The Beta Cell in Type 2 Diabetes.

PURPOSE OF REVIEW: This review summarizes the alterations in the ß-cell observed in type 2 diabetes (T2D), focusing on changes in ß-cell identity and mass and changes associated with metabolism and intracellular signaling. RECENT FINDINGS: In the setting of T2D, ß-cells undergo changes in gene expression, reverting to a more immature state and in some cases transdifferentiating into other islet cell types. Alleviation of metabolic stress, ER stress, and maladaptive prostaglandin signaling could improve ß-cell function and survival. The ß-cell defects leading to T2D likely differ in different individuals and include variations in ß-cell mass, development, ß-cell expansion, responses to ER and oxidative stress, insulin production and secretion, and intracellular signaling pathways. The recent recognition that some ß-cells undergo dedifferentiation without dying in T2D suggests strategies to revive these cells and rejuvenate their functionality.

Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy.

BACKGROUND: A perennial challenge in systemic cytotoxic cancer therapy is to eradicate primary tumors and metastatic disease while sparing normal tissue from off-target effects of chemotherapy. Anthracyclines such as doxorubicin are effective chemotherapeutic agents for which dosing is limited by development of cardiotoxicity. Our published evidence shows that targeting CD47 enhances radiation-induced growth delay of tumors while remarkably protecting soft tissues. The protection of cell viability observed with CD47 is mediated autonomously by activation of protective autophagy. However, whether CD47 protects cancer cells from cytotoxic chemotherapy is unknown. METHODS: We tested the effect of CD47 blockade on cancer cell survival using a 2-dimensional high-throughput cell proliferation assay in 4T1 breast cancer cell lines. To evaluate blockade of CD47 in combination with chemotherapy in vivo, we employed the 4T1 breast cancer model and examined tumor and cardiac tissue viability as well as autophagic flux. RESULTS: Our high-throughput screen revealed that blockade of CD47 does not interfere with the cytotoxic activity of anthracyclines against 4T1 breast cancer cells. Targeting CD47 enhanced the effect of doxorubicin chemotherapy in vivo by reducing tumor growth and metastatic spread by activation of an anti-tumor innate immune response. Moreover, systemic suppression of CD47 protected cardiac tissue viability and function in mice treated with doxorubicin. CONCLUSIONS: Our experiments indicate that the protective effects observed with CD47 blockade are mediated through upregulation of autophagic flux. However, the absence of CD47 in did not elicit a protective effect in cancer cells, but it enhanced macrophage-mediated cancer cell cytolysis. Therefore, the differential responses observed with CD47 blockade are due to autonomous activation of protective autophagy in normal tissue and enhancement immune cytotoxicity against cancer cells.