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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.

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          Anti-inflammatory therapy in chronic disease: challenges and opportunities.

          Ira Tabas, Christopher K. Glass (2013)
          A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer's disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.
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            Mechanism by which metformin reduces glucose production in type 2 diabetes.

            R. S. Hundal, M Krššák, S. Dufour … (2000)
            To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.
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              Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice.

              R W Gelling, X Q Du, D. Dichmann … (2003)
              Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic alpha cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr(-/-)). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr(-/-) mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to alpha cell, and to a lesser extent, delta cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1-37) and GLP-1 amide (1-36 amide) content and a 3- to 10-fold increase in circulating GLP-1 amide. Gcgr(-/-) mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and alpha and delta cell numbers. Furthermore, the lean phenotype of Gcgr(-/-) mice suggests glucagon action may be involved in the regulation of whole body composition.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes
                Journal ID (iso-abbrev): Diabetes
                Journal ID (hwp): diabetes
                Journal ID (pmc): diabetes
                Journal ID (publisher-id): Diabetes
                Title: Diabetes
                Publisher: American Diabetes Association
                ISSN (Print): 0012-1797
                ISSN (Electronic): 1939-327X
                Publication date (Print): October 2015
                Publication date (Electronic): 11 June 2015
                Volume: 64
                Issue: 10
                Pages: 3396-3405
                Affiliations
                [1] 1Department of Medicine, Columbia University, New York, NY
                [2] 2Department of Pathology and Cell Biology, Columbia University, New York, NY
                [3] 3Irving Institute for Clinical and Translational Research, Columbia University, New York, NY
                [4] 4Tabomedex Biosciences, Boxford, MA
                [5] 5Department of Biochemistry, Hannover Medical School, Hannover, Germany
                [6] 6Department of Physiology and Cellular Biophysics, Columbia University, New York, NY
                Author notes
                Corresponding authors: Lale Ozcan, lo2192@ 123456columbia.edu , and Ira Tabas, iat1@ 123456columbia.edu .
                Article
                Publisher ID: 1945
                DOI: 10.2337/db14-1945
                PMC ID: 4587644
                PubMed ID: 26068544
                SO-VID: c6eef886-32e2-423a-9281-2e30aee7c41d
                Copyright © © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
                History
                Date received : 29 December 2014
                Date accepted : 04 June 2015
                Page count
                Pages: 10
                Funding
                Funded by: American Heart Association http://dx.doi.org/10.13039/100000968
                Award ID: 11SDG5300022
                Funded by: New York Obesity Nutrition Research Center
                Award ID: DK26687
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: SFB 566 B12
                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Award ID: HL087123
                Award ID: HL075662
                Award ID: UL1 TR000040
                Funded by: New York Stem Cell Program
                Award ID: C0267152
                Categories
                Subject: Metabolism

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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