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Biomedical subjects

M L McCaleb

Publications and source records attributed to M L McCaleb.

32 records · Page 2Linked to original sources
PubMed1983

Cellular basis of insulin resistance in chronic uremia.

To define the cellular alterations responsible for insulin resistance during uremia, we studied insulin action in adipocytes isolated from rats 2 wk after 75% partial nephrectomy. Insulin binding to fat cells and purified liver plasma membranes prepared from uremic rats was unaltered. In contrast, hexose transport was significantly decreased, with and without insulin, in the fat cells from the uremic animals. The concentration of insulin that elicited half-maximal response was not altered. Glucose utilization was reduced in the absence or presence of insulin by partial nephrectomy. The stimulation of hexose transport and glucose metabolism by the insulin mimickers, hydrogen peroxide and vitamin K5, were also inhibited. Hexose transport activity in adipocytes obtained from uremic rats was no longer decreased when pieces of fat tissue were cultured for 20 h. Finally, hexose transport was reduced in the cells isolated from normal adipose tissue that was preincubated for 3 h with uremic serum, but insulin binding was not different than control. Thus, insulin resistance associated with uremia may be primarily accounted for by altered postreceptor events that appear to result from a circulating factor(s).

Adipose Tissue↗
PubMed1982

Affinity change of the adipocyte receptor fails to alter insulin-stimulated glucose transport.

Occupancy increased the affinity of the insulin receptor of the adipocyte. During the affinity change the half-maximal sensitivity of glucose transport to insulin stimulation was unaltered. Decreased maximum response of transport only occurred after the affinity change. There was not a simple relationship between receptor affinity and insulin stimulation of glucose transport in the adipocyte.

Adipose Tissue↗
PubMed1982

Alcohol drinking induced in the monkey by tetrahydropapaveroline (THP) infused into the cerebral ventricle.

In the female macaque monkey acclimated to a primate chair, Collison cannulae were stereotaxically implanted bilaterally in the lateral cerebral ventricle. The voluntary self-selection of ethyl alcohol versus water was determined repeatedly during a series of 12-day test sequences in which the concentration of the alcohol solution offered to the primate was increased systematically over 12 successive days from 3% to 30%. Following control preference sequences, the dopamine-dopaldehyde condensation product, tetrahydropapaveroline (THP), was infused daily in each monkey's cerebral ventricle (ICV) in a volume of 200-400 microliter. THP was dissolved in an artificial CSF, with pH adjusted to 3.8 with 0.1 mg/ml ascorbate, and infused in one of ten doses varying from 0.125-400 microgram. EAch monkey was administered one low and one high dose of the condensation product throughout each of two successive alcohol preference tests. When THP was infused in doses of less than 2.0 microgram, the monkeys' alcohol preference failed to change. However, a marked increase in alcohol intake, in terms of both g/kg/day as well as the proportion of alcohol to water selected, was produced by THP infused ICV in doses of 5.0 to 20.0 microgram. Although average intakes in the latter animals were between 4.0 and 5.0 g/kg/day, the monkeys selected certain concentrations of alcohol in amounts of up to 7.0 g/kg/day. The two highest doses of THP, 40.0 and 400.0 microgram, inhibited the self-selection of alcohol even when presented in low, non-aversive concentrations in the 3% to 6% range. Overall, these results with the primate corroborate earlier findings in the rat of abnormal alcohol intake produced by centrally infused THP. They further support the theory that amine-aldehyde metabolites, if present in certain concentrations in the brain, may constitute a causal neurochemical factor in the addictive or otherwise immoderate drinking of alcohol.

Alcohol Drinking↗
PubMed1982

Hypothalamic microinjection of norepinephrine (NE) elevates and prolongs basal efflux of unmetabolized NE from injection site.

The effect of a microinjection of norepinephrine (NE) into the diencephalon of the rat was examined in terms of the subsequent endogenous activity of this amine. A push-pull guide cannula was first implanted stereotaxically with the tip resting in the rat's hypothalamus. Several days later, NE in a dose of 20 ng, 95 ng or 3.2 micrograms was microinjected in a volume of 0.5 microliters into the perifornical region. After a 30 min interval, the injection site was perfused, by means of push-pull cannulae with an artificial CSF at a rate of 25 microliters/min. The samples of perfusate collected one hour after the microinjection were analyzed by HPLC with electrochemical detection. The results indicate that an unexpectedly high level of unmetabolized NE can be detected at the perfusion site. This NE is greater than the picogram quantities of NE present endogenously in the rat's hypothalamus. The persistent presence of the exogenously applied amine within a microinjection site could explain the longevity of a given pharmacological effect of an amine often seen with this injection procedure. Also, it suggests that the local metabolic degradation of the amine is not as rapid as one would expect.

Animals↗
PubMed1982

2-Deoxy-D-glucose and insulin modify release of norepinephrine from rat hypothalamus.

Both 2-deoxy-D-glucose (2-DG) and insulin, administered systemically, evoke spontaneous feeding in the satiated animal. To determine whether hypothalamic norepinephrine (NE) could be involved in this eating response, we examined the effect of the two compounds on the kinetics of NE release from this structure in the unrestrained rat. An individual site in the hypothalamus of the rat was radiolabeled by 1.0-2.0 microCi of [14C]NE microinjected in a volume of 0.5-1.0 microliters through a permanently implanted guide cannula. Then 30 min later, the NE-labeled tissue was perfused, by means of push-pull cannulas, with an artificial cerebrospinal fluid at a rate of 25 microliters/min. The duration of each perfusion was 5.0 min with a 5.0-min interval between successive perfusions. After two base-line samples were collected, a saline control injection or either 40 mg/kg 2-DG or 20 U/kg insulin was given intraperitoneally; then the perfusion sequence was continued for an additional 1-h period. Aliquots of the collected samples of perfusate were analyzed by combined scintillation spectrometry and high-pressure liquid chromatography. 2-DG enhanced the release of NE at sites in the medial hypothalamus, whereas insulin generally caused a suppression of catecholamine efflux particularly at sites within the lateral hypothalamic area. The changes in NE efflux were morphologically specific. Taken together with the differences in amine release, these results suggest that 2-DG and insulin modify feeding by independent neurochemical mechanisms that may involve noradrenergic neurons at the hypothalamic level.

Animals↗
PubMed1980

Feeding: satiety signal from intestine triggers brain's noradrenergic mechanism.

Noradrenergic neurons in the hypothalamus involved in feeding and satiety are activated by gastrointestinal receptors. In the unrestrained rat, sites were first identified at which norepinephrine injected in the medial hypothalamus caused spontaneous feeding, or in the lateral hypothalamus caused no response. The activity of in vivo norepinephrine at these two sites was characterized by localized push-pull perfusion. When a nutrient was infused directly into the rat's duodenum, the synaptic release of hypothalamic norepinephrine was enhanced at lateral sites insensitive to norepinephrine, but suppressed at medial sites reactive to norepinephrine. Thus, signals from duodenal receptors are conceivably sent to the rat's brain to end feeding by way of noradrenergic inhibitory neurons in the hypothalamus.

Animals↗
PubMed1980

Cholecystokinin acts on the hypothalamic "noradrenergic system" involved in feeding.

In male long Evans rats, microinjection cannulae were stereotaxically positioned to rest in sites in the preoptic area and medial hypothalamus. After the rats were satiated on wet mash, norepinephrine (NE) was infused in a dose of 2.5 micrograms and a volume of 0.75 microliter into these diencephalic sites. At loci in six animals, NE evoked spontaneous feeding of 5.0 gms or more of wet mash. Cholecystokinin (CCK) infused prior to the NE microinjection either intraperitoneally (0.5--1.0 microgram/kg) or at the NE-sensitive hypothalamic sites (75--150 ng) significantly attenuated or blocked the rat's feeding response to NE. The intake of water was unaffected by CCK in both instances. Thus, CCK may act on the diencephalic noradrenergic feeding system indirectly, through vagal afferent pathways, or directly within the animal's hypothalamus.

Animals↗
PubMedDate not supplied

Prevention of urinary albumin excretion in 6 month streptozocin-diabetic rats with the aldose reductase inhibitor tolrestat.

Recent clinical data strongly suggest that elevated urinary albumin excretion (UAE) identifies diabetic subjects at risk of developing nephropathy. Elevated UAE is attributed to increased transglomerular pressure, which is associated with poor metabolic control in rats. Because excess glucose in diabetes is metabolized via the polyol pathway, we were interested in whether the diabetes-induced elevation in UAE in rats could be prevented by inhibiting aldose reductase (AR), the first enzyme in the polyol pathway, with the AR inhibitor tolrestat. In fact, in rats made diabetic with streptozocin (35 mg/kg IV), treatment for 6 months with tolrestat (25 mg/kg/day in the diet) prevented both sorbitol accumulation in the kidney and the increase in UAE. Sorbitol accumulation and the increased UAE were not associated with statistically significant mesangial expansion, and the thickening of glomerular basement membranes was not affected by tolrestat treatment. The authors conclude that the 4.7-fold elevation in UAE in chronically diabetic rats is linked to the increased flux of glucose through the polyol pathway since it was prevented by inhibiting aldose reductase with tolrestat.

Albuminuria↗
PubMedDate not supplied

Sulfonylurea effects on target tissues for insulin.

We have examined the nonpancreatic actions of sulfonylureas on multiple aspects of insulin responsiveness in two target tissues for insulin, liver and fat. In vivo administration of tolazamide and glipizide reduced significantly the postabsorptive serum glucose levels in rats without altering the levels of insulin. This was consistent with extrapancreatic sites of drug action. The number and affinity of hepatic insulin receptors was not different from those of control rats. Using a tissue culture system for rat adipose tissue, a 20-h treatment with sulfonylureas markedly potentiated insulin action in fat cells. The primary augmentation was at the level of insulin-stimulated glucose transport. Again, there was no alteration of the insulin receptors located on the adipose tissue. Furthermore, consistent with the lack of an influence on insulin-induced receptor loss after in vitro treatment with sulfonylureas, the in vivo administration of these agents did not alter the transglutaminase activity in rat hepatic tissue. The data demonstrate that sulfonylureas potentiate the responsiveness of the target tissues for insulin. Thus, these hypoglycemic agents probably act by correcting some of the cellular lesions associated with the insulin resistance in type II diabetes mellitus.

Adipose Tissue↗