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

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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.

No MeSH data available.


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The metabolic improvement by cmpd 28 and dominant-negative MK2 in obese mice is not additive. Ten-week-old ob/ob mice were transduced with adeno-LacZ or adeno–T222A-MK2 (dominant negative), which inhibits hepatic MK2. Mice were then treated with 0.2 mg/kg body wt i.p. cmpd 28 or vehicle (Veh) for 7 days (n = 5 mice per group). After a 6-h fast, the mice were assayed for fasting blood glucose (A) and plasma insulin (B) (*P < 0.05) (mean ± SEM). n.s., nonsignificant.
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Figure 4: The metabolic improvement by cmpd 28 and dominant-negative MK2 in obese mice is not additive. Ten-week-old ob/ob mice were transduced with adeno-LacZ or adeno–T222A-MK2 (dominant negative), which inhibits hepatic MK2. Mice were then treated with 0.2 mg/kg body wt i.p. cmpd 28 or vehicle (Veh) for 7 days (n = 5 mice per group). After a 6-h fast, the mice were assayed for fasting blood glucose (A) and plasma insulin (B) (*P < 0.05) (mean ± SEM). n.s., nonsignificant.

Mentions: In order to assess whether the metabolic benefits of cmpd 28 in obese mice were due to its ability to inhibit MK2/3, we transduced ob/ob mice with adenoviral constructs encoding dominant-negative T222A-MK2 (DN-MK2) (26) or control LacZ and then treated the mice with cmpd 28 or vehicle for 7 days. We found that both dominant-negative MK2 and cmpd 28 treatment led to a decrease in blood glucose and plasma insulin (Fig. 4) in a manner that was not additive. These combined results demonstrate that MK2/3 suppression by either an allosteric inhibitor or a dominant-negative construct lowers blood glucose and improves insulin sensitivity in two models of obesity-induced insulin resistance.


Treatment of Obese Insulin-Resistant Mice With an Allosteric MAPKAPK2/3 Inhibitor Lowers Blood Glucose and Improves Insulin Sensitivity
The metabolic improvement by cmpd 28 and dominant-negative MK2 in obese mice is not additive. Ten-week-old ob/ob mice were transduced with adeno-LacZ or adeno–T222A-MK2 (dominant negative), which inhibits hepatic MK2. Mice were then treated with 0.2 mg/kg body wt i.p. cmpd 28 or vehicle (Veh) for 7 days (n = 5 mice per group). After a 6-h fast, the mice were assayed for fasting blood glucose (A) and plasma insulin (B) (*P < 0.05) (mean ± SEM). n.s., nonsignificant.
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Related In: Results  -  Collection

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Figure 4: The metabolic improvement by cmpd 28 and dominant-negative MK2 in obese mice is not additive. Ten-week-old ob/ob mice were transduced with adeno-LacZ or adeno–T222A-MK2 (dominant negative), which inhibits hepatic MK2. Mice were then treated with 0.2 mg/kg body wt i.p. cmpd 28 or vehicle (Veh) for 7 days (n = 5 mice per group). After a 6-h fast, the mice were assayed for fasting blood glucose (A) and plasma insulin (B) (*P < 0.05) (mean ± SEM). n.s., nonsignificant.
Mentions: In order to assess whether the metabolic benefits of cmpd 28 in obese mice were due to its ability to inhibit MK2/3, we transduced ob/ob mice with adenoviral constructs encoding dominant-negative T222A-MK2 (DN-MK2) (26) or control LacZ and then treated the mice with cmpd 28 or vehicle for 7 days. We found that both dominant-negative MK2 and cmpd 28 treatment led to a decrease in blood glucose and plasma insulin (Fig. 4) in a manner that was not additive. These combined results demonstrate that MK2/3 suppression by either an allosteric inhibitor or a dominant-negative construct lowers blood glucose and improves insulin sensitivity in two models of obesity-induced insulin resistance.

View Article: PubMed Central - PubMed

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), p38&alpha; 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.

No MeSH data available.


Related in: MedlinePlus