Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes

Abstract

Numerous studies suggest that rapamycin treatment promotes insulin resistance, implying that rapamycin could have negative effects on patients with, or at risk for, type 2 diabetes (T2D). New evidence, however, indicates that rapamycin treatment produces some benefits to energy metabolism, even in the context of T2D. Here, we survey 5 mouse models of T2D (KK, KK-Ay, NONcNZO10, BKS-db/db, TALLYHO) to quantify effects of rapamycin on well-recognized markers of glucose homeostasis within a wide range of T2D environments. Interestingly, dietary rapamycin treatment did not exacerbate impaired glucose or insulin tolerance, or elevate circulating lipids as T2D progressed. In fact, rapamycin increased insulin sensitivity and reduced weight gain in 3 models, and decreased hyperinsulinemia in 2 models. A key covariate of this genetically-based, differential response was pancreatic insulin content (PIC): Models with low PIC exhibited more beneficial effects than models with high PIC. However, a minimal PIC threshold may exist, below which hypoinsulinemic hyperglycemia develops, as it did in TALLYHO. Our results, along with other studies, indicate that beneficial or detrimental metabolic effects of rapamycin treatment, in a diabetic or pre-diabetic context, are driven by the interaction of rapamycin with the individual model's pancreatic physiology.

Chronic treatment with novel nanoformulated micelles of rapamycin, Rapatar, protects diabetic heart against ischaemia/reperfusion injury

“…Previously, we also demonstrated that chronic treatment with rapamycin (0.25 mg·kg −1 ·day −1 for 28 days) improves the metabolic status of diabetic mice and prevents cardiac dysfunction with attenuation of oxidative stress (Das et al ., ). A recent study from The Jackson Laboratory showed that 6 weeks of dietary treatment with rapamycin improved glucose metabolism, increased insulin sensitivity and decreased hyperinsulinaemia in T2D mice (Reifsnyder et al ., ). In contrast, a previous study with rapamycin failed to improve metabolic function in obesity‐induced diabetes (Laplante and Sabatini, ).…”

Cardioprotective effects of dietary rapamycin on adult female C57BLKS/J-Leprdbmice

“…1A), a phenotype that was consistent with male BKS- Lepr db mice administered RAPA via IP injection 32 or dietary supplementation. 28 Evaluation of body composition after the 12-week feeding study showed that approximately 23% of the weight difference between control and RAPA-treated mice was lean or fat-free mass (FFM), with the remaining component being fat mass (Fig. 1B) predominantly associated with the subcutaneous inguinal and scapular adipose tissue depots (Fig.…”

“…27 Furthermore, a survey of five mouse strains prone to development of T2D suggests that worsening of hyperglycemia following RAPA treatment is strain dependent and associated with RAPA-mediated depletion of stored pancreatic insulin content. 28 …”

Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat

“…Similarly, recent studies in genetically obese mice fed rapamycin in a chow diet, at a dose similar to our study, lost significant body weight and fat mass (Deepa et al , 2013), and showed improvements in cardiovascular function (Reifsnyder et al , 2018). In mouse models of type 2 diabetes, including TALLYHO, BKS-db/db, and NcZ10, chronic rapamycin treatment also improved insulin resistance and promoted weight loss (Reifsnyder et al , 2016). Rapamycin has also been evaluated in the setting of high fat diets.…”

“…Similarly, it is well established that transplant subjects receiving rapamycin develop abnormal metabolic profiles (Teutonico et al , 2005; Johnston et al , 2008). However, a handful of studies have shown that rapamycin improves glucose metabolism in mice (Deepa et al , 2013; Makki et al , 2014; Reifsnyder et al , 2016). Nevertheless, low-dose rapamycin has been shown to consistently extend life span in older mice in several studies (Harrison et al , 2009; Anisimov et al , 2011; Miller et al , 2011; Neff et al , 2013), and to abolish cognitive defects in a mouse model of Alzheimer’s disease (Spilman et al , 2010; Lin et al ., 2017), suggesting that mTORC1 inhibition may be beneficial in the appropriate setting.…”