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Biomedical subjects

M L Elks

Publications and source records attributed to M L Elks.

At least 37 records · Page 2Linked to original sources
PubMed1993

Chronic perifusion of rat islets with palmitate suppresses glucose-stimulated insulin release.

To test the hypothesis that the high circulating FFA levels in the diabetes of obesity could contribute to the altered dynamics of insulin secretion seen in that condition, insulin release was measured in isolated perifused rat islet cells, without or with added palmitate. Acutely, as in other systems, palmitate (1 mM) stimulated insulin release. Palmitate (1 mM) suppressed both first and second phase insulin release after 2, 3, or 4 h of perifusion, but not after 1 h. No significant effect was noted with 0.3 mM palmitate, and the effect was maximal at 1 mM. The stimulatory effects of arginine were essentially unaffected. Tolbutamide (1 mM) reversed or counteracted the effect. Glucose oxidation was suppressed in islets incubated with 1 mM palmitate for 4 h. Inhibitors of fat oxidation, alpha-bromostearate (1 mM) and methyl-3-tetradecylglycidate (100 microM) reversed the effects of palmitate on glucose-stimulated insulin release and glucose oxidation. Thus, prolonged incubation of rat islet cells with 1 mM palmitate could suppress the glucose-stimulated release of insulin from perifused rat islets. This suppression could be reversed by inhibitors of fat oxidation. This supports the hypothesis that elevated FFA levels and/or increased fat oxidation could contribute to the altered dynamics of insulin secretion in obese diabetics by fuel antagonism as well as the previously documented suppression of peripheral glucose uptake and stimulation of hepatic gluconeogenesis and may be a key link between obesity and the development of diabetes.

Animals↗
PubMed1993

The right to participate in research studies.

Institutional review boards for the use of human subjects in scientific studies were initially established to focus on protection of human subjects from the risks of research. It has become evident in recent years, however, that it is also important to protect the rights of individuals to have access to the benefits of research participation. These include, but are not limited to, certain experimental drugs or treatments, closer monitoring, free care or direct remuneration, and societal benefits of results of studies on specific populations. Researchers, so long sensitized by their respective institutional review boards to the need for protection of the subjects, now must also focus on the added burden of efforts to include individuals and the increased efforts it may take to protect the safety and rights of certain populations, including patients with AIDS, women, minorities, children, and the elderly. Additional care must be taken to design appropriate studies, recruit an appropriate spectrum of the population, craft a complete yet understandable and nondeterent informed consent form, and make efforts to assure that participants are informed.

Beneficence↗
PubMed1993

Misunderstanding in the classification of diabetes mellitus. What's in a name?

To assess whether physicians, residents, medical students, hospital diagnosis coders, and patients properly use the designations insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) that were established by criteria of the National Diabetes Data Group, we reviewed clinic and hospital records and administered questionnaires. Although essentially all cases of true IDDM were identified as such and most cases of NIDDM not requiring insulin therapy were correctly identified by all groups, patients with NIDDM on insulin therapy were misidentified as having IDDM by 38% of residents in internal medicine clinics and 68% of primary care and surgical subspecialty residents. On a survey, of 22 patients with NIDDM on insulin therapy, 17 (77%) considered themselves to have IDDM. Thus, patients who have NIDDM by the established criteria who are on insulin therapy are commonly mislabeled as having IDDM. We present an approach for dealing with this problem by adapting nomenclature focusing on insulin deficiency and resistance. It would probably also be helpful to separately identify the subset of patients with "insulin-deficient diabetes" who are ketosis-prone. It is important to use immunologic profiling (islet cell antibody testing) and insulin sensitivity or deficiency testing (C-peptide levels).

Adult↗
PubMed1990

Fat oxidation and diabetes of obesity: the Randle hypothesis revisited.

A hypothesis is presented that addresses the etiology of diabetes in the obese. Evidence from many areas of research suggests that ready availability of free fatty acids for oxidation by muscles and other tissues may lead to impairment of carbohydrate oxidation and lead to glucose intolerance as is seen in obesity and obese diabetics. In addition, free fatty acids can stimulate hepatic gluconeogenesis and alter pancreatic insulin release and subsequent metabolism, which may be the pathophysiological mechanism for these changes in obese diabetics. It is well-recognized that there are different anatomic forms of obesity and that risk of diabetes is much greater in those with abdominal rather than hip/thigh obesity. It may be that fat cells in abdominal depots (in these individuals) are more metabolically active, releasing greater amounts of free fatty acids (even after feeding when they should be suppressed), and the metabolism of these fatty acids leads to the changes described here, leading to overt diabetes.

Adipose Tissue↗
PubMed1990

Pseudohypoglycemia in adult victims of adolescent incest.

Two patients with complaints of hypoglycemia came for evaluation, and both complained of intermittent episodes of mental dullness, disorientation, confusion, and palpitations relieved by eating. Plasma glucose levels at the time of symptoms were always above 70 mg/dL. Initial onset of symptoms was within 1 to 2 years after cessation of repeated incest, and on recognition of this, both patients associated the onset of episodes of similar feelings with the acts of incest. Recognition of this connection did not decrease the frequency of episodes. Both persistently refer to the episodes as "hypoglycemia" despite recognition that no glucose level below 70 mg/dL has been recorded during an episode. Recurrent episodes of derealization and depersonalization in both patients appear to be sequelae of adolescent incest experiences, but these patients cling to the label "hypoglycemia," perhaps in part because they are unwilling to accept a psychiatric diagnosis for their episodes.

Adolescent↗
PubMed1987

Effect of N6-(L-2-phenylisopropyl)adenosine and insulin on cAMP metabolism in 3T3-L1 adipocytes.

The antilipolytic effect of N6-(L-2-phenylisopropyl)-adenosine (PIA), an adenosine analogue thought to act via cell surface receptors, was investigated in 3T3-L1 adipocytes. PIA (1 microM) was as effective as 1 nM insulin in reducing lipolysis stimulated by 1 nM isoproterenol and more effective than insulin at higher isoproterenol concentrations. In intact adipocytes, PIA reduced isoproterenol-induced cyclic AMP (cAMP) accumulation and increased particulate cAMP phosphodiesterase. In particulate preparations PIA suppressed isoproterenol stimulation of adenylate cyclase. PIA was more effective than 5'-N-ethylcarboxamide adenosine (NECA) or adenosine in inhibiting adenylate cyclase and activating phosphodiesterase. In intact adipocytes, two agents with so-called "insulin-like" activities, i.e., anti-insulin receptor antibodies and wheat germ agglutinin (WGA), also increased particulate cAMP phosphodiesterase. Pertussis toxin, which inhibits stimulation of the particulate cAMP phosphodiesterase by insulin (but not by isoproterenol), also inhibited the effects of PIA, anti-insulin receptor antibodies, and WGA. In 3T3-L1 cells, PIA appears to inhibit lipolysis by inhibiting adenylate cyclase and stimulating phosphodiesterase; these effects of PIA, as well as those of anti-insulin receptor antibodies and WGA on phosphodiesterase, may be mediated via guanyl nucleotide-binding proteins.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

A role for soluble cAMP phosphodiesterases in differentiation of 3T3-L1 adipocytes.

Differentiation of 3T3-L1 adipocytes, monitored by accumulation of neutral lipid and by increase in alpha-glycerophosphate dehydrogenase activity, is accelerated by incubation of confluent 3T3-L1 fibroblasts in media containing insulin, dexamethasone and isobutylmethylxantine (IBMX). IBMX inhibits cyclic nucleotide phosphodiesterases as well as the binding of adenosine to its receptor. Agents with relatively specific effects were utilized to examine the role of IBMX in differentiation. Ro 20-1724, a selective inhibitor of soluble cAMP phosphodiesterase activities, was as effective as IBMX in increasing alpha-glycerophosphate dehydrogenase activity and fat deposition. Neither cilostamide, which inhibits particulate but not soluble cAMP phosphodiesterase activities, 8-phenyltheophylline, an adenosine receptor antagonist with little inhibitory effect on phosphodiesterase activities, nor N6-(R phenyl-isopropyl) adenosine (PIA), a potent adenosine receptor agonist, were effective in promoting differentiation. In addition, we find that maximal increases in alpha-glycerophosphate dehydrogenase activity and lipid accumulation were observed when differentiation was initiated in the presence of 10 nM dexamethasone. These data suggest that inhibition of soluble cAMP phosphodiesterase activity and subsequent alterations in cAMP may play an important role in the mechanism whereby IBMX enhances differentiation of 3T3-L1 cells.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Antilipolytic action of insulin: role of cAMP phosphodiesterase activation.

Exposure of 3T3-L1 adipocytes to 1 nM insulin for 10 min results in activation of particulate cAMP phosphodiesterase and suppression of lipolysis stimulated by 10 nM isoproterenol. When lipolysis was increased by cilostamide, a selective inhibitor of the particulate phosphodiesterase, the antilipolytic effect of insulin was not observed. Insulin did suppress lipolysis stimulated by Ro 20-1724, an inhibitor of soluble cAMP phosphodiesterase activity. Cilostamide did not interfere with insulin stimulation of glucose uptake, nor did it have any direct effect on cAMP-dependent protein kinase. Thus, inhibition of particulate but not soluble cAMP phosphodiesterase blocked the antilipolytic effect of insulin. Our findings support the idea that insulin inhibits lipolysis, perhaps in large part by activating particulate "low Km" cAMP phosphodiesterase, which seems to be functionally closely coupled with the hormone-sensitive lipase-regulatory system influencing primarily a pool of cAMP utilized by the relevant protein kinase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Effects of thyroid hormone on regulation of lipolysis and adenosine 3',5'-monophosphate metabolism in 3T3-L1 adipocytes.

We have used cultured 3T3-L1 adipocytes to assess direct effects of T3 on beta-adrenergic-mediated regulation of lipolysis and adenylate cyclase and phosphodiesterase activities. Differentiated 3T3-L1 adipocytes were maintained under four conditions: in the presence of medium containing serum from a hypothyroid calf (hypothyroid medium), hypothyroid medium supplemented with T3 (T3-supplemented hypothyroid medium), medium with serum from a normal calf (control medium), and control medium supplemented with excess T3 (hyperthyroid medium). Compared to the two control groups, i.e. cells maintained in control medium or T3-supplemented hypothyroid medium, cells maintained in hypothyroid medium exhibited lower basal rates of lipolysis and lower sensitivity to isoproterenol. Hyperthyroid cells exhibited higher basal rates of lipolysis and higher sensitivity to isoproterenol. In the presence of maximally effective concentrations of isoproterenol, rates of lipolysis were similar in the four groups. Similarly, basal cAMP content and cAMP accumulation in the presence of isoproterenol were reduced in hypothyroid and increased in hyperthyroid adipocytes compared to those adipocytes maintained in control or T3-supplemented hypothyroid medium. Basal adenylate cyclase activity was similar in the four groups. Sensitivity to isoproterenol and maximal isoproterenol-stimulated cyclase activity were diminished in membrane preparations from hypothyroid adipocytes and increased in preparations from hyperthyroid adipocytes. Cyclase activity in the presence of NaF, however, was similar in preparations from cells maintained in hypothyroid, T3-supplemental hypothyroid, or control medium. NaF-stimulated activity was increased in preparations from hyperthyroid adipocytes. Thyroid status did not affect beta-receptor number of affinity for iodohydroxybenzylpindolol. Compared to control cells or cells maintained in T3-supplemented hypothyroid medium, both soluble and particulate cAMP phosphodiesterase activities were increased in hypothyroid cells and decreased in hyperthyroid cells. These results indicated that in 3T3-L1 adipocytes, some of the effects of thyroid hormone on cAMP content and lipolysis can be explained by alterations in both production and degradation of cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Selective effects of phosphodiesterase inhibitors on different phosphodiesterases, adenosine 3',5'-monophosphate metabolism, and lipolysis in 3T3-L1 adipocytes.

3T3-L1 adipocytes contain both soluble and particulate cAMP phosphodiesterases which can be distinguished by several criteria. Particulate phosphodiesterase activity of 3T3-L1 adipocytes, but not undifferentiated fibroblasts, was selectively increased by incubation of cells with insulin or lipolytic hormones. Particulate cAMP phosphodiesterase activity from 3T3-L1 adipocytes was very sensitive to inhibition by cilostamide in an apparently competitive fashion. Particulate activity from undifferentiated 3T3-L1 fibroblasts or supernatant activity from either type of cell was much less sensitive to cilostamide. On the other hand, supernatant cAMP phosphodiesterase activity from both undifferentiated fibroblasts and 3T3-L1 adipocytes was very sensitive to inhibition by Ro-20-1724 in an apparently competitive fashion. Ro-20-1724 was not an effective inhibitor of particulate activity from either type of cell. In fractions from 3T3-L1 adipocytes, isobutylmethylxanthine (IBMX) effectively inhibited both supernatant and particulate cAMP phosphodiesterase activities. In addition, however, IBMX was relatively more specific in inhibiting supernatant calmodulin-activated cGMP phosphodiesterase activity than supernatant calmodulin-independent or particulate cGMP phosphodiesterase activities. In intact 3T3-L1 adipocytes, cilostamide enhanced lipolysis in the absence or presence of isoproterenol and had no effect on cAMP content in the presence of low concentrations of isoproterenol. Ro-20-1724 increased lipolysis to a lesser extent than cilostamide and did not enhance isoproterenol-stimulated lipolysis, but did increase isoproterenol-stimulated accumulation of cAMP to a greater extent than cilostamide. Like cilostamide, Ro-20-1724 did not enhance accumulation of cAMP in the absence of isoproterenol. IBMX enhanced lipolysis and cAMP accumulation with or without isoproterenol. Taken together, these results support the idea that although particulate and soluble low Km phosphodiesterases influence cAMP content, the particulate enzyme may be more important in the metabolism of cAMP involved in the regulation of lipolysis. Since combinations of Ro-20-1724 and cilostamide were not as effective as IBMX in increasing cAMP content, perhaps the calmodulin-dependent phosphodiesterase, which is selectively inhibited by IBMX, is also involved in the regulation of total cell cAMP content.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Effect of dexamethasone on adenosine 3',5'-monophosphate content and phosphodiesterase activities in 3T3-L1 adipocytes.

After incubation with 0.5 mM isobutylmethylxanthine, 1 microM dexamethasone, and 1 microM insulin for 72 h, 3T3-L1 cells acquire the phenotypic characteristics of mature adipocytes, including a hormone-sensitive particulate cAMP phosphodiesterase activity. In addition, adipocytes contain soluble cAMP and calmodulin-sensitive and -insensitive cGMP phosphodiesterase activities. After exposure of the differentiated cells to 1 microM epinephrine, cAMP content increased, reaching a maximum in 2-4 min, and then declined to the control level by 20 min. After incubation of adipocytes with 10 nM dexamethasone for 72 h, the initial increment in cAMP produced by epinephrine was not altered, but the decline in cellular cAMP to basal levels was delayed. Treatment with 10 nM dexamethasone prevented hormonal activation of particulate cAMP phosphodiesterase activity without altering basal activity (11). Soluble cAMP and calmodulin-sensitive and -insensitive cGMP phosphodiesterase activities were also reduced by exposure to 10 nM dexamethasone; higher concentrations were required to decrease basal particulate phosphodiesterase activities. Estradiol did not alter phosphodiesterase activities. Incubation of either undifferentiated (fibroblasts) or differentiated (adipocytes) 3T3-L1 cells with 1 microM dexamethasone for 48 h reduced cAMP and cGMP phosphodiesterase activities. After removal of dexamethasone, phosphodiesterase activities were restored to control levels in 4-6 days. The effects of dexamethasone on phosphodiesterase activities could in part account for the observed alterations in hormone-induced accumulation of cAMP in steroid-treated cells and for the permissive effects of glucocorticoids on certain cAMP-mediated processes.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Selective regulation by pertussis toxin of insulin-induced activation of particulate cAMP phosphodiesterase activity in 3T3-L1 adipocytes.

Incubation of 3T3-L1 adipocytes with insulin or isoproterenol for 10 min increased particulate "low Km" cAMP phosphodiesterase activity by 42% and 50%, respectively. Pertussis toxin catalyzed the [32P]-ADP ribosylation of a 41,000 dalton protein in adipocyte particulate fractions; prior incubation of adipocytes with toxin markedly reduced incorporation of radiolabel. Exposure of adipocytes to pertussis toxin (0.3 microgram, 18 hr) increased glycerol production and inhibited activation of cAMP phosphodiesterase by insulin, but not by isoproterenol. These results suggest that pertussis toxin can interfere with receptor-mediated processes that stimulate cAMP hydrolysis as well as those that inhibit cAMP formation.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

Hormone-sensitive particulate cAMP phosphodiesterase activity in 3T3-L1 adipocytes. Regulation of responsiveness by dexamethasone.

Confluent 3T3-L1 fibroblasts incubated for 72 h with methylisobutylxanthine, dexamethasone, and insulin differentiate and acquire phenotypic characteristics of mature adipocytes, including hormone-sensitive cAMP phosphodiesterase activity located in a particulate fraction of homogenates. About 10 days after initiating differentiation, a maximally effective concentration of insulin (100 pM) increased particulate cAMP phosphodiesterase activity 40 to 60% in 8 min; activation persisted for at least 30 min in the presence of insulin. Incubation of adipocytes for 6-8 min with agents that increased cAMP, e.g. 1 microM epinephrine, 0.1 microM isoproterenol, corticotropin (2 mu units/ml), or thyroid-stimulating hormone (15 ng/ml), also increased particulate phosphodiesterase activity 40-60%. Changes in phosphodiesterase activity produced by epinephrine tended to lag behind changes in cAMP. Insulin, epinephrine, and corticotropin increased Vmax, not Km (0.5 microM), for cAMP. Particulate phosphodiesterase activity, solubilized with detergent, eluted in a single peak from DEAE-Bio-Gel. Insulin and epinephrine increased the activity eluted in this peak. Neither insulin nor lipolytic hormones increased activity in soluble fractions from differentiated cells or particulate or soluble fractions from undifferentiated cells. Incubation of adipocytes for 48 h with 1 microM dexamethasone prevented insulin-induced activation of the particulate phosphodiesterase and did not alter basal activity. After incubation for 72 h with 0.1 microM dexamethasone, insulin and epinephrine activation were abolished. These effects of dexamethasone on hormonal regulation of particulate phosphodiesterase activity could account for some of the so-called permissive effects of glucocorticoids on cAMP-mediated processes as well as the "anti-insulin" effects of glucocorticoids.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Auditory brain-stem responses in adrenomyeloneuropathy.

We studied three patients with adrenomyeloneuropathy. Complete audiologic assessment was obtained: two patients showed unimpaired peripheral hearing and one showed a mild high-frequency hearing loss. Auditory brain-stem responses were abnormal in both ears of all subjects, with one subject showing no response above wave I, and the other two having significant wave I to III and wave III to V interval prolongations. We concluded that auditory brain-stem response testing provides a simple, valid, reliable method for demonstrating neurologic abnormality in adrenomyeloneuropathy even prior to evidence of clinical signs.

Adolescent↗