Ghrelin function in human obesity and type 2 diabetes: a concise review.

The 28 amino acid hormone, ghrelin, has been found to have various effects on metabolism. This review will focus on the pathways integrated into ghrelin's effect within the hypothalamus, pancreas and adipocytes. The identification of molecules and pathways that regulate ghrelin-mediated lipid retention could establish new mechanisms underlying cellular energy homeostasis. The impact of acyl-ghrelin on glucose metabolism and lipid homeostasis may allow for novel preventative or early intervention therapeutic strategies to treat obesity related type 2 diabetes and associated metabolic dysfunction.

Cost-effectiveness and budget impact of Empirical vitamin D therapy on unintentional falls in older adults in the UK.

OBJECTIVES: To evaluate the health outcomes and economics associated with the current guidance relating to the prevention of falls in the elderly through vitamin D supplementation. SETTING: UK. PARTICIPANTS: UK population aged 60 years and above. INTERVENTIONS: A Markov health state transition model simulated patient transitions between key fall-related outcomes using a 5-year horizon and annual cycles to assess the costs and benefits of empirical treatment with colecalciferol 800 iu daily. PRIMARY AND SECONDARY OUTCOME MEASURES: Costs and health outcomes attributable to fall prevention following vitamin D supplementation. RESULTS: Our model shows that treating the UK population aged 60 years and above with 800 iu colecalciferol would, over a 5-year period: (1) prevent in excess of 430,000 minor falls; (2) avoid 190,000 major falls; (3) prevent 1579 acute deaths; (4) avoid 84,000 person-years of long-term care and (5) prevent 8300 deaths associated with increased mortality in long-term care. The greatest gains are seen among those 75 years and older. Based on reduction in falls alone, the intervention in all adults aged 65+ is cost-saving and leads to increased quality adjusted life years. Treating all adults aged 60+ incurs an intervention cost of £2.70bn over 5 years, yet produces a -£3.12bn reduction in fall-related costs; a net saving of £420M. Increasing the lower bound age limit by 5-year increments increases budget impact to -£1.17bn, -£1.75bn, and -£2.06bn for adults 65+, 70+ and 75+, respectively. CONCLUSIONS: This study shows that treatment of the elderly UK population with colecalciferol 800 iu daily would be associated with reductions in mortality and substantial cost-savings through fall prevention.

Hypothalamic expression of human growth hormone induces post-pubertal hypergonadotrophism in male transgenic growth retarded rats.

Growth hormone (GH) is known to regulate peripheral components of the hypothalamo-pituitary gonadal (HPG) axis, but it remains unclear whether GH exerts a significant influence on the activity of the hypothalamo-pituitary components of the HPG axis. In this study, we investigated the development of HPG axis function in the male transgenic growth retarded (Tgr) rat, a model of moderate systemic GH deficiency caused by hypothalamic expression of human (h)GH. Impaired postnatal somatotroph expansion and moderate GH deficiency in male Tgr rats were accompanied by a two- to three-fold increase in pituitary gonadotrophin content, but without a significant change in the pituitary gonadotroph population. A three- to nine-fold elevation in basal circulating luteinising hormone concentration was seen in postpubertal Tgr rats, with a smaller increase in follicle-stimulating hormone. Despite this hypergonadotrophism, there was no corresponding increase in steroidogenic (circulating testosterone and seminal vesicle weights) or gametogenic (spermatozoa counts in seminiferous tubules) activity in the postpubertal Tgr testis. Following puberty, the plasma leptin concentration also became progressively elevated in Tgr males. Circulating gonadotrophin and leptin levels were normalised in Tgr rats by peripheral physiological replacement of rat GH, but plasma testosterone concentration was unaffected. These results confirm that hGH exerts a positive influence on the central control of gonadotrophin secretion in the Tgr rat, but the absence of a corresponding elevation in the steroidogenic or gametogenic function of the Tgr testis implies that the peripheral GH/insulin-like growth factor I axis may also exert a permissive influence on testicular function. The relative contribution of somatogenic and lactogenic mechanisms and the potential influence of elevated leptin and decreased sensitivity to androgen feedback to the development of postpubertal hypergonadotrophism in Tgr males remain to be determined.

Comparative analysis of the effects of ghrelin and unacylated ghrelin on luteinizing hormone secretion in male rats.

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of diverse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.

Strength and its relationship to changes in fat-free mass, total body potassium, total body water and IGF-1 in adults with growth hormone deficiency: effect of treatment with growth hormone.

The present investigation examined changes in strength in growth hormone deficient (GHD) adults following treatment with recombinant human growth hormone (rhGH), and assessed their relationship to changes in fat-free mass (FFM), total body potassium (TBK), total body water (TBW), the concentration of TBK and TBW per kg FFM, and insulin like growth factor-1 (IGF-1). The investigation was double-blind and placebo-controlled for a period of 6 months; this was followed by a period of open treatment for a further 6 months. Patients were assigned randomly to experimental (E) and control (C) groups. In the first 6 months group E received rhGH and group C placebo; in the second 6 months both groups received rhGH. Serial data were analysed for 23 males (11 group E, 12 group C) and 20 females (10 group E, 10 group C). Body composition was assessed by dual energy X-ray absorptiometry, TBK and TBW. Muscle strength was recorded for arm flexion, leg extension and hand grip. Significant increases in FFM occurred in the first 6 months in group E (2.3 kg males, 1.4 kg females) and in the second 6 months in group C (2.4 kg males, 1.4 kg females). There was a modest increase in absolute strength with time, although only three increments were significant (knee extension in group E males and arm flexion in groups E and C females), all of which occurred during the 6-12 month period. Allometric scaling did not improve the identification of significant increments of strength. The mean concentrations of TBK (males 57.0-58.6, females 51.4-53.9 mmol) and TBW (males 0.65-0.69, females 0.65-0.68 l) per kg FFM, were significantly smaller at all stages of the trial than the reference values, suggesting that treatment had not fully normalized these variables. Likewise, the relationship between most of the increments of regional and total strength, and the corresponding increments of FFM, were generally poor and not significant. It was concluded that the reduced concentrations of TBK and TBW per kg FFM, which may be the effect of an inappropriate dose regime or mode of delivery, may, in part, contribute to the anomaly between increases in strength and FFM.

Hypokalaemia during insulin-induced hypoglycaemia in hypopituitary adults with and without growth hormone deficiency.

OBJECTIVE: We have investigated plasma potassium changes during insulin-induced hypoglycaemia (IIH) in adult patients with growth hormone deficiency (GHD) who have low total body potassium and may also have a vulnerable myocardium due to an increased prevalence of atherosclerosis. DESIGN: Hypoglycaemia was induced through the administration of intravenous soluble insulin (0.1 U/Kg, i.v.). SUBJECTS: 23 consecutive adult patients undergoing routine biochemical evaluation for hypopituitarism. MEASUREMENTS: GH, cortisol glucose, sodium and potassium levels were measured at 0, 30, 60, 90 and 120 min after insulin administration. Pituitary function was also assessed through measurement of TSH, thyroid hormones, LH/FSH, testosterone and 17-oestradiol. IGF-I concentrations were also analysed. RESULTS: All patients achieved adequate hypoglycaemia (nadir glucose < 2 mmol/l). 15 patients had GHD (peak GH < 10 mU/l) either in isolation or as part of a spectrum of pituitary hormone deficiencies. The remaining 8 patients had normal pituitary function. Plasma potassium concentrations (mean +/- SEM) fell from 3.8 +/- 0.3 mmol/l (normals) and 3.8 +/- 0.2 mmol/l (GHDs) to nadir concentrations of 3.0 +/- 0.2 mmol/l and 3.1 +/- 0.3 mmol/l, respectively (P < 0.005). Overt hypokalaemia (< 3.5 mmol/l) occurred in 13/15 GHDs and all normals. There were no significant differences between the groups. CONCLUSIONS: Insulin-induced hypoglycaemia causes similar degrees of significant hypokalaemia in patients with normal pituitary function and in those with GH deficiency, either alone or in combination with other pituitary hormone deficiencies. Therefore, insulin-induced hypoglycaemia does not appear to be associated with any greater risk of hypokalaemia in hypopituitary adults with GHD compared to those with normal anterior pituitary function.

Crude oil utilization by fungi.

Sixty fungal isolates, 34 obtained by a static enrichment technique from soils of northern Canadian oil-producing areas and 26 from culture collections, were screened for their ability to grow on n-tetradecane, toluene, naphthalene, and seven crude oils of varying composition. Forty cultures, including 28 soil isolates, were capable of growth on one or more crude oils. The genera most frequently isolated from soils were those producing abundant small condida, e.g. Penicillium and Verticillium spp. Oil-degrading strains of Beauveria bassiana, Mortieriella sp., Phoma sp., Scolecobasidium obovatum, and Tolypocladium inflatum were also isolated. Qualitative and quantitative differences were noted among the capacities of different crude oils to sustain the growth of individual fungal isolates. Data are presented which show that ability to grow on a pure n-alkane is not a good indicator of ability to grow on crude oil. Degradation of Rainbow Lake crude oil by individual isolates was demonstrated by gravimetric and gas-chromatographic techniques. The problems involved in determining the response and the potential of fungi to degrade oil spilled in the environment are discussed.