Search PubMed⌕ Search

Biomedical subjects

J D Best

Publications and source records attributed to J D Best.

At least 55 records · Page 3Linked to original sources
PubMed1996

Factors influencing Lp[a]- particle size as determined by gradient gel electrophoresis.

This study examined factors influencing the particle diameter of Lp[a]-, the low density lipoprotein (LDL)-like moiety of Lp[a], in 26 subjects chosen to provide a range of Lp[a] and triglyceride levels. Lp[a] and LDL fractions were isolated by vertical density ultracentrifugation. Lp[a] was further purified using a lysine-Sepharose affinity column and Lp[a]- obtained by incubating Lp[a] with dithiothreitol. Lp[a], LDL, and Lp[a]- fractions were run on 3-13% gradient gels to determine particle diameter. Lp[a] size correlated positively with LDL size (r = 0.62; P < 0.001), but the association between Lp[a]- size and LDL size was stronger (r = 0.82; P < 0.0001). Log triglyceride level correlated inversely with Lp[a]- size (r = -0.72; P < 0.0001) and LDL size (r = 0.69; P < 0.0001). HDL cholesterol level correlated positively with Lp[a]- size (r = 0.67; P < 0.0005) and LDL size (r = 0.64; P < 0.0005). The strong correlation between LDL size and Lp[a]- size may be due to extracellular utilization of circulating LDL in the production of Lp[a] or may reflect the same metabolic processes influencing both these particles once Lp[a] has been formed.

Apolipoproteins A↗
PubMed1995

Retinoic acid stimulates glucose transporter expression in L6 muscle cells.

Factors that regulate the tissue specific and developmental expression of the GLUT4 gene, whose transcribed protein is primarily responsible for mediating insulin stimulated glucose transport, are poorly defined. In this study we examined the effects of retinoic acid, a circulating factor that can promote cellular differentiation, on glucose uptake and glucose transporter expression in cultured L6 muscle cells. At the myoblast stage, treatment with 1 microM retinoic acid for 24 h increased both 1 h and 8 h insulin stimulated uptake of 2-deoxyglucose by more than twofold. A dose and time dependent effect of retinoic acid on 8 h insulin stimulated 2-deoxyglucose uptake was observed at both the myoblast and myocyte stage. Comparatively little effect from retinoic acid treatment was found on basal uptake at either stage. In myoblast cells, retinoic acid increased the content of GLUT4 mRNA in a dose and time dependent manner, an effect that was partially attenuated by insulin. In myocytes retinoic acid increased GLUT4 mRNA levels to 2.3 times basal. Nuclear run-on studies indicate that the increased GLUT4 mRNA represents enhanced transcriptional activity. The results suggest a role for retinoic acid in regulation of expression of the GLUT 4 gene in muscle cells.

Analysis of Variance↗
PubMed1995

The role of lipoprotein(a) in the vascular complications of diabetes mellitus.

Lipoprotein(a) has been identified as an independent risk factor for atherosclerotic vascular disease in non-diabetic populations. Because of its potential role in the pathogenesis of both microvascular and macrovascular complications in diabetes, there have recently been many reports on lipoprotein(a) in diabetic populations. Some studies indicate an association between elevated lipoprotein(a) and macrovascular disease in non-insulin-dependent diabetes mellitus (NIDDM), but this link has not been found with insulin-dependent diabetes mellitus (IDDM). In IDDM, elevated lipoprotein(a) has been found in groups with diabetic nephropathy and retinopathy, raising the possibility that it plays a causative role. The relationship between glycaemic control and the lipoprotein(a) level has not been fully resolved. Most studies have not found any connection in NIDDM, but some found higher lipoprotein(a) levels in hyperglycaemic IDDM patients. Potentially, lipoprotein(a) is an important factor linking the microvascular and macrovascular complications of diabetes.

Diabetes Mellitus, Type 1↗
PubMed1995

Modulation of glucose transport by parathyroid hormone and insulin in UMR 106-01, a clonal rat osteogenic sarcoma cell line.

This study characterizes the actions of insulin and parathyroid hormone (PTH) on the glucose transport system in the rat osteogenic sarcoma cell line UMR 106-01, which expresses a number of features of the osteoblast phenotype. Using [1,2-3H]2-deoxyglucose (2-DOG) as a label, UMR 106-01 cells were shown to possess a glucose transport system which was enhanced by insulin. In contrast, PTH influenced glucose transport in a biphasic manner with a stimulatory effect at 1 h and a more potent inhibitory effect at 16 h on basal and insulin-stimulated 2-DOG transport. To explore the mechanism of PTH action, a direct agonist of cAMP-dependent protein kinase (PKA) was tested. 8-Bromo-cAMP had no acute stimulatory effect but inhibited basal and insulin-stimulated 2-DOG transport at 16 h. This result suggested that the prolonged, but not the acute, effect of PTH was mediated by the generation of cAMP. Further studies with the cell line UMR 4-7, a UMR 106-01 clone stably transfected with an inducible mutant inactive regulatory subunit of PKA, confirmed that the inhibitory but not the stimulatory effect of PTH was mediated by the PKA pathway. Northern blot data indicated that the prolonged inhibitory effects of PTH and 8-bromo-cAMP on glucose transport were likely to be mediated in part by reduction in the levels of GLUT1 (HepG2/brain glucose transporter) mRNA.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1993

Impaired glucose tolerance after endurance exercise is associated with reduced insulin secretion rather than altered insulin sensitivity.

Paired frequently sampled intravenous glucose tolerance tests (FSIGT) were performed on five highly trained athletes within 2 hours of completing a 6-day ultramarathon run (E) and after 2 weeks of complete rest (R). Severe exercise increased free fatty acid (FFA) levels (E 1.2 +/- 0.16 v 0.42 +/- 0.07 mmol/L, P < .01) and norepinephrine levels (E 573 +/- 141 v 224 +/- 33 pg/mL, P < .01), with only moderate reductions in glucose tolerance (glucose disappearance [Kg] E 1.06 +/- 0.2 v R 1.7 +/- 0.3 min-1 x 10(2), P < .05). The minimal model analysis of FSIGT data using the method of Bergman et al (Endocr Rev 6:45-86, 1985) showed a reduced second-phase insulin secretion ([phi 2] E 5.2 +/- 1.3 v 13 +/- 2.2 microU/mL.min-2 per mg/dL, P < .05) and glucose disposition index ([SI x phi 2] E 33.8 +/- 10 v 73.9 +/- 11 mg-1.dL.min-3 x 10(4), P < .02). Insulin sensitivity (SI) and glucose-mediated glucose disposal (SG) were unchanged (SI E 6.9 +/- 1.0 v 6.0 +/- 0.6 min-1 per microU/mL x 10(4); SG E 1.8 +/- 0.6 v 1.4 +/- 0.3 min-1 x 10(2)). Reduced glucose tolerance after prolonged extreme physical exercise was accompanied by reduced phi 2 and not by alterations of SI or SG, despite the marked increase of FFA levels. Elevated norepinephrine levels, reflecting activation of the sympathetic noradrenergic system, was also associated with the reduction in Kg. The reduction in phi 2 would promote mobilization of FFA, the predominant metabolic substrate in these endurance events.

Adult↗
PubMed1993

Diabetes and vascular disease.

Reduction of morbidity and mortality rates from cardiovascular disease requires a dual approach: public health measures for the whole community and individual assessment and treatment for those people at high risk. The presence of diabetes identifies patients who require particular attention for risk factor assessment and prevention of macrovascular disease.

Cardiovascular Diseases↗
PubMed1992

Plasma apolipoprotein (a) is increased in type 2 (non-insulin-dependent) diabetic patients with microalbuminuria.

Patients with Type 2 (non-insulin-dependent) diabetes mellitus complicated by microalbuminuria or albuminuria, have an increased risk of developing macrovascular disease and of early mortality. Because lipoprotein abnormalities have been associated with diabetic nephropathy, this study tested the hypothesis that levels of apolipoprotein (a) are elevated in patients with Type 2 diabetes and increased levels of urinary albumin loss. Levels of apolipoprotein (a) in diabetic patients with microalbuminuria (n = 26, geometric mean 195 U/l, 95% confidence interval 117-324) and albuminuria (n = 19, 281 U/l, 165-479) were higher than in non-diabetic control subjects (n = 140, 107 U/l, 85-134, p < 0.05), and in the albuminuric group than diabetic patients without urinary albumin loss (n = 58, 114 U/l, 76-169, p < 0.05). Patients with microalbuminuria and albuminuria had levels comparable with patients undergoing elective coronary artery graft surgery (n = 40, 193 U/l, 126-298). Apolipoprotein (a) levels were higher in diabetic patients with macrovascular disease than in those without (n = 49, 209 U/l, 143-306 vs n = 54, 116 U/l, 78-173, p < 0.05). These preliminary results suggest that raised apolipoprotein (a) levels of Type 2 diabetic patients with microalbuminuria and albuminuria may contribute to their propensity to macrovascular disease and early mortality.

Aged↗
PubMed1992

Contrasting action of short- and long-term adrenaline infusion on dog skeletal muscle glucose metabolism.

There are important differences between the short- and long-term effects of adrenaline on determinants of glucose tolerance. To assess this metabolic adaptation at tissue level, the present study examined the effect of acute and prolonged in vivo elevation of adrenaline on glycogen metabolism and glycolysis in skeletal muscle. Adrenaline (50 ng.kg-1.min-1) was infused for 2 h or 74 h and the results compared with 1 h 0.9% NaCl infusion in six trained dogs. Muscle glycogen content was reduced by long-term adrenaline (161 +/- 17 vs NaCl 250 +/- 24 mumol/g dry weight; p less than 0.05) but not short-term adrenaline (233 +/- 21) indicating a sustained effect of adrenaline on glycogen metabolism. Acutely, glycogen synthase I was reduced (short-term adrenaline 12 +/- 6 vs NaCl 22 +/- 7 mumol glycosyl units.g-1.min-1; p less than 0.05) but returned to normal with prolonged adrenaline infusion (20 +/- 5). In contrast, Km for glycogen phosphorylase alpha was not changed acutely (short-term adrenaline 31 +/- 6 vs NaCl 27 +/- 7 mmol/l inorganic phosphate) but was reduced during long-term infusion (19 +/- 4; p less than 0.05 vs short-term adrenaline). Thus, with short- and long-term adrenaline infusion, there were different enzyme changes, although likely to promote glycogenolysis in both cases. In the glycolytic pathway the substrates glucose 6-phosphate and fructose 6-phosphate did not change significantly and hexokinase was not inhibited. Acutely, phosphofructokinase had reduced Vmax (short-term adrenaline 34 +/- 6 vs NaCl 44 +/- 5 U/g; p less than 0.05) but was still above the maximal operating rate in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

The effect of epinephrine on glucose-mediated and insulin-mediated glucose disposal in insulin-dependent diabetes.

The aim of this study was to determine the relative roles of changes in glucose-mediated glucose disposal (SG) and insulin sensitivity (SI) on the impairment of glucose disposal caused by epinephrine (EPI) infusion in type I (insulin-dependent) diabetes mellitus (IDDM). Seven non-obese young adult diabetics with minimal endogenous insulin secretion had EPI infusions at 25 ng/kg/min for 5.5 hours, after a basal overnight insulin infusion (12 mU/kg/h), and glucose infusion as required to maintain euglycemia. The EPI infusion produced approximately an eightfold increase in plasma EPI. At 2.5 hours, an intravenous glucose tolerance test (IVGTT) was performed with supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. In random order, each subject also had a control (CTR) infusion of basal insulin before the IVGTT. The results were analyzed according to a modification of the minimal model of Bergman et al. EPI infusion was associated with (1) elevated basal plasma glucose (EPI v CTR, 9.8 +/- 0.3 SE v 7.7 +/- 0.7 mmol/L, P less than .05); (2) elevated plasma nonesterified fatty acids (NEFA, 0.9 +/- 0.1 v 0.3 +/- 0.1 mmol/L, P less than .05); and (3) profoundly reduced glucose disposal (KG 0.59 +/- 0.1 v 1.91 +/- 0.33 min-1 x 10(2), P less than .02). Further analysis showed that the reduced glucose disposal was attributable to a marked decrease in SI (EPI 0.9 +/- 0.5 v CTR 7.03 +/- 3.2 min-1.mU-1.L x 10(4), P less than .05) with no significant change in SG (EPI 2.5 +/- 0.2 v CTR 3.1 +/- 0.5 min-1 x 10(2), NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

A simple method for quantitation of insulin sensitivity and insulin release from an intravenous glucose tolerance test.

Both insulin secretion and insulin sensitivity are important in the development of diabetes but current methods used for their measurements are complex and cannot be used for epidemiological surveys. This study describes a simplified approach for the estimation of first phase insulin release and insulin sensitivity from a standard 40-min intravenous glucose tolerance test (IVGTT), and compares these parameter estimations with the sophisticated minimal model analysis of a frequently sampled 3-h IVGTT and the euglycaemic clamp technique. For the simplified IVGTT, first phase insulin release was measured as the insulin area above basal post glucose load unit-1 incremental change (i.e. peak rise) in plasma glucose over 0-10 min, and insulin sensitivity as a rate of glucose disappearance (Kg) unit-1 insulin increase above basal from 0-40 min post-glucose load in 18 subjects who were studied twice, either basally or in a perturbed pathophysiological state (i.e. pre- and post-ultramarathon race, n = 5; pre- and post-20 h pulsatile hyperinsulinaemia, n = 8; pre- and post-thyrotoxic state, n = 5). A further 12 subjects were compared by IVGTT, and glucose clamp. In addition, seven dogs were studied three times by IVGTT during normal saline infusion and after short-term (1/2 hour) or long-term (72 hour) adrenaline infusions. First phase insulin release and insulin sensitivity estimated from the simplified IVGTT as calculated by the two methods correlated closely (rs = 0.89 and rs = 0.87, respectively), although less precisely in markedly insulin-resistant subjects and the slopes and y intercepts of the linear regression lines were similar in the basal and perturbed states.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1992

Effects of acute and chronic counterregulatory hormone infusions on glucose tolerance and insulin sensitivity in diabetic dogs.

The effects of elevated EPI and CORT levels on KG, SI, and SG were studied in dogs with alloxan-induced diabetes. Conscious dogs received SAL, EPI 20 ng.kg-1.min-1 for 30 min (short EPI) or 72 h (long EPI), or CORT 200 micrograms.kg-1.min-1 for 60 min (short CORT) or 72 h (long CORT) before assessment of glucose metabolism by rapid sampling for glucose and insulin levels after 300 mg/kg i.v. glucose and exogenous insulin infusion designed to simulate the normal secretory pattern. With EPI infusion, KG fell acutely from 2.9 +/- 0.4 to 2.0 +/- 0.2%/min (SAL vs. short EPI, P < 0.05), but rose to 3.4 +/- 0.4%/min during long EPI. Minimal-model analysis of the glucose response with the insulin data as input showed that SI decreased acutely from 4.7 +/- 1.8 to 2.5 +/- 0.6 x 10(-5) min-1/pM (SAL vs. short EPI, P < 0.05), but rose to 4.5 +/- 2.5 x 10(-5) min-1/pM during long EPI. The effects of EPI on SG paralleled the results for KG and SI, with acute decline from 3.9 +/- 0.4 to 2.1 +/- 0.4 x 10(-2) min-1 (SAL vs. short EPI, P < 0.05) and recovery to 3.3 +/- 0.3 x 10(-2) min-1 during long EPI. During CORT infusion, KG tended to fall (SAL 2.9 +/- 0.4 vs. short CORT 2.5 +/- 0.5 vs. long CORT 2.2 +/- 0.5%/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A modified minimal model analysis of insulin sensitivity and glucose-mediated glucose disposal in insulin-dependent diabetes.

Although glucose utilization is impaired in insulin-dependent diabetes mellitus (IDDM), it is unclear whether this is due to reductions in insulin sensitivity (Si) and/or glucose-mediated glucose disposal (SG). The minimal model of Bergman et al can be applied to a frequently sampled intravenous glucose tolerance test (FSIGT) to simultaneously estimate Sl and SG, but cannot accommodate data from diabetics. Exogenous insulin approximating the normal pattern of insulin secretion was infused during FSIGTs in eight young non-obese C-peptide-negative IDDM subjects, but with the total dose modified to achieve sufficient glucose disappearance rates (KG) to allow analysis of data. The minimal model was modified to model the effects of the exogenous insulin on glucose kinetics to estimate SI and SG. Despite deliberately achieving supranormal plasma-free insulin levels during the FSIGT ("first-phase insulin" = 62 +/- 9 SE mU/L; "second phase insulin" = 34 +/- 9 mU/L), the diabetics showed low-normal KG values (1.3 +/- 0.29 min-1 X 10(2). Using the model, good parameter resolution (fractional SD [FSD] less than .5) was achieved (IDDM v controls: SI = 2.5 +/- 0.6 v 8.3 +/- 1.5 min-1.mU-1.L-1 X 10(4); SG = 1.6 +/- 0.5 v 2.6 +/- 0.2 min-1 X 10(2); P less than .05). This reduction in SG was confirmed in the same IDDM subjects by FSIGT during basal insulin infusion only (SG = 1.0 +/- 0.3 min-1 X 10(2)).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Distinct but nonadditive effects of epinephrine and cortisol on determinants of glucose tolerance in dogs.

Effects of physiological increments of epinephrine (Epi) and cortisol (F) on glucose metabolism were assessed in dogs just before and during an intravenous glucose tolerance test performed in the last 3 h of an acute (short F + Epi, 4 h F and 3.5 h Epi) or prolonged (long F + Epi, 75 h F and Epi) infusion period. Comparison of the F + Epi effects with those of F and Epi alone enabled us to describe interactions between these hormones. The increase in plasma glucose after long F + Epi [from control (saline, Sal) of 5.2 +/- 0.1 to 5.8 +/- 0.1 mmol/l; n = 8; P less than 0.01] was not greater than the sum of the glucose increments after long F and long Epi individually. Long Epi and long F both reduced glucose tolerance (KGlc) significantly, but the decline during long F + Epi (from Sal 3.6 +/- 0.7 to 2.9 +/- 0.5%/min; P greater than 0.1) was less than during either individual infusion. Minimal model analysis showed that F attenuated the inhibitory effects of long Epi on glucose-mediated glucose disposal (SGlc), so that it was not reduced from 3.8 +/- 0.8 (Sal) during long F + Epi compared with the fall to 1.3 +/- 0.7 x 10(-2) min-1 (n = 6; P less than 0.05) during long Epi alone. F had the dominant influence on insulin sensitivity (SI) during infusion of F + Epi. The reduction of SI from 8.4 +/- 1.1 (Sal) to 6.6 +/- 1.2 (short F + Epi) and 5.1 +/- 1.1 x 10(-4) min-1 per mU/l (long F + Epi; P less than 0.05) paralleled that seen with F alone but contrasted with the acute reduction of SI during short Epi (4.8 +/- 1.5; P less than 0.02 vs. Sal) and its restoration to control values of 9.0 +/- 2.1 x 10(-4) min-1 per mU/l during long Epi. We conclude that Epi and F have distinct but nonadditive effects on determinants of glucose tolerance.

Animals↗
PubMed1991

Increased plasma apolipoprotein(a) levels in IDDM patients with microalbuminuria.

Patients with insulin-dependent diabetes mellitus (IDDM) have a significantly increased risk of macrovascular disease, particularly if they have persistent proteinuria. To determine whether altered levels of apolipoprotein(a) [apo(a)], the plasminogenlike glycoprotein of the potentially atherogenic lipoprotein(a); contribute to the increased risk of atherosclerosis, apo(a) levels were measured in 107 patients with IDDM and compared with nondiabetic control subjects and male elective coronary artery graft patients. Apo(a) levels were increased in diabetic patients with microalbuminuria (geometric mean 245 U/L, 95% confidence interval [CI] 142-427, n = 30) and albuminuria (mean 196 U/L, 95% CI 97-397, n = 18) with levels comparable to patients with coronary artery disease (mean 193 U/L, 95% CI 126-298, n = 40), which were higher than in the control group (mean 107 U/L, 95% CI 85-134, n = 140; P = 0.016). Apo(a) levels in diabetic patients without microalbuminuria (mean 86 U/L, 95% CI 63-116, n = 59) were comparable with the control population and less than in those with microalbuminuria (P less than 0.001) and albuminuria (P = 0.014). The elevated apo(a) levels found in patients with IDDM and increased urinary albumin loss may contribute to their heightened risk of macrovascular disease.

Adult↗
PubMed1991

Validation and evaluation of test for sympathetic cholinergic function in diabetes mellitus.

Skin potential response (SPR), an electrodermal measure of sudomotor nerve function, was shown in this study to examine specifically sympathetic cholinergic fibers by abolition of the response during atropine infusion but not during propranolol infusion. The difference between responses in the left and right arms (SPR-D) was used to assess autonomic nerve function in 136 patients with diabetes and 52 control subjects. In 82% of the diabetic population (112 of 136), SPR-D was greater than 2SD above the mean control response compared with 42% (57 of 137) greater than 2SD below the mean control age-related value for a standard autonomic test predominantly of parasympathetic function, the R-R interval variation with breathing. Of 15 patients with clinical diabetic autonomic neuropathy, SPR wave forms were bizarre or absent in 5 patients compared with 18 of 121 patients' without clinical autonomic neuropathy (chi 2 = 3.5, P = 0.062). Measurement of SPR-D provides an easily determined measure of sympathetic cholinergic nerve function and may be a useful component of a group of tests for autonomic nerve function in diabetes.

Adult↗
PubMed1990

Application of the SAAM modeling program to minimal model analysis of intravenous glucose tolerance test data.

The minimal model approach to analysis of intravenous glucose tolerance tests (IVGTT) yields estimates of parameters representing insulin sensitivity, glucose-mediated glucose disposal and pancreatic responsiveness. The precision of these estimates can deteriorate if the glucose and insulin data lack well-defined structure or freedom from data noise (random error). The precision of parameter estimates can be enhanced if data sets from two or more IVGTTs, obtained under different experimental conditions in the same subject, are analysed together in one data file. Following initial fitting using CONSAM, the conversational version of the modeling program SAAM, those parameters whose estimates remain at the same value under the different experimental conditions are constrained. This effectively reduces the number of adjustable parameters, and their estimates can then be fine-tuned with enhanced precision using the batch version of SAAM.

Animals↗
PubMed1990

Platelet catecholamine contents are cumulative indexes of sympathoadrenal activity.

Blood platelets continually accumulate catecholamines (CA) from plasma. Plasma CA levels fluctuate rapidly, but platelet CA appear to have a slower turnover, making them potentially useful as long-term indexes of sympathoadrenal activity. We measured the effect of different types of human physical exertion on epinephrine (E), norepinephrine (NE), and dopamine (DA) and their sulfoconjugates in both plasma and washed platelets using a radioenzymatic assay. Acute strenuous exercise caused only a small (26%) rise in unconjugated plus sulfated platelet E, but regular training (140 +/- 30 km/wk) was associated with levels of platelet CA or CA sulfates 39-112% higher than controls. After completion of an ultramarathon (607-1,020 km in 6-8 days), platelet CA and CA sulfates were 139-405% higher than controls. Platelet CA declined over several days postrace, and the loss of platelet NE was significantly slower than the loss of platelet E. Plasma CA sulfates were significantly elevated in the runners, whereas plasma CA were normal apart from a transient elevation in NE postrace. Platelet CA levels provide a useful index of chronic sympathoadrenal activity but may be affected by changes in platelet turnover or activation.

Adrenal Glands↗