Adiponectin seems to be a promising treatment choice for type 2 diabetes, but how it impacts insulin tolerance remains uncertain. Two weeks of globular adiponectin (gAcrp30) therapy decreased fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which may be due to changes in both insulin-mediated repressions of endogenous glucose production and in insulin-stimulated glucose absorption in muscle and adipose tissues. These increases in liver and muscle sensitivity were associated with approximately 50% decreases in liver and muscle triglyceride content, which occurred irrespective of reductions in overall ceramide content. Reductions in plasma PM DAG levels were associated with reduced PKCε translocation in the liver and skeletal muscle, which resulted in PKCθ and PKCε translocation, decreased insulin-stimulated PI3K activity, and decreased Akt phosphorylation. Both G protein-coupled receptor 30, and full-length adiponectin activated the cAMP/protein kinase A cascade, as well as muscle fatty acid oxidation. gAcrp30 and Acrp30 injections improved TAG absorption in eWAT and may have been due to increased LPL activity. These results indicate that adiponectin and adiponectin associated molecules reverse lipid-induced liver and muscle insulin resistance by decreasing ectopic lipid storage in these tissues, resulting in reduced plasma membrane sn-1,2-DAG-induced PKA activity and increased insulin signaling. Adiponectin is also responsible for stimulating the accumulation of TAG in the eWAT and muscle, but also for stimulating the use of fat for energy output in the muscles.

Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are among the leading causes of morbidity and mortality in the adult population worldwide and are correlated with disease in multiple organ systems, including atherosclerotic vascular disease. (ASCVD). Insulin resistance is a key factor in the progression of type 2 diabetes and metabolic syndrome. Adiponectin, an adipokine, is associated with many disorders including anti-diabetic, anti-inflammatory, and anti-atherosclerotic effects. Plasma adiponectin levels are inversely associated with obesity and insulin resistance and have reduced in T2DM. Adiponectin is found in humans in its maximum length and in its C-terminal globular (AKAP30) shape (gAcrp30). The C-terminal globular fragment is formed by proteolytic cleavage and a biologically active molecule is produced. Adiponectin plays a pivotal function in insulin resistance, but the mechanism by which it functions and affects insulin resistance is not well known.