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Biomedical subjects

K Ekberg

Publications and source records attributed to K Ekberg.

At least 37 records · Page 2Linked to original sources
PubMed2001

C-peptide: a new potential in the treatment of diabetic nephropathy.

C-peptide is formed in the biosynthesis of insulin and the two peptides are subsequently released in equimolar amounts to the circulation. C-peptide has long been considered to be without physiologic effects. Recent data now demonstrate that C-peptide in the nanomolar concentration range binds specifically to cell surfaces, probably to G protein-coupled receptors, with subsequent activation of Ca(2+)-dependent intracellular signaling pathways and stimulation of Na+, K(+)-ATPase activities. C-peptide replacement in animal models of type 1 diabetes results in diminished hyperfiltration, improved functional reserve, reduction of urinary albumin excretion, and prevention of glomerular and renal hypertrophy. Administration of C-peptide to physiologic concentrations in patients with type 1 diabetes and incipient nephropathy for periods of 3 hours to 3 months is accompanied by reduced glomerular hyperfiltration and filtration fraction, and diminished urinary albumin excretion. C-peptide replacement together with insulin therapy may be beneficial in type 1 diabetes patients with nephropathy.

Animals↗
PubMed2001

Quantitative contributions of gluconeogenesis to glucose production during fasting in type 2 diabetes mellitus.

Contributions of gluconeogenesis to glucose production were determined between 14 to 22 hours into a fast in type 2 diabetics (n = 9) and age-weight-matched controls (n = 7); ages, 60.4 +/- 2.3 versus 55.6 +/- 1.2 years and body mass indices (BMI) 28.6 +/- 2.3 versus 26.6 +/- 0.8 kg/m2. Production was measured using a primed-continuous [6,6-2H2]glucose infusion and gluconeogenesis from 2H enrichment at carbons 2 and 5 of blood glucose on 2H2O ingestion. Plasma glucose concentration declined from 9.6 +/- 0.6 at 14 hours to 7.3 +/- 0.6 at 22 hours in the diabetics (P = .001) and from 5.4 +/- 0.1 to 5.0 +/- 0.1 in the controls (P < .05). Production from the 17th to 22nd hour declined 27.1% +/- 0.6% in the diabetics versus 18.5% +/- 0.8% in the controls (P = .001); from 10.4 +/- 0.3 to 7.6 +/- 0.2 versus 10.0 +/- 0.4 to 8.2 +/- 0.4 micromol/kg/min. Percent contributions of gluconeogenesis to production measured at 1 1/2 to 2-hour intervals beginning the 15th hour were 6.8% +/- 1.0% more in the diabetics than controls. The quantity of glucose contributed by gluconeogenesis declined 19.8% +/- 3.8% (P < .001) in the diabetics and 6.9% +/- 2.3% in the controls (P = .05); 7.21 +/- 0.32 to 5.74 +/- 0.26 versus 6.20 +/- 0.28 to 5.75 +/- 0.24 micromol/kg/min. The contribution of glycogenolysis to production, estimated from the difference between production and gluconeogenesis, declined to the same extent in diabetic and control subjects, 40.7% +/- 6.6% and 37.7% +/- 4.1%; from 3.23 +/- 0.35 to 1.86 +/- 0.26 versus 3.81 +/- 0.22 to 2.42 +/- 0.28 micromol/kg/min. Thus, gluconeogenesis contributed more to glucose production in the diabetic than control subjects. Production and the contribution of gluconeogenesis declined more in the diabetic subjects during the fast. The factors regulating these changes remain uncertain.

Deuterium↗
PubMed2001

Lipid metabolism during fasting.

These studies were conducted to understand the relationship between measures of systemic free fatty acid (FFA) reesterification and regional FFA, glycerol, and triglyceride metabolism during fasting. Indirect calorimetry was used to measure fatty acid oxidation in six men after a 60-h fast. Systemic and regional (splanchnic, renal, and leg) FFA ([(3)H]palmitate) and glycerol ([(3)H]glycerol) kinetics, as well as splanchnic triglyceride release, were measured. The rate of systemic FFA reesterification was 366 +/- 93 micromol/min, which was greater (P < 0.05) than splanchnic triglyceride fatty acid output (64 +/- 6 micromol/min), a measure of VLDL triglyceride fatty acid export. The majority of glycerol uptake occurred in the splanchnic and renal beds, although some leg glycerol uptake was detected. Systemic FFA release was approximately double that usually present in overnight postabsorptive men, yet the regional FFA release rates were of the same proportions previously observed in overnight postabsorptive men. In conclusion, FFA reesterification at rest during fasting far exceeds splanchnic triglyceride fatty acid output. This indicates that nonhepatic sites of FFA reesterification are important, and that peripheral reesterification of FFA exceeds the rate of simultaneous intracellular triglyceride fatty acid oxidation.

3-Hydroxybutyric Acid↗
PubMed2001

Sources of blood glycerol during fasting.

To determine the source(s) of blood and very low density lipoprotein (VLDL)-triglyceride glycerol during fasting, four men ingested (2)H(2)O from 14 to 20 h into a 60-h fast to achieve ~0.5% body water enrichment. At 60 h of fasting, glycerol flux was measured using [2-(14)C]glycerol. Blood was taken for measurement of (2)H enrichment at carbon 6 of glucose and at carbon 3 of free glycerol and VLDL-triglyceride glycerol. (2)H enrichment of the 2 hydrogens bound to carbon 3 of VLDL-triglyceride glycerol was 105 +/- 2% of the (2)H enrichment of the 2 hydrogens bound to carbon 6 of glucose, indicating isotopic equilibrium between hepatic glyceraldehyde 3-P and glycerol 3-P. The (2)H enrichment of the 2 hydrogens bound to carbon 3 of free glycerol was 17 +/- 3% of VLDL-triglyceride glycerol, indicating that a significant percentage of free glycerol in blood originated from the hydrolysis of circulating VLDL-triglyceride or a pool of glycerol with similar (2)H enrichment. Glycerol flux was 6.3 +/- 1.1 micromol. kg(-1). min(-1). Glycerol appearing from nonadipose tissue sources was then approximately 1.1 micromol. kg(-1). min(-1). Seven other subjects were fasted for 12, 42, and 60 h. A small percentage of glycerol in the circulation after 12 h of fasting was enriched with (2)H. The enrichment of the 2 hydrogens bound to carbon 3 of free glycerol in the longer periods of fasting was approximately 16% of the enrichment of the 2 hydrogens bound to carbon 6 of glucose. Therefore, as much as 15-20% of systemic glycerol turnover during fasting is not from lipolysis of adipose tissue triglyceride.

Adult↗
PubMed2001

Diminished skin blood flow in Type I diabetes: evidence for non-endothelium-dependent dysfunction.

The purpose of this study was to quantify the extent to which skin blood flow (SBF) responses to application of endothelium-dependent and -independent vasodilating agents differ between Type I diabetic patients and healthy subjects. Patients and matched controls were studied after an overnight fast. SBF was determined with laser Doppler perfusion imaging before and after iontophoresis of acetylcholine (Ach; endothelium-dependent) and sodium nitroprusside (SNP; endothelium-independent). Basal SBF did not differ significantly between groups. Iontophoresis of ACh and SNP increased SBF 20-fold in controls. In the patients, the increases in SBF following iontophoresis of ACh and SNP were reduced by 18% and 19%, respectively, versus controls (P<0.05 for both). These data demonstrate that Type I diabetic patients have similar diminished SBF responses to iontophoresis of ACh and SNP, which suggests that non-endothelial-dependent factors are primarily responsible for the diminished SBF responses.

Acetylcholine↗
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

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↗
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

Brain substrate utilisation during acute hypoglycaemia.

AIMS/HYPOTHESIS: Our study was undertaken to examine directly the utilisation of glucose and alternative substrates, in particular amino acids, during hypoglycaemia. METHODS: Catheters were positioned in the jugular venous bulb and an artery in six healthy subjects in the overnight fasted state. Arterio-venous differences for glucose, amino acids, lactate and pyruvate were measured in the basal state, during hyperinsulinaemic euglycaemia and during hyperinsulinaemic hypoglycaemia. The subjects were studied on two different occasions, once during intravenous infusion of amino acids and once during infusion of saline. RESULTS: In the basal state the fractional extraction of glucose across the brain was 10 +/- 2%, glucose uptake accounted for 106 +/- 5% of the brain's oxidative metabolism. There was a small release of lactate and pyruvate. During hyperinsulinaemia glucose uptake continued to account for the entire fuel requirement of the brain. Hyperaminoacidaemia did not result in net amino acid uptake by the brain. During hypoglycaemia (2.4 +/- 0.2 mmol/l) fractional extraction of glucose by the brain increased (p < 0.01) and glucose uptake accounted for 90 +/- 15% of the brain's oxidative metabolism. Uptake of amino acids, lactate or pyruvate could not be detected. CONCLUSION/INTERPRETATION: 1) Brain fractional extraction of glucose increases during hypoglycaemia, 2) hyperinsulinaemia does not change fractional extraction of glucose by the brain, 3) augmented availability of amino acids does not result in brain amino acid uptake during euglycaemia or hypoglycaemia and 4) under the present study conditions glucose remains the major substrate for cerebral metabolism during hypoglycaemia; lactate or pyruvate uptake by the brain can not be detected.

Acute Disease↗
PubMed1999

Splanchnic exchange of insulin-like growth factor binding protein-1 (IGFBP-1), IGF-I and acid-labile subunit (ALS) during normo- and hyper-insulinaemia in healthy subjects.

OBJECTIVE: The main source of circulating IGF-I, insulin like growth factor binding protein-1 (IGFBP-1) and acid-labile subunit (ALS) is considered to be the liver, but their production rates have not been determined in healthy individuals. Thus, the splanchnic exchange of IGFBP-1, IGF-I, ALS and glucose were studied. STUDY DESIGN: In five overnight fasting healthy, normal weight men (mean age 29 +/- 1 years) blood samples were taken from a hepatic vein, a brachial artery and a peripheral vein in the basal state and during 3 h i.v. infusion of insulin (1.0 mU/kg/min). Normoglycaemia was maintained with a variable glucose infusion and splanchnic blood flow was determined using a constant rate indicator infusion technique. RESULTS: The basal net splanchnic glucose output amounted 0.96 +/- 0. 09 mmol/min and the splanchnic production of IGFBP-1 was 7 +/- 2 microg/min. There was a net splanchnic uptake of IGF-I (7 +/- 2 microg/min) in the basal state, while no significant splanchnic exchange of ALS was found. During the insulin infusion, insulin concentration increased from 78 +/- 12 to 660 +/- 30 pmol/l, resulting in a complete inhibition of splanchnic glucose production after 40 min of infusion. Splanchnic IGFBP-1 production rose initially to 13 +/- 4 microg/min (P < 0.05) and then gradually decreased and was completely inhibited at 180 min (P < 0.05). Insulin infusion influenced neither ALS nor IGF-I splanchnic exchange. CONCLUSION: Splanchnic production of IGFBP-1 in the basal state was demonstrated and it is completely inhibited after 180 min of hyperinsulinaemia. In contrast to what is generally held, there was no net splanchnic production of IGF-I in the basal state or during insulin stimulation.

Adult↗
PubMed1999

Whole body protein kinetics using Phe and Tyr tracers: an evaluation of the accuracy of approximated flux values.

Phenylalanine (Phe) kinetics are increasingly used in studies of amino acid kinetics, because the metabolic fate of Phe is limited to incorporation into protein (protein synthesis, Sp) and catabolism via hydroxylation (Qpt) to tyrosine (Tyr). Besides an infusion of labeled Phe to measure Phe flux (Qp), a priming dose of Tyr and an independent Tyr tracer are used to measure Tyr flux (Qt) and Qpt. Alternatively, Qt, Qpt, and Sp can be approximated by using equations, based on Phe and Tyr concentrations in body proteins, that eliminate the need for a Tyr tracer. To evaluate the accuracy of this approach, data were obtained from 12 type I diabetic patients and 24 nondiabetic control subjects who were studied with the full complement of tracers both with and without insulin infusion. Sp approximations closely matched measured values in both groups (mean difference <2%, all values <5%), but the agreement was poor for Qpt (error range = -8 to +43%) and Qt (error range -22 to +41%). Insulin status had no effect on these comparisons. The lower approximation error for Sp vs. Qpt is due to the small contribution ( approximately 10%) of Qpt to Qp. Approximation error for Qpt (r > 0.99) can be explained by variability in the ratio of Tyr to Phe coming from protein breakdown, (Qt - Qpt)/Qp. Ideally, all fluxes should be directly measured, but these data suggest that whole body Sp can be approximated with an acceptably small margin of error. However, the same equations do not yield reliably accurate values for Qpt or Qt.

Adult↗
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

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

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↗