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

Peter C. Reifsnyder,David E. Harrison,Austen Te,Kevin Flurkey

doi:10.18632/aging.101117

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.

Highlights

Rapamycin increases lifespan in mice and several other organisms [1,2,3,4,5,6,7,8], presumably via inhibition of mTORC. mTORC activation is associated with the response to nutrients, and it is involved in the regulation of insulin and glucose homeostasis [9,10,11,12,13]
Rapamycin is the first drug found to reliably increase maximum lifespan in a mammalian www.aging‐us.com model [1, 2], suggesting that numerous age-related diseases may respond to rapamycin treatment [33]
An important concern regarding rapamycin treatment is the elevation of circulating glucose observed in some patients

Summary

Introduction

Rapamycin increases lifespan in mice and several other organisms [1,2,3,4,5,6,7,8], presumably via inhibition of mTORC (mechanistic Target Of Rapamycin Complex). mTORC activation is associated with the response to nutrients, and it is involved in the regulation of insulin and glucose homeostasis [9,10,11,12,13]. MTORC activation is associated with the response to nutrients, and it is involved in the regulation of insulin and glucose homeostasis [9,10,11,12,13]. Because rapamycin may alter glucose homeostasis, researchers have evaluated effects of rapamycin on glucose clearance, insulin sensitivity, and adiposity in mice [1022]. Rapamycin treatment delays glucose clearance but reduces weight gain and adiposity ( when mice are fed a high fat diet). Effects of rapamycin on glucose clearance in already glucose intolerant strains have not been reported, but increased insulin sensitivity has been shown in the insulin resistant BKS-db/db mouse [17]. In a non-diabetic heterogeneous mouse model, negative effects on glucose clearance and insulin sensitivity faded with treatment duration [13]. The 5 models selected represent distinct type 2 diabetic etiologies (Table 1), with differing severities of obesity, hyperglycemia, and hyperinsulinemia [23,24,25,26,27,28]

Methods

Results

Discussion

Conclusion