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)

We previously provided evidence that glucagon-like peptide 1 (GLP-1) induces pancreatic beta-cell growth nonadditively with glucose in a phosphatidylinositol (PI) 3-kinase- and protein kinase C zeta-dependent manner. However, the exact mechanism by which the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor (GPCR) superfamily, activates the PI 3-kinase signaling pathway to promote beta-cell growth remains unknown. We hypothesized that the GLP-1R could activate PI 3-kinase and promote beta-cell proliferation through transactivation of the epidermal growth factor (EGF) receptor (EGFR), an event possibly linked to GPCRs via activation of c-Src and the production of putative endogenous EGF-like ligands. Both the c-Src inhibitor PP1 and the EGFR-specific inhibitor AG1478 blocked GLP-1-induced [(3)H]thymidine incorporation in INS(832/13) cells as well as in isolated rat islets, while only AG1478 inhibited the proliferative action of betacellulin (BTC), an EGFR agonist. Both compounds also suppressed GLP-1-induced PI 3-kinase activation. A time-dependent increase in tyrosine phosphorylation of the EGFR in response to GLP-1 was observed in INS(832/13) cells. This transactivation of the EGFR was sensitive to both the pharmacological agents PP1 and AG1478. The action of GLP-1 and BTC on INS cell proliferation was found to be not additive. Overexpression of a dominant-negative EGFR in INS cells with a retroviral expression vector curtailed GLP-1-induced beta-cell proliferation. GLP-1 treatment of INS cells caused a decrease in cell surface-associated BTC, as shown by FACS analysis. Also, the metalloproteinase inhibitor GM6001 and an anti-BTC neutralizing antibody suppressed the GLP-1 proliferative effect. Finally, coculturing the prostatic cancer cell line LNCaP that lacks GLP-1 responsiveness with INS cells increased LNCaP cell proliferation in the presence of GLP-1, thus revealing that INS cells secrete a growth factor in response to GLP-1. GM6001 and an anti-BTC neutralizing antibody suppressed increased LNCaP cell proliferation in the presence of GLP-1 in the coculture experiments. The results are consistent with a model in which GLP-1 increases PI 3-kinase activity and enhances beta-cell proliferation via transactivation of the EGFR that would require the proteolytic processing of membrane-anchored BTC or other EGF-like ligands.
Diabetes 2003 Jan
PMID:Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. 1250 2

Many diseases or traits exhibit a varying age at onset. Recent data examples of prostate cancer and childhood diabetes show that compared to simply treating the disease outcome as affected vs. unaffected, incorporation of age-at-onset information into the transmission/disequilibrium type of test (TDT) does not appear to change the results much. In this paper, we evaluate the power of TDT as a function of age at onset, and show that age-at-onset information is most useful when the disease is common, or the relative risk associated with the high-risk genotype varies with age. Moreover, an extremely old unaffected subject can contribute substantially to the power of the TDT, sometimes as much as old-onset subjects. We propose a modified test statistic for testing no association between the marker at the candidate locus and age at onset. The simulation study was conducted to evaluate the finite sample properties of proposed and the TDT test statistics under various sampling schemes for trios of parents and offspring, as well as for sibling clusters where unaffected siblings were used as controls.
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PMID:Genetic association tests with age at onset. 1254 73

The current trends in favor of androgen deprivation therapy (ADT) for nonmetastatic prostate cancer at the stage of biochemical recurrence or increasing prostate-specific antigen (PSA) raises the issue of exposing otherwise asymptomatic patients to potential side effects over the longer term. Some of these side effects can have deleterious effects on quality of life, and others may contribute to increased risks for serious health concerns associated with aging. Sexual side effects are the most well-recognized adverse effects from ADT and include loss of libido, erectile dysfunction (ED), and hot flashes. Loss of libido is distressing to many men, and they may not pursue treatments for ED. However, for those who do maintain sexual interest, various remedies are available. The incidence of hot flashes, which may not abate over the course of ADT, is close to 80%. Estrogens, progestin megestrol acetate, medroxyprogesterone acetate, venlafaxine, and cyproterone acetate have been shown to alleviate hot flashes and associated symptoms. Physiologic effects, including gynecomastia, changes in body composition (weight gain, reduced muscle mass, increase in body fat), and changes in lipids, are less commonly recognized as side effects of ADT. These may lead to an exacerbation of potentially more serious conditions, such as hypertension, diabetes, and coronary artery disease. Loss of bone mineral density, anemia, and hair changes also may occur. Additionally, both the diagnosis of prostate cancer and the hormonal therapy can cause psychological distress. These side effects need more systematic study in clinical trials. Physicians should be aware of far-reaching consequences of ADT and should incorporate strategies for preventing and managing toxicities into routine practice.
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PMID:Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. 1266 85

We conducted a review of previous cohort studies on the association between a history of diabetes mellitus (DM) and the occurrence of cancer. We limited the papers to those concerning cohort studies on 9 cancer sites, i.e. the kidney, liver, biliary tract, pancreas, colon or rectum, prostate, breast, endometrium, and ovary, in addition to all cancers. With regard to kidney, liver, biliary tract, pancreatic, colorectal, breast, and endometrial cancers, the risk of cancer development has been consistently reported to be positively associated with DM by two or more cohort studies. In contrast, DM was shown to relate negatively to the risk of prostate cancer by two cohort studies. However, there were no cohort studies which showed an either significantly positive or negative association of DM with ovarian cancer. Elevated levels of insulin or IGFs among DM patients have been proposed as a causal mechanism of increased risk for most of the reviewed cancers. In addition, increased estrogen levels in DM patients have been suggested to explain the casual mechanism of increased risk for kidney, breast and endometrial cancers, and decreased risk for prostate cancer. On the other hand, the possibility of detection bias has been suggested in the association of DM with the risk of most of these cancers. Obesity and heavy consumption of alcohol have been indicated as confounding factors in the relationship of DM to the risk for some of them. Thus, further studies are necessary for firm conclusions regarding the association of DM with cancer risk.
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PMID:A Review of Cohort Studies on the Association Between History of Diabetes Mellitus and Occurrence of Cancer. 1271 99

Previous epidemiologic studies evaluating risk factors for lower urinary tract symptoms (LUTS) have focused on White populations. Between September 1996 and January 1998, in a population-based sample of African-American men aged 40-79 years in Flint, Michigan, the authors assessed the role of putative sociodemographic, lifestyle, and medical history risk factors in moderate to severe LUTS, including the subcategories of obstructive and irritative symptoms. After the exclusion of men with prostate cancer or prior prostate surgery and men who were taking alpha-blockers for urinary tract symptoms, 708 participants provided responses to a structured interviewer-administered questionnaire. After multivariable adjustment, current and former smokers were at increased risk of moderate to severe LUTS, including obstructive symptoms. Heavy alcohol consumption and a history of hypertension or diabetes were positively associated with LUTS, and high income (>/=$30,000) was inversely associated with LUTS and with obstructive and irritative symptoms. A history of heart disease was positively associated with LUTS and with irritative symptoms. To the authors' knowledge, this was the first population-based study undertaken in African-American men to evaluate putative risk factors for moderate to severe LUTS, including subcategories of obstructive and irritative urinary symptoms. These results describe associations with specific lifestyle and medical history risk factors.
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PMID:Risk factors for lower urinary tract symptoms in a population-based sample of African-American men. 1274 43

The authors define a trait "wellness" for good health in 6109 men in the National Academy of Sciences-National Research (NAS-NRC) twin panel aged 70 years and up surveyed by mail in the fall of 1998. Men who responded that they had not had a heart attack, coronary surgery, stroke, diabetes or prostate cancer in the survey questionnaire (Q8) met the broad definition of wellness. A more narrow definition included the absence of hypertension. Genetic analysis indicated that over 50% of the population variance for liability to either wellness definition was genetic. A subset of the NAS-NRC twins also participates in the National Heart, Lung and Blood Institute (NHLBI) twin study. NHLBI examinations and medical record review was done in 1986-1987 and 1995-1997 for 389 individuals who completed Q8. Excellent agreement (kappa > 0.8) was found between Q8 and outcome review for each condition comprising the wellness definition, ranging from 0.81 for coronary surgery to 0.88 for diabetes. Substantial agreement (kappa = 0.67) was found for hypertension. Kappa values for wellness were 0.82 for the broader definition and 0.74 if high blood pressure was included. Fraternal twin-pairs concordant for the wellness definitions are currently being recruited for linkage studies.
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PMID:Heritability and validity of healthy physical aging (wellness) in elderly male twins. 1285 72

The life-stage approach, which views the behaviours and exposures of an individual from the preconceptual situation of the parent through pregnancy, infancy, childhood and adolescence, and into the advancing years through adulthood, is the basis of analysis of strategies to improve long-term health. Among the behaviours of note is the dietary selection pattern, conditioning our exposure to nutrients and dietary constituents that influences growth, nutriture, cognitive and physical performance, and disease resistance and susceptibility. The African Diaspora created a population displaced from Africa to the Western Hemisphere as part of the African slave trade from the 16th to 18th centuries. It continues to manifest distinct dietary and lifestyle practices in the context of a health experience that is different both from the population in their African countries of origin and from the other ethnicities in their countries of displacement and current residence. Afro-Americans are more susceptible to a series of diseases and conditions including low birth weight, violence, and HIV/AIDS, as well as the non-communicable diseases: obesity, diabetes mellitus, cardiovascular disease, hypertension, stroke, renal failure, breast cancer, prostate cancer and lead poisoning. The differential nature of dietary practices are conditioned at times by the poverty and marginalisation of the populace, resulting in either disadvantageous or beneficial outcomes relative to others' eating habits. Serious consideration must be given to the possibility that ethnic difference give rise to different requirements and tolerances for essential nutrients and distinct protective or adverse responses to foods and dietary substances. The major challenges to health improvement for the African Diaspora is coming to grips with the policy and programmatic nuances of differential treatment and the effecting the behavioural changes that would be needed in a population skeptical of the motives of media and of the power elites of their societies.
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PMID:Diet and long-term health: an African Diaspora perspective. 1450 96

Living to a late age without suffering any major health problems is a genetically influenced trait. To identify the genes contributing to this important phenotype, a 10 cM genome screen was performed in 95 pairs of male fraternal twins concordant for healthy aging. Individuals meeting these criteria were defined as those attaining the age of 70 free of cardiovascular disease (coronary surgery, diabetes, heart attack, and stroke) and prostate cancer. Six chromosomal regions were identified with logarithm of odds (LOD) scores greater than 1.2 (p<.01). A region on chromosome 4 at marker D4S1564 produced a LOD score of 1.67; this was the same marker previously linked to extreme longevity segregating as an autosomal dominant trait in centenarian families. Our results provide independent evidence that a locus on the long arm of chromosome 4 is associated with better physical aging and/or longevity.
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PMID:Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging. 1503 6

The issue of a possible relationship between type 2 diabetes and cancer is still debated. Such chronic diseases show a high incidence in the general population. In their pathophysiology both genetic and environmental factors are involved, inducing important modifications of metabolism. Diabetes is associated to profound metabolic alterations, such as hyperinsulinemia and insulin resistance, which are common in various diseases, i.e. obesity, hypertension, dyslipidemia and hyperuricemia. Those illnesses form the so-called metabolic syndrome. Insulin resistance, hyperestrinism and the associated hyperandrogenism may play a role in the onset of some malignancies, such as endometrium cancer, breast cancer and prostate cancer. Low plasma levels of IGF-1 are able to reduce the risk of cancer in type 2 diabetes patients. This goal can be obtained with preventive measures, as physical activity, diet and drugs that can reduce insulin resistance (metformin and thiazolidinediones).
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PMID:Evidence for a putative relationship between type 2 diabetes and neoplasia with particular reference to breast cancer: role of hormones, growth factors and specific receptors. 1503 27

Some studies have suggested that diabetes mellitus may decrease the risk of prostate cancer because of lower insulin levels. To further investigate the relation between diabetes and prostate cancer, a nested case-control study was conducted within the US Physicians' Health Study. Cases (n = 1,110) had been diagnosed with prostate cancer, confirmed on medical record review, during follow-up in 1982-1995. Controls (n = 1,110) were selected randomly from men free of prostate cancer and were matched on age and date of randomization. Information on personal history of diabetes and other diseases, lifestyle habits, and body weight/height was self-reported. Logistic regression analysis showed that the odds ratio for prostate cancer was 0.64 (95% confidence interval (CI): 0.43, 0.95) for men with diabetes, relative to those without the disease, after adjustment for potential confounders. Odds ratio estimates were 0.63 (95% CI: 0.35, 1.14), 0.77 (95% CI: 0.35, 1.72), 0.59 (95% CI: 0.21, 1.66), and 0.59 (95% CI: 0.27, 1.27) for diabetes diagnosed 1-5, 6-10, 11-15, and > or = 16 years prior to prostate cancer diagnosis (p for trend < 0.05). Adjusted odds ratios were 1.44 (95% CI: 0.34, 6.17) for stage A prostate cancer and 0.48 (95% CI: 0.28, 0.83) for stages B-D. Results suggest that history of diabetes may be associated with a decreased risk of prostate cancer, especially late-stage tumors.
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PMID:History of diabetes mellitus and risk of prostate cancer in physicians. 1512 10


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