[2018 scientific breakthroughs in ambulatory general internal medicine]. / Avancées scientifiques de 2018 en médecine interne générale ambulatoire.

Mindfulness meditation and cognitive-behavioral therapy are more cost-effective than conventional management of chronic low back pain. Women with iron deficiency can be treated with oral iron substitution every other day to improve tolerance. Smokers who smoke four or less cigarettes per day have a disproportionately high risk of cardiovascular and cerebrovascular events. All antidepressants are effective in cases of severe depression. Cannabis derivatives have no analgesic effect and do not improve the quality of life of people with neuropathic pain. Cognitive training is effective in cases of mild cognitive impairment. Delegated medical protocols can aid with blood pressure control in hypertensive patients. Nitrofurantoin is the antibiotic of choice for uncomplicated cystitis.

La méditation de pleine conscience et la thérapie cognitivo-comportementale présentent un profil coût-efficacité plus avantageux qu'une prise en charge classique des lombalgies chroniques. Les femmes avec un déficit en fer peuvent être traitées par une substitution orale en fer prise un jour sur deux afin d'améliorer la tolérance. Les fumeurs de 4 ou moins cigarettes par jour ont un risque d'événement cardiovasculaire et cérébrovasculaire élevé. Les antidépresseurs sont tous efficaces en cas d'état dépressif sévère. Les dérivés du cannabis n'ont pas d'effet antalgique significatif et n'améliorent pas la qualité de vie des personnes avec douleurs neuropathiques. L'entraînement cognitif est efficace en cas de déficit cognitif léger. L'hypertension artérielle peut être contrôlée par des protocoles médico-délégués. La nitrofurantoïne est l'antibiotique de choix en cas de cystite non compliquée.

[General internal medicine : 2017 scientific breakthroughs in ambulatory care]. / Médecine interne générale ambulatoire : avancées scientifiques en 2017.

Bariatric surgery improves glycemic control in obese patients with diabetes type 2. Dual antiplatelet therapy can be maintained beyond 12 months after a myocardial infarction. Levothyroxine is not beneficial among patients ≥ 65 years that have subclinical hypothyroidism. Prophylactic anticoagulation in lower limb immobilisation should be reserved only for patients with a high risk of thromboembolism. A diagnosis of asthma should be initially confirmed by a spirometry if clinically suspected. A proton pump inhibitor is indicated for patients ≥ 65 years that are treated with aspirin. Beta-lactams should not be avoided in patients with a previous history of non-severe allergy. General internists overestimate harms and benefits of common medical tests and treatments.

La chirurgie bariatrique améliore le contrôle glycémique chez les patients obèses diabétiques. La double antiagrégation plaquettaire peut être poursuivie au-delà des 12 mois postinfarctus du myocarde. La lévothyroxine chez les patients ≥ 65 ans avec une hypothyroïdie subclinique n'est pas bénéfique. L'anticoagulation prophylactique après une immobilisation du membre inférieur doit être réservée aux patients avec haut risque thromboembolique. Le diagnostic d'asthme devrait être confirmé par une spirométrie en cas de suspicion clinique. Un inhibiteur de la pompe à protons est indiqué chez les patients ≥ 65 ans traités par aspirine. En cas d'anamnèse de réaction allergique peu sévère, une ß-lactamine pourrait tout de même être administrée. Les médecins généralistes surestiment les risques et les bénéfices de différentes interventions médicales.

Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes.

INTRODUCTION: Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has now been identified as a specific factor which can worsen breast cancer prognosis. In breast cancer, a high rate of mortality persists due to the emergence of pulmonary metastases. METHODS: Using a hyperinsulinemic mouse model (MKR+/+) and the metastatic, c-Myc-transformed mammary carcinoma cell line Mvt1, we investigated how high systemic insulin levels would affect the progression of orthotopically inoculated primary mammary tumors to lung metastases. RESULTS: We found that orthotopically injected Mvt1 cells gave rise to larger mammary tumors and to a significantly higher mean number of pulmonary macrometastases in hyperinsulinemic mice over a period of six weeks (hyperinsulinemic, 19.4 ± 2.7 vs. control, 4.0 ± 1.3). When Mvt1-mediated mammary tumors were allowed to develop and metastasize for approximately two weeks and were then surgically removed, hyperinsulinemic mice demonstrated a significantly higher number of lung metastases after a four-week period (hyperinsulinemic, 25.1 ± 4.6 vs. control, 7.4 ± 0.42). Similarly, when Mvt1 cells were injected intravenously, hyperinsulinemic mice demonstrated a significantly higher metastatic burden in the lung than controls after a three-week period (hyperinsulinemic, 6.0 ± 1.63 vs. control, 1.5 ± 0.68). Analysis of Mvt1 cells both in vitro and in vivo revealed a significant up-regulation of the transcription factor c-Myc under hyperinsulinemic conditions, suggesting that hyperinsulinemia may promote c-Myc signaling in breast cancer. Furthermore, insulin-lowering therapy using the beta-adrenergic receptor agonist CL-316243 reduced metastatic burden in hyperinsulinemic mice to control levels. CONCLUSIONS: Hyperinsulinemia in a mouse model promotes breast cancer metastasis to the lung. Therapies to reduce insulin levels in hyperinsulinemic patients suffering from breast cancer could lessen the likelihood of metastatic progression.

The pathway from diabetes and obesity to cancer, on the route to targeted therapy.

OBJECTIVE: To review the epidemiologic studies that describe the relationships among diabetes, obesity, and cancer; animal studies that have helped to decipher the mechanisms of cancer development; and some of the therapeutic targets undergoing investigation. METHODS: An electronic search was performed of Medline, Scopus, Google Scholar, and ClinicalTrials.gov to identify English-language articles and studies published from 1995 through 2010 relating to obesity, insulin, insulinlike growth factors, diabetes mellitus, and cancer. RESULTS: Epidemiologic studies have reported that diabetes and obesity are linked to an increased risk of certain cancers in association with higher levels of insulin, C-peptide, and insulinlike growth factor 1. Animal models have demonstrated that increased insulin, insulinlike growth factor 1, and insulinlike growth factor 2 signaling can enhance tumor growth, while inhibiting this signaling can reduce tumorigenesis. Therapies that target insulin and insulinlike growth factor 1 signaling pathways have been developed and are currently in clinical trials to treat cancer. CONCLUSIONS: Insulin, insulinlike growth factor 1, and insulinlike growth factor 2 signaling through the insulin receptor and the insulinlike growth factor 1 receptor can induce tumorigenesis, accounting to some extent for the link between diabetes, obesity, and cancer. Knowledge of these pathways has enhanced our understanding of tumor development and allowed for the discovery of novel cancer treatments.

Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes.

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.

Type 2 diabetes and cancer: what is the connection?

Epidemiological studies have demonstrated an association between type 2 diabetes and cancer. Type 2 diabetes is characterized by insulin resistance and hyperinsulinemia. Hyperinsulinemia may lead to cancer through insulin's effect on its cognate receptor and the insulin-like growth factor system. The effects of insulin and insulin-like growth factor I on cancer development and progression have been demonstrated in animal and human studies. Type 2 diabetes has been positively associated with cancers of the breast, colon, and pancreas. An inverse relationship has been observed between type 2 diabetes and prostate cancer, and this may be due to lower testosterone levels in men with type 2 diabetes. Medications used to treat type 2 diabetes may affect cancer cells directly or indirectly by affecting serum insulin levels. Hyperinsulinemia may be an important risk factor for cancer as well as a target for cancer therapy.

Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes.

Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis,and that the IR and/or the IGF-IR are major mediators of these effects.

Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression.

OBJECTIVE: Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia has been identified as a major factor linking these two diseases. Thus, we hypothesized that pharmacological reduction of elevated insulin levels would attenuate type 2 diabetes-mediated mammary tumor progression. RESEARCH DESIGN AND METHODS: We studied mammary tumor development in MKR(+/+) mice, a nonobese, hyperinsulinemic mouse model of type 2 diabetes. MKR(+/+) mice were either crossed with mice expressing the polyoma virus middle T oncogene specifically in the mammary gland or inoculated orthotopically with the mouse mammary tumor cell lines Met-1 and MCNeuA. MKR(+/+) or control mice harboring tumors were treated with CL-316243, a specific beta3-adrenergic receptor agonist, which sensitizes insulin action but has no direct effect on the mouse mammary epithelium or Met-1 and MCNeuA cells. RESULTS: CL-316243 treatment significantly reduced the elevated insulin levels in MKR(+/+) mice and, as a consequence, attenuated mammary tumor progression in the three tumor models tested. This effect was accompanied by reductions in phosphorylation of insulin and IGF-I receptors in transformed mammary tissue. CONCLUSIONS: Insulin-sensitizing treatment is sufficient to abrogate type 2 diabetes-mediated mammary tumor progression. Therefore, early administration of insulin-sensitizing therapy may reduce breast cancer risk and mortality in patients with type 2 diabetes.