Reversal of insulin resistance in type I diabetes after treatment with continuous subcutaneous insulin infusion.
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Diabetes Mellitus, Type 1↗
Biomedical subjects
A C Collins
Publications and source records attributed to A C Collins.
Effects of ethanol and salsolinol on catecholamine function in LS and SS mice.
Long Sleep (LS) and Short Sleep (SS) mice differ in duration of ethanol-induced sleep time because of differences in brain sensitivity to the depressant effects of alcohols. These lines of mice also differ in their sensitivity to salsolinol, the condensation product of acetaldehyde with dopamine. Some of ethanol's acute effects may be due to salsolinol interactions with catecholamine systems. In the present study, the half-lives of salsolinol were found to be 12.8 min (LS) and 12.3 min (SS). Salsolinol administration resulted in a decrease in brain norepinephrine content in LS but not SS mice. Dopamine levels were not altered by salsolinol. Ethanol or salsolinol, in vitro, inhibited dopamine uptake by striatal synaptosomes. The IC50 values for ethanol were 491 mM (LS) and 514 mM (SS), and for salsolinol, 300 microM (SS). Thus, the mouse line which is most sensitive to the behavioral effects of salsolinol is also most sensitive to salsolinol's effects on norepinephrine levels and inhibition of dopamine uptake. However, much higher concentrations are required to alter dopamine uptake in vitro than are required to alter behavior in vivo.
Animals↗
Chronic scopolamine treatment and brain cholinergic function.
Scopolamine was either continuously infused or injected once daily into C3H mice. Chronic infusion resulted in mice that were supersensitive to the hypothermia and tremor produced by the muscarinic agonist, oxotremorine. Chronic scopolamine infusion did not alter brain acetylcholinesterase (AChE) or choline acetyltransferase (ChAT) activities but it did produce an increase in brain muscarinic receptors, as measured by quinuclidinyl benzilate (QNB) binding. The maximal increase in QNB binding was seen at the 0.2 mg/kg/hr dose. Further increase in dose resulted in a return to control QNB binding in all brain regions studied except cortex. These animals were still supersensitive to oxotremorine, suggesting a dissociation between receptor number and response to agonist. Animals injected once daily for 10 days with 5 mg/kg exhibited an increase in QNB binding while no increase was seen at 20 mg/kg/day. Chronic oxotremorine infusion resulted in tolerance to the hypothermia-producing effects of oxotremorine. This was accompanied by a decrease in brain QNB binding. Coinfusion of scopolamine with oxotremorine blocked both the tolerance development and receptor changes. These experiments demonstrate that chronic scopolamine treatment can elicit an increase in brain muscarinic receptors which is accompanied by supersensitivity to agonists. However, this effect is not clearly dose related, and a strict relationship between receptor number and agonist response does not exist.
Acetylcholine↗
Behavioral effects of ethanol and salsolinol in mice selectively bred for acute sensitivity to ethanol.
The effects of intracerebral injection of salsolinol, the condensation product of dopamine and acetaldehyde, were compared in LS and SS mice selectively bred for differential sleep time following an intraperitoneal injection of ethanol. Salsolinol differentially affected open-field activity in the two mouse lines. Low doses of salsolinol increased open-field activity in the SS line; no such effects were obtained in the LS line. Larger doses decreased activity in both lines but the LS mice were more sensitive to this effect. Similar effects on open-field activity have been reported for ethanol in these same lines of mice. A 40 micrograms dose of salsolinol increased ethanol-induced sleep time in both lines but the increase was greater in the LS line. With lower doses of salsolinol the duration of ethanol-induced sleep time decreased in SS mice and increased in LS mice. This effect of salsolinol on sleep time most likely involves some CNS mechanism since salsolinol did not alter ethanol elimination rate in the two lines of mice. A more severe and prolonged hypothermia developed in LS mice following injections of salsolinol or equal doses of ethanol; however, equi-hypnotic doses of ethanol elicited similar hypothermic responses. Taken together, these data support a possible role for salsolinol in ethanol's actions.
Animals↗
A diallel analysis of nicotine-induced hypothermia.
The hypothermic responses of mice that occur after acute injection of nicotine show genetic influences. The body temperatures of mice of all five strains tested decreased after injection of either 0.75 or 1.5 mg/kg nicotine, but mice of the C3H strain were less affected than were those of the DBA, BALB, or C57BL strains. Mice of the A strain were the most sensitive to nicotine's effects. Genetic effects on nicotine-induced hypothermia were further examined using a five-by-five diallel cross. Additive genetic variance occurred at both nicotine doses. Substantial dominance variance, including directional dominance toward a large hypothermic response induced by injection of a low dose of nicotine (0.75 mg/kg), suggested that an intense response to a low drug dose is adaptive. The directional dominance was absent after treatment with a high dose (1.5 mg/kg) of the drug. Epistatic interactions occurring in crosses involving C57BL mice were pronounced.
Alleles↗
Prostaglandin E1 accelerates subcutaneous insulin absorption in insulin-dependent diabetic patients.
The powerful vasodilator, prostaglandin E1 (PGE1), was added to Actrapid insulin to try to accelerate the early phase of subcutaneous insulin absorption through increasing injection site blood flow. Actrapid insulin alone (6U) and insulin containing PGE1 (7.5 X 10(-6) M) were injected on different days into 13 fasting insulin-dependent diabetics. With the insulin/PGE1 mixture, increases in both free and total plasma insulin concentrations were greater at all times up to 120 minutes after injection than with insulin alone, with significant differences in the first 40 minutes. With insulin/PGE1 the area under the total plasma insulin curve increased significantly more rapidly between 80 and 120 minutes. Plasma glucose concentrations fell consistently more rapidly with insulin/PGE1 than with insulin alone although the differences were small (mean fall +/- S.E.M. at 120 minutes: 4.9 +/- 0.5 mmol/l vs 4.0 +/- 0.6; p = 0.02). Addition of local hyperaemic agents to short-acting insulin preparations could be therapeutically useful in hastening insulin entry to the circulation at mealtimes.
Adolescent↗
Urinary insulin excretion rate: an index of free insulinaemia in insulin-dependent diabetics.
In 25 insulin-dependent diabetics, 14 managed by conventional insulin injection treatment (CIT) and 11 treated by continuous subcutaneous insulin infusion (CSII), there was a highly significant correlation between urinary insulin excretion rate (IER) per 1.73 m2 and mean serum free insulin concentration (r = 0.73, p less than 0.001), measured over a 24 h period. Urinary IER and mean daily serum free insulin levels were significantly higher in diabetics than in non-diabetics. CSII-treated patients had significantly lower mean 24 h plasma glucose levels than CIT-treated patients despite similar values of urinary IER and mean daily serum free insulin in the two groups. Urinary IER may be a useful indicator of average insulinaemia in large scale studies, avoiding the problems of multiple blood sampling and immunoassay in the presence of anti-insulin antibodies.
Adult↗
Classical genetic analysis of nicotine-induced seizures and nicotinic receptors.
C3H/2lbg mice are more sensitive to nicotine-induced seizures than are DBA/2lbg mice. There are also differences in alpha-bungarotoxin (alpha-BTX) binding in the hippocampus and midbrain of these two strains, with the C3H mice having greater binding. Because alpha-BTX and nicotine appear to bind to nicotinic receptors in the central nervous system, it is possible that there may be a relationship between seizure sensitivity after a nicotine dose and nicotinic receptor concentration. To examine this relationship, a classical cross producing F1, F2 and backcross (F1 X C3H and F1 X DBA) generations from these two strains was utilized. Dose-response curves for nicotine-induced seizures were constructed for both parental strains and all crosses derived from them. Nicotinic receptors were also measured in three brain regions: cortex, midbrain and hippocampus. Both DL-[3H]nicotine and alpha-[125I]BTX were used to measure nicotinic receptors. The pattern of results for the six generations for alpha-BTX binding in the hippocampus paralleled that for seizure sensitivity. These results suggest that strain differences for both seizure sensitivity and receptor concentration in the hippocampus may be due to allelic differences at a single autosomal locus, with dominance for low seizure susceptibility and fewer alpha-BTX receptors.
Animals↗
Differential effects of long-chain alcohols in long- and short-sleep mice.
Observations that the long-sleep (LS) and short-sleep (SS( mouse lines differ in their depressant response to barbiturates, and that the difference between lines becomes greater as lipid solubility increases, prompted this investigation of the effects of alcohols that differ in lipid solubility. Results indicate that LS and SS mice differ significantly in their sleep time responses to propanol, butanol, and 3-methyl butanol, as well as ethanol: their hypothermic responses showed a similar pattern, but only the response to ethanol differed significantly between lines. For both sleep time and hypothermia, the difference between lines decreased with increasing lipid solubility. In all cases, the LS mice were more sensitive than the SS to the depressant effects of the alcohol. Similar ratios of SS:LS waking brain ethanol and butanol levels indicated that CNS sensitivity to long-chain alcohols is similar to that for ethanol. A pharmacokinetic study revealed higher ethanol levels for LS than for SS mice at all time points in blood, fat, and brain body compartments. Blood ethanol elimination curves showed that the SS mice eliminate ethanol at a faster rate than do the LS.
Animals↗
Differential effects of ethanol concentration on blood pH, PCO2 and PO2 in LS and SS mice.
Concentration-dependent effects of ethanol upon behavior and upon physiological regulatory mechanisms have been suggested. In a previous study, we found that the concentration of an acute ethanol injection confounded dose-response relationships for measures of blood pH, PCO2, and PO2. Two lines of mice that differ in CNS sensitivity to the hypnotic effects of ethanol (long sleep, LS; short sleep, SS) have also been found to differ in sensitivity to the physiological depressant effects of this drug. Therefore, we designed the present study to examine how intraperitoneal (IP) injections of varying ethanol concentrations differentially affect blood parameters (pH, PCO2, and PO2) and respiration rate in the LS and SS mouse lines. Different groups of LS female mice were injected IP with 165.0, 198.8, 248.1, or 330.0 mg/ml ethanol at a constant dose of 3.3 g/kg. Groups of SS female mice received 205.0, 247.0, 308.3, or 410.0 mg/ml ethanol at a dose of 4.1 g/kg. Blood parameters and respiration rate were measured at 60 min post-injection. In both the LS and SS mice, increasing concentrations of ethanol caused a progressive decline in respiration rate and blood pH. Blood PCO2 values were greater than control only at the highest ethanol concentration. Concentration-dependent effects of ethanol on blood PO2 values were not found in either line. However, LS PO2 was significantly elevated from the control value at all ethanol concentrations. These results suggest that a dose-response relationship may be obtained by varying ethanol concentration for some physiological measures, but not for others. Thus, attention should be paid to differences in concentration as well as amount of ethanol when dose-response curves are to be constructed.
Acid-Base Equilibrium↗
Circadian and genetic influences on tissue sensitivity and sleep time to ethanol in LS and SS mice.
Circadian variations in response to ethanol were studied in long-sleep (LS) and short-sleep (SS) mice. Each LS animal received a 2.5 g/kg intraperitoneal ethanol injection, while the SS animals were injected with 4.1 or 5.0 g/kg. Different groups of mice were assessed for sleep time, waking blood alcohol concentration (BAC), and waking brain ethanol concentration (BREC) at 03.00, 09.00, 15.00, or 21.00 hr. Sleep times, waking BACs, and waking BRECs showed circadian variations in the LS mice. SS animals given the 4.1 g/kg dose showed circadian variations for waking BAC and waking BREC, but not for sleep time. The observed variations in the physiological parameters for these animals may have been confounded by a short sleep time so that they reflected circadian variations in drug absorption and/or distribution rather than in CNS sensitivity. SS mice given the 5.0 g/kg dose slept longer than those given the 4.1 g/kg dose and did not show circadian variations for sleep time, waking BAC, or waking BREC. These results suggest both circadian and genetic influences on tissue sensitivity to ethanol.
Animals↗
Quantitation of tolerance development after chronic oxotremorine treatment.
A new procedure was developed to quantitate the tolerance which develops as mice are chronically infused with the muscarinic agonist, oxotremorine. Cumulative dose-response curves were constructed for the effects of oxotremorine on body temperature and rotarod performance by administering sequential injections to individual animals. These dose-response curves compare favorably to those constructed by injecting individual animals with one of several doses. The sequential injection technique was used to assess the magnitude of tolerance development to oxotremorine. A linear relationship between oxotremorine infusion rate (dose) and magnitude of change of the ED50 value for impairment of rotarod performance was observed, with animals receiving an infusion rate of 1.0 mg/kg/hr showing a 24-fold increase in ED50. Dose-response curves for tolerant animals were parallel to those constructed for naive animals. The oxotremorine dose required to decrease body temperature to 35 degrees C (ED35 degrees) was 80-fold greater than control in the group treated with 1.0 mg/kg/hr. The dose-response curves for tolerant animals were not parallel to those seen in naive animals. Time courses of recovery from a challenge dose of oxotremorine suggest little change in metabolism occurred during chronic infusion. Chronic oxotremorine infusion resulted in a decrease in the total number of QNB binding sites. Both high- and low-affinity sites were reduced in number. Since no change in K1 for the muscarinic agonist, carbamylcholine, was observed, it seems unlikely that a change occurs in the affinity of the muscarinic receptor for agonists. Significant change in receptor number was detected only in animals that received higher doses of oxotremorine. Chronic oxotremorine treatment had no effect on choline uptake by synaptosomes prepared from any of five brain regions.
Animals↗
Antagonism of alcohol hypnosis by blockade of prostaglandin synthesis and activity: genotype and time course effects.
Pretreatment of mice with prostaglandin synthetase inhibitors (PGSI's) antagonizes alcohol-induced behaviors. This study examined genetic and time course factors of this effect and studied the effects of a putative prostaglandin antagonist (SC-19220) on ethanol sleep time. Long Sleep (LS) and Short Sleep (SS) mice, lines bred for differential response to an hypnotic dose of ethanol, showed a four-fold difference in their dose-response curves for indomethacin antagonism of ethanol-induced hypnosis. Females of both lines required higher amounts of indomethacin relative to males. Indomethacin pretreated animals regained the righting response at a higher blood ethanol concentration than did saline pretreated animals. In addition, indomethacin pretreatment failed to alter the rate of ethanol disappearance from blood. In general, both lines showed effects with low doses of indomethacin at early time points and with high doses of indomethacin at later time points. Indomethacin did not antagonize ethanol-induced hypnosis if given after ethanol. In C3H mice, pretreatment with low doses of SC-19220, a dibenzoxazepine derivative, produced a significant decrease in ethanol sleep time, moderate doses produced no effect, and high levels increased sleep time. These results further substantiate and expand our previous reports. Possible mechanisms for the biphasic effects of indomethacin treatment are presented and discussed.
Animals↗
Nonlinear pharmacokinetics of ethanol elimination in long sleep and short sleep mice.
Pharmacokinetic studies of ethanol elimination in humans and dogs have suggested that elimination from the blood can be best described through the application of Michaelis-Menten enzyme kinetics. In an attempt to extend the application of the Michaelis-Menten model to ethanol elimination in mice, we measured elimination rates using serial blood samples obtained from the long sleep (LS) and short sleep (SS) selected mouse lines following a bolus, intravenous ethanol infusion. A comparison was made between elimination rates as predicted by Widmark's linear model and by the nonlinear Michaelis-Menten model. Volume of distribution was also determined for each mouse line. Ethanol elimination in these mice conformed to the nonlinear model. Significantly greater Vmax and Km values were obtained for the SS mice than for the LS; however, no significant difference in linear elimination rates was found between lines. The LS mice exhibited a significantly greater volume of distribution than did the SS. The Michaelis-Menten model predicts that SS ethanol metabolism should be greater than LS metabolism at blood ethanol concentrations greater than 120 mg%. The results support the suggestion that ethanol elimination can be best described by Michaelis-Menten kinetics. Line differences in ethanol elimination may have resulted from changes in the doses used to select these mice and/or the induction of specific ethanol metabolizing systems.
Animals↗
Concentration-dependent effects of ethanol in long-sleep and short-sleep mice.
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Animals↗
Lipid solubility is correlated with hypnotic and hypothermic responses of long-sleep (LS) and short-sleep (SS) mice to various depressant drugs.
The long-sleep (LS) and short-sleep (SS) lines of mice have been selected for a difference in duration of ethanol-induced sleep time. In our previous study, recent generations of the two lines were found to exhibit differential hypnotic and hypothermic responses to pentobarbital which appear to be explained by differences in elimination. Casual observation that the LS mice were fatter than the SS suggested that this discrepancy may influence the responses of these animals to sedative-hypnotic drugs which differ in lipid solubility. The present study was designed to determine whether the LS and SS mice differ in hypnotic and hypothermic responses to two barbiturates which differ in lipid solubility; to the highly lipid soluble tertiary alcohol, ethchlorvynol; and to the water soluble depressant, methyprylon. Mice of the SS line were more responsive to the lipid soluble depressants than were LS mice, and increasing the lipid solubility of the barbiturates resulted in a greater difference between the lines. LS mice were more responsive to the water soluble depressant, apparently due to differential central nervous system sensitivity rather than to differences in elimination. The whole-body lipid content of the LS mice is double that of the SS mice. The influence of body lipid content on drug disposition may accentuate the elimination differences that result in the lesser responsivity of LS mice to barbiturates and possibly ethchlorvynol. This study indicates that sedative-hypnotic drugs of varying lipid solubilities may not share common mechanisms of action.
Animals↗
Genetics of nicotine response in four inbred strains of mice.
The effects of nicotine on five behavioral and physiological measures were determined in four inbred mouse strains (BALB, C57BL, DBA and C3H). In addition, the binding characteristics of nicotine and alpha-bungarotoxin, two ligands which appear to label different nicotinic receptors, were measured in seven discrete brain regions, as well as in whole brain. A number of differences in response to nicotine were found among the four inbred strains. Whereas nicotine depressed open-field activity of BALB, C57BL and DBA mice in a dose-dependent manner, low doses of nicotine increased locomotor activity in C3H mice. The doses of nicotine tested reduced Rotarod performance in DBA and C57BL mice but not in C3H and BALB mice. All four strains displayed a dose-dependent decrease in body temperature after nicotine administration. The BALB mice were more sensitive to the drug than were the C3H, whereas the effects on C57BL and DBA mice were intermediate. All four strains showed a transient increase in respiration only after a high (2.0 mg/kg) nicotine dose. No dose of nicotine was found to have an effect on the startle response after auditory stimulation in three of the strains; only the C3H mice exhibited enhanced startle after nicotine was administered. Differences in DL-[ 3H ]nicotine binding among the seven brain regions were noted in each strain, but no differences among strains were observed. The IC50 values for inhibition of this binding by nicotine did not differ among brain regions within any strain or within any region among strains. Similarly, nicotine inhibited alpha-[125I]bungarotoxin binding with equal potency in all brain regions of each of the four strains; however, the binding of this ligand was significantly lower in the midbrain and hippocampus of DBA mice than it was in these regions in the other three strains. Thus, genetic factors influence response to nicotine, but variation in response is not easily explained by differences in brain nicotinic receptors.
Animals↗
Effects of chronic nicotine infusion on tolerance development and nicotinic receptors.
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Animals↗