Use of Antibiotics and Risk of Type 2 Diabetes:A Population-Based Case-Control Study

CONTEXT AND OBJECTIVE: Evidence that bacteria in the human gut may influence nutrient metabolism is accumulating. We investigated whether use of antibiotics influences the risk of developing type 2 diabetes and whether the effect can be attributed to specific types of antibiotics. METHODS: We conducted a population-based case-control study of incident type 2 diabetes cases in Denmark (population 5.6 million) between January 1, 2000, and December 31, 2012. Data from the Danish National Registry of Patients, the Danish National Prescription Registry, and the Danish Person Registry were combined. RESULTS: The odds ratio (OR) associating type 2 diabetes with exposure to antibiotics of any type was 1.53 (95% confidence interval 1.50–1.55) with redemption of more than or equal to 5 versus 0–1 prescriptions. Although no individual group of antibiotics was specifically associated with type 2 diabetes risk, slightly higher ORs for type 2 diabetes were seen with narrow-spectrum and bactericidal antibiotics (OR 1.55 and 1.48) compared to broad-spectrum and bacteriostatic types of antibiotics (OR 1.31 and 1.39), respectively. A clear dose-response effect was seen with increasing cumulative load of antibiotics. The increased use of antibiotics in patients with type 2 diabetes was found up to 15 years before diagnosis of type 2 diabetes as well as after the diagnosis. CONCLUSIONS: Our results could support the possibility that antibiotics exposure increases type 2 diabetes risk. However, the findings may also represent an increased demand for antibiotics from increased risk of infections in patients with yet-undiagnosed diabetes

Normal hematopoiesis and lack of β-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain of function mutations

Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of β-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of β-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require β-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of β-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate β-catenin signaling in osteoblasts. Consistent with a lack of β-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of β-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate β-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza

Epigenetic signature of birth weight discordance in adult twins

Molecular Epidemiolog

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUN