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Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6

Jason G Anderson¹, Giorgio Ramadori², Rafael M Ioris³

¹Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Molecular Metabolism

|December 3, 2015

Abstract

Objective:

Available treatment for obesity and type 2 diabetes mellitus (T2DM) is suboptimal. Thus, identifying novel molecular target(s) exerting protective effects against these metabolic imbalances is of enormous medical significance. Sirt6 loss- and gain-of-function studies have generated confounding data regarding the role of this sirtuin on energy and glucose homeostasis, leaving unclear whether activation or inhibition of SIRT6 may be beneficial for the treatment of obesity and/or T2DM.

Methods:

To address these issues, we developed and studied a novel mouse model designed to produce eutopic and physiological overexpression of SIRT6 (Sirt6BAC mice). These mutants and their controls underwent several metabolic analyses. These include whole-blood reverse phase high-performance liquid chromatography assay, glucose and pyruvate tolerance tests, hyperinsulinemic-euglycemic clamp assays, and assessment of basal and insulin-induced level of phosphorylated AKT (p-AKT)/AKT in gastrocnemius muscle.

Results:

Sirt6BAC mice physiologically overexpress functionally competent SIRT6 protein. While Sirt6BAC mice have normal body weight and adiposity, they are protected from developing high-caloric-diet (HCD)-induced hyperglycemia and glucose intolerance. Also, Sirt6BAC mice display increased circulating level of the polyamine spermidine. The ability of insulin to suppress endogenous glucose production was significantly enhanced in Sirt6BAC mice compared to wild-type controls. Insulin-stimulated glucose uptake was increased in Sirt6BAC mice in both gastrocnemius and soleus muscle, but not in brain, interscapular brown adipose, or epididymal adipose tissue. Insulin-induced p-AKT/AKT ratio was increased in gastrocnemius muscle of Sirt6BAC mice compared to wild-type controls.

Conclusions:

Our data indicate that moderate, physiological overexpression of SIRT6 enhances insulin sensitivity in skeletal muscle and liver, engendering protective actions against diet-induced T2DM. Hence, the present study provides support for the anti-T2DM effect of SIRT6 and suggests SIRT6 as a putative molecular target for anti-T2DM treatment.

Insights

Physiological overexpression of SIRT6 enhances insulin sensitivity and protects against diet-induced type 2 diabetes (T2DM). This suggests SIRT6 is a promising molecular target for T2DM treatments.

Area of Science:

Metabolic research
Molecular biology
Endocrinology

Background:

Current obesity and type 2 diabetes mellitus (T2DM) treatments are suboptimal.
The role of Sirtuin 6 (SIRT6) in energy and glucose homeostasis is unclear due to conflicting data.
Identifying novel molecular targets is crucial for metabolic disease treatment.

Purpose of the Study:

To investigate the role of physiological SIRT6 overexpression in metabolic regulation.
To determine if SIRT6 activation can offer protection against diet-induced metabolic imbalances.
To evaluate SIRT6 as a potential therapeutic target for T2DM.

Main Methods:

Development of a novel mouse model with physiological SIRT6 overexpression (Sirt6BAC mice).
Comprehensive metabolic analyses including glucose and pyruvate tolerance tests.
Hyperinsulinemic-euglycemic clamp assays and assessment of insulin signaling pathways (p-AKT/AKT).

Main Results:

Sirt6BAC mice exhibited normal body weight but were protected against high-caloric-diet-induced hyperglycemia and glucose intolerance.
Enhanced insulin sensitivity was observed in skeletal muscle and liver, with increased glucose uptake and suppressed glucose production.
Increased circulating spermidine levels and elevated insulin-induced p-AKT/AKT ratio in muscle were noted in Sirt6BAC mice.

Conclusions:

Moderate, physiological SIRT6 overexpression improves insulin sensitivity in key metabolic tissues.
SIRT6 plays a protective role against diet-induced T2DM.
SIRT6 represents a promising molecular target for the development of novel anti-T2DM therapies.

Read full analysis

Keywords:

BAC, bacterial artificial chromosome Diabetes EndoRa, endogenous glucose appearance rate GIR, glucose infusion rate Glucose homeostasis HCD, high-caloric diet IPGTT, intraperitoneal glucose tolerance test IPPTT, intraperitoneal pyruvate tolerance test Insulin sensitivity Rd, glucose disposal rate Rg, tissue-specific glucose uptake rate SIRT6 overexpression Sirtuin T2DM, type 2 diabetes mellitus

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