Abstract. The effect of ascorbic acid depletion on the amidation of alphamelanocyte stimulating hormone (αMSH) was studied in vivo in guinea pig pituitary. After four weeks, the concentration of ascorbic acid was 1.20 ± 0.11 μmol/g tissue (mean ± sd) in the pituitary and 0.34 ± 0.07 μmol/g tissue in the cerebral cortex from the depleted animals versus 7.58 ± 0.08 and 1.51 ± 0.32 μmol/g tissue, respectively, in the control animals. In the pituitaries from the animals depleted of ascorbate (N = 4), the relative amount of αMSH was reduced to approximately half the values obtained in the control group (from 66.5 ± 4.6% of total ACTH-related peptides to 31.1 ± 12.2% (P < 0.0025)). A concomitant increase (from 5.9 ±3.1% to 19.4 ± 4.3% (P < 0.004)) in ACTH (1–14) (the glycine-extended precursor of αMSH) immunoreactivity and a smaller increase in ACTH (1–39) immunoreactivity was observed in the depleted guinea pigs. Gel chromatography and reversed-phase high-performance luquid chromatography showed that the αMSH and ACTH (1–14) immunoreactivity was of low molecular weight and partly mono- or diacetylated. Depletion of ascorbic acid had no influence on the degree of acetylation of αMSH and ACTH (1–14). It is concluded that depletion of ascorbic acid reduces the in vivo amidation of ACTH (1–14) in the guinea pig pituitary.
Mogens Fenger and Linda Hilsted
Søren Boesgaard, Claus Hagen, Anders Nyboe Andersen, Mogens Fenger and Ebbe Eldrup
The regulation of the hypothalamic-pituitary-adrenal axis by dopamine is not fully understood. Therefore, we have studied the effect of dopamine, metoclopramide, a D-2 receptor antagonist, and fenoldopam, a specific D-1 receptor agonist, on ACTH and cortisol levels in normal subjects. Normal women received 5-h infusions of either glucose (N = 6) or dopamine at rates of 0.04 (N = 6), 0.4 (N = 6) and 4.0 μg · kg−1· min−1 (N = 8). After 3 h, 10 mg metoclopramide was given iv. No intergroup differences regarding ACTH and cortisol levels were observed (p>0.05). In a second study six women received dopamine (4.0 μg·kg−1·min−1) or glucose for 18 h. During the infusions cortisol and ACTH levels were similar on the two study days. Administration of metoclopramide (10 mg) after 17 h induced a significant increase in cortisol levels during dopamine infusion (p<0.05), whereas no effect was observed during placebo infusion. ACTH levels were unaffected by metoclopramide. In a third study, 9 normal women and 9 normal men received fenoldopam (0.5 μg·kg −1·min−) or placebo infusions for 3 h. In males, median ACTH and cortisol levels were significantly lower (p<0.05) during fenoldopam compared with placebo infusion. In contrast, fenoldopam did not affect ACTH and cortisol levels in normal women. The results suggest that the effect of dopamine D-1 receptor stimulation on ACTH and cortisol secretion is mainly at the hypothalamic level and that this effect is sex-dependent. In addition, we hypothesize that raised dopaminergic activity for a prolonged period of time may have an inhibitory effect on the hypothalamic-pituitary-adrenal axis. This may be triggered by low estrogen levels.
Søren Boesgaard, Claus Hagen, Anders Nyboe Andersen, Henning Djursing and Mogens Fenger
Abstract. Patients with functional amenorrhea have raised central dopaminergic activity and opioid-mediated GnRH inhibition leading to inhibition of hypothalamic-pituitary-ovarian function. In the present study, basal serum cortisol and ACTH levels were measured in normoprolactinemic amenorrheic patients with (N = 14) and without (N = 7) insulin-dependent diabetes mellitus. Basal serum cortisol levels was significantly (P < 0.01) elevated in patients with normoprolactinemic amenorrhea compared with normal women. Basal serum cortisol was significantly (P < 0.02) elevated in amenorheic diabetic patients compared with menstruating diabetic women. In the amenorrheic groups both cortisol and ACTH levels increased significantly (P <0.01) after dopamine D-2 receptor blockade, whereas no hormonal changes occurred in the control groups. It is concluded that patients with normoprolactinemic amenorrhea have elevated basal serum cortisol, the reason probably being hypersecretion of corticotropin-releasing hormone. Secondly that dopaminergic blockade with metoclopramide stimulates ACTH and cortisol secretion in patients presumed to have raised dopaminergic activity.
Steen B Haugaard, Ove Andersen, Flemming Dela, Jens Juul Holst, Heidi Storgaard, Mogens Fenger, Johan Iversen and Sten Madsbad
Objectives: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects of glucose metabolism, lipid metabolism and β-cell function in lipodystrophic HIV-infected patients.
Methods: [3-3H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naïve to antiretroviral therapy (NAÏVE) respectively). β-cell function was evaluated by an intravenous glucose tolerance test.
Results: Compared with NONLIPO and NAÏVE separately, LIPO displayed markedly reduced ratio of limb to trunk fat (RLF; >34%, P < 0.001), hepatic insulin sensitivity (>40%, P < 0.03), incremental glucose disposal (>50%, P < 0.001) and incremental exogenous glucose storage (>50%, P < 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P < 0.01), increased clamp free fatty acids (P < 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P < 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r = 0.69), incremental glucose disposal (r = 0.71) and incremental exogenous glucose storage (r = 0.40), all P < 0.01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P = 0.05) in LIPO compared with the combined groups of NONLIPO and NAÏVE, indicating an impaired adaptation of β-cell function to insulin resistance in LIPO.
Conclusion: Our data suggest that normoglycaemic lipodystrophic HIV-infected patients display impaired glucose and lipid metabolism in multiple pathways involving liver, muscle tissue and β-cell function.
Nicole Jacqueline Jensen, Malin Nilsson, Jonas Schultz Ingerslev, Dorte Aalund Olsen, Mogens Fenger, Mads Svart, Niels Møller, Mette Zander, Kamilla Woznica Miskowiak and Jørgen Rungby
Cognitive impairment in type 2 diabetes is associated with cerebral glucose hypometabolism. Providing a glucose substitute such as ketone bodies might restore metabolic balance in glucose-compromised neurones and improve cognitive performance. We aimed to investigate if β-hydroxybutyrate (ketone body) infusion acutely affects cognitive performance, measured by a neuropsychological test battery, in patients with type 2 diabetes.
Randomised, placebo-controlled, double-blind cross-over trial.
Eighteen patients with type 2 diabetes received i.v. ketone body (β-hydroxybutyrate) and placebo (saline) infusion in a randomised order on two separate occasions. On both days of examination, blood glucose was clamped at 7.5 mmol/L and a neuropsychological test battery was used to assess global cognitive performance (primary outcome) and specialized cognitive measures of verbal memory, working memory, executive function, psychomotor speed, and sustained attention.
During neurocognitive testing, β-hydroxybutyrate concentrations were 2.4 vs 0.1 mmol/L. Working memory assessed by Wechsler Adult Intelligence Scale letter-number-sequencing significantly improved by 1.6 points (95% CI: 0.7, 2.4; non-adjusted P < 0.001) corresponding to a 17% increase in performance during ketone infusion compared to placebo. There was no change for global cognitive performance or any other cognitive measure after adjusting for multiple comparisons. Blood concentrations of β-hydroxybutyrate and glycaemic status did not associate with test performance; however, insulin resistance measured by HOMA was related to improved working memory performance during ketone infusion (β = 4%; 95% CI: 1.1, 7.7; P = 0.012).
Ketone infusion specifically improved working memory performance in patients with type 2 diabetes in the absence of changes in global cognition.