AMPD1: a novel therapeutic target for reversing insulin resistance

Abstract

BackgroundInsulin resistance is one of the hallmark manifestations of obesity and Type II diabetes and reversal of this pathogenic abnormality is an attractive target for new therapies for Type II diabetes. A recent report that metformin, a drug known to reverse insulin resistance, demonstrated in vitro the metformin can inhibit AMP deaminase (AMPD) activity. Skeletal muscle is one of the primary organs contributing to insulin resistance and that the AMPD1 gene is selectively expressed at high levels in skeletal muscle.MethodsRecognizing the background above, we asked if genetic disruption of the AMPD1 gene might ameliorate the manifestations of insulin resistance. AMPD1 deficient homozygous mice and control mice fed normal chow diet or a high-fat diet, and blood analysis, glucose tolerance test and insulin tolerance test were performed. Also, skeletal muscle metabolism and gene expression including nucleotide levels and activation of AMP activated protein kinase (AMP kinase) were evaluated in both conditions.ResultsDisruption of the AMPD1 gene leads to a less severe state of insulin resistance, improved glucose tolerance and enhanced insulin clearance in mice fed a high fat diet. Given the central role of AMP kinase in insulin action, and its response to changes in AMP concentrations in the cell, we examined the skeletal muscle of the AMPD1 deficient mice and found that they have greater AMP kinase activity as evidenced by higher levels of phosphorylated AMP kinase.ConclusionsTaken together these data suggest that AMPD may be a new drug target for the reversal of insulin resistance and the treatment of Type II diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/1472-6823-14-96) contains supplementary material, which is available to authorized users.

Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion

“…Such temporal segregation argues against the dependence of glucose utilization on BCAA catabolism. In addition, genetic disruption of BCAA catabolism ameliorates, rather than exacerbates, insulin resistance in animal models 55, 56 . The elevated BCAA in T2D patients is most likely to be an outcome of nutrient overload, and could contribute to repression of glucose utilization through fuel competition, either directly or via facilitating fat entry or burning in muscle 57 .…”

AMPD1 regulates mTORC1-p70 S6 kinase axis in the control of insulin sensitivity in skeletal muscle

“…A lower incidence of type 2 diabetes in AMPD1 deficient human subjects is also demonstrated [ 6 ]. Therefore, we have studied roles of AMPD1 in the regulation of glucose metabolism using AMPD1 deficient mice made by the gene targeting [ 7 , 8 ]. We demonstrated that AMPD1 deficient mice show augmented glucose tolerance and attenuated insulin resistance under high fat diet feeding triggering insulin resistance [ 8 ].…”

JAZF1 promotes proliferation of C2C12 cells, but retards their myogenic differentiation through transcriptional repression of MEF2C and MRF4—Implications for the role of Jazf1 variants in oncogenesis and type 2 diabetes

“…Its deficient expression leads to a less severe state of insulin resistance, improved glucose tolerance and enhanced insulin clearance in mice fed a high fat diet [47]. The activity of AMPD1 purified from skeletal muscle is inhibited by metformin, the most widely used drug for T2D, suggesting a pathogenetic relationship between AMPD1 activity and T2D [48].…”