The crystal structure of guanylate kinase (GK) from yeast (Saccharomyces cerevisiae) with a non-acetylated N terminus has been determined in its unligated form (apo-GK) as well as in complex with GMP (GK.GMP). The structure of apo-GK was solved with multiwavelength anomalous diffraction data and refined to an R-factor of 0.164 (R(free)=0.199) at 2.3 A resolution. The structure of GK.GMP was det...

Glucokinase (GK) has a major role in the control of blood glucose homeostasis and is a strong potential target for the pharmacological treatment of type 2 diabetes. We report here the mechanism of action of two novel and potent direct activators of GK: 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]nicotinic acid(GKA1) and 5-([3-isopropoxy-5-[2-(3-thienyl)ethoxy]benzoyl]amino)-1,3,4-thiadiazole-2-ca...

H. Brezis and L. Nirenberg proved that if (gk) ⊂ C(S , S ) and g ∈ C(S , S ) (N ≥ 1) are such that gk → g in BMO(S ), then deg gk → deg g. On the other hand, if g ∈ C(S , S ), then Kronecker’s formula asserts that deg g = 1 |SN | ∫ SN det(∇g) dσ. Consequently, ∫ SN det(∇gk) dσ converges to ∫ SN det(∇g) dσ provided gk → g in BMO(S N ). In the same spirit, we consider the quantity J(g, ψ) := ∫ SN...

Glucokinase (GK), the hexokinase involved in glucose sensing in pancreatic β cells, is also expressed in hypothalamic tanycytes, which cover the ventricular walls of the basal hypothalamus and are implicated in an indirect control of neuronal activity by glucose. Previously, we demonstrated that GK was preferentially localized in tanycyte nuclei in euglycemic rats, which has been reported in he...

The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) was recently identified as a new intracellular binding partner for glucokinase (GK). Therefore, we studied the importance of this interaction for the activity status of GK and glucose metabolism in insulin-producing cells by overexpression of the rat liver and pancreatic islet isoforms of PFK-2/FBPase-...

Type 2 diabetes mellitus (T2DM) arises owing to insulin resistance and β-cell dysfunction. Chronic inflammation is widely identified as a cause of T2DM. The Goto-Kakizaki (GK) rat is a spontaneous rodent model for T2DM with chronic inflammation. The purpose of this study was to characterize diabetes progression in GK rats and evaluate the potential role of the anti-inflammatory agent salsalate....

OBJECTIVE The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use glucokinase (GK) as the rate-limiting step in glucose's regulation of neuronal activity. Since conditions associated with increased VMH GK expression are associated with a blunted counterregulatory respons...

Influences of genetic and nutritional factors on body weight, fat mass, and leptin production and effects of leptin were assessed in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats by mechanism-based modeling. The study included 60 WKY and 60 GK rats; half received high-fat diet (HF), and the others received normal rat chow (N). Body weights and food consumption were measured...

BACKGROUND Although cardiac autonomic neuropathy is one of major complications of diabetes mellitus (DM), anatomical data on cardiac innervation of diabetic animal models is scant and controversial. We performed this study to check whether long-term diabetic state impacts the anatomy of intracardiac ganglia in Goto-Kakizaki (GK) rats, a genetic model of type 2 DM. METHODS Twelve GK rats (276 ...