Effect of intranasal growth hormone-releasing hormone and corticotropin-releasing hormone administration on growth hormone and cortisol release: improved bioavailability by means of sodium-glycocholate.

Several peptide hormones are effective when administered intranasally (in); these include oxytocin, vasopressin, insulin, glucagon, and calcitonin. With regard to GHRH and CRH, previous studies demonstrated that their bioavailability following in administration was very low. In this study we evaluated the serum GH response to 50 micrograms GHRH iv and to 700 micrograms GHRH in, the latter given alone and with 5 and 15 mg sodium-glycocholate (SGC), a surfactant, in six normal men. The bioavailability of in GHRH, calculated as net GH secretory area, was very low, and increased to 7% that of iv GHRH when SGC was used. In the same men, 50 micrograms CRH was administered both iv and in, alone and with 5 and 15 mg SGC. The bioavailability of in CRH, calculated as net cortisol secretory area, was very low and increased to 100% that of iv CRH when 15 mg SGC was used. These data indicate that the efficacy of GHRH and CRH administered in is significantly augmented by SGC.

Abnormal sensitivity to glucose of human islets cultured in a high glucose medium: partial reversibility after an additional culture in a normal glucose medium.

In the experimental animal chronic hyperglycemia alters the islet's sensitivity to glucose. In the present study the glucose sensitivity of human pancreatic islets, isolated and purified, obtained from seven human pancreases using an automated method was evaluated. After a 12-h stabilization period, islets were cultured for 48 h in normal (5.5 mmol/L) or high glucose (16.7 mmol/L) medium. Islets were then perifused to study their insulin response to glucose. Islets cultured in the high glucose medium lost glucose-induced insulin release and, when challenged with an acute fall of glucose concentration in the perifusate, showed a paradoxical insulin release. Insulin release in response to 10 mmol/L L-arginine was preserved in these islets, suggesting a selective reduction of the insulin response to glucose. An additional 48-h culture in 5.5 mmol/L glucose medium partially restored the sensitivity to glucose of the previously unresponsive islets. These findings indicate that short term exposure to high glucose concentrations induces a selective glucose insensitivity of human islets, which can be partially reversed by an additional culture in normal glucose medium.

Human islets chronically exposed in vitro to different stimuli become unresponsive to the same stimuli given acutely: evidence supporting specific desensitization rather than beta-cell exhaustion.

The aim of this study was to evaluate the effects of long term in vitro exposure of human pancreatic islets to different secretagogues on their subsequent secretory activity. Therefore, groups of 100 islets were cultured for 48 h in standard tissue culture medium (CMRL 1066) in the presence of 1 of the following: 5.5 mmol/L glucose, 16.7 mmol/L glucose, 5.5 mmol/L glucose plus 10 mmol/L L-arginine, or 5.5 mmol/L glucose plus 100 mumol/L tolbutamide. Insulin levels in the culture medium declined with time under all culture conditions. Islets were then perifused and acutely stimulated with glucose (16.7 mmol/L), L-arginine (10 mmol/L), and tolbutamide (100 mumol/L). Islets cultured in 16.7 mmol/L glucose showed no response to 16.7 mmol/L glucose [net area under the curve (delta AUC), 11% of control], and a reduced response to acute tolbutamide (delta AUC, 35% of control), but responded to L-arginine (delta AUC, 75% of control). Islets cultured in the presence of 10 mmol/L L-arginine had reduced responses to glucose (delta AUC, 11% of control) and tolbutamide (delta AUC, 27% of control), but responded to L-arginine (delta AUC, 75% of control). Islets cultured in tolbutamide did not respond to tolbutamide (delta AUC, 14% of control) and showed a reduced responses to acute glucose (delta AUC, 36% of control) and L-arginine (delta AUC, 24% of control). In a second set of experiments, islets cultured in 5.5 or 16.7 mmol/L glucose showed an insulin response to a supramaximal glucose stimulation (30 mmol/L glucose plus 0.5 mmol/L isobutylmethylxanthine) that was not statistically different. Similarly, islets that were cultured in the presence of 100 mumol/L tolbutamide still responded to 1 mmol/L tolbutamide. In conclusion, all stimuli evaluated in this study, chronically applied, reduced the insulin response to further acute stimulations. The different patterns of unresponsiveness observed together with the finding of a preserved insulin content in the islets after perifusions and a maintained capability to release insulin in response to supramaximal stimulations suggest that after chronic exposure to different stimuli, human islets become selectively desensitized to the same stimuli given acutely and do not become exhausted.

Metabolic effects of graded glucagon infusions in man: inhibition of glucagon, insulin, and somatostatin response to arginine.

Insulin inhibits its own release (autofeedback), and growth hormone (GH) inhibits the GH response to a variety of stimuli. The aim of this study was to evaluate whether glucagon (G) can modify pancreatic G (IRG) release in humans. Seven healthy men received intravenous (i.v.) arginine (30 g in 30 minutes) 240 minutes after the beginning of a 0.9% NaCI saline infusion and a 2.5-, 4.0-, and 8.0-ng/kg.min-1 porcine G infusion, with each infusion lasting 360 minutes. All G infusions yielded stable and dose-related plasma IRG levels, and the 4.0- and 8.0-ng/kg.min-1 G infusions decreased plasma free fatty acids (FFA) and blood glycerol and beta-OH-butyrate levels and elicited insulin (IRI) release, and the 8.0-ng/kg.min-1 G infusion elicited GH release and increased blood glucose (BG) levels; somatostatin (SRIF) levels were not affected by G infusions. At 240 minutes, plasma IRG levels were higher during G infusion than during saline infusion, whereas serum IRI and BG levels had returned to preinfusion levels. At this point, G infusions decreased the integrated (240 to 300 minutes) IRG, IRI, BG, and SRIF responses, but not the GH response to arginine. These data indicate that prolonged G infusions decrease the IRG response to arginine; in addition, G decreases plasma FFA levels, and higher G doses stimulate IRI release and exert a self-limited hyperglycemic effect. The fact that the IRI response to arginine was decreased by G could be due to a refractoriness of beta cells to subsequent stimuli; the decreased SRIF response to arginine is likely due to G itself or to a decrease of plasma FFA levels.

Acipimox-induced facial skin flush: frequency, thermographic evaluation and relationship to plasma acipimox level.

Facial skin flush is the most frequent adverse effect induced by acipimox (ACX), a nicotinic acid analogue used in the management of hyperlipidaemia. The aims of the study were to evaluate the frequency, magnitude and reproducibility of the ACX flush in previously unexposed healthy subjects and to assess any possible relationship with the dose and plasma level of ACX. Seventy four healthy subjects received, on two different mornings, ACX 250 mg and placebo (P), according to a single blind, randomized, cross-over design; 33 had a clear flush after ACX and not after P.25 of those subjects were retested on five different mornings, with P, and with ACX 31.2, 62.5, 125.0, 250.0 mg, according to a double blind, randomized, cross-over design. Any increase in the local skin temperature was recorded by a thermocouple fixed to the left check. Subjective and objective assessment of the flush were strongly correlated with thermographic recordings. They indicated that a 120 min flush occurred after doses of ACX greater than 62.5 mg. In 12 of the 25 subjects, 6 with the highest and 6 with the lowest thermographic recordings, plasma ACX levels were determined. Subjects with different thermographic records had superimposable plasma ACX levels after all doses of ACX. Only the 6 subjects with the highest skin temperatures showed a significant relationship between the thermographic record and the plasma ACX. The data indicate that flush is a frequent, reproducible and dose-related adverse effect of ACX.