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Published on: November 16, 2011
Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes
Peter C Reifsnyder1, Kevin Flurkey1, Austen Te1
1The Jackson Laboratory, Bar Harbor, ME 04609, USA.
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.
Insights
Rapamycin may benefit type 2 diabetes (T2D) by improving insulin sensitivity and reducing weight gain. However, its effects depend on pancreatic insulin content, suggesting personalized treatment approaches for T2D.
Area of Science:
- Metabolic research
- Endocrinology
- Pharmacology
Background:
- Rapamycin is often linked to insulin resistance, posing potential risks for type 2 diabetes (T2D) patients.
- Emerging data suggest rapamycin may offer metabolic benefits in T2D contexts.
Purpose of the Study:
- To investigate the metabolic effects of rapamycin across diverse mouse models of type 2 diabetes (T2D).
- To identify factors influencing rapamycin's impact on glucose homeostasis and energy metabolism in T2D.
Main Methods:
- Utilized five distinct mouse models of T2D (KK, KK-Ay, NONcNZO10, BKS-db/db, TALLYHO).
- Administered dietary rapamycin and assessed key markers of glucose homeostasis, insulin sensitivity, weight, and lipid profiles.
- Correlated treatment outcomes with pancreatic insulin content (PIC).
Main Results:
- Rapamycin did not worsen glucose intolerance or hyperlipidemia in any T2D model.
- Observed increased insulin sensitivity and reduced weight gain in three models.
- Decreased hyperinsulinemia in two models, with effects linked to baseline PIC.
- Identified a potential PIC threshold below which hyperglycemia may occur.
Conclusions:
- Rapamycin's metabolic effects in T2D are context-dependent, influenced by individual pancreatic physiology.
- The interaction between rapamycin and pancreatic insulin content dictates beneficial or detrimental outcomes.
- Findings suggest a need for personalized therapeutic strategies involving rapamycin for T2D management.
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