Treatment of Obese Insulin-Resistant Mice With an Allosteric MAPKAPK2/3 Inhibitor Lowers Blood Glucose and Improves Insulin Sensitivity

Abstract

The prevalence of obesity-induced type 2 diabetes (T2D) is increasing worldwide, and new treatment strategies are needed. We recently discovered that obesity activates a previously unknown pathway that promotes both excessive hepatic glucose production (HGP) and defective insulin signaling in hepatocytes, leading to exacerbation of hyperglycemia and insulin resistance in obesity. At the hub of this new pathway is a kinase cascade involving calcium/calmodulin-dependent protein kinase II (CaMKII), p38α mitogen-activated protein kinase (MAPK), and MAPKAPK2/3 (MK2/3). Genetic-based inhibition of these kinases improves metabolism in obese mice. Here, we report that treatment of obese insulin-resistant mice with an allosteric MK2/3 inhibitor, compound (cmpd) 28, ameliorates glucose homeostasis by suppressing excessive HGP and enhancing insulin signaling. The metabolic improvement seen with cmpd 28 is additive with the leading T2D drug, metformin, but it is not additive with dominant-negative MK2, suggesting an on-target mechanism of action. Allosteric MK2/3 inhibitors represent a potentially new approach to T2D that is highly mechanism based, has links to human T2D, and is predicted to avoid certain adverse effects seen with current T2D drugs.

Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance

“…Nonetheless, future studies will likely reveal additional DACH1 targets in HCs that may shed additional light on gene expression changes in obesity. Finally, we recently published that drug-mediated inhibition of MK2, an enzyme linked to CaMKII in HCs in obesity, improves metabolism in obese mice (Ozcan et al, 2015), which is consistent with genetic studies conducted by our group (Ozcan et al, 2013) and an independent laboratory (Ruiz et al, 2015). Given that the upstream kinase pathway promotes diabetes by suppressing ATF6, the findings in this report provide important mechanistic underpinnings for future therapeutic strategies that attempt to improve metabolism in obese T2D subjects by targeting this pathway.…”

“…We have recently identified activation of hepatocyte (HC) CaMKII/p38 as a major contributor to aberrant HGP and perturbed insulin signaling in obesity (Ozcan et al, 2013; Ozcan et al, 2012). Treatment of obese mice with a drug inhibitor of the pathway lowers plasma glucose and corrects hyperinsulinemia and is additive in these benefits with the current leading T2D drug, metformin (Ozcan et al, 2015). The CaMKII pathway in HCs perturbs metabolism by lowering the transcription factor ATF6, which can function as a homeostatic regulator of the endoplasmic reticulum (ER) stress response by inducing the chaperone, p58 IPK (Wu et al, 2007).…”

Genome-wide identification of directed gene networks using large-scale population genomics data

“…This pathway has been observed to be upregulated in type II diabetic patients (reviewed in 44 ). In addition, inhibition of MAPKAP2 and MAPKAP3 in obese, insulin-resistant mice has been shown to result in improved metabolism 45 , in line with the association between upregulation of PLAGL1 and the development of TNDM. Furthermore, PLAGL1 may be implicated in lipid metabolism and obesity through its effect on IDI1, PNPLA1, JAK3 , and RAB37 expression 46–49 .…”

MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction

“…To circumvent p38MAPK inhibitor toxicity, an alternative strategy is to target one of the downstream targets of this kinase, such as PRAK/MK5, MSK1/2, MK3, or MK2. Interestingly, similar to p38MAPK, MK2 was recently reported to be activated in diabetic liver (11) and heart (13), and MK2 inhibition improves glucose homeostasis and insulin sensitivity in obese mice (14). Furthermore, mice lacking both MK2 and MK3 display differences in the expression of various genes involved in lipid and carbohydrate metabolism in skeletal muscle (15).…”