Overexpression of a glucokinase point mutant in the treatment of diabetes mellitus.

Glucokinase (GCK) is an important enzyme critical for glucose metabolism, and has been targeted as such in the pursuit of a cure for diabetes mellitus. We show that streptozotocin (STZ)-induced diabetic murine model exhibits low GCK expression with high blood glucose levels; moreover, aggravated glomerulonephritis is observed in the model when there is IL10 deficiency. Although T cells infiltrate into the liver and pancreas in STZ-induced diabetes mice, T helper 1 (Th1) and T helper 17 (Th17) cells decrease significantly with STZ addition in in vitro polarization. Using a mutant GCK gene (GCK 262) with a knocked out cytosine at position 2643 results in lower protein expression and more ubiquitination-led protein degradation compared with wild-type GCK (GCK 261). We further observed that hsa-mir-1302 can bind to 3'-untranslated region of mutant GCK, which can decrease GCK mRNA translation. Finally, delivery of mutant GCK by subcutaneous injection is more effective at decreasing blood glucose in the STZ-treated (STZ) murine diabetes model than insulin treatment alone. Similarly, mutant GCK consistently and moderately decreases blood glucose levels in GK rats over a period of 12 and 70 days without inducing hypoglycemia, whereas insulin is only effective over 12 h. These results suggest that mutant GCK may be a future cure for diabetes.

[New pharmacological treatment methods of type 2 diabetes]. / Nye farmakologiske behandlingsmodaliteter ved type 2-diabetes.

The variable pathogenesis and progressive nature of type 2 diabetes emphasise the need for new antidiabetic treatments. The long acting glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors have improved the treatment. Novel approaches include inhibitors of sodium glucose co-transporter 2, which increase renal glucose elimination, G-protein-coupled receptor agonists, which potentiate insulin and incretin hormone secretion. Proof of principle has been shown for glucagon receptor agonists, glucokinase activators and treatment with dual intestinal peptides, which all induce weight loss and improve glucose tolerance.

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)

Ethanol withdrawal and proclivity are inversely related in rats selectively bred for differential saccharin intake.

Withdrawal severity and voluntary alcohol consumption are inversely related in rats and mice. The present study demonstrated this empirical relation and extended it in two ways. First, the rats were selectively bred for low (LoS) and high (HiS) saccharin intake, a phenotype that correlates positively with ethanol intake and inversely with emotional reactivity. Withdrawal has not yet been studied in these rats. Second, proclivity to consume ethanol was measured as conditioned preference for an ethanol-paired flavor. After 2 weeks of forced exposure to ethanol and a period of abstinence, LoS rats showed elevated acoustic startle; HiS rats did not (Exp. 1). When ethanol- and no-ethanol solutions were available freely during conditioning, both LoS and HiS rats preferred a flavor paired with 4% ethanol, but only HiS rats preferred a flavor paired with 10% ethanol (Exp. 2A); when exposure to the two solutions was controlled, all groups except LoS males preferred flavors paired with 4% or 10% ethanol (Exp. 2B). Thus, as predicted, withdrawal was more severe in the line with less ethanol proclivity (LoS). These results implicate basic associative and affective processes in individual differences in patterns of alcohol use.