Modulation of de novo purine biosynthesis leads to activation of AMPK and results in improved glucose handling and insulin sensitivity

Journal of Diabetes & Metabolic Disorders

Raghavendra Pralhada Rao¹  Madanalli R Jagannath¹  Anup Mammen Oommen¹  Khaiser Mehdi Khan¹  Nethra Siddaraju¹  Jaideep Singh¹  Balamuralikrishna Vasamsetti¹  Satish Kumar Sadasivan¹ 

[1] Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India

关键词: Metabolic syndrome;    Obesity;    T2DM;    ADSL;    AMPK;    Purines;   

Others  :  803531
DOI  :  10.1186/2251-6581-13-51

 received in 2014-01-08, accepted in 2014-04-10,  发布年份 2014

【 摘 要 】

Background

AMP activated protein kinase (AMPK) regulates key metabolic reactions and plays a major role in glucose homeostasis. Activating the AMPK is considered as one of the potential therapeutic strategies in treating type-2 diabetes. However, targeting AMPK by small molecule mediated approach can be challenging owing to diverse isoforms of the enzyme and their varied combination in different tissues. In the current study we employ a novel strategy of achieving AMPK activation through increasing the levels of cellular AMP (an allosteric activator of AMPK) levels by activating the enzyme involved in AMP biosynthesis namely Adenylosuccinate lyase (ADSL).

Methods

Rat primary hepatocytes were cultured under metabolic overload conditions (500 μM palmitate) to induce insulin resistance. ADSL was overexpressed in these hepatocytes and its effect on hepatic glucose output, and triglyceride accumulation was checked. In addition to this, ADSL was overexpressed in high fat diet induced obese mice by hydrodynamic tail vein injection and its effect on fasting glucose, glucose tolerance and pyruvate tolerance were checked.

Results

Rat primary hepatocytes when cultured under metabolic overload conditions developed insulin resistance as measured in terms of failure of insulin to suppress the glucose output. Overexpressing the ADSL in these hepatocytes resulted in increased AMPK phosporylation and improved the insulin sensitivity and also resulted in reduced triglyceride accumulation and inflammatory cytokine levels. In addition to this, when ADSL was overexpressed in high fat diet induced obese mice, it resulted in reduced the fasting hyperglycemia (20% reduction), and increased glucose and pyruvate tolerance.

Conclusions

This study indicates that activating ADSL can be a potential mechanism to achieve the activation of AMPK in the cells. This leads to a novel idea of exploring the purine nucleotide metabolic pathway as a promising therapeutic target for diabetes and metabolic syndrome.

【 授权许可】

   
2014 Sadasivan et al.; licensee BioMed Central Ltd.

【 图 表 】

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