title: Modulation of de novo purine biosynthesis leads to activation of AMPK and results in improved glucose handling and insulin sensitivity.
abstract: 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.
authors.affiliation: Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India.
authors.forename: Satish Kumar
authors.initials: SK
authors.lastname: Sadasivan
authors.affiliation: Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India.
authors.forename: Balamuralikrishna
authors.initials: B
authors.lastname: Vasamsetti
authors.affiliation: Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Singh
authors.affiliation: Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India.
authors.forename: Nethra
authors.initials: N
authors.lastname: Siddaraju
authors.affiliation: Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India.
authors.forename: Khaiser Mehdi
authors.initials: KM
authors.lastname: Khan
authors.affiliation: Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India.
authors.forename: Anup Mammen
authors.initials: AM
authors.lastname: Oommen
authors.affiliation: Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India.
authors.forename: Madanalli R
authors.initials: MR
authors.lastname: Jagannath
authors.affiliation: Connexios life sciences private limited, JP nagara 3rd phase, Bangalore 560078, India.
authors.forename: Raghavendra Pralhada
authors.initials: RP
authors.lastname: Rao
keywords: ADSL; AMPK; Metabolic syndrome; Obesity; Purines; T2DM