Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulinsensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P؉) versus placebo (P؊) in nine subjects with type 2 diabetes (HbA 1c , 10.9 ؎ 0.6%; BMI, 31.9 ؎ 1.5 kg/m 2 ). Total adiponectin levels increased by approximately twofold in P؉ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-3 H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P؉ ؍ 0.9 ؎ 0.1 vs. P؊ ؍ 1.7 ؎ 0.3 mg ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.05) at physiologic hyperinsulinemia (ϳ50 U/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r 2 ؍ 0.90). Maximal insulin stimulation (ϳ400 U/ml) revealed pioglitazone-associated increases in glucose uptake (P؉ ؍ 10.5 ؎ 0.9 vs. P؊ ؍ 8.9 ؎ 0.8 mg ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.
To elucidate the role cAMP-dependent protein kinase (PKA) phosphorylations on tau play in Alzheimer's disease, we have generated highly specific monoclonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphorylations of ser214 and ser409 in tau respectively. The present study demonstrates by immunohistochemical analysis, CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer's disease, but not in normal brain tissue and demonstrates that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau. Studies using heat-stable preparations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demonstrates that the  catalytic subunit of PKA (C), the  II regulatory subunit of PKA (RII), and the 79 kDa A-kinase-anchoringprotein (AKAP79), are tightly associated with the neurofibrillary pathology, positioning cAMP-dependent protein kinase to participate directly in the pathological hyperphosphorylation of tau seen in Alzheimer's disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.