Prevention of fat-induced insulin resistance by salicylate.

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may involve fat-induced activation of a serine kinase cascade involving IKK-beta. To test this hypothesis, we first examined insulin action and signaling in awake rats during hyperinsulinemic-euglycemic clamps after a lipid infusion with or without pretreatment with salicylate, a known inhibitor of IKK-beta. Whole-body glucose uptake and metabolism were estimated using [3-(3)H]glucose infusion, and glucose uptake in individual tissues was estimated using [1-(14)C]2-deoxyglucose injection during the clamp. Here we show that lipid infusion decreased insulin-stimulated glucose uptake and activation of IRS-1-associated PI 3-kinase in skeletal muscle but that salicylate pretreatment prevented these lipid-induced effects. To examine the mechanism of salicylate action, we studied the effects of lipid infusion on insulin action and signaling during the clamp in awake mice lacking IKK-beta. Unlike the response in wild-type mice, IKK-beta knockout mice did not exhibit altered skeletal muscle insulin signaling and action following lipid infusion. In summary, high-dose salicylate and inactivation of IKK-beta prevent fat-induced insulin resistance in skeletal muscle by blocking fat-induced defects in insulin signaling and action and represent a potentially novel class of therapeutic agents for type 2 diabetes.

Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4.

Using cre/loxP gene targeting, transgenic mice with muscle-specific inactivation of the GLUT4 gene (muscle GLUT4 KO) were generated and shown to develop a diabetes phenotype. To determine the mechanism, we examined insulin-stimulated glucose uptake and metabolism during hyperinsulinemic-euglycemic clamp in control and muscle GLUT4 KO mice before and after development of diabetes. Insulin-stimulated whole body glucose uptake was decreased by 55% in muscle GLUT4 KO mice, an effect that could be attributed to a 92% decrease in insulin-stimulated muscle glucose uptake. Surprisingly, insulin's ability to stimulate adipose tissue glucose uptake and suppress hepatic glucose production was significantly impaired in muscle GLUT4 KO mice. To address whether these latter changes were caused by glucose toxicity, we treated muscle GLUT4 KO mice with phloridzin to prevent hyperglycemia and found that insulin-stimulated whole body and skeletal muscle glucose uptake were decreased substantially, whereas insulin-stimulated glucose uptake in adipose tissue and suppression of hepatic glucose production were normal after phloridzin treatment. In conclusion, these findings demonstrate that a primary defect in muscle glucose transport can lead to secondary defects in insulin action in adipose tissue and liver due to glucose toxicity. These secondary defects contribute to insulin resistance and to the development of diabetes.

Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.

Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle-lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e., diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones.

A simple institutional educational intervention to decrease use of selected expensive medications.

OBJECTIVE: To determine whether a simple educational intervention can influence use of prescription medications at an institution. DESIGN: Cost-effectiveness analysis of prescribing behavior before and after an educational intervention. SETTING: A large, urban, free-standing academic rehabilitation hospital. PARTICIPANTS: Physicians, residents, and physician extenders. INTERVENTIONS: The hospital's pharmacy department provided simple written educational material about cost differences of various prescription medications to attending and resident physicians, nurse leaders, and case managers. Telephoned reminders were given when targeted medications were prescribed. MAIN OUTCOME MEASURES: Total prescription medication use was recorded monthly for 12 months before and after the intervention. Pharmaceuticals monitored were subcutaneously administered anticoagulants, histamine type 2 (H2) blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs). RESULTS: A 32% decrease in use of the more costly anticoagulant and a 20% increase in use of the less costly anticoagulant (p <.0001), representing an estimated annual savings of nearly $66,000. Use of more costly H2 antagonist decreased 50% and use of less costly H2 antagonist increased 128% (p <.0001). With written intervention only, use of more costly NSAIDs declined 28%, whereas use of less costly NSAIDs increased 58% (p <.0020). CONCLUSION: Providing physicians with simple pharmaceutical cost information and telephone reminders decreased the use of targeted more costly medications.

Chronic repeated cocaine administration increases dopamine D1 receptor-mediated signal transduction.

Alteration in dopamine D1 receptor-mediated signal transduction following repeated cocaine administration was investigated. Male Fischer rats were administered saline or cocaine HC1 (15 mg/kg, i.p.) three times daily at 1-h intervals for 1, 7, or 14 days. Stimulation of adenylyl cyclase activity by dopamine and the selective dopamine D1 receptor agonist, (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2, 3,4,5-tetra-hydro-1 H-3-benzazepine hydrobromide (SKF 82958), was significantly greater in the nucleus accumbens and caudate putamen of animals injected with cocaine for 14 days compared with control animals, but was unchanged in animals administered cocaine for 1 or 7 days. These results suggest that dopamine D1 receptor signal transduction in the nucleus accumbens and caudate putamen is enhanced following chronic repeated administration of cocaine.

Finance and marketing: birth of a profitable relationship.

As competition increases, the finance and marketing departments must work together to increase market share and improve the bottom line. If financial managers understand the functions of the marketing department, they can create a mutually beneficial and profitable relationship.