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

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), 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.


Related in: MedlinePlus

Cmpd 28 treatment improves glucose homeostasis in DIO mice. DIO mice (17 weeks old) were injected with 0.2 mg/kg body wt i.p. cmpd 28 or vehicle (control [Con]) each day for 3 weeks (n = 6 mice per group). The mice were then assayed for fasting blood glucose (A), fed blood glucose (B), fasting plasma insulin (C), and fed plasma insulin (D), and body weight was determined (E) (*P < 0.05) (mean ± SEM).
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Figure 3: Cmpd 28 treatment improves glucose homeostasis in DIO mice. DIO mice (17 weeks old) were injected with 0.2 mg/kg body wt i.p. cmpd 28 or vehicle (control [Con]) each day for 3 weeks (n = 6 mice per group). The mice were then assayed for fasting blood glucose (A), fed blood glucose (B), fasting plasma insulin (C), and fed plasma insulin (D), and body weight was determined (E) (*P < 0.05) (mean ± SEM).

Mentions: To investigate the effect of MK2/3 inhibition on hepatic glucose metabolism in the setting of obesity, we treated ob/ob mice with injections of cmpd 28 (0.2 mg/kg body wt i.p.) or vehicle control. A dose range was estimated from in vitro potency data (19), and a pilot experiment showed that 8 days of daily treatment with 0.2 mg/kg body wt i.p. cmpd 28 effectively lowered fasting blood glucose in obese mice, whereas 0.02 mg/kg body wt had little effect, and no further effect was observed at 2 mg/kg body wt. Another pilot experiment showed that a single injection of 0.2 mg/kg body wt i.p. cmpd 28 led to peak plasma concentrations of ∼45 ng/mL after 5 min, followed by significant levels of cmpd 28 accumulating in the liver, peaking at 15 min. The plasma half-life of cmpd 28 was ∼1–2 h, and the liver half-life was ∼2.75 h. After 3 weeks of once-daily i.p. injections of ob/ob mice with 0.2 mg/kg body wt cmpd 28, MK2/3 activity in the liver was inhibited as evidenced by reduced p-hsp25 levels (Fig. 2A). During the course of the treatment, cmpd 28 had no effect on body weight or food intake (Supplementary Fig. 3A and B), and plasma lipids showed a nonsignificant trend toward lower values (Supplementary Fig. 3C–E). Most importantly, cmpd 28 significantly lowered blood glucose and circulating plasma insulin levels of ob/ob mice as early as 3 days after treatment (Fig. 2B and C), and both end points remained lower during the 3-week course of the study (Fig. 2D–F). Drug treatment improved blood glucose response to glucose challenge and enhanced glucose disposal in response to insulin stimulation (Fig. 2G and H), which indicates an increase in insulin sensitivity. Drug-treated mice also displayed lower plasma glucose in response to pyruvate, which is a measure of hepatic glucose production (Fig. 2I). Cmpd 28 had similar effects in DIO mice; i.e., it lowered fasted and fed blood glucose and plasma insulin in the absence of any change in body weight (Fig. 3).


Treatment of Obese Insulin-Resistant Mice With an Allosteric MAPKAPK2/3 Inhibitor Lowers Blood Glucose and Improves Insulin Sensitivity
Cmpd 28 treatment improves glucose homeostasis in DIO mice. DIO mice (17 weeks old) were injected with 0.2 mg/kg body wt i.p. cmpd 28 or vehicle (control [Con]) each day for 3 weeks (n = 6 mice per group). The mice were then assayed for fasting blood glucose (A), fed blood glucose (B), fasting plasma insulin (C), and fed plasma insulin (D), and body weight was determined (E) (*P < 0.05) (mean ± SEM).
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Related In: Results  -  Collection

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Figure 3: Cmpd 28 treatment improves glucose homeostasis in DIO mice. DIO mice (17 weeks old) were injected with 0.2 mg/kg body wt i.p. cmpd 28 or vehicle (control [Con]) each day for 3 weeks (n = 6 mice per group). The mice were then assayed for fasting blood glucose (A), fed blood glucose (B), fasting plasma insulin (C), and fed plasma insulin (D), and body weight was determined (E) (*P < 0.05) (mean ± SEM).
Mentions: To investigate the effect of MK2/3 inhibition on hepatic glucose metabolism in the setting of obesity, we treated ob/ob mice with injections of cmpd 28 (0.2 mg/kg body wt i.p.) or vehicle control. A dose range was estimated from in vitro potency data (19), and a pilot experiment showed that 8 days of daily treatment with 0.2 mg/kg body wt i.p. cmpd 28 effectively lowered fasting blood glucose in obese mice, whereas 0.02 mg/kg body wt had little effect, and no further effect was observed at 2 mg/kg body wt. Another pilot experiment showed that a single injection of 0.2 mg/kg body wt i.p. cmpd 28 led to peak plasma concentrations of ∼45 ng/mL after 5 min, followed by significant levels of cmpd 28 accumulating in the liver, peaking at 15 min. The plasma half-life of cmpd 28 was ∼1–2 h, and the liver half-life was ∼2.75 h. After 3 weeks of once-daily i.p. injections of ob/ob mice with 0.2 mg/kg body wt cmpd 28, MK2/3 activity in the liver was inhibited as evidenced by reduced p-hsp25 levels (Fig. 2A). During the course of the treatment, cmpd 28 had no effect on body weight or food intake (Supplementary Fig. 3A and B), and plasma lipids showed a nonsignificant trend toward lower values (Supplementary Fig. 3C–E). Most importantly, cmpd 28 significantly lowered blood glucose and circulating plasma insulin levels of ob/ob mice as early as 3 days after treatment (Fig. 2B and C), and both end points remained lower during the 3-week course of the study (Fig. 2D–F). Drug treatment improved blood glucose response to glucose challenge and enhanced glucose disposal in response to insulin stimulation (Fig. 2G and H), which indicates an increase in insulin sensitivity. Drug-treated mice also displayed lower plasma glucose in response to pyruvate, which is a measure of hepatic glucose production (Fig. 2I). Cmpd 28 had similar effects in DIO mice; i.e., it lowered fasted and fed blood glucose and plasma insulin in the absence of any change in body weight (Fig. 3).

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