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. 2010 Jun 16:2:43.
doi: 10.3410/M2-43.

Glucokinase activators (GKAs) promise a new pharmacotherapy for diabetics

Franz M Matschinsky, Daniel Porte

Glucokinase activators (GKAs) promise a new pharmacotherapy for diabetics

Franz M Matschinsky et al. F1000 Med Rep. .

Abstract

The glucose-phosphorylating enzyme glucokinase, a promising target for developing new antidiabetic agents, was identified through the combined efforts of basic research and human biochemical genetics. Allosteric glucokinase activators (GKAs) were discovered by high-throughput screening of a large compound library and first reported in 2003. GKAs stimulate insulin release and glucose metabolism in the liver thereby lowering blood sugar, and promising trials in humans demonstrate that they are highly effective in patients with type 2 diabetes mellitus. Many companies are now attempting to develop effective and safe GKAs for treating diabetics.

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Figures

Figure 1.
Figure 1.. Chemical structures of glucokinase activators
Chemical structures of glucokinase activators used in extensive preclinical studies using (a) RO-0274375-000 (Cpd A) or (b) RO-0281675-000 (Cpd R) and short-term phase II trials in type 2 diabetes mellitus with (c) RO-4389620-000 (piragliatin) [1-6,8-10]. Cpd, compound.
Figure 2.
Figure 2.. Effect of glucose and glucokinase activator (GKA) binding on the configuration of the allosteric activator site of glucokinase (GK)
A critical cutout of the GK structure is presented to show the conformational change induced by glucose allowing GKA to bind. Note the marked rearrangement of known contact amino acids in the drug receptor region of the enzyme. Based on structures reported by Kamata et al. [13].
Figure 3.
Figure 3.. The network of glucokinase (GK)-containing tissues throughout the body and their connections
Expression of GK in the pancreatic islet alpha and beta cells, other endocrine cells (including pituitary cells), and cells in the portal vascular tree and central nervous system (including the hypothalamus and brain stem) makes up about 0.1% of the body’s total GK complement. The liver produces the rest (about 99.9%). The pancreatic islet cells and the liver constitute the basic GK-dependent regulatory system maintaining glucose homeostasis. ANS, autonomic nervous system; GKA, glucokinase activator. Modified from Matschinsky [1], Nat Rev Drug Discov 2009.
See this image and copyright information in PMC

References

    1. Matschinsky FM. Assessing the potential of glucokinase activators in diabetes therapy. Nat Rev Drug Discov. 2009;8:399–416. doi: 10.1038/nrd2850. - DOI - PubMed
    1. Grimsby J, Sarabu R, Corbett WL, Haynes N-E, Bizzarro FT, Coffey JW, Guertin KR, Hilliard DW, Kester RF, Mahaney PE, Marcus L, Qi L, Spence CL, Tengi J, Magnuson MA, Chu CA, Dvorozniak MT, Matschinsky FM, Grippo JF. Allosteric activators of glucokinase: potential role in diabetes therapy. Science. 2003;301:370–3. doi: 10.1126/science.1084073. - DOI - PubMed

    2. <ext-link ext-link-type="uri" xlink:href="http://www.f1000biology.com/article/id/1006204">F1000 Factor 3.0 Recommended</ext-link>

      Evaluated by Barry Stoddard 20 Aug 2003

    1. Pal M. Recent advances in glucokinase activators for treatment of type 2 diabetes. Drug Discovery Today. 2009;14:784–92. doi: 10.1016/j.drudis.2009.05.013. - DOI - PubMed
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    1. Bonadonna RC, Kapitza C, Heinse T, Avogaro A, Boldrin M, Grimsby J, Mulligan ME, Arbet-Engles C, Balena R. Glucokinase activator RO4389620 improves beta cell function and plasma glucose indexes in patients with type 2 diabetes. Diabetologia. 2008;51(Suppl 1):S371. Abstract 927.