Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice

Abstract

The use of rapamycin to extend lifespan and delay age-related disease in mice is well-established despite its potential to impair glucose metabolism which is driven partially due to increased hepatic gluconeogenesis. We tested whether a combination therapeutic approach using rapamycin and metformin could diminish some of the known metabolic defects caused by rapamycin treatment in mice. In genetically heterogeneous HET3 mice, we found that chronic administration of encapsulated rapamycin by diet caused a measurable defect in glucose metabolism in both male and female mice as early as 1 month after treatment. In female mice, this defect was alleviated over time by simultaneous treatment with metformin, also by diet, such that females treated with both drugs where indistinguishable from control mice during glucose tolerance tests. While rapamycin-mediated glucose intolerance was unaffected by metformin in males, we found metformin prevented rapamycin-mediated reduction in insulin and leptin concentrations following 9 months of co-treatment. Recently, the Interventions Testing Program showed that mice treated with metformin and rapamycin live at least as long as those treated with rapamycin alone. Together, our data provide compelling evidence that the pro-longevity effects of rapamycin can be uncoupled from its detrimental effects on metabolism through combined therapeutic approaches.

Evaluation of the pharmacokinetics of metformin and acarbose in the common marmoset

“…Though equivocal, metformin has been reported to extend male median lifespan only [2]. However, we showed sex-specific effects of metformin on glucose metabolism in mice, with female responding in part due to higher blood concentrations of metformin at a single given dose [25]. Understanding this relationship between drug interaction and genetic and hormonal sex will be important for future studies.…”

Aging research using the common marmoset: Focus on aging interventions

“…While this suggests the basic biochemical properties of this drug intervention can be translated between these species, other results from our pilot study support the notion that physiological outcomes of such an intervention may differ between species. For example, one of the relatively consistent ancillary effects of rapamycin treatment in mice has been development of glucose intolerance, likely due to an inhibitory effect of rapamycin on mTORC2 signaling in the liver [15,[100][101][102]. However, in marmosets treated with rapamycin we found no evidence of glucose intolerance measured by oral glucose tolerance tests or indices of insulin resistance [103].…”

Long‐term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle‐aged marmosets

“…One report suggests that among genetically heterogeneous HET3 mice fed encapsulated rapamycin, female mice have significantly higher concentrations of rapamycin in the blood than male mice (Miller et al, 2014). However, others suggest no difference between sexes in either HET3 mice or inbred C57BL/6 mice fed encapsulated rapamycin or C57BL/6 mice injected with rapamycin (Bitto et al, 2016; Harrison et al, 2009; Weiss, Fernandez, Liu, Strong, & Salmon, 2018; Zhang et al, 2014). At least one human study using relatively healthy subjects also reported no clear sex difference (Kraig et al, 2018).…”

“…The approximate dose used here has been used in both rodents and marmosets for relatively long-periods of time and is known to have species-specific effects on physiological markers. For example, rodents, particularly mice, develop transient dysfunctions in glucose metabolism when treated with rapamycin (Lamming et al, 2012; Liu et al, 2014; Weiss et al, 2018). On the other hand, we previously showed that a similar dose of rapamycin in marmosets does not significantly alter fasting glucose or glucose tolerance in marmosets (Ross et al, 2015).…”