Single administration of recombinant IL-6 restores the gene expression of lipogenic enzymes in liver of fasting IL-6-deficient mice.

BACKGROUND AND PURPOSE: Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL-6 in mediating fasting/re-feeding changes in the expression of hepatic lipogenic enzymes. EXPERIMENTAL APPROACH: Gene and protein expression of lipogenic enzymes were examined in livers of wild-type (WT) and IL-6-deficient (IL-6(-/-) ) mice during fasting and re-feeding conditions. Effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated by using siRNA in human HepG2 cells. KEY RESULTS: During feeding, the up-regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL-6(-/-) mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL-6(-/-) mice. Protein levels of hepatic lipogenic enzymes were lower in IL-6(-/-) than in WT mice at the end of the fasting period. In WT, circulating IL-6 levels paralleled gene expression of hepatic lipogenic enzymes. IL-6 administration in vivo and in vitro showed that IL-6-mediated signalling was associated with the up-regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL-6 mediated up-regulation of lipogenic gene transcription levels. CONCLUSIONS AND IMPLICATIONS: IL-6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3-associated signalling cytokines, particularly against steatosis, should be undertaken with caution.

Patterns of insulin resistance in the general population of southeast Spain.

The aim of this study was to evaluate patterns of insulin resistance in the general population. The study was cross sectional. Clinical, anthropometric, and lipid measurements were made in 1226 persons aged 18-65 years. An oral glucose tolerance test (OGTT) was performed in 1020 subjects, with insulin levels determined at baseline and after 2 h. The homeostasis model assessment insulin resistance index (HOMA IR) and HOMA beta-cell function were calculated. Compared with subjects with normal glucose tolerance, the groups with abnormal OGTT had different baseline insulinemia, 2 h post OGTT insulinemia, HOMA IR and HOMA beta-cell indices. Serum insulin levels at baseline and 2 h after OGTT showed a characteristic pattern for each category of glucose tolerance, resulting from the different insulin responses. In the subjects with normal glucose tolerance, the pattern of the relationships between both types of serum insulin levels was exactly the same, so that it was possible to determine risk groups according to the ratio of baseline serum insulin/2 h insulin. HOMA IR and HOMA beta-cell were significantly associated with the risk of impaired fasting glucose, previously unknown diabetes mellitus, and known diabetes mellitus. These results support the rationale for introducing preventive measures against insulin resistance in the general population.

Defectos genéticos de la glucocinasa y alteraciones del metabolismo hidrocarbonado / Defects in the glucokinase gene and alterations in carbohydrate metabolism

La glucocinasa es una enzima fosforilante que controla la entrada de glucosa a la ruta glucolítica catalizando la transferencia de un fosfato desde el adenosintrifosfato a la glucosa, para dar lugar a la glucosa-6-fosfato en la primera y limitante reacción de la glucólisis. Debido a sus características cinéticas y funcionales, se considera el sensor de la glucosa sanguínea en los tejidos donde se expresa. En la célula ß pancreática gobierna la secreción de insulina estimulada por la glucosa; en la célula * pancreática está implicada en la secreción de glucagón, y en el hepatocito es de gran importancia en la capacidad de almacenamiento de glucógeno. El papel que desempeña la glucocinasa en el mantenimiento de la homeostasis de la glucosa es de tal importancia que mutaciones en el gen que codifica por la enzima glucocinasa van a dar lugar a cuadros patológicos, que abarcan desde diabetes mellitus neonatal permanente de carácter grave y con necesidad de tratamiento insulínico desde el primer día de vida, hasta hipoglucemia hiperinsulinémica familiar de carácter muy grave y refractaria a tratamiento quirúrgico. No obstante, la forma más común de presentación de la patología de la glucocinasa es como diabetes monogénica MODY (maturity onset diabetes of the young) 2, de carácter leve. La reciente descripción de un activador alostérico de la glucocinasa demuestra que esta enzima puede ser una diana adecuada para compuestos que actúen sobre ella y sobre su funcionalidad para el tratamiento de la diabetes (AU)

Glucokinase is a phosphorylating enzyme that controls the entry of glucose to the glycolytic pathway by catalyzing the transfer of a phosphate group from ATP to glucose to produce glucose-6-phosphate in the first and limiting reaction of glycolysis. Because of its kinetic and functional characteristics, glucokinase is considered as a blood glucose sensor in the tissues in which it is expressed. In pancreatic b cells it governs insulin secretion stimulated by glucose, in pancreatic a cells it is involved in glucagon secretion and in hepatocytes it is highly important in glycogen storage capacity. Because of the importance of glucokinase in maintaining glucose homeostasis, mutations in the gene coding for the glucokinase enzyme give rise to diseases that range from permanent severe neonatal diabetes mellitus requiring insulin treatment from the first day of life to severe familial hyperinsulinemic hypoglycemia refractory to surgical treatment. Nevertheless, the most common form of presentation of glucokinase defects is mild monogenic diabetes (MODY 2). The recent description of an allosteric glucokinase activator demonstrates that this enzyme could be a suitable target for compounds that act on it and on its functionality in the treatment of diabetes (AU)