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Biomedical subjects

D Porte

Publications and source records attributed to D Porte.

At least 127 records · Page 7Linked to original sources
PubMed1984

Variations in circulating catecholamines fail to alter human platelet alpha-2-adrenergic receptor number or affinity for [3H]yohimbine or [3H]dihydroergocryptine.

A series of studies were performed to determine the relationship between physiologic levels of circulating plasma norepinephrine and epinephrine and human platelet alpha-2 binding site number and the affinity (KD) of these sites for antagonist radioligands. In one study, alpha-2-adrenergic binding site number and affinity were compared using both [3H]yohimbine and [3H]dihydroergocryptine as radioligands. There was good absolute and relative comparison for binding site number, but only a relative relationship for KD. In 46 normal subjects, there was no significant relationship between site number or KD and age, plasma epinephrine, or plasma norepinephrine concentration. Even after plasma epinephrine was raised nearly 20-fold by means of an intravenous infusion for 4 h in seven normal subjects, neither sites (608 +/- 68 vs. 567 +/- 120 sites/platelet) nor KD (2.01 +/- 0.94 vs. 2.14 +/- 1.15 nM) were significantly changed. Similarly, neither sites (445 +/- 55 vs. 421 +/- 53 sites/platelet) nor KD (1.44 +/- 0.29 vs. 2.10 +/- 0.75 nM) were significantly changed in six normal subjects when plasma norepinephrine levels increased during oral administration of prazosin for 1 wk. Thus, in a cross-sectional analysis and after a change in plasma catecholamine concentrations, there was no relationship in normal subjects between platelet alpha-2 binding site number or affinity of these sites for antagonist radioligands and the circulating catecholamine levels to which the platelets were exposed. In a group (n = 7) of patients who lack epinephrine-induced platelet aggregation due to abnormal thrombopoiesis, binding site number was decreased (304 +/- 36 vs. 572 +/- 29 sites/platelet, P less than 0.001) and KD tended to be greater (8.69 +/- 2.44 vs. 5.40 +/- 0.31 nM, P = NS) than in normal subjects (n = 46), despite having similar plasma catecholamine levels. There was no difference in binding site number (491 +/- 116 sites/platelet) and KD (5.61 +/- 0.84 nM) in patients (n = 5) with autonomic insufficiency and low levels of upright plasma norepinephrine when compared with the normal subjects. Two patients were examined before and after the removal of a pheochromocytoma. Their binding site number and KD were normal before the operation and essentially unchanged after the tumor removal and fall of plasma catecholamines. Thus, this study demonstrates that within the physiologic and pathophysiologic range of plasma catecholamines (in men), there is no relationship between the circulating catecholamine concentration and either platelet alpha-2 adrenergic binding site number or the affinity of these sites for antagonist radioligands.

Adult↗
PubMed1984

Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus.

In order to assess whether patients with noninsulin-dependent diabetes mellitus (NIDDM) possess normal insulin secretory capacity, maximal B cell responsiveness to the potentiating effects of glucose was estimated in eight untreated patients with NIDDM and in eight nondiabetic controls. The acute insulin response to 5 g intravenous arginine was measured at five matched plasma glucose levels that ranged from approximately 100-615 mg/dl. The upper asymptote approached by acute insulin responses (AIRmax) and the plasma glucose concentration at half-maximal responsiveness (PG50) were estimated using nonlinear regression to fit a modification of the Michaelis-Menten equation. In addition, glucagon responses to arginine were measured at these same glucose levels to compare maximal A cell suppression by hyperglycemia in diabetics and controls. Insulin responses to arginine were lower in diabetics than in controls at all matched glucose levels (P less than 0.001 at all levels). In addition, estimated AIRmax was much lower in diabetics than in controls (83 +/- 21 vs. 450 +/- 93 microU/ml, P less than 0.01). In contrast, PG50 was similar in diabetics and controls (234 +/- 28 vs. 197 +/- 20 mg/dl, P equals NS) and insulin responses in both groups approached or attained maxima at a glucose level of approximately 460 mg/dl. Acute glucagon responses to arginine in patients with NIDDM were significantly higher than responses in controls at all glucose levels. In addition, although glucagon responses in control subjects reached a minimum at a glucose level of approximately 460 mg/dl, responses in diabetics declined continuously throughout the glucose range and did not reach a minimum. Thus, A cell sensitivity to changes in glucose level may be diminished in patients with NIDDM. In summary, patients with NIDDM possess markedly decreased maximal insulin responsiveness to the potentiating effects of glucose. Such a defect indicates the presence of a reduced B cell secretory capacity and suggests a marked generalized impairment of B cell function in patients with NIDDM.

Adult↗
PubMed1984

Prolonged infusion of somatostatin with glucagon replacement increases plasma glucose and glucose turnover in man.

To determine the effect of isolated beta-cell impairment on glucose turnover, we administered a 46-h infusion of somatostatin (200 micrograms/h) with glucagon replacement (0.75 ng/kg X min) to eight normal men. Fasting plasma insulin levels fell slightly, but significantly, from 8 +/- 2 (+/- SEM; control) to 6 +/- 2 microU/ml 46 h after beginning the infusion (P less than 0.001). Over the same period, fasting plasma glucose rose from 89 +/- 2 to 114 +/- 2 mg/dl (P less than 0.001), and plasma glucagon levels remained unchanged (79 +/- 5 vs. 82 +/- 8 pg/ml P = NS). Glucose turnover was measured by isotope dilution using [3-3H]glucose. The glucose production rate rose consistently from a baseline value of 2.08 +/- 0.04 to 2.45 +/- 0.06 mg/kg X min (P less than 0.01). The glucose disposal rate also rose consistently from 2.11 +/- 0.04 to 2.53 +/- 0.09 mg/kg X min (P less than 0.01). We conclude that prolonged mild selective insulin deficiency produced by infusion of somatostatin with glucagon replacement in normal men causes an elevation of the fasting plasma glucose level, which is maintained by glucose overproduction rather than by glucose underutilization. Overproduction of glucose may also be important in maintaining basal hyperglycemia in patients with noninsulin-dependent diabetes mellitus who have a similar impairment of insulin secretion.

Adolescent↗
PubMed1983

Aldose reductase inhibition improves nerve conduction velocity in diabetic patients.

To assess the potential role of polyol-pathway activity in diabetic neuropathy, we measured the effects of sorbinil--a potent inhibitor of the key polyol-pathway enzyme aldose reductase--on nerve conduction velocity in 39 stable diabetics in a randomized, double-blind, cross-over trial. During nine weeks of treatment with sorbinil (250 mg per day), nerve conduction velocity was greater than during a nine-week placebo period for all three nerves tested: the peroneal motor nerve (mean increase [+/- S.E.M.], 0.70 +/- 0.24 m per second, P less than 0.008), the median motor nerve (mean increase, 0.66 +/- 0.27, P less than 0.005), and the median sensory nerve (mean increase, 1.16 +/- 0.50, P less than 0.035). Conduction velocity for all three nerves declined significantly within three weeks after cessation of the drug. These effects of sorbinil were not related to glycemic control, which was constant during the study. Although the effect of sorbinil in improving nerve conduction velocity in diabetics was small, the findings suggest that polyol-pathway activity contributes to slowed nerve conduction in diabetics. The clinical applicability of these observations remains to be determined, but they encourage further exploration of this approach to the treatment or prevention of diabetic neuropathy.

Adult↗
PubMed1983

Regional concentrations of insulin in the rat brain.

Recent evidence that insulin receptors are concentrated in the hypothalamus and olfactory bulb suggests that insulin may have an important regulatory function in these regions. This hypothesis would be supported by finding that insulin itself is concentrated in the hypothalamus and olfactory bulb. Therefore, we extracted the hypothalamus and olfactory bulb, as well as the amygdala, hippocampus, cerebral cortex, hindbrain, midbrain, and whole brains, of fasted male Wistar rats and measured immunoreactive insulin (IRI). Recovery of insulin added to extraction volumes of 500-1000 microliters was 90-100%, whereas recovery of insulin from tissue extracts was 63%. Mean IRI concentrations were relatively uniform throughout the brain (0.19 ng/g wet wt; uncorrected for recovery) and were significantly lower than plasma levels (1.03 ng/ml). Nevertheless, IRI concentrations were significantly higher in hypothalamus (0.39 +/- 0.02 ng/g; P less than 0.01) and olfactory bulb (0.37 +/- 0.02 ng/g; P less than 0.05) compared to those in other brain regions sampled.

Animals↗
PubMed1983

Immunocytochemical detection of insulin in rat hypothalamus and its possible uptake from cerebrospinal fluid.

Insulin-like immunoreactivity (IRI) was detected in the rat hypothalamus, particularly in the paraventricular, periventricular, supraoptic, suprachiasmatic, arcuate, and lateral hypothalamic nuclei. The immunostainable IRI was diffusely distributed in comparison to the neuronal concentrations of immunostainable vasopressin in the periventricular nucleus, or of IRI in islet B cells, suggesting that immunostainable IRI in the hypothalamus is not concentrated in neuronal perikarya. To determine if insulin in cerebrospinal fluid (CSF) may be a source of some insulin in brain tissue, [125I]iodoinsulin was stereotaxically injected into a lateral cerebral ventricle, and the uptake of radioactivity into periventricular hypothalamus was localized by both quantitative autoradiography of paraffin-embedded brain sections and by measuring the radioactivity present in microdissected brain regions. In brains that received lateral ventricular injections of labeled insulin, the concentration of radioactivity in the periventricular region of the hypothalamus, as revealed by autoradiographic grains, was significantly greater than that in the periventricular region of brains that received lateral ventricular injections of labeled insulin mixed with an equimolar excess of an unlabeled peptide (insulin, ribonuclease, or both together). The highest levels of radioactivity detected in both autoradiographic and microdissection procedures were in regions nearest to the third ventricle, suggesting that insulin in the lateral ventricles has access to the periventricular neuropile in the hypothalamus. The staining pattern of immunostainable insulin in the hypothalamus along with the distribution of radioactivity after CSF injection of labeled insulin are consistent with the hypothesis that insulin is taken up into brain from the CSF.

Animals↗
PubMed1983

Immunoreactive insulin levels are elevated in the cerebrospinal fluid of genetically obese Zucker rats.

Immunoreactive insulin (IRI) concentrations were measured in plasma and cerebrospinal fluid (CSF) of four-month old genetically obese Zucker rats, their heterozygote lean littermates, and age-matched normal-weight Wistar rats. Basal plasma IRI was 201 + 35 microU/ml (means +/- SEM) in the obese animals and was significantly elevated compared to both lean Zucker rats (18 +/- 2.4 microU/ml, P less than 0.001) and Wistar rats (12 +/- 2.4 microU/ml, P less than 0.001). The mean CSF IRI concentration of fasted obese Zucker rats was 1.59 +/- 0.19 microU/ml; this was significantly higher than the CSF IRI level of either fasted Zucker lean rats (0.31 +/- 0.08 microU/ml, P less than 0.001) or Wistar rats (0.34 +/- 0.12 microU/ml, P less than 0.001). Plasma and CSF IRI concentrations were increased in free-feeding as compared with fasted animals. These data provide evidence that endogenous CSF insulin is derived from circulating plasma insulin in the rat and suggest that the hyperphagia and obesity of the Zucker fatty rat are not due to an inability of circulating insulin to gain access to the CSF.

Animals↗
PubMed1983

Suppression of glucagon secretion during a tolbutamide infusion in normal and noninsulin-dependent diabetic subjects.

To determine the effect of tolbutamide on glucagon release in noninsulin-dependent diabetic and normal subjects and how plasma glucose levels may modulate this effect, the acute glucagon response (AGR) to a 5-g iv arginine pulse was determined before and during a tolbutamide infusion. There was a decrease in plasma glucose concentration in both normal and diabetic subjects (both P less than 0.001); there tended to be a suppression of the AGR (4 of 6 normals and 8 of 11 diabetics), but this suppression was not statistically significant. In separate studies, when the plasma glucose level was clamped at baseline values by a variable rate of glucose infusion, the AGR was suppressed during the tolbutamide infusion in all 7 normal [change in AGR (delta AGR) = -35 +/- 12 pg/ml; P less than 0.05] and all 6 noninsulin-dependent diabetic subjects (delta AGR = -14 +/- 5 pg/ml, p less than .05). In 6 insulin-dependent diabetic subjects, there was no evidence of glucagon suppression by tolbutamide (delta AGR = +2 +/- 2 pg/ml). These results are consistent with the hypothesis that sulfonylureas suppress glucagon secretion by augmenting insulin secretion, an effect that falling glucose levels can mask. Consideration of this observation is necessary when interpreting the effects of a sulfonylurea on islet cell responses.

Adult↗
PubMed1983

Modulation of arginine-induced glucagon release by epinephrine and glucose levels in man.

To assess how physiological epinephrine (EPI) elevations and EPI-induced hyperglycemia interact in the regulation of glucagon secretion, we measured acute glucagon responses (AGR) to arginine at controlled glucose levels during EPI infusions in man. With glucose levels matched at 166 +/- 5 mg/dl using glucose clamp techniques, the AGR (mean change at 2-5 min) to a 5-g iv arginine injection was greater in each subject during the infusion of 15 ng/kg . min EPI (low EPI) than during the control glucose infusion and was still greater during the infusion of 80 ng/kg . min EPI (high EPI; 69 +/- 15, 76 +/- 13, and 142 +/- 22 pg/ml, respectively; n = 8; P less than 0.003). With glucose levels matched at 256 +/- 5 mg/dl, a similar dose-related enhancement of AGR by EPI was seen (control, 53 +/- 12 pg/ml; low EPI, 63 +/- 5 pg/ml; high EPI, 130 +/- 20 pg/ml; P less than 0.008). During control infusions, raising the glucose level from 102 +/- 2 to 166 +/- 5 to 256 +/- 5 mg/dl suppressed AGR from 77 +/- 17 to 69 +/- 15 to 53 +/- 12 pg/ml (P less than 0.002). During low EPI, the same glycemic increments lowered GR from 108 +/- 19 to 76 +/- 13 to 63 +/- 5 pg/ml (P less than 0.02). This suppression of AGR by hyperglycemia was sufficient to obscure stimulation by EPI: at a glucose level of 102 +/- 2 mg/dl during control infusions, AGR was 77 +/- 17 pg/ml, compared to only 76 +/- 13 pg/ml during low EPI with the glucose level higher (166 +/- 5 mg/dl). Multiple linear regression analysis showed a highly significant dependence of AGR on both EPI and glucose levels, accounting for 80% of the within-subject variation in AGR (P less than 0.0001). These data show that 1) EPI is a dose-dependent amplifier of arginine-induced glucagon secretion in man, and 2) hyperglycemia suppresses arginine-induced glucagon secretion, potentially masking the stimulation caused by EPI. The findings suggest that the feedback effect of hyperglycemia on glucagon secretion may help regulate the level of hyperglycemia resulting from adrenergic stimulation.

Adult↗
PubMed1983

Hyperglycemia and beta-cell adaptation during prolonged somatostatin infusion with glucagon replacement in man.

To assess the relationship between beta-cell function and the level and duration of hyperglycemia during generalized beta-cell impairment, we studied the effects of acute and prolonged infusion of somatostatin in seven normal men. Twenty minutes after beginning an acute infusion of somatostatin (200 microgram/h) plus glucagon replacement (0.75 ng/kg/min), plasma glucose (PG) remained unchanged, but plasma insulin (IRI) and acute insulin response to isoproterenol had fallen markedly. Seventy minutes after beginning somatostatin-plus-glucagon, a rise in PG was associated with an increase in the acute insulin response to isoproterenol, though not to the control level. In a separate study, after 46 h of the somatostatin-plus-glucagon infusion, at a glucose level similar to the 70-min level, plasma insulin had returned nearly to the control level and the acute insulin response to isoproterenol had returned completely to the control level. Such increases inb basal and stimulated insulin secretion most likely represent a time-dependent adaptation by the beta-cells to the persistent hyperglycemia. First- and second-phase insulin responses to intravenous glucose were markedly inhibited after 46 h of somatostatin-plus-glucagon. In summary, a 46-h infusion of somatostatin with glucagon replacement in humans leads to hyperglycemia, a slightly diminished basal insulin level, markedly decreased insulin responses to glucose, and an insulin response to isoproterenol maintained at a normal level by acute and probably chronic adaptation to the hyperglycemia. We speculate that beta-cell adaptation to hyperglycemia may explain the similar abnormalities of islet function observed in patients with NIDDM.

Adaptation, Physiological↗
PubMed1983

The response of plasma triglyceride, cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial hypertriglyceridemia.

The effects of treatment on plasma total triglyceride, total cholesterol, and plasma postheparin lipase activities have not been evaluated in non-insulin-dependent diabetic (NIDD) subjects without a coexisting familial lipid disorder. In 49 untreated NIDD subjects, there was a linear relationship between glycosylated hemoglobin (GHb) and triglyceride (r = 0.35, P less than 0.02). This correlation was improved after adjusting for the effects of obesity by a partial correlation analysis. After therapy, there was a significant relationship between the change in GHb and the change in triglyceride. To determine whether changes in lipid removal from plasma may contribute to the decrease in plasma lipid concentrations during treatment, the plasma postheparin lipoprotein lipase and hepatic lipase activities were evaluated in a subgroup (N = 8) of these NIDD subjects before and after 1 and 3 mo of therapy. Plasma postheparin hepatic lipase activity in the NIDD subjects was not different from that observed in six normal control subjects and did not change during therapy. In contrast, plasma postheparin lipoprotein lipase activity was lower in the untreated NIDD subjects than in the control subjects. Analysis of the two phases (early and late) of the postheparin lipoprotein lipase activity in plasma showed that the abnormal early phase in untreated NIDD corrected to normal values in less than a month, but the late phase was not corrected until the 3-mo measurement. These findings suggest that some NIDD subjects have a defect in heparin releasable lipoprotein lipase activity, which is reversed with improved glycemic control.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1982

Morphine suppresses plasma catecholamine responses to laparotomy but not to 2-deoxyglucose.

The increase of plasma catecholamines that occurs during surgery can be reduced by administration of morphine. To test the hypothesis that morphine specifically blocks nociceptive stimulation during surgery, we compared the effects of morphine administration on the plasma catecholamine response to a laparotomy in pentobarbital-anesthetized dogs with the effect of morphine on the plasma catecholamine response to the neuroglucopenic agent, 2-deoxy-D-glucose (2DG, 300 mg/kg iv). In control dogs, plasma epinephrine (Epi) and plasma norepinephrine (NE) both increased progressively with time following a midline laparotomy (delta Epi by 50 min, +133 +/- 42 pg/ml, P less than 0.01 and delta NE by 50 min, +108 +/- 38 pg/ml, P less than 0.01, mean +/- SE, n = 12). 2-Deoxy-D-glucose produced a similar increase of both plasma NE and Epi. In dogs that received the anesthesia alone, plasma catecholamines did not increase from base line during the experiment. The analgesic morphine (15 mg iv), given 15 min after the completion of laparotomy, not only prevented the progressive rise of plasma catecholamines after laparotomy, but also caused a small but significant decline (P less than 0.05). Naloxone (0.4 mg iv) totally reversed the suppressive effects of morphine, restoring both catecholamines to the levels of their time-related control. In marked contrast, neither morphine nor naloxone affected the plasma NE and Epi increases following the administration of 2DG. These data suggest that morphine suppression of plasma catecholamines during surgery is not due to a generalized attenuation of sympathetic outflow, but rather to a specific interaction with an opiate receptor that either mediates analgesia or lies within the neural pathway stimulated by laparotomy but not by 2DG.

Animals↗
PubMed1982

Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose.

To determine the effect of chronic sulfonylurea therapy on islet function in noninsulin-dependent diabetes mellitus (NIDDM), studies were performed in 18 untreated NIDDM patients before and after 12-16 weeks of chlorpropamide therapy. Fasting plasma glucose (FPG) fell with chlorpropamide therapy from 249 +/- 16 to 157 +/- 8 mg/dl (mean +/- SEM; P less than 0.001), and basal insulin increased from 17 +/- 2 to 24 +/- 3 microU/ml (P less than 0.001). The percent change in basal insulin correlated with the pretreatment FPG (r = 0.62; P less than 0.01) and inversely with the change in FPG during chlorpropamide (r = -0.57; P less than 0.025). Thus, patients with the highest pretreatment FPG showed the largest relative increase in basal insulin and the largest fall of FPG with chlorpropamide therapy. In nine patients, arginine-stimulated acute insulin responses (AIR) were studied at each of three plasma glucose (PG) levels both before and during chlorpropamide treatment. AIR at FPG was not different before and during treatment. However, when PG during treatment was matched by glucose infusion to the pretreatment FPG, the AIR was clearly increased during chlorpropamide therapy (176 +/- 65 vs. 49 +/- 11 microU/ml; P less than 0.02). When AIR is plotted against PG for each individual, the slope of the regression line generated (slope of glucose potentiation) is a measure of that patient's islet sensitivity to glucose. The logarithm of the slope of glucose potentiation correlated inversely with FPG (r = -0.92; P less than 0.001). Chlorpropamide treatment increased the slopes of potentiation from 0.26 +/- 0.11 to 1.47 +/- 0.70 (P less than 0.01). We conclude that chronic chlorpropamide therapy augments both basal and stimulated insulin secretion in NIDDM and that this may be an important mechanism of the drug's hypoglycemic effect. The data support the hypothesis that the hyperglycemia of NIDDM is related to islet insensitivity to glucose and that chlorpropamide treatment improves this impairment.

Aged↗
PubMed1982

Central and peripheral nervous system complications.

Symptomatic neuropathy is a common manifestation of diabetes mellitus, and sensory, motor, or autonomic symptoms occur in approximately 10% of all diabetic patients. Animal models may be useful to study the metabolic and electrophysiologic abnormalities peculiar to diabetic neuropathy. Genetic animal models, including the Chinese hamster, ob/ob mouse, db/db mouse, BB-wistar rat, and SSDR rat or chemically induced or nutritional models of diabetes mellitus provide the potential to use animals to study human neuropathy; however, to date, few characteristics of human diabetic neuropathy have been clearly demonstrated in any of these animal models. Better characterization of the neuropathy of existing animal models with emphasis on evaluation over long periods of time is recommended. These studies should include a cross-disciplinary approach using biochemical, electrophysiologic and morphologic techniques. Specific future approaches to study diabetic neuropathy using chemical models is outlined in this chapter.

Alloxan↗
PubMed1982

Insulin responses to nonglucose stimuli in non-insulin-dependent diabetes mellitus during a tolbutamide infusion.

To determine the effect of tolbutamide on insulin release to nonglucose stimuli in non-insulin-dependent diabetes mellitus and how plasma glucose levels may modulate this effect, the acute insulin response (AIR) to an isoproterenol (12 Micrograms) or an arginine (5 g) i.v. pulse was determined before and during a tolbutamide infusion (7.5 mg/m2/min) in 25 male subjects. During the tolbutamide infusion, there was an increase in the AIR to both isoproterenol (% delta AIR = +49 +/- 21%, N = 11, P less than 0.05) and arginine (% delta AIR = +52 +/- 15%, N = 12, P less than 0.005) and a decrease in plasma glucose (delta plasma glucose for isoproterenol = -24 +/- 6 mg/dl, P less than 0.005; for arginine = -26 +/- 3 mg/dl, P less than 0.001). In separate studies, when the plasma glucose was clamped at baseline values by a variable rate of glucose infusion, there was a greater effect of tolbutamide on AIR when compared with the unclamped tolbutamide studies (isoproterenol: % delta AIR = +132 +/- 25%, P less than 0.025; arginine: % delta AIR = +95 +/- 12%, P less than 0.05). Thus, tolbutamide increases the AIR of nonglucose stimuli, but this augmentation by tolbutamide is blunted by the concomitant decrease in plasma glucose. Consideration of this observation is necessary when interpretating the effects of a sulfonylurea on islet cell responses.

Adult↗