 9799-9804). Combining previous data with new data on 12 healthy volunteers, the arteriovenous difference between levels of this oxysterol in the internal jugular vein and in a peripheral artery was found to be -10.2 +/- 2.8 ng/ml (mean +/- SEM) corresponding to a net flux of 24S-hydroxycholesterol from the brain of about 6.4 mg/24 h. The arteriovenous difference between levels of 24S-hydroxycholesterol in the hepatic vein and a peripheral artery of 12 other volunteers was found to be 7.4 +/- 2.2 ng/ml, corresponding to a hepatic uptake of about 7.6 mg/24 h. The concentrations of 24S-hydroxycholesterol in the renal vein were about the same as those in a peripheral artery, indicating that a renal elimination is not of importance. Intravenously injected deuterium-labeled racemic 24-hydroxycholesterol was eliminated from the circulation of two human volunteers with half-lives of 10 h and 14 h, respectively. A positive correlation was found between the levels of circulating cholesterol and 24S-hydroxycholesterol. The results are consistent with a cerebral origin of most of the circulating 24S-hydroxycholesterol and suggest that the liver is the major eliminating organ. It is concluded that conversion into 24S-hydroxycholesterol is a quantitatively important mechanism for elimination of cholesterol from human brain. The possibility is discussed that circulating levels of 24S-hydroxycholesterol can be used as a marker for pathological and/or developmental changes in the brain.

Adult↗
PubMed1997

Smokeless tobacco use and atherosclerosis: an ultrasonographic investigation of carotid intima media thickness in healthy middle-aged men.

There is well-documented evidence of accelerated atherosclerosis in smokers but the mechanisms still remain unclear. The relationship to the use of smokeless tobacco, involving high exposure to nicotine, have not been evaluated before. The possible role of nicotine was investigated in a clinical study of the intima media thickness in the carotid artery of 143 healthy, middle-aged men (35-60 years old) with different tobacco consumption habits. B-mode ultrasonography was performed and biochemical risk factors for cardiovascular disease (serum lipids, serum lipoproteins and plasma fibrinogen) were determined. Long term smokeless tobacco users (n = 28) did not differ significantly from never-users (n = 40) regarding bulb intima media thickness (0.80 +/- 0.13 versus 0.78 +/- 0.12 mm) or common carotid intima media thickness (0.67 +/- 0.11 versus 0.68 +/- 0.11 mm), whereas smokers (n = 29) had significantly increased wall measurements (bulb 0.87 +/- 0.19, P = 0.002 common carotid 0.74 +/- 0.13, P = 0.03) compared to never-users. Only in smokers were biochemical risk factors significantly altered towards an elevated risk. Significant effects of interaction of smoking and increased s-cholesterol levels on carotid intima media thickness were also found. Smokeless tobacco users showed similar tendencies, but without definite statistical significance. On the basis of these data, it appears most likely that the increased occurrence of atherosclerosis in smokers is caused by other components of tobacco smoke than nicotine.

Adult↗