No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis.

AIMS/HYPOTHESIS: Recent epidemiological studies suggest that treatment with insulin glargine (A21Gly,B31Arg,B32Arg human insulin) may promote cancer growth. The present meta-analysis was performed to assess the risk of cancer during treatment with insulin detemir (B29Lys(epsilon-tetradecanoyl),desB30 human insulin), another long-acting insulin analogue. METHODS: This meta-analysis was performed in a population of 8,693 patients with type 1 or type 2 diabetes, who were included in Novo Nordisk-sponsored, randomised and controlled diabetes trials of at least 12 weeks in duration that compared insulin detemir with NPH insulin or insulin glargine. In a blinded manner, the adverse events with suspected treatment-emergent malignant tumours were obtained from these studies under three system-organ classes: 'Neoplasms benign, malignant and unspecified (including cysts and polyps)', 'Neoplasm' and 'Surgical and medical procedures'. Conditional ORs were estimated applying both the Mantel-Haenzel and Peto methods to ensure robustness of results. RESULTS: Separate analyses were performed for trials comparing insulin detemir with NPH insulin and insulin detemir with insulin glargine. In the first analysis, 16 studies were included with a total of 3,983 patients treated with insulin detemir and 2,661 patients treated with NPH insulin. In the second analysis, five studies were included with a total of 1,219 patients treated with insulin detemir and 830 patients treated with insulin glargine. The estimated OR for a cancer diagnosis between NPH insulin and insulin detemir was statistically significantly >1, with the ratio favouring insulin detemir. There was a more than twofold higher cancer occurrence in the NPH insulin-treated population. For the insulin detemir comparison with insulin glargine, there was a non-significant difference in ORs in favour of insulin detemir. CONCLUSIONS/INTERPRETATION: In these randomised controlled diabetes trials, patients treated with insulin detemir had a lower or similar occurrence of a cancer diagnosis compared with patients treated with NPH insulin or insulin glargine, respectively.

Repaglinide at a cellular level.

To investigate the hormonal and cellular selectivity of the prandial glucose regulators, we have undertaken a series of experiments, in which we characterised the effects of repaglinide and nateglinide on ATP-sensitive potassium ion (KATP) channel activity, membrane potential and exocytosis in rat pancreatic alpha-cells and somatotrophs. We found a pharmacological dissociation between the actions on KATP channels and exocytosis and suggest that compounds that, unlike repaglinide, have direct stimulatory effects on exocytosis in somatotrophs and alpha- and beta-cells, such as sulphonylureas and nateglinide, may have a clinically undesirable general stimulatory effect on cells within the endocrine system.

Studies on the renal kinetics of growth hormone (GH) and on the GH receptor and related effects in animals.

Growth hormone (GH) is filtered through the kidney, and may exert effects on renal function when presented via the circulation. Investigations on kidney-related aspects of GH are increasing in number. Using in vitro and in vivo approaches, the present study attempted to provide answers to a number of unresolved or debated issues. In vitro, we detected both GH and type 1 IGF receptors (R) in a porcine renal epithelial cell line. The saturation and down regulation kinetics of the GH-R indicate that it has the properties of a classical GH-R. Furthermore, the simultaneous presence of GH-R and IGF-R on a phenotypically homogeneous cell line suggests the presence of GH-induced auto-/paracrine IGF-1 bioactivity in the kidney. Experiments with isolated proximal rabbit tubules incubated with physiological concentrations of 125I-GH demonstrated a time-and dose-dependent increase in unlabelled GH-displaceable cell-associated radioactivity, lending support to the concept of GH mediating its renal effects via proximal tubular GH-R. Short term administration of GH to rats and humans elicited electrolyte and water retention that may cause edema in adults. In the present study, long term administration of GH to rats caused only a minor increase in serum phosphate levels, with no changes observed in the renal electrolyte clearance. During the first 4 days of GH treatment in rats, no change in plasma renin activity was detected and we were thus unable to confirm the hypothesis that the renin-angiotensin system is responsible for the early phase of GH-associated fluid retention. Pharmacokinetically, when GH was administered to rats with functional disconnection of the kidneys as a model of renal insufficiency, the whole body clearance of GH decreased by ca. two thirds, and was reflected by an increase in the mean residence time and AUCplasma for GH. The plasma half-life, however, was not significantly affected, suggesting that the volume of distribution (Vd) had decreased for the GH administered to the renally compromised animals. A renal contribution to the Vd was visualized as intense radioactive staining in the kidney region on whole body autoradiographs (WBA) of rats dosed with 125I-labelled hGH. The liver region was also intensely stained. Kidney-associated radioactivity was found to be related not only to glomerular filtration, but also to peritubular uptake, since the renal clearance of free GH was found to exceed the GFR.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological variation in random and leukotriene B4-directed migration of canine neutrophils.

Seasonal, sexual, parental and age-related effects on peripheral blood neutrophil migration were studied in 25 dogs. Random and chemotactic movements were estimated by measuring migration towards buffer and leukotriene B4, respectively. Significant effects were seen only in the comparison between the two sexes. Neutrophils from bitches exhibited 19% greater random migration but 10% smaller chemotactic responsiveness than neutrophils from male dogs. A progesterone-mediated suppression of chemotaxis is hypothesized in metoestral bitches. It is concluded that the observed differences are probably too subtle to play any role in combatting bacterial infections, but may constitute a source of bias in the evaluation of isolated cases of disease-associated defective chemotaxis.