Zusammenfassung
In diesem Beitrag soll am Beispiel der metabolischen Stimulus-Sekretionskopplung der
pankreatischen b-Zelle gezeigt werden, wie aus der Grundlagenforschung heraus neue
Strategien zur Therapie des Typ-2-Diabetes-mellitus entwickelt werden können. Die
metabolische Stimulus-Sekretionskopplung setzt die Verstoffwechselung von Stimuli
der Insulinsekretion voraus, die Nährstoffcharakter besitzen. Die Änderung der ATP/ADP-Ratio
in der b-Zelle löst dann die Exozytose der Insulingranula aus. Das glukosephosphorylierende
Enzym Glukokinase fungiert als metabolischer Glukosesensor, der Änderungen der physiologischen
Glukosekonzentrationen in den b-Zellen des Pankreas und auch der Leber an den Intermediärstoffwechsel,
d.h. Glykolyse, Citratzyklus und Atmungskettenphosphorylierung, koppelt und hierdurch
die Insulinsekretion und den Leberstoffwechsel positiv beeinflusst. Verschiedene Pharmaunternehmen
(Roche, Merck, Astra-Zeneca, Lilly) haben inzwischen erste Glukokinase-aktivierende
Substanzen entwickelt und ihre Wirksamkeit in der Behandlung von Tiermodellen des
Typ-2-Diabetes belegt. Diese Glukokinase-Aktivatoren verhindern, dass die Glukokinase
eine katalytisch inaktive strukturelle Konformation einnimmt. Sie erhöhen die Glukose-Affinität
des Enzyms und stabilisieren eine katalytisch aktive Form des Glukokinaseproteins.
Hierdurch steigern Glukokinase-Aktivatoren die glukoseinduzierte Insulinsekretion
und hemmen die hepatische Glukoneogenese. Glukokinaseaktivatoren stellen eine interessante
Innovation für die künftige Behandlung des Typ-2-Diabetes dar, da ihre Wirkung an
der b-Zelle und der Leber von Änderungen der Blutglukosekonzentrationen abhängt.
Summary
Using the metabolic stimulus-secretion coupling of pancreatic beta cells as an example,
this review illustrates how new strategies in the treatment of type 2 diabetes mellitus
can be developed from the results of basic research. Metabolic stimulus-secretion
coupling presupposes the metabolizing of those stimuli of insulin secretion that have
the properties of nutritional substances. Changes in the ATP/ADP ratio within the
beta cells will then trigger the release of insulin granules from them. Glucokinase,
a glucose phosphorylating enzyme, functions as a metabolic glucose sensor, which couples
changes in physiological glucose concentration in the pancreatic beta cells and in
the liver to the intermediary metabolism, i.e. glycolysis, the citrate cycle and respiratory-chain
phosphorylation. In this way insulin secretion and hepatic metabolism are positively
influenced. Several pharmaceutical companies (Roche, Merck, Astra-Zeneca, Lilly) have
recently developed first examples of glucokinase-activating compounds and demonstrated
in animal models their efficacy in the treatment of type 2 diabetes mellitus. These
glucokinase activators prevent glucokinase from changing into a catalytically inactive
structure. They also increase glucose affinity of the enzyme and stabilize a catalytically
active form of glucokinase proteins. In this way glucokinase activators increase
glucose-induced insulin secretion and inhibit hepatic glucogenesis. Glucokinase activators
are an interesting innovation in the future treatment of type 2 diabetes, because
their action on beta cells and the liver is caused by changes in blood glucose concentration.
Literatur
- 1
Agius L, Peak M.
Binding and translocation of glucokinase in hepatocytes.
Biochem Soc Trans.
1997;
25
145-150
- 2
Baltrusch S, Lenzen S, Okar D A, Lange A J, Tiedge M.
Characterization of glucokinase-binding protein epitopes by a phage-displayed peptide
library. Identification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase as
a novel interaction partner.
J Biol Chem.
2001;
276
43915-43923
- 3 Baltrusch S, Wu C, Okar D A, Tiedge M, Lange A. Interaction of GK with the bifunctional
enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF2K/F26P2ase). Basel,
Karger In Glucokinase and glycemic disease Matschinsky FM, Magnuson MA, Eds 2004:
262-274
- 4
Brocklehurst K J, Payne V A, Davies R A. et al .
Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators.
Diabetes.
2004;
53
535-541
- 5
Chen C, Hosokawa H, Bumbalo L M, Leahy J L.
Regulatory effects of glucose on the catalytic activity and cellular content of glucokinase
in the pancreatic beta cell. Study using cultured rat islets.
J Clin Invest.
1994;
94
1616-1620
- 6
Efanov A M, Barrett D G, Brenner M B. et al .
A novel glucokinase activator modulates pancreatic islet and hepatocyte function.
Endocrinology.
2005;
146
3696-3701
- 7
Grimsby J, Sarabu R, Corbett W L. et al .
Allosteric activators of glucokinase: potential role in diabetes therapy.
Science.
2003;
301
370-373
- 8
Henquin J C.
Pathways in beta-cell stimulus-secretion coupling as targets for therapeutic insulin
secretagogues.
Diabetes.
2004;
(Suppl 3)
53
S48-58
- 9
Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y.
Structural basis for allosteric regulation of the monomeric allosteric enzyme human
glucokinase.
Structure.
2004;
12
429-438
- 10
Lenzen S.
Hexose recognition mechanisms in pancreatic B-cells.
Biochem Soc Trans.
1990;
18
105-107
- 11
Lenzen S, Panten U.
Signal recognition by pancreatic B-cells.
Biochem Pharmacol.
1988;
37
371-378
- 12
Liang Y, Jetton T L, Zimmerman E C. et al .
Effects of glucose on insulin secretion, glucokinase activity, and transgene expression
in transgenic mouse islets containing an upstream glucokinase promoter-human growth
hormone fusion gene.
Diabetes.
1994;
43
1138-1145
- 13
Massa L, Baltrusch S, Okar D A, Lange A J, Lenzen S, Tiedge M.
Interaction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2)
with glucokinase activates glucose phosphorylation and glucose metabolism in insulin-producing
cells.
Diabetes.
2004;
53
1020-1029
- 14
Matschinsky F M.
Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells
and hepatocytes.
Diabetes.
1990;
39
647-652
- 15
Matschinsky F M.
Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase
glucose sensor paradigm.
Diabetes.
1996;
45
223-241
- 16
Matschinsky F M.
Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics.
Diabetes.
2002;
(Suppl 3)
51
S394-404
- 17
Matschinsky F M, Magnuson M A, Zelent D. et al .
The network of glucokinase-expressing cells in glucose homeostasis and the potential
of glucokinase activators for diabetes therapy.
Diabetes.
2006;
55
1-12
- 18
Newgard C B, McGarry J D.
Metabolic coupling factors in pancreatic beta-cell signal transduction.
Annu Rev Biochem.
1995;
64
689-719
- 19
Okar D A, Manzano A, Navarro-Sabate A, Riera L, Bartrons R, Lange A J.
PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate.
Trends Biochem Sci.
2001;
26
30-35
- 20
Rizzo M A, Magnuson M A, Drain P F, Piston D W.
A functional link between glucokinase binding to insulin granules and conformational
alterations in response to glucose and insulin.
J Biol Chem.
2002;
277
34168-34175
- 21
Tiedge M, Krug U, Lenzen S.
Modulation of human glucokinase intrinsic activity by SH reagents mirrors post-translational
regulation of enzyme activity.
Biochem Biophys Acta.
1997;
1337
175-190
- 22
Tiedge M, Richter T, Lenzen S.
Importance of cysteine residues for the stability and catalytic activity of human
pancreatic beta cell glucokinase.
Arch Biochem Biophys.
2000;
315
251-260
- 23
Tiedge M, Steffeck H, Elsner M, Lenzen S.
Metabolic regulation, activity state, and intracellular binding of glucokinase in
insulin-secreting cells.
Diabetes.
1999;
48
514-523
- 24
Van Schaftingen E.
Short-term regulation of glucokinase.
Diabetologia.
1994;
37
(Suppl 2)
S43-S47
- 25 Van Schaftingen E, Veiga-da-Cunha M. Discovery and role of glucokinase regulatory
protein. Basel, Karger In Glucokinase and glycemic disease - From basics to novel
therapeutics Matschinsky FM, Magnuson MA, Eds 2004: 193-207
- 26
Wang H, Iynedjian P.
Modulation of glucose responsiveness of insulinoma beta-cells by graded overexpression
of glucokinase.
Proc Natl Acad Sci U S A.
1997;
94
4372-4377
Prof. Dr. Markus Tiedge
Institut für Medizinische Biochemie und Molekularbiologie
Schillingallee 70
18057 Rostock
Phone: 0381/4945750
Fax: 0381/4945752
Email: markus.tiedge@med.uni-rostock.de
