CNX-012-570, a direct AMPK activator provides strong glycemic and lipid control along with significant reduction in body weight; studies from both diet-induced obese mice and db/db mice models.

Abstract

OBJECTIVES:

AMP activated protein kinase (AMPK) regulates the coordination of anabolic and catabolic processes and is an attractive therapeutic target for T2DM, obesity and metabolic syndrome. We report the anti-hyperglycemic and anti-hyperlipidemic effects of CNX-012-570 is an orally bioavailable small molecule (molecular weight of 530 Daltons) that directly activates AMPK in DIO and db/db animal models of diabetes.

METHODS:

Activity and efficacy of the compound was tested in cell based as well as cell free systems in vitro. Male C57BL/6 mice fed with high fat diet (HFD) were assigned to either vehicle or CNX-012-570 (3 mg/kg, orally once a day) for 8 weeks (n = 8). Genetically diabetic db/db mice on chow diet were dosed with vehicle control or CNX-012-570 (2.5 mg/kg, orally once a day) for 6 weeks (n = 8).

RESULTS:

CNX-012-570 is a highly potent and orally bioavailable compound activating AMPK in both cell and cell free systems. It inhibits lipolysis (33%) and gluconeogenesis (28%) in 3T3L1 cells and rat primary hepatocytes respectively. The efficacy of the molecule was translated to both DIO and db/db animal models of diabetes. CNX-012-570 has reduced fasting blood glucose levels by 14%, body weight by 24% and fasting serum triglycerides (TG) by 24%. CNX-012-570 showed a 22% reduction in fed serum cholesterol levels and 19% increase in HDL levels.In db/db mice model, CNX-012-570 has shown 18% decrease in fed glucose and 32% decrease in fasting glucose with a 2.57% reduction in absolute HbA1c. Decrease in serum insulin and glucose AUC indicates the increased insulin sensitivity. Body weight was reduced by 13% with increased browning of adipose tissue and decreased inguinal and mesenteric fat mass. There was significant reduction in liver TG and liver total cholesterol.

CONCLUSIONS:

CNX-012-570 has the potential to control hyperglycemia and hyperlipidemia. It also reduces body weight gain with an additional benefit of minimizing cardiovascular risks in diabetics.

• Authors: Tharappel M Anil, Chandrashekaran Harish, Mudigere N Lakshmi, Krishnareddy Harsha, Mallappa Onkaramurthy, Venkatesh Sathish Kumar, Nitya Shree, Venkatachalaiah Geetha, Gundalmandikal V Balamurali, Aralakuppe S Gopala, Bobbili Madhusudhan Reddy, Madabosse K Govind, Mammen O Anup, Yoganand Moolemath, Marikunte V Venkataranganna, Madanahalli R Jagannath, Baggavalli P Somesh
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 13 Pg. 27 (Jan 25 2014) ISSN: 1475-2840 [Electronic] England
• PMID: 24460834 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Hypolipidemic Agents
• Triglycerides
• Cholesterol
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Blood Glucose (drug effects, metabolism)
• Body Weight (drug effects, physiology)
• Cholesterol (blood)
• Diet, High-Fat (adverse effects)
• Enzyme Activation (drug effects, physiology)
• Glycemic Index (drug effects, physiology)
• Hep G2 Cells
• Humans
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Hypolipidemic Agents (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (drug therapy, enzymology)
• Triglycerides (blood)