Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. (Funded by the British Heart Foundation and others; ASCEND Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. This substance, [R-(R*,S*)]-5-chloro-N-[3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC 50 of 0.13 M in the presence of 7.5 mM glucose. CP-91149 resembles caffeine, a known allosteric phosphorylase inhibitor, in that it is 5-to 10-fold less potent in the absence of glucose. Further analysis, however, suggests that CP-91149 and caffeine are kinetically distinct. Functionally, CP-91149 inhibited glucagon-stimulated glycogenolysis in isolated rat hepatocytes (P < 0.05 at 10-100 M) and in primary human hepatocytes (2.1 M IC 50 ). In vivo, oral administration of CP-91149 to diabetic ob͞ob mice at 25-50 mg͞kg resulted in rapid (3 h) glucose lowering by 100-120 mg͞dl (P < 0.001) without producing hypoglycemia. Further, CP-91149 treatment did not lower glucose levels in normoglycemic, nondiabetic mice. In ob͞ob mice pretreated with 14 C-glucose to label liver glycogen, CP-91149 administration reduced 14 C-glycogen breakdown, confirming that glucose lowering resulted from inhibition of glycogenolysis in vivo. These findings support the use of CP-91149 in investigating glycogenolytic versus gluconeogenic f lux in hepatic glucose production, and they demonstrate that glycogenolysis inhibitors may be useful in the treatment of type 2 diabetes.

Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. (Funded by the British Heart Foundation and others; Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

We have identified the binding site of a new class of allosteric HLGP inhibitors. The crystal structure revealed the details of inhibitor binding, led to the design of a new class of compounds, and should accelerate efforts to develop therapeutically relevant molecules for the treatment of diabetes.

To examine the physiological role of the GLUT4/muscle-fat specific facilitative glucose transporter in regulating glucose homeostasis, we have generated transgenic mice expressing high levels of this protein in an appropriate tissue-specific manner. Examination of two independent founder lines demonstrated that high-level expression of GLUT4 protein resulted in a marked reduction of fasting glucose levels (=70 mg/dl) compared to wild-type mice ("'130 mg/dl). Surprisingly, 30 min following an oral glucose challenge the GLUT4 transgenic mice had only a slight elevation in plasma glucose levels (Q"90 mg/dl), whereas wild-type mice displayed a typical 2-to 3-fold increase (==250-300 mg/dl). In parallel to the changes in plasma glucose, insulin levels were --2-fold lower in the transgenic mice compared to the wild-type mice. Furthermore, isolated adipocytes from the GLUT4 transgenic mice had increased basal glucose uptake and subcellular fractionation indicated elevated levels of cell surface-associated GLUT4 protein. Consistent with these results, in situ immunocytochemical localization of GLUT4 protein in adipocytes and cardiac myocytes indicated a marked increase in plasma membrane-associated GLUT4 protein in the basal state. Taken together these data demonstrate that increased expression of the human GLUT4 gene in vivo results in a constitutively high level of cell surface GLUT4 protein expression and more efficient metabolic control over fluctuations in plasma glucose concentrations.The GLUT4/muscle-fat glucose transporter is one member of the facilitative glucose transporter super-gene family that is specifically expressed in muscle and adipose tissues (1, 2). In contrast to the other glucose transporter isoforms, GLUT4 contains specific amino acid targeting sequences (3-5) responsible for its localization to unique intracellular vesicular compartments found in adipocytes and muscle cells (6)(7)(8)(9)(10)(11). In response to acute insulin stimulation, these preformed GLUT4-containing vesicles rapidly translocate to the plasma membrane in a GTP-dependent process, resulting in a large increase in plasma membrane-associated GLUT4 protein (9-17).In contrast to this acute pathway of insulin action, catabolic states such as fasting and non-insulin-dependent diabetes are directly associated with a marked resistance of adipose and muscle tissue to insulin-stimulated glucose uptake (18)(19)(20). Recently, several studies have suggested that a decrease in GLUT4 expression may be the initial cause of insulin resistance in adipose tissue, which contributes to the maintenance ofinsulin resistance in muscle (21)(22)(23)(24)(25)(26)(27)(28)(29). Since the pathophysiological mechanisms responsible for insulin resistance are poorly understood, we have recently generated transgenic mice expressing high levels of the human GLUT4The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indi...