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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potentially enhanced mitogenic activity of insulin analogs represents a safety risk that requires detailed analysis of new analogs considered for therapeutic applications. We assessed the signaling properties and mitogenic potency of two novel rapid-acting insulin analogs, Lys(B3),Glu(B29) insulin (HMR 1964) and Lys(B3),Ile(B28) insulin (HMR 1153) using myoblasts and cardiomyocytes. In myoblasts, both binding and internalization were two- to threefold higher for Asp(B10) insulin and HMR 1153 when compared with HMR 1964 and regular insulin. This finding correlated with a prominent Shc/IGF-I receptor interaction, tyrosine phosphorylation of Shc, activation of extracellular signal-regulated protein kinase (ERK)-1 and -2, and stimulation of DNA synthesis by HMR 1153 and Asp(B10) insulin. In contrast, HMR 1964 produced a marginal activation of the Shc/ERK kinase cascade and was equipotent to insulin in stimulating DNA synthesis in myoblasts. Further, the in vivo growth-promoting activity of this analog was found to be identical to that of regular human insulin. In myoblasts, HMR 1964 produced a minor activation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation, but a prominent activation of IRS-2, with a significantly stronger effect than insulin in human myoblasts. Predominant activation of IRS-2 was also observed in adult cardiomyocytes where HMR 1964 increased 3-O-methylglucose transport and the activation of Akt and glycogen synthase kinase-3 to the same extent as human insulin. We concluded that 1) the mitogenic properties of insulin analogs may result from a series of initial receptor interactions, including internalization and phosphorylation; 2) the mitogenic and metabolic potential of HMR 1964 is identical to that of insulin; and 3) predominant activation of IRS-2 may open new avenues for optimized insulin therapies.
Diabetes 2003 Sep
PMID:A novel insulin analog with unique properties: LysB3,GluB29 insulin induces prominent activation of insulin receptor substrate 2, but marginal phosphorylation of insulin receptor substrate 1. 1294 61

Nektar Therapeutics (formerly Inhale Therapeutic Systems) has developed a pulmonary drug delivery system for insulin [HMR 4006, Exubera]. The rationale behind developing a pulmonary drug delivery system is to ensure that insulin powder is delivered deep into the lungs, where it is easily absorbed into the bloodstream, in a hand-held inhalation device. The device converts the insulin powder particles into an aerosol cloud for the patient to inhale. No propellants are used. The inhaler requires no power source and the clear chamber ensures that the patient knows immediately when all the insulin has been inhaled. Nektar Therapeutics, developers of the inhalation device and formulation process, has licensed the system to Pfizer. Under the terms of the agreement, Pfizer will lead the clinical development of inhaled insulin, while working with Nektar Therapeutics to develop the technology required for packaging the product. Pfizer has an agreement with Hoechst Marion Roussel (now Aventis Pharma) for developing, manufacturing and promoting inhaled insulin. Under the terms of the collaboration, Aventis Pharma will supply recombinant insulin to Nektar Therapeutics to process it into dry powder for incorporation into the inhaler device. Nektar Therapeutics will receive royalties on sales of inhaled insulin marketed by Pfizer and Aventis Pharma, and milestone payments and research support from Pfizer. Aventis Pharma's codename for the product is HMR 4006.Profil, a CRO in Germany, is cooperating with Pfizer/Aventis Pharma in the development of inhaled insulin. In March 2004, Pfizer and Aventis announced that the European Medicines Evaluation Agency (EMEA) accepted the filing of the MAA for inhaled insulin (Exubera) for the treatment of type 1 and type 2 diabetes mellitus. The two companies are working with the US FDA to determine the timing for the submission of the NDA in the US. Pfizer completed five pivotal phase III clinical trials with inhaled insulin in patients with type 1 and type 2 diabetes mellitus in 120 centres worldwide, and will use a fourth prototype inhaler device that is half the size of the first prototype, and has reduced manufacturing costs. Pfizer and its partner, Aventis Pharma, are conducting additional long-term pulmonary safety data studies in patients with type 1 and type 2 diabetes. Pfizer is also conducting phase III clinical trials with inhaled insulin in paediatric patients aged 6-17 years. Nektar Therapeutics is using its Advanced PEGylation technology to develop a dry powder-inhaled polyethylene glycol (PEG) formulation for delivering peptides efficiently across the lungs and to promote prolonged serum concentration of the peptide. PEG is a neutral, water-soluble, nontoxic polymer comprising any number of repeating units of ethylene oxide. PEGylation is designed to increase the size of the active molecule and ultimately improve drug performance by optimising pharmacokinetics, increasing bioavailability, and decreasing immunogenicity and dosing frequency. The investigation has begun with inhaled, long-acting (PEGylated) insulin [inhaled PEG-insulin, PEGylated insulin--Nektar], and is funded by Pfizer. Preclinical results of a dry powder formulation of inhaled PEG-insulin presented at the 63rd Scientific Sessions of the American Diabetes Association (ADA-2003) [June 2003, New Orleans, LA, USA] demonstrated prolonged systemic activity of insulin in dogs. Nektar Therapeutics was granted US patent 5,997,848 on a method for delivering inhalable insulin. The patent covers a method for delivering of 0.5-15 mg of aerosol dry powder insulin per dosing session in 1-4 individual dosages into the deep lung for systemic absorption. The patent does not specify the formulation of insulin or aerosol delivery device. Nektar Therapeutics estimated in June 2002 that Exubera could earn the company potential revenues of >200 million US dollars.
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PMID:Insulin inhalation--Pfizer/Nektar Therapeutics: HMR 4006, inhaled PEG-insulin--Nektar, PEGylated insulin--Nektar. 1513 80

Vascular reactivity to nitric oxide (NO) is mediated by NO-sensitive soluble guanylyl cyclase (sGC). Since a diminished activity of vascular sGC has been reported in an animal model of type 2 diabetes, the sGC activity was assayed in vitro in internal mammary artery specimens obtained during bypass surgery from patients with and without type 2 diabetes. The sensitivity of sGC to NO, which is dependent on Fe(2+)-containing heme, was measured in vitro using stimulation with diethylamine NONOate (DEA/NO). In addition, the novel cyclic guanosine monophosphate-elevating compound HMR-1766 was used to test the stimulation of the oxidized heme-Fe(3+)-containing form of sGC. Basal activity of sGC and its sensitivity to stimulation by DEA/NO and HMR-1766 were not different between control and type 2 diabetic patients: maximum stimulation by DEA/NO amounted to 475 +/- 67 and 418 +/- 59 pmol. mg(-1). min(-1) in control and type 2 diabetic patients, respectively. The maximum effects of HMR-1766 were 95 +/- 18 (control subjects) and 83 +/- 11 pmol. mg(-1). min(-1) (type 2 diabetic patients). Hypertension, hyperlipidemia, drug treatment with statins, ACE inhibitors, or nitrates had no effect on sGC activity. In conclusion, the present findings do not support the hypothesis that desensitization of sGC contributes to the pathogenesis of diabetic vascular dysfunction in humans.
Diabetes 2004 Oct
PMID:Nitric oxide-sensitive soluble guanylyl cyclase activity is preserved in internal mammary artery of type 2 diabetic patients. 1544 95

The aim of this study was to evaluate the effects of treatment of breast cancer explants with tamoxifen (TMX) or RU486 on GH secretory dynamics in the presence of exogenous estrogen (E2), progesterone (P4) or both. Explants obtained during surgery were divided according to their sex steroid hormone receptor status. P4 (10(-7) M) or 17beta-estradiol (10(-5) M) or both were tested in vitro for their ability to induce hGH secretion and cell proliferation. TMX (10(-7) M) was added to E2, RU486 (10(-7) M) to P4, and both were applied to E2 plus P4-supplemented cultures. The stimulatory action of P4 on GH secretion was noted in hormone-dependent (ER+/PR+) but not in hormone-independent explants (ER-/PR-). RU486 did not abolish this effect. The stimulatory action of P4 on GH release was not parallel to the stimulation of cell proliferation. E2 alone was without effect on GH secretion by both types of breast cancer explants. Combined treatment with both steroids stimulated GH secretion and cell proliferation by (ER+/PR+) explants. Both TMX and RU486 reversed this effect on cell proliferation while only RU486 abolished augmentation of GH secretion. In none of the hormone-dependent breast cancers, the combined treatment with E2 and P4 had any effect on GH secretion and cell proliferation. Taken together, these results lead us to the hypothesis that P4 but not E2 potentiates local GH secretion by hormone-dependent breast cancer explants. The fact that RU486 reversed neither GH secretion nor cell proliferation in hormone-dependent explants indicates its non-receptor-mediated mechanism of action.
Exp Clin Endocrinol Diabetes 2005 Feb
PMID:Progesterone but not estradiol 17beta potentiates local GH secretions by hormone-dependent breast cancer explants. An in vitro study. 1577 6

Insulin glargine is a biosynthetic human insulin analog which has been developed by Aventis Pharma (formerly Hoechst Marion Roussel, HMR), for the treatment of types I and II diabetes. In April 1999, HMR filed insulin glargine for approval in both Europe and the US [322507]. In April 2000, the FDA approved insulin glargine (as Lantus) for the treatment of adult patients with type II diabetes mellitus, who require basal insulin for the control of hyperglycemia, and for adult and pediatric patients with type I diabetes mellitus [363836]. Aventis expects to launch this product during 2000 [361988]. In June 2000, the EMEA approved insulin glargine for the treatment of both type I and II diabetes [370984]. In April 1999, the FDA recommended that HMR should initially submit 6-month efficacy and safety data, instead of the usual 12- month data, to hasten the FDA approval procedure. The rest of the phase III data would be added to the filing at a later date [279466]. Insulin glargine is in phase III trials in Japan as a substitute for basal insulin in the treatment of Type I diabetes [216445]. Two formulations of insulin glargine with zinc have also been tested in phase I trials. HOE-71/GT15 and GT80 contain 15 and 80 mu g/ml of zinc. These formulations appear to have longer duration of action with a reduced peak insulin effect [177507]. This insulin analog has a lower receptor binding affinity compared with human insulin, but shows equal potency in vivo [320724]. Insulin glargine was designated as a medium priority project by HMR, which means the project had been set tight deadlines which if not achieved, would have resulted in discontinuation [221118]. In April 2000, Novo Nordisk filed a complaint in Germany against Aventis claiming that the production and sale of insulin glargine infringes two German patents held by Novo Nordisk [364362]. In July 2000, Credit Lyonnais Securities Europe predicted that insulin glargine was likely to enjoy a strong competitive position for several years in Europe and the US, following launch in these territories during 2000, while it was predicted that a registration dossier would be submitted in Japn in 2002. Sales were predicted to reach Euro 600 million by 2005. In April 1999, ABN Amro predicted annual sales of DM 75 million in 2000, rising to DM 200 million in 2002 [328676].
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PMID:Insulin glargine (Aventis Pharma). 1604 68

Previous studies have shown that intracavernous injection of vascular endothelial growth factor (VEGF) restored erectile function in diabetic rats. However, the mechanism of VEGF in diabetes-related erectile dysfunction (ED) has not been fully investigated. We hypothesize that intracavernous injection of VEGF may reverse diabetes-related ED through modulation of the insulin-like growth factor system and sex hormone receptors. To test this hypothesis the erectile function of treated and control rats was analyzed by measurement of intracavernous pressure (ICP) following electrostimulation of the cavernous nerves. Mean ICP was significantly lower in non-treated diabetic rats compared to controls. After VEGF injection, ICP was significantly higher than in non-treated diabetic rats. IGFBP-3 mRNA and protein expression was significantly higher in non-treated diabetic rat crura than controls, while VEGF-treated animals had control levels. ER-beta and PR mRNA and protein expression was significantly lower in non-treated diabetic rat crura. After VEGF injection, ER-beta and PR mRNA and protein expression was similar to control levels. Expression of AR and ER-alpha was the same in all groups. These findings suggest that orthotopic injection of VEGF may improve the functional recovery of diabetes-related ED through modulation of the insulin-like growth factor system and sex hormone receptors. To our knowledge, this is the first study demonstrating that VEGF treatment restores erectile function through restoration of the insulin-like growth factor system and sex hormone receptor genes at the mRNA and protein levels in diabetic rat crura. These results may be important in understanding the pathogenesis of diabetes-related ED and also in providing better strategies for management of this disease.
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PMID:Vascular endothelial growth factor restores erectile function through modulation of the insulin-like growth factor system and sex hormone receptors in diabetic rat. 1645 52

Type 2 diabetes mellitus is associated with increased incidence and inferior outcome of various malignancies. The aim of this study was to explore the impact of type 2 diabetes on breast cancer characteristics at presentation. The study population included 79 diabetic and 158 age-matched non-diabetic patients. Parity, country of birth, co-morbidity other than diabetes, and mode of diagnosis were similar in both groups. Mean body mass index (BMI) was higher among diabetic patients. Tumour stage and size were higher among diabetic patients and the differences remained significant after adjustment for BMI. Moreover, after adjustment for BMI, breast cancer among diabetic patients was more often hormone receptor negative. Our results show that diabetes mellitus is associated with negative prognostic factors at breast cancer presentation.
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PMID:Association between diabetes mellitus and adverse characteristics of breast cancer at presentation. 1657 4

Lesions of the male breast are rather rare. The most frequent lesion is gynecomastia followed by breast cancer. Gynecomastia is well known but male breast cancer is a rather rare tumor. It occurs in less than 1% of all cancers in men and of breast cancers. The mean age is high with a median of 68 years. Predisposing factors appear to be associated with hyperestrogenism such as testicular factors including maldescensus, orchitis and infertility. Other factors are Klinefelter, adipositas, diabetes mellitus and liver disease. In recent years an increased risk of male breast cancer has been reported in families with positive family history and in which BRCA2 mutations have been identified. Diagnostic procedures for male breast lesions should be the same as for the female breast. Underdiagnosis of male breast lesions is a frequently reported problem. Histology of male breast cancer differs in some aspects from female breast cancer. Male breast cancers are more frequently invasive ductal, G3 and steroid hormone receptor positive. In case of intraductal cancer male lesions are more frequently papillary. Lobular carcinomas almost never occur. Prognostic factors for male breast cancer are similar to female breast cancer. For male breast cancer no randomised therapy studies are described. Therefore all therapy strategies are extrapolated from female breast cancer. The existing main therapeutic problem is undertreatment.
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PMID:[Lesions of the male breast]. 1689 48

Chronic intake of arsenic (As) has been associated with increased risk of cancer, diabetes, developmental and reproductive problems, and cardiovascular disease. Recent studies suggest increased health risks with drinking water levels as low as 5-10 ppb. We previously reported that As disrupts glucocorticoid receptor (GR) mediated transcription in a very complex fashion. Low As levels (0.1-0.7 microM) stimulated transcription, whereas slightly higher levels (1-3 microM) were inhibitory. The DNA binding domain (DBD) was the minimal region of GR required for the response to As. Mutations in the DBD that alter the conformation of the dimerization domain (D-loop) to a DNA-bound GR conformation abolished the stimulatory effect and enhanced the inhibitory response to As. Here we report that receptors for progesterone (PR) and mineralocorticoids display a complex As response similar to that of the GR, suggesting a common mechanism for this effect. The complex response to As is not due to altered steroid or receptor levels. Moreover, a well-characterized GR dimerization mutant displayed a wild-type biphasic response to As for several divergent reporter genes, suggesting that dimerization is not critical for the response to As. Fluorescence polarization studies with purified PR and GR demonstrated that the specific PR/GR-DNA interaction is not altered in the presence of As. These results indicate that the numerous and diverse human health effects associated with As exposure may be mediated, at least in part, through its ability to simultaneously disrupt multiple hormone receptor systems.
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PMID:Arsenic disruption of steroid receptor gene activation: Complex dose-response effects are shared by several steroid receptors. 1717 75

To date, diabetes-associated skin ulcerations represent a therapeutic problem of clinical importance. The insulin-resistant type II diabetic phenotype is functionally connected to obesity in rodent models of metabolic syndrome through the release of inflammatory mediators from adipose tissue. Here, we used the impaired wound-healing process in obese/obese (ob/ob) mice to investigate the impact of obesity-mediated systemic inflammation on cutaneous wound-healing processes. Systemic administration of neutralizing monoclonal antibodies against tumor necrosis factor (TNF)alpha (V1q) or monocyte/macrophage-expressed EGF-like module-containing mucin-like hormone receptor-like (Emr)-1 (F4/80) into wounded ob/ob mice at the end of acute wound inflammation initiated a rapid and complete neo-epidermal coverage of impaired wound tissue in the presence of a persisting diabetic phenotype. Wound closure in antibody-treated mice was paralleled by a marked attenuation of wound inflammation. Remarkably, anti-TNFalpha- and anti-F4/80-treated mice exhibited a strong reduction in circulating monocytic cells and reduced numbers of viable macrophages at the wound site. Our data provide strong evidence that anti-TNFalpha therapy, widely used in chronic inflammatory diseases in humans, might also exert effects by targeting "activated" TNFalpha-expressing macrophage subsets, and that inactivation or depletion of misbehaving macrophages from impaired wounds might be a novel therapeutic clue to improve healing of skin ulcers.
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PMID:Systemic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages. 1746 Jul 30


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