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We have previously shown that a single dose of nicotine elevates plasma adrenocorticotropin (ACTH) levels in rats and has a biphasic effect on plasma prolactin (PRL). The stimulatory effect of nicotine on these stress responsive hormones desensitizes after a single injection of nicotine. Continuous exposure to nicotine also induces tolerance to its locomotor depressive and hypothermic effects, which have been associated with an increase of central [3H]nicotine binding. Thus, the acute and chronic administration of nicotine might induce changes in central nicotinic cholinergic circuits that affect the ACTH and PRL responses to stress. In the present study, a single dose of nicotine (0.75-3.0 mg/kg b.wt.) significantly inhibited the elevation of plasma PRL due to restraint stress initiated 60 min afterward. Five injections of nicotine during 1 day produced a similar attenuation of the PRL response to restraint stress but neither of these paradigms affected ACTH. In contrast, intermittent delivery of nicotine for 7 days failed to affect the PRL response to restraint stress; however, after withholding nicotine for 14 hr, high dose nicotine attenuated the PRL response to stress, whereas low dose nicotine remained ineffective. On the other hand, administration of the same schedule of low dose nicotine did significantly diminish the expected release of PRL in response to a final injection of nicotine (0.5-2.0 mg/kg b.wt.) in unstressed animals. In summary, a single dose or 5 doses of nicotine in 1 day attenuated the PRL response to restraint stress, whereas, after chronic administration, this effect was lost.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To evaluate plasma C-peptide levels in middle-aged and elderly patients with type II diabetes, to clarify their practical use in assessing the need for insulin therapy, and to determine their sensitivity in distinguishing insulin-requiring from non-insulin-requiring diabetes after improved baseline glycemic control. Methods: Plasma glucose and C-peptide levels were measured in a fasting state and 2 hours after an oral challenge with 100 g of glucose in groups of obese and normal-weight, glycemic-controlled, middle-aged and elderly patients with diabetes treated with insulin or an orally administered hypoglycemic agent (OHA). Basal and glucose-stimulated C-peptide levels as well as increased stimulated glucose values were contrasted in insulin- versus OHA-treated groups. In a second protocol, basal and glucose-stimulated C-peptide reactivity and stimulated glucose levels were also measured in eight patients with diabetes, before and after glycemic control. Results: Irrespective of the age difference, stimulated C-peptide levels in the insulin-treated patients were significantly lower than those in the weight-matched OHA patients. Similarly, for both the middle-aged and elderly patients, stimulated glucose levels and degree of glucose elevation were higher in the insulin-treated patients. In the second protocol, as hyperglycemia was reduced, b-cell secretion measured by C-peptide responses to glucose was significantly increased, in conjunction with a decrease in the stimulated glucose levels. Conclusion: These results indicate that measurements of C-peptide responses to glucose stimulation are helpful to determine the decision to use insulin in both elderly and middle-aged patients with diabetes. Blunted insulin responses identify those patients who require insulin treatment, whereas high C-peptide values in insulin-treated patients suggest the possibility of discontinuing insulin therapy.

Numerous investigators have reported abnormalities of hepatic drug metabolism in hypoinsulinemic animal models with chemically induced diabetes mellitus, but there has been little assessment of hepatic drug metabolism in recently described animal models with genetic diabetes mellitus characterized by hyperinsulinemia and insulin resistance rather than insulin deficiency. Hepatic microsomal cytochrome P-450 content and drug metabolizing activity in obese, diabetic C57BL/KsJ mice homozygous for the diabetes gene mutation (db/db) have been compared with levels found in livers of 1) lean, nondiabetic control mice with the same C57BL/KsJ genetic background and 2) lean C57BL/6J animals made diabetic by streptozotocin treatment. No changes in specific enzyme content or activity were seen in young db/db mice, but microsomal protein and total hepatic cytochrome P-450 content and meperidine demethylation and pentobarbital hydroxylation activity were markedly increased compared to controls. In hyperglycemic, hypoinsulinemic mice with streptozotocin-induced diabetes mellitus, the amount of microsomal protein did not change, but hepatic cytochrome P-450 content and enzyme activity were significantly increased whether expressed per milligram of microsomal protein or as totals per liver. In old db/db animals, hyperglycemia persisted but plasma insulin levels fell into the normal range so that the insulin-glucose profile of these animals resembled that seen in the streptozotocin treatment group. In association with these changes, hepatic enzyme specific activities in the old db/db mice approximated values found in the streptozotocin group rather than in the young db/db animals. These differences in hepatic microsomal enzymes between hyperinsulinemic and hypoinsulinemic mice with diabetes mellitus suggest that both hyperglycemia and insulin separately and significantly influence cytochrome P-450 turnover and mixed function oxidase activity.

Pyroglutamyl-N3im-methyl-histidyl-prolineamide (methyl-thyrotrophin releasing hormone, methyl-TRH) is a potent synthetic analogue of TRH. N3im-Methyl-histidine is present in mammalian brain and it has been suggested that methyl-TRH is a physiological releasing hormone normally present in the hypothalamus. A non-gradient cation-exchange chromatography system that uses SP-Sephadex C-25 and completely resolves methyl-TRH and TRH has been developed. Because methyl-TRH cross-reacts in the immunoassay for TRH, this assay was used to measure TRH and methyl-TRH in the chromatographic fractions. By this means it has been demonstrated that the amount of methyl-TRH present in the rat is less than 0·025 ng/hypothalamus.