Glucokinase activity in diabetes: too much of a good thing?

Type 2 diabetes (T2D) is a global health problem characterised by chronic hyperglycaemia due to inadequate insulin secretion. Because glucose must be metabolised to stimulate insulin release it was initially argued that drugs that stimulate glucokinase (the first enzyme in glucose metabolism) would enhance insulin secretion in diabetes. However, in the long term, glucokinase activators have been largely disappointing. Recent studies show it is hyperactivation of glucose metabolism, not glucose itself, that underlies the progressive decline in beta-cell function in diabetes. This perspective discusses if glucokinase activators exacerbate this decline (by promoting glucose metabolism) and, counterintuitively, if glucokinase inhibitors might be a better therapeutic strategy for preserving beta-cell function in T2D.

The effect of insulin-loaded gold and carboxymethyl chitosan nanoparticles on gene expression of glucokinase and pyruvate kinase in rats with diabetes type 1.

The goal of this study was to see how effective subcutaneous (SC) insulin is and two different types of oral insulin-loaded nanoparticles (INS) including carboxymethyl chitosan nanoparticles (CMCNPs) and gold nanoparticles (AuNPs) separately and compare their effects on glucokinase, pyruvate kinase gene expressions, and other parameters in diabetes type one male Wistar rats. Seven groups of ten male Wistar rats for each group were formed at random including four control groups (n = 10) and three treatment groups (n = 10). The control groups consisted of four control groups (10 rats for each) and three treatment groups (10 rats for each). Normal control rats were not given any treatment, as were diabetic rats that were not given any treatment, and diabetic rats that were given oral nanoparticles (CMCNPs and AuNPs). Diabetic rats were given subcutaneous insulin, oral insulin-loaded carboxymethyl chitosan nanoparticles (INS-CMCNPs), and oral insulin-loaded gold nanoparticles (INS-AuNPs). The rats were treated for the final 3 weeks of the experiment, which lasted 4 weeks. CMCNPs and AuNPs presented a promising effect on pyruvate kinase and Glucokinase gene expressions compared to subcutaneous insulin. We also discovered that conjugating insulin to CMCNPs and AuNPs protects them from the insulin-degrading enzyme, which offers managed bioavailability. Furthermore, we investigated the effects of CMCNPs and AuNPs on several parameters and discovered that both have a significant effect in vivo, which enables glucose level regulation, and improves patient organ activity for better glucose consumption. PRACTICAL APPLICATIONS: In this paper, we discussed the effect of oral INS-CMCNPs and INS-AuNPs, and compared their effects on Glucokinase and pyruvate kinase gene expressions and other biochemical parameters in diabetes type one male Wistar rats. On the other hand, we investigated the impact of oral INS and subcutaneous insulin separately on the same parameters and their effect on the histology of the liver and pancreas of diabetic rats. According to our research, as we discussed the different mechanisms of INS-CMCNPs and INS-AuNPs, they presented a promising effect compared to SC insulin. They can be used to keep oral insulin safe from the environment of the gastrointestinal system to overcome all the barriers, improve the therapeutic, and clinical outcomes of insulin by maintaining its desired concentration inside the body, ending the panic of the patient from receiving insulin by the SC injection by increasing his satisfaction with receiving accurate oral insulin doses.

Discovery of antichagasic inhibitors by high-throughput screening with Trypanosoma cruzi glucokinase.

A high-throughput screening (HTS) campaign was carried out for Trypanosoma cruzi glucokinase (TcGlcK), a potential drug-target of the pathogenic protozoan parasite. Glycolysis and the pentose phosphate pathway (PPP) are important metabolic pathways for T. cruzi and the inhibition of the glucose kinases (i.e. glucokinase and hexokinase) may be a strategic approach for drug discovery. Glucose kinases phosphorylate d-glucose with co-substrate ATP to yield G6P, and moreover, the produced G6P enters both pathways for catabolism. The TcGlcK - HTS campaign revealed 25 novel enzyme inhibitors that were distributed in nine chemical classes and were discovered from a primary screen of 13,040 compounds. Thirteen of these compounds were found to have low micromolar IC50 enzyme - inhibition values; strikingly, four of those compounds exhibited low toxicity towards NIH-3T3 murine host cells and notable in vitro trypanocidal activity. These compounds were of three chemical classes: (a) the 3-nitro-2-phenyl-2H-chromene scaffold, (b) the N-phenyl-benzenesulfonamide scaffold, and (c) the gossypol scaffold. Two compounds from the 3-nitro-2-phenyl-2H-chromene scaffold were determined to be hit-to-lead candidates that can proceed further down the early-stage drug discovery process.

Hiperglucemia en ayunas y polimorfismo en el promotor de la glucoquinasa (rs1799884) / Fasting hyperglycaemia and polymorphism in glucokinase promoter (rs1799884)

La glucoquinasa es uno de los principales reguladores de la glucemia plasmática en ayunas. Numerosas mutaciones en el gen de la glucoquinasa (GCK) se han identificado como base molecular de la diabetes monogénica. Recientemente se han descrito polimorfismos en su promotor que se asocian a incrementos en la glucemia plasmática en ayunas. Se presenta a un niño de 7 años y 7 meses con sobrepeso y antecedentes de diabetes en dos generaciones previas. En la sobrecarga oral de glucosa presentó alteración de la glucemia en ayunas y a las 2h, con respuesta de insulina elevada. Las alteraciones analíticas mejoraron tras pérdida ponderal manteniendo una discreta hiperglucemia en ayunas. El estudio de las diabetes monogénicas más frecuentes, MODY subtipos 1, 2 y 3, fue negativo, encontrándose la variante alélica (G/A) en el polimorfismo rs1799884, localizado en el promotor de GCK (AU)

Glucokinase is one of the most important regulators of fasting glucose levels. There are several mutations in the glucokinase gene (GCK) which are linked with monogenic diabetes. Recently, a polymorphism in its promoter has been described, which is associated with impaired fasting glucose levels. We present a 7 years and 7 months old boy with overweight and a familial background of diabetes in two previous generations. In the oral glucose tolerance test, he had impaired fasting glucose levels and after two hours, with a high insulin response. Laboratory abnormalities improved after weight loss, but he maintains a slight fasting hyperglycaemia. The molecular study of the most common monogenic diabetes forms, MODY subtypes 1, 2, and 3, was negative. The allelic variant G/A was however detected at the GCK promoter polymorphism rs1799884 (AU)

La contribución de la diabetes tipo MODY a nuestros conocimientos sobre los mecanismos moleculares que intervienen en la diabetes tipo 2 / The contribution of MODY diabetes to our understanding of molecular mechanisms involved in type 2 diabetes

Naturity onset diabetes of the young (MODY) es una forma autosómica dominante de diabetes resultante de mutaciones de los genes de las células beta pancreáticas. En cambio, la diabetes tipo 2 (DT2) es una enfermedad multifactorial de comienzo tardío en la que los factores ambientales y los genéticos son importantes en su desarrollo, y la disfunción de las células beta y la resistencia a la insulina lo son en su fisiopatología. Aunque son escasas las similitudes fenotípicas existentes entre MODY y DT2, en ambas existe disfunción de las células beta, y en estudios recientes se ha demostrado que variantes comunes de los genes MODY, son excelentes genes candidatos para la susceptibilidad a la DT2. Se revisan las pruebas acerca de las variantes comunes de los genes MODY que predisponen a la DT2. De entre los genes MODY que se han analizado a fondo, existen pruebas convincentes de que las variantes de HNF1α, HNF4α, IPF1 y glucocinasa predisponen a la DT2 o influyen sobre un rasgo afín a la diabetes. Se concluye que los genes MODY son unos excelentes genes candidatos para la diabetes tipo 2, y que es necesario investigar con profundidad los genes MODY en la DT2 (AU)

Maturity onset diabetes of the young (MODY) is a young-onset, autosomal dominant form of diabetes, resulting from mutations in pancreatic beta-cell genes. In contrast, type 2 diabetes (T2D) is a late-onset, multi-factorial disease, with both environmental and genetic factors important in its development and both beta-cell dysfunction and insulin resistance important in its pathophysiology. Although there is limited phenotypic similarity between MODY and T2D, both show beta-cell dysfunction, and recent studies have demonstrated that common variation in MODY genes are excellent T2D susceptibility candidate genes. Here we review the evidence for common variants of MODY genes predisposing to T2D. Of the MODY genes that have been extensively analysed, there is convincing evidence that variants of HNF1α, HNF4α, IPF1 and glucokinase predispose to T2D or affect a diabetes related trait. We conclude that MODY genes are excellent candidate genes for Type 2 diabetes and further comprehensive analysis of the MODY genes in T2D is required (AU)

Exploración clínica, funcional y molecular de la diabetes tipo MODY en la práctica clínica / Clinical, functional and molecular investigation of MODY diabetes in clinical practice

La diabetes tipo MODY (maturity onset diabetes of the young) es una enfermedad monogénica para la cual se han descrito 6 genes responsables. Esta heterogeneidad genética se traduce en importantes diferencias clínicas y fisiológicas que condicionan su presentación, evolución y tratamiento. Estas características se han podido poner de manifiesto en los 2 tipos de MODY más prevalentes: MODY 2 y MODY 3. Los pacientes con mutaciones en el gen de la glucocinasa tienen una hiperglucemia que se mantiene estable durante mucho tiempo, no suelen necesitar tratamiento especial y no presentan complicaciones. Por el contrario, las mutaciones en el gen del factor nuclear hepático 1α comportan un deterioro progresivo de la secreción de la célula β pancreática, con el consiguiente incremento de la glucemia plasmática. A partir de estos datos y atendiendo a la complejidad del estudio genético, en este capítulo se revisan los estudios bioquímicos y funcionales que pueden aportar datos previos y orientar el estudio molecular (AU)

MODY diabetes is a monogenic disease. Six genes have been found to cause this entity. This genetic heterogeneity translates into significant clinical and physiological differences that affect its presentation, outcome and treatment. These characteristics have been revealed in the two most prevalent forms of MODY: MODY 2 and MODY 3. Patients with mutations in the glucokinase gene show hyperglycemia that remains stable over long periods, do not usually require specific treatment and do not develop complications. In contrast, mutations in hepatic nuclear factor (HNF)-1α produce progressive deterioration in pancreatic β cell secretion with a consequent increase in plasma glycemia. Based on these data and bearing in mind the complexity of genetic study, the present article reviews the biochemical and functional studies that provide previous data and guide molecular study (AU)

Diabetes mellitus en la edad pediátrica: diabetes tipo 1, diabetes tipo 2 y MODY / Diabetes mellitus in the pediatric age group: type 1 diabetes, type 2 diabetes and MODY

La diabetes mellitus es una de las patologías crónicas más frecuentes de la edad pediátrica. Se caracteriza por la existencia de hiperglucemia en ayunas y postingesta, y es secundaria a una deficiente secreción o acción de la insulina. La diabetes no es una enfermedad única, sino que engloba a un grupo heterogéneo de alteraciones con distinto patrón genético, así como diversas causas etiológicas y mecanismos fisiopatológicos. En la infancia predomina la diabetes tipo 1, autoinmune, ligada al complejo principal de histocompatibilidad, con poca carga familiar, de comienzo agudo y predominio en la pubertad, aunque su incidencia se ha incrementado por debajo de los 5 años. El diagnóstico se basa en la presencia de marcadores de autoinmunidad e insulinopenia. La diabetes tipo 2, cuya presencia va aumentando junto al incremento de la obesidad en la edad pediátrica, se da sobre todo en ciertas etnias, en la pubertad, de predominio en mujeres y en sujetos con marcadores de insulinorresistencia. Hasta el 25% se diagnostica en cetosis, presenta concentraciones normales o altas de insulina y ausencia de marcadores de inmunidad. Por último, la diabetes tipo MODY (maturity onset diabetes of the young) se caracteriza por una herencia autosómica dominante, insulinopenia, ausencia de obesidad y de marcadores tanto de insulinorresistencia como de inmunidad. En la edad pediátrica se expresa el MODY 2, que se manifiesta desde el nacimiento con hiperglucemia leve sin necesidad de tratamiento, y el MODY 3 y 1, que pueden expresarse en la pubertad y, en general, se controlan con dieta o antidiabéticos orales. Es importante un diagnóstico adecuado del tipo de diabetes, pues éste comportará diferentes actitudes terapéuticas (AU)

Diabetes mellitus is one of the most frequent chronic diseases in the pediatric age group. It is characterized by fasting and post-ingestion hyperglycemia and is secondary to impairment in insulin secretion or insulin action. Diabetes is not a single entity but includes a heterogeneous group of alterations with distinct genetic pattern, as well as different etiologies and physiopathologic mechanisms. The main form of diabetes in childhood is autoimmune, HLA-linked, type 1 diabetes, with low familial risk. Onset is usually acute and occurs mainly in puberty, although the incidence has increased in children aged less than 5 years. Diagnosis is based on markers of autoimmunity and insulinopenia. Type 2 diabetes, which, together with obesity, is on the increase in the pediatric age group, occurs especially in certain ethnic groups, in puberty, mainly in women and in individuals with markers of insulin resistance. Up to 25% of patients who receive a diagnosis show ketosis, normal or high insulin levels and the absence of markers of immunity. Finally, MODY diabetes is characterized by an autosomal dominant pattern of inheritance, and the absence of obesity and of markers of insulin resistance and immunity. The MODY forms occurring in the pediatric age group are MODY 2, which manifests from birth with mild hyperglycemia not requiring treatment, and MODY 3 and 1, which can manifest in puberty and, in general, are controlled with diet or oral antidiabetic agents. Accurate diagnosis of the type of diabetes is essential since the therapeutic approach varies with each form (AU)

Adenovirus-mediated expression of glucokinase in the liver as an adjuvant treatment for type 1 diabetes.

Glucokinase (GK) plays a crucial role in hepatic glucose disposal. Its activity is decreased in patients with maturity-onset diabetes of the young and in some animal models of diabetes. We investigated the feasibility of manipulating GK expression as an adjuvant treatment for type 1 diabetes, using an E1/E3-deleted adenoviral vector (Ad.EF1(alpha)GK) delivered to the liver of streptozotocin-induced type 1 diabetic rats. First, we studied the metabolic impact of constitutive glucokinase expression in the absence of insulin. Normal blood glucose levels were observed after gene transfer, and glucose tolerance was substantially enhanced compared with diabetic control animals, suggesting that hepatic GK expression is a feasible mechanism to enhance glucose disposal. In a second study we administered Ad.EF1(alpha)GK together with subcutaneous insulin injections to determine whether the combined action of insulin plus GK activity would provide better glucose homeostasis than insulin treatment alone. This combination approach resulted in constant, near-normal glucose values under fed conditions. Furthermore, the animals stayed in the normoglycemic range after an overnight fast, indicating that the risk to develop hypoglycemia is not increased by expression of GK. Alterations of other metabolic routes were observed, suggesting that insulin-regulated expression of GK may be necessary to use the strategy as a treatment of type 1 diabetes.