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Constitutive expression of hypoxia-inducible factor (HIF) has been implicated in several proliferative disorders. Constitutive expression of HIF1α and HIF2α has been linked to a number of human cancers, especially renal cell carcinoma (RCC), in which HIF2α expression is the more important contributor. Expression of HIF1α is dependent on the mammalian target of rapamycin (mTOR) and is sensitive to rapamycin. In contrast, there have been no reports linking HIF2α expression with mTOR. mTOR exists in two complexes, mTORC1 and mTORC2, which are differentially sensitive to rapamycin. We report here that although there are clear differences in the sensitivity of HIF1α and HIF2α to rapamycin, both HIF1α and HIF2α expression is dependent on mTOR. HIF1α expression was dependent on both Raptor (a constituent of mTORC1) and Rictor (a constitutive of mTORC2). In contrast, HIF2α was dependent only on the mTORC2 constituent Rictor. These data indicate that although HIF1α is dependent on both mTORC1 and mTORC2, HIF2α is dependent only on mTORC2. We also examined the dependence of HIFα expression on the mTORC2 substrate Akt, which exists as three different isoforms, Aktl, Akt2, and Akt3. Interestingly, the expression of HIF2α was dependent on Akt2, whereas that of HIF1α was dependent on Akt3. Because HIF2α is apparently more critical in RCC, this study underscores the importance of targeting mTORC2 and perhaps Akt2 signaling in RCC and other proliferative disorders in which HIF2α has been implicated. [ABSTRACT FROM AUTHOR]

Aim: To compare the change in urinary albumin to creatinine ratio (UACR) in type 2 diabetes (T2DM) patients with albuminuria who initiate sitagliptin to those who initiate a sulfonylurea (SU) as add-on to metformin monotherapy.Method: A cohort of T2DM patients with albuminuria (UACR >30mg/g) who initiated sitagliptin or SU as add-on dual therapy to metformin between 2008 and 2014 was extracted from the computerized medical records of a large managed care organization in Israel. Patients with albuminuria and UACR measurements available at treatment initiation and 120-365days afterwards were included. Propensity scores were calculated based on 17 factors, including demography, comorbidities, baseline levels of HbA1c, UACR, BMI, eGFR, and ACE/ARB use, and patients were matched in a 1:1 ratio. Changes in UACR were compared between the matched pairs using generalized estimating equations.Results: A total of 282 eligible pairs (sitagliptin:SU) were identified. During a mean follow-up of 9months, median UACR changes were -35% (IQR=-73% to 5%) and -31% (IQR=-72% to 21%) in the sitagliptin and SU groups, respectively. Mean absolute HbA1c reductions among sitagliptin and SU groups were 0.9% and 1.0%, respectively. The magnitude of UACR reduction generally increased with greater magnitude of HbA1c reduction in both treatment groups. However, after controlling for HbA1c reduction and the interaction between HbA1c reduction and UACR reduction, sitagliptin users demonstrated a trend toward an increased likelihood of UACR reduction compared to SU users (odds ratio=1.20; 95% confidence interval: 0.99-1.47, P=0.063).Conclusion: Our results suggest that both sitagliptin and SU reduce albuminuria as an add-on therapy to metformin, but that sitagliptin may provide greater reductions in albuminuria independent of glycemic control when compared to SU. Larger population studies are required to further explore this. [ABSTRACT FROM AUTHOR]

Abstract: A characteristic of cancer cells is the generation of lactate from glucose in spite of adequate oxygen for oxidative phosphorylation. This property – known as the “Warburg effect” or aerobic glycolysis – contrasts with anaerobic glycolysis, which is triggered in hypoxic normal cells. The Warburg effect is thought to provide a means for cancer cells to survive under conditions where oxygen is limited and to generate metabolites necessary for cell growth. The shift from oxidative phosphorylation to glycolysis in response to hypoxia is mediated by the production of hypoxia-inducible factor (HIF) – a transcription factor family that stimulates the expression of proteins involved in glucose uptake and glycolysis. We reported previously that elevated phospholipase D (PLD) activity in renal and breast cancer cells is required for the expression of the α subunits of HIF1 and HIF2. We report here that the aerobic glycolysis observed in human breast and renal cancer cells is dependent on the elevated PLD activity. Intriguingly, the effect of PLD on the Warburg phenotype was dependent on the mammalian target of rapamycin complex 1 (mTORC1) in the breast cancer cells and on mTORC2 in the renal cancer cells. These data indicate that elevated PLD-mTOR signaling, which is common in human cancer cells, is critical for the metabolic shift to aerobic glycolysis. [ABSTRACT FROM AUTHOR]