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P Wallace

Publications and source records attributed to P Wallace.

At least 127 records · Page 7Linked to original sources
PubMed1987

Somatostatin does not increase insulin-stimulated glucose uptake in humans.

Somatostatin (SRIF) has been widely used in the study of in vivo carbohydrate metabolism to suppress pancreatic hormone secretion and thereby interrupt the glucoregulatory feedback loops between insulin, glucagon, and glucose. A critical assumption in the use of SRIF is that it has no effect on hepatic or peripheral glucose metabolism other than those mediated through the inhibition of hormone secretion. To assess whether doses of SRIF commonly used in human investigation have any effect on insulin-stimulated glucose disposal rates, we measured the rate in 6 normal subjects (mean fasting serum glucose level, 93 +/- 2 mg/dl) during euglycemic (approximately equal to 85 mg/dl) hyperinsulinemic (40 mU X m-2 X min-1) clamp studies both with and without the concomitant infusion of SRIF (600 micrograms/hr). The steady-state insulin levels achieved were 85 +/- 6 microU/ml and 74 +/- 8 microU/ml with and without SRIF, respectively (difference not significant). Glucose disposal rates between 120 and 180 min of the clamp were 7.11 +/- 0.10 and 7.35 +/- 0.10 mg X kg-1 X min-1 with and without SRIF, respectively (difference not significant). We concluded that in doses commonly used in human investigation, SRIF does not increase glucose disposal.

Adult↗
PubMed1987

Effects of fasting on plasma glucose and prolonged tracer measurement of hepatic glucose output in NIDDM.

We studied the measurement of hepatic glucose output (HGO) with prolonged [3-3H]glucose infusion in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM). Over the course of 10.5 h, plasma glucose concentration fell with fasting by one-third, from 234 +/- 21 to 152 +/- 12 mg/dl, and HGO fell from 2.35 +/- 0.18 to 1.36 +/- 0.07 mg . kg-1 . min-1 (P less than .001). In the basal state, HGO and glucose were significantly correlated (r = 0.68, P = .03), and in individual patients, HGO and glucose were closely correlated as both fell with fasting (mean r = 0.79, P less than .01). Plasma [3-3H]glucose radioactivity approached a steady state only 5-6 h after initiation of the primed continuous infusion, and a 20% overestimate of HGO was demonstrated by not allowing sufficient time for tracer labeling of the glucose pool. Assumption of steady-state instead of non-steady-state kinetics in using Steele's equations to calculate glucose turnover resulted in a 9-24% overestimate of HGO. Stimulation of glycogenolysis by glucagon injection demonstrated no incorporation of [3-3H]glucose in hepatic glycogen during the prolonged tracer infusion. In a separate study, plasma glucose was maintained at fasting levels (207 +/- 17 mg/dl) for 8 h with the glucose-clamp technique. Total glucose turnover rates remained constant during this prolonged tracer infusion. However, HGO fell to 30% of the basal value simply by maintaining fasting hyperglycemia in the presence of basal insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1987

In vivo regulation of non-insulin-mediated and insulin-mediated glucose uptake by cortisol.

In vivo glucose uptake (Rd) occurs via two mechanisms: insulin-mediated glucose uptake (IMGU), which occurs in insulin-sensitive tissues, and non-insulin-mediated glucose uptake (NIMGU), which occurs in both insulin-sensitive and non-insulin-sensitive tissues. To determine whether these two pathways for in vivo glucose disposal are regulated independently, we studied the effect of stress levels of cortisol on IMGU and NIMGU in seven normal subjects after an overnight fast. To study NIMGU, somatostatin (SRIF, 600 micrograms/h) was infused to suppress endogenous insulin secretion and create severe insulinopenia, and glucose turnover was measured isotopically while serum glucose was clamped at approximately 200 mg/dl for 240 min. Separate studies were performed during the overnight infusion of saline or hydrocortisone (HCT; 2.0 micrograms.kg-1.min-1). The final 120 min of each study were used for data analysis. Under these conditions, insulin action is absent, and Rd = NIMGU. NIMGU was 204 +/- 11 mg/min and 208 +/- 8 mg/dl during saline and HCT, respectively (P NS). Therefore, HCT did not modulate NIMGU. To measure the effect of cortisol on Rd, hyperglycemic (200 mg/dl)-hyperinsulinemic clamp studies (30 mU.m-2. min-1) were performed during the infusion of saline or HCT. The results demonstrate that during saline infusion, steady-state rates of Rd (10.4 +/- 0.8 mg.kg-1.min-1) were achieved by 160 min; in contrast, during HCT infusion, Rd never reached steady state but increased from 4.5 +/- 0.2 in the 2nd h to 7.6 +/- 0.4 mg.kg-1.min-1 in the 4th h, P less than .01.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1987

Hyperinsulinemia does not compensate for peripheral insulin resistance in obesity.

Based on previous steady-state measures of the biologic activity of insulin, it was thought that postprandial hyperinsulinemia in obesity compensated for insulin resistance. However, we recently demonstrated kinetic defects in insulin action in insulin-resistant nondiabetic obese subjects: activation of insulin-stimulated glucose disposal was slower and deactivation was faster in obese than in normal subjects. In view of these kinetic defects in peripheral insulin action and of the fact that insulin is normally secreted in a phasic manner after meals, we postulated that the hyperinsulinemia of obesity does not compensate for insulin resistance and that the abnormal kinetics of insulin action in obesity are functionally important. To test this hypothesis, oral glucose tolerance tests (OGTTs) were performed in five control (mean age, 33 +/- 2 yr) and five obese (mean age, 41 +/- 5 yr) subjects. All controls had normal glucose tolerance; two obese subjects had normal and three had impaired glucose tolerance. After the results of the OGTTs were available, euglycemic clamp studies were performed in which insulin was infused in a phasic stepped fashion to mimic the rise and fall of mean peripheral insulin levels during the OGTTs. Each subject was clamped at both the "normal" and "obese" OGTT insulin profiles. During the OGTT, glucose and insulin levels were significantly elevated in the obese subjects compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Direct and indirect effects of insulin to inhibit hepatic glucose output in obese subjects.

The effects of small increases in plasma insulin on hepatic glucose production are incompletely understood. To partially elucidate this issue we have studied seven obese subjects with the euglycemic clamp technique with a low-dose insulin infusion rate of 15 mU X m-2 X min-1 over 3 h. Basal insulin levels were 24 +/- 7 microU/ml and increased to steady-state levels of 35 +/- 3 microU/ml during insulin infusion. Endogenous insulin secretion, quantitated by C-peptide measurements, decreased by 58% of the basal value after peripheral insulin infusion. Based on C-peptide measurements and the contribution of the peripheral insulin infusion to the circulating insulin concentrations, calculated portal insulin levels either decreased or remained unchanged during the clamp studies. Basal glucagon levels were 165 +/- 18 and did not change during the insulin infusion. The basal glucose disposal rate was 86 +/- 2 mg X m-2 X min-1 and did not increase significantly during the clamp studies. In contrast, hepatic glucose output (HGO) was suppressed by 82 +/- 5% of the basal value. In summary, in a group of insulin-resistant obese subjects, glucose-clamp studies were performed at peripheral insulin levels of 35 +/- 3 microU/ml; glucose disposal did not increase, whereas HGO was suppressed by 82%. At the same time, glucagon levels remained constant and estimated portal insulin levels either decreased or remained unchanged. These findings suggest that insulin can suppress HGO through indirect extrahepatic actions.

Adult↗
PubMed1987

cis-Retinoic acid stimulates the clonal growth of some myeloid leukemia cells in vitro.

We studied the effects of cis-retinoic acid (cisRA) on the clonogenic growth of samples of leukemic cells from 35 patients with acute nonlymphocytic leukemia (ANLL). We observed significant inhibition of leukemic colony growth in 17 samples by 10(-7) to 10(-6)M cisRA. However, we found that retinoid exposure resulted in striking stimulation of clonal growth in ten samples at the same drug concentrations. With the exception of cases with promyelocytic features, there was no morphologic or functional evidence that cisRA induced the leukemic blasts to differentiate. Both inhibition and stimulation were dose-dependent and observable at pharmacologically achievable levels of cisRA. Leukemic cells with monocytic features more frequently demonstrated a stimulatory response than did those without monocytic features. Depletion of T lymphocytes and monocytes did not alter the type of growth response. Assays for cellular retinoic acid-binding protein (CRABP) were performed on five samples (two with inhibitory growth responses, two with stimulatory responses, and one with no growth) and failed to reveal detectable levels of CRABP in any case. The addition of cisRA to liquid suspensions of leukemic cells produced no significant change in the number of viable cells. We conclude that the effects of cisRA on leukemic colony growth are not cytotoxic and not mediated by T lymphocytes, monocytes, or CRABP. More importantly, cisRA appears to enhance the growth of certain human leukemia cells in vitro. Taking into account the increasing use of retinoids in clinical trials for patients with leukemia, the latter findings may represent a significant cautionary note.

Bone Marrow↗
PubMed1987

Blood pressure, smoking, obesity and alcohol consumption in black and white patients in general practice.

A comparison of blood pressure (BP), smoking, alcohol consumption and obesity between whites and blacks of Caribbean origin aged 17-70 was undertaken in a general practice in North West London. Mean systolic and diastolic blood pressures (DBP) showed no consistent overall differences between the two ethnic groups, though DBP rose significantly more with age in black males than white males. Somewhat higher proportions of the black patients were receiving anti-hyper-tensive treatment compared with the whites, the difference was statistically significant in the case of males (P less than 0.02). This observation did not appear to be due to more effective detection of hypertension amongst black males. Overall, fewer than one-third of black females were current cigarette smokers compared with around one-half of white females (P less than 0.001). Amongst males, however, the proportions of never, ex and current smokers were similar in the two ethnic groups. Young black patients of both sexes were more likely to smoke than older blacks. Blacks who smoked tended to smoke fewer cigarettes than white smokers. Eleven of 190 (5.8%) black males had consumed 35 units or more of alcohol within the last week compared with 87 of 452 (19.2%) of white males, (P less than .001). Amongst females the differences were smaller, 5 of 227 (2.2%) of black females had consumed 21 units or more in the last week compared with 23 of 490 (4.7%) of white females (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Cardiovascular effects of urotensin II in anesthetized and pithed rats.

Gillichthys urotensin II (GUII; 1.5-150 nmol kg-1) reduced blood pressure in anesthetized rats, diastolic pressure being reduced to a greater extent than systolic. The effect was slow in onset (peak at 4-5 min) and longlasting (up to 60 min), and was accompanied by a reflex tachycardia. The hypotension was not blocked by propranolol or by mepyramine. In pithed rats, GUII (150 nmol kg-1) reduced the pressor responses to sympathetic nerve stimulation, noradrenaline, and Arg-vasopressin. Somatostatin (150 nmol kg-1) had no effect on the sympathetic pressor response but reduced heart rate. It is concluded that GUII is a vasodilator in the rat, an action not shared with somatostatin.

Anesthesia↗
PubMed1986

Effects of aging on glucose-mediated glucose disposal and glucose transport.

To assess the effects of aging on glucose-mediated glucose disposal and glucose transport, glucose disposal rates were measured in 10 nonelderly (32 +/- 4 yr) and 11 elderly (64 +/- 4 yr) subjects at five different plasma glucose concentrations. Glucose disposal was decreased by 30-35% in the elderly at each level of glycemia (100-350 mg/dl) in the presence of similar levels of hyperinsulinemia (approximately 100 microU/ml), and the 50% effective concentration (EC50) was similar in both the nonelderly (100 +/- 9) and elderly (103 +/- 5 mg/dl). The Michaelis constant (Km) of 3-O-methyl glucose transport in adipocytes was unchanged with aging (3.8 +/- 0.5 vs. 3.2 +/- 0.2 mM) while the maximum velocity of insulin stimulated transport was reduced by 34% in the elderly (8.3 +/- 1.3 vs. 12.6 +/- 1.5 pmol/5 X 10(4) cells per s, P less than 0.05). The insulin resistance of aging is therefore due to a reduction in the capacity of the glucose uptake system, while the affinity of glucose utilization (EC50 and Km) is unchanged. This supports the hypothesis that a reduction in the number of glucose transport and metabolic units occurs with aging, but that each unit functions normally.

3-O-Methylglucose↗
PubMed1986

In vivo kinetics of insulin action on peripheral glucose disposal and hepatic glucose output in normal and obese subjects.

To determine whether abnormal kinetics of insulin's biologic actions contribute to the overall insulin resistance in obesity, we compared the rate of activation and deactivation of insulin's effects to stimulate glucose disposal rate (Rd) and inhibit hepatic glucose output (HGO) in 12 nonobese and 10 obese subjects using the euglycemic clamp technique at insulin infusion rates of 15, 40, 120, and 1,200 mU/M2 per min. In both groups, stimulation of Rd was faster the higher the insulin infusion rate and the time to reach half maximal stimulation (A50 value) in normals was 52 +/- 4, 44 +/- 2, 29 +/- 3, and 21 +/- 2 min at infusion rates of 15, 40, 120, and 1,200 mU/M2 per min, respectively. In the obese subjects, the rate of activation was slower (higher A50 values) with A50 values of 74 +/- 6, P less than 0.001 (compared to normal), 64 +/- 8 min, P less than 0.001, and 28 +/- 3 min, P less than 0.01, at the 40, 120, and 1,200 mU/M2 per min insulin infusions. Deactivation of the insulin effect to stimulate glucose disposal rate (Rd) was faster in the obese group compared with normal individuals after all comparable insulin infusions. In summary: for both groups, the higher the insulin infusion rate, the higher the steady state Rd value, the faster the rate of activation and the slower the subsequent rate of deactivation. In insulin-resistant obese subjects, the rate of activation of insulin action was slower and the rate of deactivation faster at comparable insulin infusion rates. The rate of suppression of HGO was comparable in normal and obese subjects, but the rate of recovery of HGO back to basal values was faster in the obese group. And in view of the phasic manner in which insulin is normally secreted following meals, steady state insulin action is not normally achieved. Therefore, the abnormal kinetics of insulin action in insulin-resistant obese individuals may represent functionally important manifestations of the insulin resistance in this condition.

Adult↗
PubMed1986

Interleukin 1 stimulates granulocyte macrophage colony-stimulating activity release by vascular endothelial cells.

Studies designed to characterize monocyte-derived recruiting activity (MRA) a monokine that stimulates endothelial cells to produce granulocyte macrophage-colony-stimulating activity (CSA) by endothelial cells, show that it is a thermolabile protein of from 12,000 to 24,000 D which, on chromatofocusing, shows three separate peaks of eluted activity from pH 7.5 to 5.0. Because these and many other properties of MRA are identical to those of interleukin 1 (IL-1), we tested the hypothesis that MRA and IL-1 are identical. We cultured vascular endothelial cells with various concentrations of purified native and recombinant IL-1 (pI 7 form), then tested the endothelial cell supernatants for GM-CSA. Purified native IL-1 and recombinant IL-1 stimulated endothelial cells to release CSA. The MRA of native IL-1, recombinant IL-1, and unfractionated monocyte conditioned medium was neutralized by a highly specific rabbit anti-human IL-1 antiserum. Chromatofocusing fractions that contained MRA contained immunoreactive IL-1 on immunoblotting and the bioactivity was neutralized completely by treatment with the antiserum. We conclude that IL-1 induces the release of CSA by vascular endothelial cells, that IL-1 is constitutively produced by monocytes in vitro, and that MRA and IL-1 are biologically, biophysically and, immunologically identical.

Animals↗
PubMed1986

The effects of proinsulin pretreatment on the combined actions of insulin and proinsulin in normal man.

With the recent availability of biosynthetic human proinsulin there has been a renewed interest in evaluating its metabolic effects, either alone or in combination with insulin. It has been suggested that pretreatment with proinsulin enhances the hypoglycemic response to subsequently administered insulin. On the other hand, the simultaneous administration of proinsulin and insulin has additive, not synergistic, effects. To clarify this question we used the euglycemic glucose clamp technique in 10 normal subjects to compare the steady state effects on glucose disposal of combined infusions of insulin (0.54 microgram/M2 . min, equivalent to 15 mU/M2 . min) and proinsulin (2.75 micrograms/M2 . min) given both simultaneously and sequentially. The mean +/- SEM steady state glucose disposal rates were similar whether the two hormones were given simultaneously (7.2 +/- 0.7 mg/min . kg), after proinsulin pretreatment (7.7 +/- 0.7 mg/min . kg), or after insulin pretreatment (7.1 +/- 0.7 mg/min . kg). The serum proinsulin concentration of 5.39 +/- 0.3 pmol/ml during the infusion of proinsulin alone was unchanged by the simultaneous infusion of insulin, suggesting that in the doses used, insulin did not affect proinsulin clearance. We conclude that in normal subjects there is no enhancement of the combined action of insulin and proinsulin to stimulate glucose disposal by pretreatment with proinsulin or insulin.

Adult↗
PubMed1986

In vivo deactivation of proinsulin action on glucose disposal and hepatic glucose production in normal man.

We have studied the deactivation of the in vivo actions of insulin and biosynthetic human proinsulin (recombinant DNA) to stimulate the glucose disposal rate (GDR) and to inhibit hepatic glucose output (HGO) in man. Twelve healthy, lean, young subjects were studied using a modification of the euglycemic glucose clamp technique. Subjects received 4-h infusions on separate occasions of insulin (15 mU/m2/min equivalent to 0.54 microgram/m2/min) or proinsulin (2.75 micrograms/m2/min), achieving steady-state serum levels of 32 +/- 3 microU/ml (equivalent to 0.23 +/- 0.02 pmol/ml) and 3.7 +/- 0.2 pmol/ml, respectively. Suppression of HGO was similar (83-84%) with proinsulin and insulin, but stimulation of GDR above basal was greater with insulin (3.41 +/- 0.43 versus 1.98 +/- 0.28 mg/kg/min, P less than 0.001). Following cessation of the hormone infusions, serum proinsulin concentration fell in a biphasic fashion with half-times of 25 and 146 min for the two phases. Serum half-disappearance time for insulin was 5 min. Deactivation of the hormone's effects to stimulate GDR was 50% complete by 35 min after insulin and 71 min after proinsulin. In contrast, 50% of the recovery times for the effect on suppression of HGO were 55 min after insulin and 188 min after proinsulin. Serum glucagon levels did not differ significantly after the insulin and proinsulin infusions. In summary: (1) Deactivation of proinsulin and insulin's effects to suppress HGO proceeds more slowly than deactivation of their effects to stimulate GDR; and (2) There is a markedly prolonged and disproportionately delayed deactivation of proinsulin's effects on suppression of HGO. This later finding may prove of therapeutic value in the treatment of diabetes mellitus.

Adult↗
PubMed1986

Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes mellitus.

To quantitate the effects of weight loss on the mechanisms responsible for hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), eight obese subjects with NIDDM were studied before and after weight reduction with posttreatment assessment after 3 wks of isocaloric (weight maintenance) refeeding. After weight loss of 16.8 +/- 2.7 kg (mean +/- SE), the fasting plasma glucose level decreased 55% from 277 +/- 21 to 123 +/- 8 mg/dl. The individual fasting glucose levels were highly correlated with the elevated basal rates of hepatic glucose output (HGO) (r = 0.91, P less than .001), which fell from 138 +/- 11 to 87 +/- 5 mg X m-2 X min-1 after weight loss. The change in fasting plasma glucose also correlated significantly with the change in the basal rates of HGO (r = 0.74, P less than .05). This was associated with reduced fasting serum levels of glucagon (from 229 +/- 15 to 141 +/- 12 pg/ml), reduced free fatty acids (from 791 +/- 87 to 379 +/- 35 mu eq/L), and unchanged basal insulin levels (17 +/- 4 to 15 +/- 2 microU/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

3-O-Methylglucose↗