Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases.
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PMID:The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design. 2407 92

Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence regarding the association between pioglitazone and bladder cancer risk is confusing. A systematic search of databases was carried out, and other relevant papers were also identified. Then, the analyses were conducted according to the PRISMA and MOOSE guidelines. After quality assessment, nine datasets from 10 available studies were included on the basis of inclusion criteria. The incidence of bladder cancer among pioglitazone ever users and never users, pooled from four cohort and one randomized studies, were 84.51 and 66.68 per 100,000 person-years, respectively. Nine studies representing 2,596,856 diabetic patients were recognized as eligible for overall study; the result suggested an increased risk of bladder cancer in patients exposed to pioglitazone. A persistent significance was detected after being adjusted by age, gender, and use of other diabetes medications. Subgroup analyses indicated that the significantly increased incidence of bladder cancer was found in men, but not in women. Additionally, the analyses addressing increasing exposure to pioglitazone observed a dose-response relation between exclusive ever use of pioglitazone and bladder cancer in terms of cumulative duration of use and cumulative dosage. With some limitations, our results suggest an increased risk of bladder cancer in diabetic patients using pioglitazone, especially for men with long-term and high-dose exposure. Additional studies are needed to provide more precise evidences to support our results.
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PMID:Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis. 2409 76

Distribution of humic acids (HA) in rats was studied using radioiodinated HA injected intraperitoneally. Distribution of (125)I was also studied for comparison. The distribution pattern of HA differed greatly from that of (125)I. Except in the thyroid and skin, (125)I was excreted from the body within 24 hours, whereas a large proportion of HA remained in the liver, kidney, skin, thyroid, bone and muscle. The difference in the distribution pattern and organ/serum radioactivity ratio suggests different kinetics for (125)I and (125)I-HA. The distribution pattern of HA correlated very well with the increased prevalences of organ diseases in the blackfoot disease endemic area, as reflected in epidemiologic studies. It is hypothesised that HA-metal complexes are possible etiological factors of diseases such as goitre, hepatoma, bladder cancer, vascular disease and diabetes mellitus, and that free radicals are the common causative factor.
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PMID:Tissue distribution of absorbed humic acids. 2419 32

Over the last few years a number of important drugs like rofecoxib, rosiglitazone, gatifloxacin (in diabetics) have lost their position in disease management. The newest controversy revolves around Pioglitazone, a thiozolidindione, which improves insulin sensitivity and is reputed to have cardioprotective actions, but is riddled with several controversies related to weight gain, distal fractures of long bones, recent reports of bladder cancer and others. There are now new groups of drugs, which have been introduced with stringent FDA approval. These include DPP-4 inhibitors, GLP-1 analogues and bromocriptine (old wine in a new bottle). Early in 2013 we are also looking at the launch of another new agent - SGLT-2 inhibitors. These newer agents are associated with not only a significant glucose lowering effect but also positive extra-glycaemic benefits principally in the areas of hypoglycaemia and weight gain. This raises a very important question - do we really need such a controversial agent when such a plethora of agents are available to us with possibly better metabolic profile than pioglitazone? This review addresses this highly contentious area dissecting the pros and cons as we see it.
Diabetes Metab Syndr
PMID:Pioglitazone--do we really need it to manage type 2 diabetes? 2429 93

Diabetes remains a burgeoning global problem, necessitating ongoing efforts on the part of pharmaceutical and device manufacturers, patients, and society to curb the frightening trends in morbidity and mortality attributable to the malady. Since 1835 when phlorizin was discovered, sodium glucose co-transporter 2 (SGLT-2) inhibitors have rested tantalizingly on the horizon, promising a more physiological approach to glucose control. These agents lower glucose by enhancing its excretion by blocking reabsorption in the renal tubules, thus eliminating glucose from the body along with the molecules' attendant effects on caloric balance, plasma osmolality, and lipids. Consequently, SGLT-2 inhibitors improve glucose control to an extent comparable to other hypoglycemic agents while simultaneously reducing body weight, blood pressure, and cholesterol - an admirable portfolio. One agent, canagliflozin, has recently been approved by the US Food and Drug Administration (FDA) and two other agents have progressed through Phase III trials, including dapagliflozin and empagliflozin. Collectively, when used as monotherapy, these agents have demonstrated reductions in hemoglobin A1c (HbA1c), body weight, and blood pressure of -0.34% to -1.03%, -2.0 to -3.4 kg, and -1.7 to -6.4 mmHg/-0.3 to -2.6 mmHg (systolic blood pressure/diastolic blood pressure), respectively. SGLT-2 inhibitors have been well tolerated, with hypoglycemia (0.9% to 4.3%) occurring infrequently in clinical trials. Safety signals related to breast and bladder cancer have arisen with dapagliflozin, though these are unsubstantiated and likely ascribed to the presence of preexisting cancer. As these agents emerge, clinicians should embrace the addition to the formulary for treating type 2 diabetes, but must also weight the risk-benefit of this new class in deciding which patient types are most likely to benefit from their novel mechanism of action.
Diabetes Metab Syndr Obes 2013 Nov 27
PMID:SGLT-2 inhibitors and their potential in the treatment of diabetes. 2434 59

In the month of June 2013 the Government of India suddenly suspended three drugs for use. The suspension of the anti-diabetic agent came as a rude shock to the medical community who has been utilizing this insulin sensitizer for more than a decade. We took a close look at the controversies surrounding this agent, the current state in the global scenario and how India has reacted in this mini review. Like most of the drugs utilized in the management of medical disorders pioglitazone also has been under the scanner for quite some time. However no definitive cause and effect association with any of the adverse events namely bladder cancer, anemia, fractures and heart failure was found. The international community responded with caution and refrained from banning the drug outright except for France. The ban in India in the absence of incriminating data on the Indian population seems out of place.
Diabetes Metab Syndr
PMID:India suspends pioglitazone: is it justified? 2466 60

Pioglitazone improves glycemic control by acting as an insulin sensitizer and is used in the management of Type 2 diabetes mellitus. Pioglitazone has recently been at the center of a controversy with regards to its safety. There is no clear consensus on how, when and in what dose the drug should be used in the management of diabetes. We have summarized our strategy on pioglitazone use in Type 2 diabetes in a large private tertiary care center - Medanta, the Medicity- which may help in generating further thought about positioning of this anti-diabetic molecule. We use pioglitazone as the fourth in the pecking order of oral anti-diabetic agents. We typically use pioglitazone in a dose of 15 mg/day. We avoid using pioglitazone with insulin. We do not use pioglitazone under following situations: In the presence of significant or proven cardiac disease, in patients who are struggling with their weight or need to lose weight, in patients at high risk for osteoporotic fractures, in patients with macular edema, in patients with pre-existing bladder cancer and would discontinue in case hematuria or any other symptom of bladder cancer develops. We continue to use the drug in patients well controlled on it without any evident side-effects or contraindications.
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PMID:Usage of pioglitazone at Medanta, the Medicity. 2470 40

Diabetes increases cancer risk, which may be modulated by careful choice of treatment. Experimental reports showed efficacy of glitazones in various in vitro and in vivo models of carcinogenesis, but procarcinogenic effects in some models were reported too, and, similarly, data on cancer incidence in glitazone users are inconsistent. This review summarizes oncostatic effects of glitazones in preclinical and clinical studies and brings a brief summary of their impact on cancer risk in diabetic patients, with a focus on the association between pioglitazone use and bladder cancer.
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PMID:Positive and negative effects of glitazones in carcinogenesis: experimental models vs. clinical practice. 2502 82

Risk of increasing breast and bladder cancer remains a safety issue of SGLT2 (sodium glucose cotransporter type 2) inhibitors, a novel class of antidiabetic agent. We reviewed related papers published before January 29, 2014, through Pubmed search. Dapagliflozin and canagliflozin are the first two approved SGLT2 inhibitors for diabetes therapy. Although preclinical animal toxicology did not suggest a cancer risk of dapagliflozin and overall tumor did not increase, excess numbers of female breast cancer and male bladder cancer were noted in preclinical trials (without statistical significance). This concern of cancer risk hindered its approval by the US FDA in January, 2012. New clinical data suggested that the imbalance of bladder and breast cancer might be due to early diagnosis rather than a real increase of cancer incidence. No increased risk of overall bladder or breast cancer was noted for canagliflozin. Therefore, the imbalance observed with dapagliflozin treatment should not be considered as a class effect of SGLT2 inhibitors and the relationship with cancer for each specific SGLT2 inhibitor should be examined individually. Relationship between SGLT2 inhibition and cancer formation is still inconclusive and studies with larger sample size, longer exposure duration, and different ethnicities are warranted.
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PMID:A Review on the Relationship between SGLT2 Inhibitors and Cancer. 2525 45

Arsenic is a unique element with distinct physical characteristics and toxicity whose importance in public health is well recognized. The toxicity of arsenic varies across its different forms. While the carcinogenicity of arsenic has been confirmed, the mechanisms behind the diseases occurring after acute or chronic exposure to arsenic are not well understood. Inorganic arsenic has been confirmed as a human carcinogen that can induce skin, lung, and bladder cancer. There are also reports of its significant association to liver, prostate, and bladder cancer. Recent studies have also suggested a relationship with diabetes, neurological effects, cardiac disorders, and reproductive organs, but further studies are required to confirm these associations. The majority of research to date has examined cancer incidence after a high exposure to high concentrations of arsenic. However, numerous studies have reported various health effects caused by chronic exposure to low concentrations of arsenic. An assessment of the health effects to arsenic exposure has never been performed in the South Korean population; thus, objective estimates of exposure levels are needed. Data should be collected on the biological exposure level for the total arsenic concentration, and individual arsenic concentration by species. In South Korea, we believe that biological exposure assessment should be the first step, followed by regular health effect assessments.
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PMID:Health effects of chronic arsenic exposure. 2528 95


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