Oral contraception and adolescent women with insulin-dependent diabetes mellitus: risks, benefits, and implications for practice.

Healthcare providers who work with adolescents with diabetes are in an ideal position to provide education and support regarding contraceptive issues. Diabetes educators and other health professionals who counsel teens focus on other aspects of diabetes care and management but frequently do not address sexual issues or assess contraceptive practices. The purpose of this paper is to review oral contraceptive issues for teens with diabetes and to provide practice implications for health professionals who are in a favorable position to influence the quality of diabetes and general health care for these adolescents.

PIP: 50% of all teens aged 15-19 are sexually active. Like other adolescent women, female adolescents with insulin-dependent diabetes mellitus (IDDM) are at risk of pregnancy. Female adolescents with IDDM, however, are at greater risk of experiencing congenital malformations in their offspring. Contraceptive counseling is now an integral part of adolescent health care. Such counseling for adolescents with diabetes is even more important given the potential complications of diabetes, the high risk of congenital malformations in young women with less-than-optimal glycemic control, and the contraceptive options available. Markedly lower anomaly rates have been observed among women with intensively managed diabetes prior to conception. Health professionals who work with adolescents with diabetes are in an ideal position to provide education and support on contraception. However, diabetes educators and other health professionals who counsel teens tend to focus upon other aspects of diabetes care and management without addressing sexual issues or assessing contraceptive practices. This paper reviews oral contraceptive issues for teens with diabetes and offers practical implications for health professionals who can influence the quality of diabetes and general health care for such adolescents.

Comparative behavioural profile of centrally administered tachykinin NK1, NK2 and NK3 receptor agonists in the guinea-pig.

1. The NK1 tachykinin receptor agonists, septide, [Sar9,Met(O2)11]SP and [Pro9]SP produced locomotor hyperactivity (10-20 min) when injected intracerebroventricularly (i.c.v.) in the guinea-pig. The most potent in eliciting this hyperactivity was septide (from 0.63 to 5 micrograms), compared to [Sar9,Met(O2)11]SP, which was active at 2.5 and 5 micrograms and [Pro9]SP which induced a non-significant increase even at 10 micrograms. 2. Wet-dog shakes were elicited by septide, [Sar9,Met(O2)11]SP and [Pro9]SP injected by the i.c.v. route in the guinea-pig. [Sar9,Met(O2)11]SP, active from 0.16 to 2.5 micrograms was more potent than septide (active at 1.25 micrograms) and [Pro9]SP (active at 0.63 micrograms) in eliciting such behaviour. To a lesser extent, grooming was also observed after injection of these agonists. 3. The NK2 tachykinin receptor agonist, [Lys5,MeLeu9,Nle10]NKA(4-10), up to the dose of 10 micrograms i.c.v. had no effect in the guinea-pig. It neither modified locomotor activity nor induced a characteristic behavioural response. At higher doses (20 micrograms), some toxic effects were noted. 4. The NK3 tachykinin receptor agonist, senktide, contrasts with the NK1 receptor agonists in that it elicited only wet-dog shakes, at doses ranging from 0.32 to 1.25 micrograms. It neither modified locomotor activity (1 microgram) nor induced grooming (up to 5 micrograms) in the guinea-pig. 5. To our knowledge, these results are the first demonstration that the guinea-pig could be useful to differentiate tachykinin agonists on the basis of their behavioural profile, distinct from those obtained in mice and rats.

Frequency and determinants of diabetes patient education among adults in the U.S. population.

OBJECTIVE: To determine the proportion of adults with diabetes in the U.S. who have received diabetes patient education and to assess factors that determine whether patients receive this education. RESEARCH DESIGN AND METHODS: A questionnaire on diabetes was administered to a representative sample of 2,405 diabetic individuals > or = 18 years of age in the U.S. population. The questionnaire inquired about whether these individuals had ever attended a diabetes education class or program. Sociodemographic and clinical factors that may influence participation in patient education were also determined. RESULTS: Of all people with diabetes, 35.1% had attended a class or program about diabetes at some time during the course of their disease, including 58.6% of individuals with insulin-dependent diabetes mellitus, 48.9% of insulin-treated individuals with non-insulin-dependent diabetes mellitus (NIDDM), and 23.7% of NIDDM individuals not treated with insulin. Younger age, black race, residence in the midwest region of the U.S., higher level of education, and presence of diabetes complications were consistently associated with having had diabetes education for people with NIDDM. Although increasing income was associated with patient education for NIDDM individuals not treated with insulin, it was not an independent determinant for insulin-treated NIDDM individuals. NIDDM individuals not treated with insulin who lived alone were more likely to have had patient education than those who did not live alone. Not having a diabetes physician or not visiting one in the past year was associated with a higher likelihood of patient education for non-insulin-treated NIDDM individuals. CONCLUSIONS: A large proportion of patients with diabetes has never received diabetes education. Patient education has been recognized for its contributions to reducing the morbidity and mortality of diabetes. Consequently, special attention should be directed to the subgroups of individuals, such as those not taking insulin, those with lower socioeconomic status, and those living outside urban areas, in which the frequency of diabetes patient education is particularly low.

Differential ability of tachykinin NK-1 and NK-2 agonists to produce scratching and grooming behaviours in mice.

Potent and selective NK-1 and NK-2 agonists as well as compounds with lower selectivity and affinity for NK-1 binding sites were compared in their ability to produce scratching and grooming behaviours when injected intracerebroventricularly in mice. Septide, an agonist with a low affinity for NK-1 binding sites, [Sar9, Met(O2)11]SP and to a lesser extent [Pro9]SP, two potent and selective NK-1 agonists were the most effective drugs in stimulating these behaviours. Only high doses of [Apa9,10]SP and [Lys5, Tyr7, Pro8]NKA(4-10), two agonists with low affinity for NK-1 binding sites, produced scratching and grooming responses. Similarly, only high doses of [Lys5, MeLeu9, NLe10]NKA(4-10), a potent NK-2 agonist, produced grooming behaviour. When coinjected with the endopeptidase enzyme inhibitor phosphoramidon, the effects of [Apa9,10]SP, [Lys5, Tyr7, Pro8]NKA(4-10) and [Pro9]SP were markedly enhanced. Analyses of the potency of the different agents to displace 3H-SP binding in mouse subcortical structures revealed that the affinities of the agonists for NK-1 receptors are similar to those previously reported in rat brain. The efficacy of the agonists at producing behavioural responses was not equivalent to their potency to bind to central NK-1 receptors. These findings therefore suggest that a stimulation of NK-1 but also non classical NK-1 receptors are involved in the induction of scratching and grooming behaviours.

Children and adolescents with diabetes.

IDDM in children and adolescents requires that complex daily management skills be learned by children and their families. Insulin administration, nutrition therapy, and daily monitoring place the burden of self-management on parents and children, who already may be stressed. The unrelenting care required to observe and treat young children produces anxiety in parents whose children are potentially poised between hypoglycemia and DKA. Health care professionals must understand the dynamic nature of childhood diabetes and not underestimate the impact on specific developmental levels or the amount of support and education required.

Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist.

1. RP 62203 (2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8- ca]isothiazole-1,1-dioxide) is a novel naphtosultam derivative which shows very high affinity for 5-HT2 receptors in the rat cerebral cortex (Ki = 50.0 pM). 2. RP 62203 is relatively selective for this sub-type of 5-hydroxytryptamine (5-HT) receptor, having lower affinity for the 5-HT1A receptor and very low affinity for the 5-HT, receptor. RP 62203 displayed low to moderate affinity for alpha 1-adrenoceptors, dopamine D2 receptors and histamine H1 receptors. 3. In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long-lasting (greater than 6 h) occupation of cortical 5-HT2 receptors (ID50 = 0.39 mgkg-1). 4. In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5-HT, with an IC50 of 7.76 nM. 5. The activity of neurones in the raphé and their responses to microiontophoretically applied 5-HT were studied with extracellular recording electrodes in the anaesthetized rat. RP 62203 potently and dose-dependently blocked excitations evoked by 5-HT when administered at doses of 0.5-4.0 mg kg-1, i.p. In contrast, neither 5-HT-evoked depressions nor glutamate-evoked excitations of raphé neuronal firing were blocked by RP 62203 at doses as high as 8.0 mg kg-1, i.p. 6. Head twitches induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) could be abolished by low doses of RP 62203 in mice (ED50 = 0.44 mg kg-1, p.o.) and in rats (ED50 = 1.54 p.o.). Similar results were obtained with mescaline and 5-hydroxytryptophan (5-HTP). 7. The potency of RP 62203 was compared with that of three other 5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ICI 170,809. In all models, RP 62203 showed similar activity to ritanserin, whilst either ICI 169,369 or ICI 170,809 was several fold less active. 8. It is concluded that RP 62203 is a potent and selective antagonist at 5-HT2 receptors in the rodent central nervous system.

Effect of chronic undernutrition on hepatocyte insulin receptors in rats.

The effect of moderate chronic undernutrition on insulin receptors was studied in male rats, pair-fed 60% of the daily food intake of ad libitum-fed littermates, for 8 weeks. Body weights of undernourished rats were consistently found to be 35% to 40% less than control littermates, with no period of growth arrest at any point in the 8-week study. The binding-displacement curves of labeled insulin to hepatocyte receptors in the two groups in the presence of unlabeled insulin were significantly different (P = .0258 after repeated measures ANOVA). Significantly lower binding was observed in hepatocytes from the undernourished group (P less than .01) at all unlabeled insulin concentrations less than 20 nmol/L. In the absence of any unlabeled insulin, specific binding was reduced from 8.8% +/- 0.7%, (mean +/- SE) in controls, to 7.4% +/- 0.3% in undernourished rats (P less than .01). Half-maximal specific hormone binding to hepatocytes was achieved at a free insulin concentration of 362 nmol/L in the control group, compared with 447 nmol/L in the undernourished group, reflecting an increase of approximately 20%. The hypoglycemic response to intravenous insulin (0.1 U/kg body weight) was tested in a parallel experiment involving seven paired littermate rats, and found to be significantly impaired in the undernourished group (P = .0041 by repeated measures ANOVA).(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclopyrrolones, unlike some benzodiazepines, do not induce physical dependence in mice.

In a model of physical dependence in mice, treatment with cyclopyrrolones such as zopiclone and suriclone (from 4 to 400 mg/kg/day), did not modify the sensitivity of the gamma-aminobutyric acid (GABA) receptor complex to the partial inverse agonist FG 7142 following their withdrawal, whereas sensitivity changes were observed after treatment and withdrawal from some benzodiazepines (e.g. lorazepam, diazepam, flunitrazepam and triazolam). These data suggest that, in contrast to some benzodiazepines, zopiclone and suriclone may not produce physical dependence.

The effect of menhaden oil on choline-deficiency-induced hepatic ornithine decarboxylase activity and hepatocyte insulin receptor binding.

The effects of menhaden oil on the choline-deficient (CD) diet tumor promotion regimen-induced alterations in hepatocyte insulin receptors and the cellular ornithine decarboxylase (ODC) activity have been investigated in this study. Male Sprague-Dawley rats exposed to the tumor-promoting regimen of a CD diet for 10 days showed increases in hepatic ODC activity from 2.68 +/- 0.42 pmol 14CO2/mg protein/h in the animals fed basal control chow (C) to 13.54 +/- 2.38 (P less than 0.02) in the rats fed CD diet. These changes in ODC occur simultaneously with the alterations in hormone receptor binding as reported previously for insulin. Replacement of the lipid present in the control diet with 15% menhaden oil (CMO) had no significant effect on ODC activity (0.91 +/- 0.21), or on the number of insulin receptors (206,000 +/- 37,000) and the Kd (7.4 +/- 1.6). Sequential treatment with 10 days of CD diet and then 10 days of the C diet, resulted in a reversal in the elevated, CD-induced hepatic ODC activity to the control levels; however, substituting 15% menhaden oil for the fat present in the CD diet (CDMO) enhanced this enzymatic activity. In contrast, both sequential and CDMO treatments prevented the insulin receptor alterations induced by the CD diet. These data demonstrate that the CD diet-induced insulin receptor alterations occur concurrently with the induction of ODC activity. But insulin receptor changes and the increased ODC activity are affected differently by CDMO treatment, suggesting that their induction by the CD diet is through distinct mechanisms and only the receptor alterations correspond with the tumor-promoting action of CD diet regimen.

Alterations induced by phenobarbital, a liver tumor promoter, in hepatocyte receptors for insulin and glucagon and glycogen metabolism.

Exposure of rats to phenobarbital (PB), a tumor promoter in the two-stage hepatocarcinogenesis model, in their diet (0.06%) induces alterations in insulin receptors in the hepatocytes. There is a decrease both in the number of receptors and the dissociation constant (Kd) when compared with animals fed control laboratory diet. The number of insulin receptors/cell and the Kd were respectively: 183,000 +/- 19,000 and 15.3 +/- 2.5 nM for controls; 47,000 +/- 5000 and 2.8 +/- 0.3 nM for PB. The glycogen synthesis in response to insulin was found to be unresponsive in the hepatocytes from rats exposed to PB. Glucagon receptors on hepatocytes, however, were unaltered in animals treated with PB or fed a choline-deficient (CD) diet and the glucagon-stimulated glycogenolytic responses were also comparable to the controls. There is, therefore, a selective alteration in the hepatocyte surface membrane receptors. Both PB and CD have been shown to reduce the hepatic cell membrane receptors for epidermal growth factor, indicating that the two different tumor promoters alter peptide receptors with endogenous protein kinase activities. This similar though selective effect of the tumor promoters on cell surface receptors may be of significance in their action in carcinogenesis by having an effect on the alteration of regulation of cell growth and metabolism.

Modulation of epidermal growth factor receptors in rat hepatocytes by two liver tumor-promoting regimens, a choline-deficient and a phenobarbital diet.

The effect of two liver tumor-promoting regimens, a choline-deficient (CD) and a phenobarbital (.06% PB) diet, on the level of epidermal growth factor (EGF) receptor in rat hepatocytes was examined at 3, 10, and 28 days of feeding. Both diets produced a significant decrease in the number of cell surface receptors at 10 and 28 days of treatment. When PB was included in a CD diet, the decrease in the receptor number was evident even after 3 days feeding of the combined diet. Neither diet alone had any effect on the binding at that time. Along with the changes in the receptor number, the binding affinity of EGF to its receptor was also altered by these diets. Furthermore, PB and PB plus CD diets also decreased the EGF binding at the intracellular sites whereas CD diet showed no effects indicating that the decrease in surface binding of EGF by the promoter-treated hepatocytes was not due to rapid internalization of the receptors. The reduced level of hepatocyte surface EGF receptors represents the common property shared by two diverse types of the liver tumor promoters, and may thus be related to the tumor-promoting ability of these agents.

Evaluation of a new system for self blood glucose monitoring.

A new combination reflectance meter/visually interpretable system (Glucometer II/Glucostix, Ames Division, Miles Laboratories, Elkhart, IN) has been designed for self blood glucose monitoring. Performance evaluation of this system demonstrates a linear relationship between meter-determined blood glucose values and laboratory-determined whole blood glucose values (y = 0.95x + 2.86, r = 0.97). In addition, 95% of visually interpreted blood glucose values are within one color block of YSI comparative values. Error grid analysis, a new method for determining the clinical accuracy of patient-determined blood glucose results, demonstrated that components of this new system produce clinically accurate blood glucose results.

Free radical injury and liver tumor promotion.

One of the underlying mechanisms of tumor promotion both in the skin and liver involves free radical mediated injury to informational macromolecules of target cells. A choline-deficient (CD) diet, which is an efficient liver tumor promoter, induces peroxidative damage of liver cell membrane lipids. By modifying components of a CD diet, we have shown that the efficacy of the promotion is correlated with the extent of lipid peroxidation. The substitution of fats in a CD diet with predominantly polyunsaturated fat and the addition of methapyrilene to a CD diet enhances membrane lipid peroxidation and the promoting effects. An antioxidant (BHT) and hypolipidemic peroxisome proliferators (BR931 and DEHP) suppress both of these effects. Contrary to these findings, phenobarbital did not induce membrane lipid peroxidation, and its addition to a CD diet inhibited the diet-induced lipid peroxidation, though such a combination exerted a stronger promoting action. Thus, a CD diet and phenobarbital exert their promoting actions through different mechanisms. The consequence of membrane lipid peroxidation in the liver cells induced by a CD diet may be multiple. Our recent study of surface membrane insulin receptors of liver cells of rats fed a CD diet showed a decrease in number and an enhanced binding affinity leading to altered responsiveness of liver cells to insulin mediated glycogen synthesis. It is suggested that CD diet-induced lipid peroxidation leads to functional alterations of membrane receptors involved in cell growth control and may thereby exert its promoting action.

Alterations in hepatocyte insulin receptors in rats fed a choline-deficient diet.

Specific insulin binding and glycogen synthesis were studied in control hepatocytes, hepatocytes from rats fed a choline-deficient (CD) diet for 7 to 14 days, and hepatoma cells induced with a CD diet and DL-ethionine in culture. Both the binding affinity and the number of receptors were affected in hepatocytes by the CD diet. The number of receptor sites was 26,000/cell and the dissociation constant (Kd) for the high affinity binding site was 2.6 nM at 30 degrees C, in contrast to the control values of 205,000 sites/cell and 23.2 nM, respectively. In the hepatoma cells, receptor cell number and Kd were further diminished to 6,400 sites/cell and Kd = 1.1 nM. The basal level of glycogen synthesis in control hepatocytes and in CD hepatocytes was similar; however, the basal rate of glycogen synthesis in hepatoma cells was only 16% of that in the control cells. The glycogen synthesis in hepatoma cells was stimulated by insulin, but at a 3-log higher concentration compared to the control cells. This loss of sensitivity to insulin is consistent with the marked decrease in insulin receptors. CD hepatocytes had a decrease in insulin receptors with a concurrent decrease in Kd (increase in binding affinity), such that, sensitivity to insulin did not differ significantly from that of control hepatocytes. However, the maximal stimulation of glycogen synthesis was only 27% that of the control cells. The changes in receptor number and Kd of hepatocytes from rats fed a CD diet may be due to alterations in cell membrane lipid composition and this alteration may be responsible for the enhanced sensitivity of hepatocytes to chemical carcinogens and for the tumor promoting effect of the diet.