Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non‐diabetic controls

Bannister, Christian; Holden, Sarah E.; Jenkins‐Jones, Sara; Morgan, Christopher L.; Halcox, Julian; Schernthaner, Guntram; Mukherjee, Jayanti; Currie, Craig John

doi:10.1111/dom.12354

Cited by 313 publications

(220 citation statements)

References 37 publications

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“…The participants were either euglycemic normal controls (i), diabetics treated with sulfonylurea (ii), or diabetics treated with metformin (iii) (Table 1B). The sulfonylurea group was added in the study because diabetic individuals treated with metformin have increased survival compared with nondiabetics and with diabetics on sulfonylurea (Bannister et al ., 2014). All groups were matched based on age, sex, race and body mass index (BMI) ( n = 20 per group; Table 1B).…”

Section: Resultsmentioning

confidence: 99%

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

et al. 2016

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SummaryMetformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age‐related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA‐processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post‐transcriptional mechanism involving the RNA‐binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life‐extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR‐20a, miR‐34a, miR‐130a, miR‐106b, miR‐125, and let‐7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1‐dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence‐associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age‐related disease.

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Section: Resultsmentioning

confidence: 99%

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

et al. 2016

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“…In C57BL/6 mice, Met was toxic at a higher concentration of 10 000 ppm (1%) (Martin‐Montalvo et al ., 2013), and it is possible that evaluation of doses higher or lower than the 1000 ppm dose we used might have produced stronger evidence of benefit. Observational data suggest that patients with diabetes who take metformin have lower mortality risks than age‐matched non‐diabetic patients (Bannister et al ., 2014). These suggestive reports, together with the strong evidence that Met can be administered with few side effects over many years in people, have prompted suggestions that this agent should be used in large‐scale clinical trials to prevent age‐associated disease in non‐diabetic subjects (Hall, 2015).…”

Section: Discussionmentioning

confidence: 99%

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

et al. 2016

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SummaryThe National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.

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“…The data indicating that metformin can be used as a potential geroprotector show that it is effective in alleviating various age‐associated disorders, including cardiovascular disease, cancer, and cognitive decline, and decreasing the number of deaths of elderly diabetic patients (Bannister et al., 2014). In addition, the effects of metformin on elongating lifespan have been demonstrated in animal models, including worms (Cabreiro et al., 2013; De Haes et al., 2014; Onken & Driscoll, 2010; Wu et al., 2016), mice (Martin‐Montalvo et al., 2013), and rats (Smith et al., 2010).…”

Section: Introductionmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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SummaryMetformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.

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Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non‐diabetic controls

Cited by 313 publications

References 37 publications

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

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