A prospective trial of risk factors for sulfonylurea-induced hypoglycemia in type 2 diabetes mellitus.

CONTEXT: Retrospective studies have identified oral sulfonylureas, age, and fasting as major risk factors for hypoglycemia in patients with type 2 diabetes. Sulfonylureas may be withheld from elderly patients out of concern for hypoglycemia. OBJECTIVE: To evaluate the hypoglycemic effects of maximum doses of once-daily second-generation sulfonylureas administered to fasting elderly patients. DESIGN: A prospective, randomized, double-blind clinical trial. SETTING: The University of New Mexico General Clinical Research Center. PATIENTS: Fifty-two sulfonylurea-treated subjects with type 2 diabetes with a mean (SD) age of 65.1 (5.7) years. INTERVENTIONS: Subjects were randomly assigned to glyburide or glipizide gastrointestinal therapeutic system (GITS). Each subject participated in three 23-hour fasting studies after the sequential administration of 1 week of placebo and 1 week of 10 mg and 1 week of 20 mg of the assigned sulfonylurea. MAIN OUTCOME MEASURES: Occurrence of hypoglycemia (defined as plasma glucose level <3.33 mmol/L [60 mg/dL]) and hormonal parameters during the final 9 hours of the 23-hour fast in patients who had taken sulfonylureas vs placebo. RESULTS: No hypoglycemia was observed during 156 fasting studies. Plasma glucose level was decreased (nadir, 4.9 mmol/L [88 mg/dL] for a 20-mg dose of glyburide vs 8.3 mmol/L [150 mg/dL] for placebo; nadir, 5.8 mmol/L [105 mg/dL] for a 20-mg dose of glipizide GITS vs 8.7 mmol/L [157 mg/dL] for placebo), and serum insulin was increased in the sulfonylurea studies compared with placebo (P<.001). Plasma glucose parameters did not differ between the 2 sulfonylureas, but C peptide concentrations were increased in the glyburide group compared with glipizide GITS in the 20-mg study (P=.05). Concentrations of epinephrine were increased in the sulfonylurea studies compared with placebo (P<.001). Epinephrine secretion increased when glucose concentration fell below the mean (SD) level of 9.10 (2.66) mmol/L (164 [48] mg/dL) in the 10-mg study and 8.77 (2.83) mmol/L (158 [51] mg/ dL) in the 20-mg study. CONCLUSIONS: Fasting was well tolerated among these elderly patients with type 2 diabetes treated with sulfonylureas. Older age should not be considered a contraindication to sulfonylurea treatment for diabetes. Stimulation of epinephrine secretion at normal or elevated plasma glucose levels appears to be the primary mechanism of protection against hypoglycemia in this study.

Adrenal steroid modulation of vasoactive intestinal peptide effect on serotonin1 binding sites in the rat brain shown by in vitro quantitative autoradiography.

In the present work we demonstrate by means of quantitative in vitro autoradiography that the vasoactive intestinal peptide (VIP) is able to increase the number of serotonin1 (5-HT1) binding sites in the dorsal subiculum of the rat hippocampus and to decrease them in the suprachiasmatic nucleus (SCN). Bilateral adrenalectomy (ADX) for 6 days counteracted the stimulatory effect of VIP on 5-HT1 binding sites in the dorsal subiculum, but did not modify the inhibitory effect of the peptide in the SCN. Moreover, ADX increased 5-HT1 binding sites in response to VIP in various subfields of the hippocampus as well as in the superior colliculus and in the dorsal lateral septum, but this effect was not observed in normal or in ADX rats bearing a corticosterone implant. The present data are suggestive of a possible interaction between VIP and 5-HT in the regulation of the SCN and of a modulatory role of adrenal steroids in VIP activity in the hippocampal formation.

Sex steroid modulation of the serotonin behavioral syndrome.

The sex difference observed in frequency of rats exhibiting the serotonin behavioral syndrome induced by pargyline/1-tryptophan depends on hormonal state. Castration eliminated the sex difference in drug response in adult and prepubertal males, whereas ovariectomy had little effect. Dihydrotestosterone administration to males (10-30 days) reinstated the sex difference, but had little effect in females. Testicular feminized mutants (Tfm/y), deficient in androgen receptors, respond like females. Estrogen administration has no effect in either sex. Manipulation of the hormonal environment on postnatal days 0-7 (blockade of aromatization in males or estradiol administration to females) has no effect on the expression of the sex difference when the animals were tested as adults. Therefore, androgens acting via androgen receptors appear to mediate this subsensitivity of male rats to the drug challenge. The results of these experiments indicate that sex and hormonal environment are important variables in determining the experimental and perhaps clinical responses to drugs.

Modulation by vasoactive intestinal peptide (VIP) of serotonin receptors in membranes from rat hippocampus.

The vasoactive intestinal peptide (VIP) has been located in various structures of the rat brain, but few actions of the peptide have been reported as yet. Because VIP might interact with classical neurotransmitter systems in the central nervous system as it does in the periphery, we investigated whether VIP can modulate serotonin (5-HT1) receptors in membrane preparations obtained from brain areas which contain various amounts of VIP and 5-HT receptors. The presence of bacitracin alone, which protects VIP from proteolytic degradation, decreases the affinity of [3H]5-HT binding in almost all of the structures tested. Scatchard analysis indicates that, in the presence of bacitracin, VIP significantly decreases the affinity and increases the number of specific high affinity binding sites for [3H]5-HT in the dorsal hippocampus. VIP induces a dose-dependent increase in the number of 5-HT1 receptors with a maximal response of 60% with 10(-7) M VIP. At the same concentration, neither secretin nor glucagon modifies 5-HT1 receptor density. No effect of VIP is observed in the ventral hippocampus, parietal cortex, whole hypothalamus, and midbrain. This effect of VIP is not observed when bacitracin is omitted, and the presence of calcium ions does not alter the efficacy of the VIP effect. No effect of VIP is obtained on [3H]spiperone binding assayed with 10 microM mianserin to define specific binding. The present data suggest that some of the effects of 5-HT in the hippocampus may be modulated by VIP.

Sex differences in serotonin 1 receptor binding in rat brain.

Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

Modulation by vasoactive intestinal peptide of serotonin receptors in the dorsal hippocampus of the rat brain: an autoradiographic study.

Brain sections of 32 microns from the hippocampus were incubated with tritiated serotonin (5-HT) in the presence or absence of 10(-7) M vasoactive intestinal peptide (VIP). Sections were run for biochemical Scatchard analysis or quantitative autoradiography by means of LKB 3H-Ultrofilm. On sections from dorsal hippocampus, VIP increases the amount of 5-HT1 receptors and decreases the affinity for the ligand. Densities measurements show that this effect is located in a discrete area of the hippocampus, the dorsal subiculum. The present data suggest that some of the neurotransmitter effects of 5-HT in the central nervous system can be modulated by VIP.

Energetic limits on reproduction: interaction of thermal and dietary factors.

The time that food-restricted Norway rat dams spent in contact with their offspring was elevated only during that portion of the day in which their body temperatures were depressed. These data support a thermal model for the limitation of mother-young contact. The depression in maternal body temperature appeared to be due to a direct limitation on available fuel, rather than being mediated by a depression in circulating hormone levels.

Serotonin receptor modulation by estrogen in discrete brain nuclei.

The effect of estradiol on serotonin (5HT1) receptors of ovariectomized female rats was studied in discrete brain nuclei by a micro-binding assay and quantitative autoradiography. The two methods show similar distribution of the 5HT1 receptor and estradiol significantly increases the density of receptors in the preoptic area, anterior hypothalamus, lateral septum and arcuate-median eminence. The increase in 5HT1 receptors in these particular nuclei may be related to estrogen control of ovulation and/or other estrogen-mediated central phenomena.