Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

Gloyn, Anna L.; Noordam, C.; Willemsen, M.A.A.P.; Ellard, Sian; Lam, Wayne; Campbell, Ian W; Midgley, Paula; Shiota, Chyio; Buettger, Carol; Magnuson, Mark A.; Matschinsky, Franz M.; Hattersley, Andrew T.

doi:10.2337/diabetes.52.9.2433

Cited by 151 publications

(171 citation statements)

References 27 publications

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“…GK activator interacts with GK-specific novel allosteric sites located in the hinge region where several gain-of-functional mutations are clustered (10,18). Compound A has more metabolic stability than previous compound (10), enabling its use in in vivo studies.…”

Section: Discussionmentioning

confidence: 99%

An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism

Futamura

Hosaka

Kadotani

et al. 2006

Journal of Biological Chemistry

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Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V max ) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRPassociated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes.There are three key aspects of type 2 diabetes pathogenesis, which are the focus of current and future therapies: insulin resistance, defective insulin secretion, and increased hepatic glucose production. Glucokinase (GK) 2 is the predominant glucose phosphorylation enzyme in pancreatic ␤-cells and hepatocytes. GK plays an important role as a glucose sensor for controlling plasma glucose homeostasis by enhancing insulin secretion from pancreatic ␤-cells and glucose metabolism in the liver (1, 2), which provides rational expectations that enhancement of GK activity would be a novel therapeutic strategy for type 2 diabetes. Consistent with this rationale, recently discovered small molecule allosteric activators of GK have been demonstrated to have antidiabetic efficacy in rodents (3, 4).To investigate the mechanism of action of GK activators, the interaction between GK and glucokinase regulatory protein (GKRP) is a key aspect. It is well known that hepatic GK activity is modulated by the endogenous inhibitor, glucokinase regulatory protein (GKRP) (5-8). GK is localized in the nucleus as an inactive complex with GKRP at low glucose concentrations and is dissociated from the GK⅐GKRP complex and translocated to the cytoplasm at high glucose concentrations, which triggers glucose disposal (9). Modulators of the GK-GKRP interaction have been shown to enhance hepatic glucose disposal (7). We recently solved the co-crystal structure of hepatic GK complex with GK activator, in which GK undergoes a large conformational change between the active and inactive forms at diffe...

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Section: Discussionmentioning

confidence: 99%

An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism

Futamura

Hosaka

Kadotani

et al. 2006

Journal of Biological Chemistry

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“…Loss of both GK alleles results in permanent neonatal diabetes, whereas heterozygous inactivating mutations of GK lead to maturity-onset diabetes of the young (MODY2; Hattersley et al 1992). Conversely, rare activating mutations of GK result in hyperinsulinaemic hypoglycaemia (Glaser et al 1998, Christesen et al 2002, Gloyn et al 2003, Cuesta-Munoz et al 2004.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

Gill¹,

Brocklehurst²,

Brown³

et al. 2011

Journal of Molecular Endocrinology

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Glucokinase (GK) plays a critical role in controlling blood glucose; GK activators have been shown to stimulate insulin secretion acutely both in vitro and in vivo. Sustained stimulation of insulin secretion could potentially lead to b-cell exhaustion; this study examines the effect of chronic GK activation on b-cells. Gene expression and insulin secretion were measured in rodent islets treated in vitro with GKA71 for 72 h. Key b-cell gene expression was measured in rat, mouse and global GK heterozygous knockout mouse islets (gk del/wt ). Insulin secretion, after chronic exposure to GKA71, was measured in perifused rat islets. GKA71 acutely increased insulin secretion in rat islets in a glucose-dependent manner. Chronic culture of mouse islets with GKA71 in 5 mmol/l glucose significantly increased the expression of insulin, IAPP, GLUT2, PDX1 and PC1 and decreased the expression of C/EBPb compared with 5 mmol/l glucose alone. Similar increases were shown for insulin, GLUT2, IAPP and PC1 in chronically treated rat islets. Insulin mRNA was also increased in GKA71-treated gk del/wt islets. No changes in GK mRNA were observed. Glucose-stimulated insulin secretion was improved in perifused rat islets following chronic treatment with GKA71. This was associated with a greater insulin content and GK protein level. Chronic treatment of rodent islets with GKA71 showed an upregulation of key b-cell genes including insulin and an increase in insulin content and GK protein compared with glucose alone.

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“…A ativação dessa enzima aumenta a oxidação de glutamato e aumenta a relação ATP/ADP na célula B. As mutações ativadoras de GCK (7p15-p13) reduzem o limite da secreção de insulina estimulada pela glicose (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41).…”

Section: Glud1 E Gckunclassified

Hipoglicemia hiperinsulinêmica da infância

Liberatore

Martinelli

2011

Arq Bras Endocrinol Metab

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SUMÁRIOA hipoglicemia hiperinsulinêmica da infância (HHI) é uma emergência no período neonatal. Após curtos períodos de jejum, o cérebro ávido por glicose corre o risco de ficar sem seu principal substrato energético. Os critérios de diagnóstico de HH, tanto no período neonatal quanto na criança maior e na adolescência, foram revisados. Foram descritas as etiologias e a fisiopatologia da HHI. As alterações moleculares frequentemente encontradas, bem como a descrição das principais mutações, são abordadas. Arq Bras Endocrinol Metab. 2011;55(3):177-83 Descritores Hipoglicemia; insulina; hiperinsulinismo SUMMARYThe hypoglycemia hyperinsulinemic of the infancy (HHI) is an emergency in the neonatal period. After a short period of fast the avid brain runs out of its main energy substrate. The authors overhaul the diagnosis of HH, not only in the neonatal period, but also in the late infant and in the adolescence. The aspects of the molecular alterations found in these cases, as well like the description of the main mutations are also approached. Nesses períodos, o tecido cerebral ainda não completamente maduro, marcado por intensa atividade metabólica e extremamente ávido por glicose, torna-se bastante sensível às reduções de níveis glicêmicos mesmo que fugazes.Dessa forma, a ocorrência de episódios repetidos de hipoglicemia nessa fase da vida pode trazer danos cerebrais, na maioria das vezes graves e irreversíveis (1-4).A secreção inapropriadamente aumentada de insulina, sem relação com os níveis de glicemia, caracteriza hiperinsulinemia, que é a principal causa de hipoglicemia persistente e recorrente nessa fase da vida (1,5,6).Essa situação clínica é marcada pelo aumento da utilização da glicose pelos tecidos sensíveis às ações da insulina, ao mesmo tempo que o aumento da concentração de insulina inibe a produção endógena de glicose, bloqueando a glicólise e a neoglicogênese. Em decorrência desse bloqueio, não ocorre produção de corpos cetônicos, substrato energético alternativo para o tecido cerebral (6).A queda acentuada dos níveis glicêmicos e a falta de produção de corpos cetônicos são as causas dos danos cerebrais frequentemente associados a essa condição clí-nica. O cérebro em desenvolvimento ávido por combustível não tem como utilizar nenhuma fonte energética. Assim, essa situação clínica se transforma em uma das emergências do período neonatal.A identificação precoce e a correta abordagem da hipoglicemia hiperinsulinêmica (HH) são, dessa forma, de extrema importância para reduzir a morbi-mortalidade dessa patologia. ETIOLOGIASVárias são as causas da HH. Essas podem ser congênitas, secundárias, associadas a síndromes genéticas ou associadas a doenças metabólicas (1,3,6).

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Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations

Cited by 151 publications

References 27 publications

An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism

An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

Hipoglicemia hiperinsulinêmica da infância

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