Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes

There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80–90 g [300–400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances

Metabolic syndrome and the risk of calcium stones

Background. The metabolic syndrome (MS) is associated with increased prevalence of kidney stones, yet the specific stone type remains largely unknown. This study was conducted to assess whether risk factors associated with calcium nephrolithiasis increase with individual characteristics of the MS. Methods. A retrospective analysis was performed in 109 non-stone-forming subjects and 128 recurrent calcium stone formers from Dallas, Texas. A separate analysis was performed in 140 recurrent calcium stone formers from Bern, Switzerland. Demographic, anthropometric, serum and urinary profiles were measured. Results. In non-stone formers from Dallas, urinary calcium (3.6 ± 1.8 to 6.0 ± 2.9 mmol/day, P 0.0003 for trend, zero to four features) increased with increasing features of the MS. This change was attendant with a significant rise in supersaturation index (SI) of calcium oxalate (CaOx) (2.76 ± 1.21 to 4.45 ± 1.65, P < 0.0001; zero to four features). In calcium stone formers from Dallas, urinary calcium marginally increased (5.2 ± 2.3 to 7.0 ± 4.0 mmol/day, P 0.09; zero to four features), while urinary oxalate (356 ± 141 to 504 ± 203 μmol/day, P 0.001; zero to four features) and SI CaOx (4.46 ± 1.80 to 6.16 ± 3.71, P 0.009; zero to four features) significantly increased with features of the MS. However, when adjusted for confounding variables such as total volume, age, gender, urine sodium and urine sulfate, urinary calcium and SI CaOx showed no significant changes in stone formers yet remained significant in non-stone formers. In a separate cohort from Bern, Switzerland urinary calcium (6.9 ± 3.6 versus 7.0 ± 3.2, P 0.8) and SI CaOx (3.37 ± 1.98 versus 4.04 ± 2.78, P 0.5) did not differ between subjects with and without the MS. Conclusion. sIn non-stone formers, the risk of CaOx stone formation increases with the number of features of the MS. However, in stone-forming subjects, the propensity for CaOx precipitation is much higher but is not independently associated with increasing features of the MS. © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved

Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice

Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established. Here we report lifespan and healthspan extension in a mouse model with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a Phe121Ala mutation in beclin 1 (Becn1(F121A/F121A)) that decreases its interaction with the negative regulator BCL2. We demonstrate that the interaction between beclin 1 and BCL2 is disrupted in several tissues in Becn1(F121A/F121A) knock-in mice in association with higher levels of basal autophagic flux. Compared to wild-type littermates, the lifespan of both male and female knock-in mice is significantly increased. The healthspan of the knock-in mice also improves, as phenotypes such as age-related renal and cardiac pathological changes and spontaneous tumorigenesis are diminished. Moreover, mice deficient in the anti-ageing protein klotho have increased beclin 1 and BCL2 interaction and decreased autophagy. These phenotypes, along with premature lethality and infertility, are rescued by the beclin 1(F121A) mutation. Together, our data demonstrate that disruption of the beclin 1-BCL2 complex is an effective mechanism to increase autophagy, prevent premature ageing, improve healthspan and promote longevity in mammals

The chromatin landscape of healthy and injured cell types in the human kidney

There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney’s active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks. © 2024, The Author(s).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]