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Biomedical subjects

L A Leiter

Publications and source records attributed to L A Leiter.

At least 19 recordsLinked to original sources
PubMed1996

Use of bioelectrical impedance analysis measurements in patients with diabetes. The Diabetes Control and Complications Trial Research Group.

Weight gain is an important consequence of the intensive treatment of insulin-dependent diabetes mellitus (IDDM). Despite this, body composition in this disorder has not been well studied. Bioelectrical impedance analysis (BIA) has been shown to be a reliable, noninvasive method of assessing body composition but little is known about its use in IDDM. Therefore, a regression model estimating fat-free volume mass from bioelectrical impedance measurements obtained with proximal electrode placements was developed in 46 adults with IDDM through use of dual-energy X-ray absorptiometry (DXA) for reference values of fat-free mass. No effect of blood glucose concentration or prandial state on the impedance characteristics was observed. A regression model was developed incorporating the ratio of height squared to the minimum resistance of four limb-lead combinations (H2/R), total body weight, and a weight-sex interaction. With this model, BIA correlated closely with DXA (R2 = 0.982, residual SD = 1.3 kg). The applicability of these equations to non-insulin-dependent diabetes mellitus is unknown.

Absorptiometry, Photon↗
PubMed1996

Case report: retinopathy and neuropathy associated with complete apolipoprotein A-I deficiency.

Genetic deficiencies of plasma high-density lipoprotein cholesterol are associated variably with diseases of the eyes and nervous system. We ascertained a proband with undetectable plasma HDL-cholesterol due to homozygosity for a DNA mutation, APOA1 Q[-2]X, which encodes premature termination of translation of apolipoprotein in HDL. This person had a unique retinopathy, ataxia, and electrophysiologic abnormalities suggesting multifocal central nervous system deficits. Other gene carriers in this family had similar neurologic features, but only the proband had the retinopathy. The presence of retinopathy and neuropathy in affected family members was highly variable. This heterogeneity might results from time-dependent interactions with other genetic or environmental factors.

Adult↗
PubMed1996

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance.

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.

Acarbose↗
PubMed1995

Stimulation of glucose uptake and increased plasma membrane content of glucose transporters in L6 skeletal muscle cells by the sulfonylureas gliclazide and glyburide.

Many studies suggest that sulfonylureas (SUs) have direct extrapancreatic actions. The action of gliclazide, a new SU, was examined and compared to that of glyburide in L6 myotubes, a model of skeletal muscle. Gliclazide and glyburide increased 2-deoxy-D-glucose (2DG) uptake in a time- and dose-dependent fashion after 24 h to a maximum of 179% and 202% of the basal value, respectively (P < 0.001). Acute (30-min) insulin (10(-7) M) stimulated 2DG uptake to similar levels (203% of basal), but this effect was absent after maximum stimulation by SU. SU action did not require insulin and was not blocked by the protein synthesis inhibitor cycloheximide. To investigate the mechanism of stimulation of 2DG uptake, cells were fractionated, and total plasma membrane and internal membrane levels of glucose transporter (GLUT) isoforms were determined by immunoblotting. Both drugs significantly increased the total content (1.7-fold) and plasma membrane level (1.8-fold) of GLUT1, with no change in internal membrane. Total content and plasma membrane levels of GLUT4 and GLUT3 did not change or showed a small decrease. We conclude that the stimulation of glucose uptake in L6 cells by gliclazide and glyburide is associated not with a redistribution but, rather, with an increase in the total membrane content and plasma membrane level of GLUT1, which is independent of protein synthesis. These data suggest a novel action of SU to stabilize GLUT1 protein at the plasma membrane.

Animals↗
PubMed1995

Positive methane-producing status associated with increased serum cholesterol in subjects with impaired glucose tolerance.

OBJECTIVE: To determine if those who produce methane (i.e., have presence of methane in breath) have higher serum cholesterol than those who do not produce methane in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: We measured breath gases and fasting serum total and high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels in 21 subjects with IGT. RESULTS: The 11 methane-producers were well matched to the 10 non-methane-producers for age, sex, and body mass index. Methane-producers had higher fasting serum total (6.5 +/- 0.3 vs. 5.5 +/- 0.2 mmol/l; P < 0.02) and low-density lipoprotein (4.3 +/- 0.3 vs. 3.4 +/- 0.2 mmol/l; P < 0.05) cholesterol concentrations with no difference in TG or HDL levels. CONCLUSIONS: The results suggest that in subjects with IGT, positive methane-producing status may be associated with increased serum cholesterol levels.

Blood Glucose↗
PubMed1994

Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia.

We report a Canadian kindred with a novel mutation in the apolipoprotein (apo) A-I gene causing analphalipoproteinemia. The 34-yr-old proband, product of a consanguineous marriage, had bilateral retinopathy, bilateral cataracts, spinocerebellar ataxia, and tendon xanthomata. High density lipoprotein cholesterol (HDL-C) was < 0.1 mM and apoA-I was undetectable. Genomic DNA sequencing of the proband's apoA-I gene identified a nonsense mutation at codon [-2], which we designate as Q[-2]X. This mutation causes a loss of endonuclease digestion sites for both BbvI and Fnu4HI. Genotyping identified four additional homozygotes, four heterozygotes, and two unaffected subjects among the first-degree relatives. Q[-2]X homozygosity causes a selective failure to produce any portion of mature apoA-I, resulting in very low plasma level of HDL. Heterozygosity results in approximately half-normal apoA-I and HDL. Gradient gel electrophoresis and differential electroimmunodiffusion assay revealed that the HDL particles of the homozygotes had peak Stokes diameter of 7.9 nm and contained apoA-II without apoA-I (Lp-AII). Heterozygotes had an additional fraction of HDL3-like particles. Two of the proband's affected sisters had documented premature coronary heart disease. This kindred, the third reported apoA-I gene mutation causing isolated complete apoA-I deficiency, appears to be at significantly increased risk for atherosclerosis.

Adolescent↗
PubMed1994

Detection of a new apolipoprotein-E mutation in type III hyperlipidemia using deoxyribonucleic acid restriction isotyping.

While determining the apolipoprotein-E (apo-E) genotype of 22 patients with type III hyperlipidemia (HLP III) by restriction isotyping, we identified a new mutant form of apo-E by its unusual DNA restriction fragment length polymorphism pattern. DNA sequence analysis of a polymerase chain reaction-amplified portion of the proband's apo-E gene revealed the substitution of cysteine (TGC) for arginine (CGC) at position 136 in the mutant allele (designated R136C). Lipoproteins containing this mutant protein bound defectively to macrophages in vitro, confirming the contribution of R136C to the expression of HLP III in the proband. The proband's two siblings carried the mutant allele and were also heterozygous for E2. Each also had dysbetalipoproteinemia (indicated by the presence of beta-very low density lipoprotein), but neither was hyperlipidemic, attesting to the importance of other factors for the full expression of HLP III. The mutant allele appears to contribute to the inheritance of HLP III in a recessive fashion. Restriction isotyping facilitates the diagnosis of subjects with HLP III, aids in the identification of affected individuals through family screening, and can contribute to the discovery of new mutations that help explain the pathogenesis of HLP III.

Adult↗
PubMed1994

The use of bioelectrical impedance analysis (BIA) to estimate body composition in the Diabetes Control and Complications Trial (DCCT).

Although weight gain often accompanies intensive treatment regimens designed to achieve near-normal glycemia in insulin-dependent diabetes mellitus (IDDM), body composition (BC) has not been well studied. Bioelectrical impedance analysis (BIA) is a safe, rapid, and non-invasive method of assessing BC but has not been utilized widely in IDDM. Data from 46 adults with IDDM were used to develop a regression model estimating fat-free body mass (FFM) from bioimpedance measurements obtained using a proximal electrode placement. Reference values of FFM were determined by dual x-ray absorptiometry (DXA). A model using the ratio of height squared to the minimum resistance of 4 limb-lead combinations (H2/R), total body weight, and a weight-gender interaction achieved a high level of accuracy (R2 = 0.982, residual standard deviation = 1.43 kg), while studies of 10 subjects before and after a light meal found no short-term effect of glycemia on measured BIA variables. BIA will therefore be used in combination with waist-to-hip ratios to study the composition and distribution of the increased weight associated with intensive therapy in the DCCT.

Absorptiometry, Photon↗
PubMed1993

Consuming aspartame with and without taste: differential effects on appetite and food intake of young adult males.

Despite some reports that aspartame (APM)-sweetened beverages may increase subjective appetite, previously we demonstrated that drinking 280 ml of an APM-sweetened soft drink (170 mg APM) had no effect on appetite, and 560 ml of the same soft drink (340 mg APM) reduced appetite. The present study examined this appetite reduction to determine its cause. Eighteen normal weight young adult males received five treatments (beverage preloads) at 1100 h in a randomized order, one per week: 280 ml of carbonated mineral water (CMW) (control), 560 ml of CMW, 280 ml of CMW with 340 mg of encapsulated APM, 280 ml of CMW sweetened with 340 mg APM, 560 ml of an APM-sweetened soft drink (340 mg APM). Subjective hunger and food appeal were measured from 0930 a.m. to 1230 h, and food intake from a buffet lunch offered at 1205 h was measured. Treatment had no effect on food intake or macronutrient selection. Both 560 ml of CMW or soft drink suppressed appetite, although 280 ml of APM-sweetened mineral water significantly increased subjective appetite relative to the control. Encapsulated APM had no effect on appetite. Therefore, appetite reduction following consumption of an APM-sweetened drink is likely due to drink volume and not the APM content. In addition, consuming APM-sweetened CMW produces a short-term increase in subjective appetite.

Adult↗
PubMed1992

Glucose transport in human skeletal muscle cells in culture. Stimulation by insulin and metformin.

Primary human muscle cell cultures were established and the regulation of glucose transport was investigated. Primary cultures were allowed to proceed to the stage of myotubes through fusion of myoblasts or were used for clonal selection based on fusion potential. In clonally selected cultures, hexose (2-deoxy-glucose) uptake into myotubes was linear within the time of study and inhibitable by cytochalasin B (IC50 = 400 nM). Cytochalasin B photolabeled a protein(s) of 45,000-50,000 D in a D-glucose-protectable manner, suggesting identity with the glucose transporters. In the myotube stage, the cells expressed both the GLUT1 and GLUT4 glucose transporter protein isoforms at an average molar ratio of 7:1. Preincubation in media of increasing glucose concentrations (range 5-25 mM) progressively decreased the rate of 2-deoxyglucose uptake. Insulin elevated 2-deoxyglucose uptake in a dose-dependent manner, with half maximal stimulation achieved at 3.5 nM. Insulin also stimulated the transport of the nonmetabolizable hexose 3-O-methylglucose, as well as the activity of glycogen synthase, responsible for nonoxidative glucose metabolism. The oral antihyperglycemic drug metformin stimulated the cytochalasin B-sensitive component of both 2-deoxyglucose and 3-O-methylglucose uptake. Maximal stimulation was observed at 8 h of exposure to 50 microM metformin, and this effect was not prevented by incubation with the protein-synthesis inhibitor cycloheximide. The relative effect of metformin was higher in cells incubated in 25 mM glucose than in 5 mM glucose, consistent with its selective action in hyperglycemic conditions in vivo. Metformin (50 microM for 24 h) was more effective than insulin (1 microM for 1 h) in stimulating hexose uptake and the hormone was effective on top of the stimulation caused by the biguanide, suggesting independent mechanisms of action.

Biological Transport↗
PubMed1992

Stimulation of hexose transport by metformin in L6 muscle cells in culture.

L6 muscle cells grown in culture to the stage of fused myotubes were incubated with the oral hypoglycemic drug metformin to test the effects of this drug on glucose transport. Metformin increased the initial rate of uptake of 2-deoxyglucose and 3-O-methylglucose. The effect was time dependent, with half-maximal stimulation at 5-6 h and maximal stimulation by about 16 h. The stimulation of hexose uptake was not prevented by cycloheximide. In 15 mM glucose medium, the basal rate of transport was lower than in 5 mM glucose medium. The stimulation of hexose uptake by metformin was comparable in absolute units in both media; hence, relative to basal uptake, stimulation was greater in the high glucose medium than in the low glucose medium. In 5 mM glucose medium, half-maximal stimulation was obtained with 800 microM metformin when tested for 24 h. The stimulation of hexose transport by metformin was only detectable in fused myotubes and not in perfusion myoblasts. No significant changes were observed in glucose transporter levels in total cell membranes from L6 myotubes (measured as D-glucose-protectable binding sites for cytochalasin-B) or in the total levels of the immunoreactive glucose transporter isoforms GLUT4 or GLUT1. It is concluded that metformin stimulates hexose transport into differentiated muscle cells by acting at a posttranslational level. We speculate that this might also constitute the basis for the ability of the drug to lower glycemia in diabetic individuals.

3-O-Methylglucose↗
PubMed1992

Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells.

The effects of the oral hypoglycemic drug metformin on glucose and amino acid transporter activity and subcellular localization of GLUT1 and GLUT4 glucose transporters were tested in cultured L6 myotubes. In muscle cells preexposed to maximal doses of metformin (2 mM, for 16 h), 2-deoxyglucose uptake was stimulated by over 2-fold from 5.9 +/- 0.3 to 13.3 +/- 0.5 pmol/min.mg protein. Uptake of the nonmetabolizable amino acid analog methylaminoisobutyrate was unaffected by treatment with the drug under identical conditions. Extracellular calcium was required to preserve the full response to the biguanide. Exposure of muscle cells to insulin in the presence of metformin resulted in further activation of 2-deoxyglucose transport. The latter effect was additive to the maximum effect of metformin, suggesting that the biguanide stimulates hexose uptake into muscle cells by an insulin-independent mechanism. Glucose transporter number quantified by performing studies of D-glucose-protectable binding of cytochalasin-B in plasma membranes (PM) and internal membranes (IM) prepared from L6 myotubes revealed that a 16-h treatment with 800 microM metformin significantly elevated glucose transporter number in the PM (by 47%), with an equivalent decrement in glucose transporter number (47%) in the IM. Western blot analysis using antisera reactive with the GLUT1 and GLUT4 isoforms of glucose transporters showed that metformin caused a reduction in GLUT1 content in the IM fraction and a concomitant increase in the PM. Unlike insulin, metformin treatment had no effect on the subcellular distribution of GLUT4. We propose that the molecular basis of metformin action in skeletal muscle involves the subcellular redistribution of GLUT1 proteins from an intracellular compartment to the plasma membrane. Such a recruitment process may form an integral part of the mechanism by which the drug stimulates glucose uptake (and utilization) in skeletal muscle and facilitates lowering of blood glucose in the management of type II diabetes.

Aminoisobutyric Acids↗
PubMed1991

Soft drinks with aspartame: effect on subjective hunger, food selection, and food intake of young adult males.

Ingestion of aspartame-sweetened beverages has been reported to increase subjective measures of appetite. This study examined the effects of familiar carbonated soft drinks sweetened with aspartame on subjective hunger, energy intake and macronutrient selection at a lunch-time meal. Subjects were 20 normal weight young adult males, classified as either restrained or nonrestrained eaters. Four treatments of carbonated beverages included 280 ml of mineral water, one can of a soft drink (280 ml) consumed in either 2 or 10 minutes, or two cans of a soft drink (560 ml) consumed in 10 minutes, administered at 11:00 a.m. Subjective hunger and food appeal were measured from 9:30 a.m. to 12:30 p.m., and food intake data were obtained from a buffet lunch given at 12:00 noon. There were no treatment effects on energy intake, macronutrient selection or food choice at the lunch-time meal, or food appeal, though restrained eaters consumed more than nonrestrained eaters in all four treatment conditions. Consumption of two soft drinks (560 ml, 320 mg aspartame) significantly reduced subjective hunger from 11:05 a.m. to 11:30 a.m. compared to one soft drink (280 ml, 160 mg aspartame) or 280 ml of mineral water. Thus ingestion of soft drinks containing aspartame did not increase short-term subjective hunger or food intake.

Adult↗
PubMed1990

Cellular mechanism of action of metformin.

Metformin is a hypoglycemic drug effective in the treatment of non-insulin-dependent diabetes mellitus and increasingly used in Canada and Europe. Effects on intestinal glucose absorption, insulin secretion, and hepatic glucose production are insufficient to explain its hypoglycemic action, with most evidence suggesting that the major effect of the drug is on glucose utilization. In vivo and in vitro studies have demonstrated that metformin stimulates the insulin-induced component of glucose uptake into skeletal muscle and adipocytes in both diabetic individuals and animal models. This increase is more significant in diabetic than in nondiabetic animals, suggesting an enhanced action of the drug in the hyperglycemic state. The increase in glucose uptake is also reflected in an increase in the insulin-dependent portion of glucose oxidation. Potential sites of action of metformin are the insulin receptor and the glucose transporters. Although metformin increases insulin binding in various cell types, this effect is not universal and does not correlate with stimulation of glucose utilization. In contrast, direct effects of the drug on the glucose-transport system have been demonstrated. Metformin elevates the uptake of nonmetabolizable analogues of glucose in both nondiabetic rat adipocytes and diabetic mouse muscle. In the latter, the stimulatory effect of the drug is additive to that of insulin. In human and rat muscle cells in culture, metformin increases glucose-analogue transport independently of and additive to insulin, suggesting an insulin-dependent action. Most of these results suggest that the basis for the hypoglycemic effect of this biguanide is probably at the level of skeletal muscle by increasing glucose transport across the cell membrane.

Animals↗
PubMed1990

Aspartame: effects on learning, behavior, and mood.

The effect of aspartame on the learning, behavior, and mood of children was evaluated in two experiments. After an overnight fast and a standard breakfast, 20 healthy 9- to 10-year-old children were given the treatments in a double-blind crossover design at 10:30 AM. Lunch was served at 12:00 noon. In experiment 1, the treatment consisted of an ice slurry of strawberry Kool-Aid containing 1.75 g/kg of carbohydrate (polycose) plus either aspartame (34 mg/kg) or the equivalent sweetness as sodium cyclamate and amino acids as alanine. In experiment 2, the treatment consisted of a drink of cold unsweetened strawberry Kool-Aid, containing either 1.75 g/kg of sucrose or 9.7 mg/kg of aspartame. Measures of associative learning, arithmetic calculation, activity level, social interaction, and mood were unaffected by treatment in experiment 1. In experiment 2, the only significant treatment effect was that on the frequency of minor and gross motor behaviors, which were less frequent after the consumption of sucrose than after aspartame. Thus, the effect of aspartame on the short-term behavior of healthy 9- to 10-year-old children appears to be related to its absence of metabolic consequences rather than to its amino acid composition and putative neurochemical impact.

Affect↗
PubMed1989

Aspartame: effect on lunch-time food intake, appetite and hedonic response in children.

Two experiments were conducted, each with 20 healthy 9-10-year-old children. After an overnight fast, subjects were given a standardized breakfast at 0830 hrs, the treatments at 1030 hrs, and a lunch containing an excess of foods at 1200 hrs. Visual analog scales of hunger, fullness, and desire to eat were administered 5 min before and 20 and 85 min after treatment. Lunch-time food intake was measured. In experiment 1, either aspartame (34 mg/kg), or the equivalent sweetness of sodium cyclamate, was given in an ice slurry (300 ml) of unsweetened strawberry Kool-Aid with carbohydrate (1.75 g/kg polycose). In experiment 2, drinks (300 ml) contained either sucrose (1.75 g/kg) or aspartame (9.7 mg/kg). In both experiments, significant meal- and time-dependent effects were observed for subjective feelings of hunger, fullness and desire to eat. Treatments, however, did not affect either subjective feelings of appetite or lunch-time food intake. Thus, aspartame consumed without or with carbohydrate, did not affect either hunger or food intake of children when compared with the sweeteners sodium cyclamate and sucrose, respectively.

Appetite↗