Citations

Abstract Oncogenic osteomalacia (OOM) is associated with primitive mesenchymal tumors that secrete phosphaturic factors resulting in low serum concentrations of phosphate and calcitriol, phosphaturia, and defective bone mineralization. To identify overexpressed genes in these tumors, we compared gene expression profiles of tumors resected from patients with OOM and histologically similar control tumors using serial analysis of gene expression (SAGE). Three hundred and sixty-four genes were expressed at least twofold greater in OOM tumors compared with control tumors. A subset of 67 highly expressed genes underwent validation with an extended set of OOM and control tumors using array analysis or reverse-transcription polymerase chain reaction (RT-PCR). Ten of these validated genes were consistently overexpressed in all OOM tumors relative to control tumors. Strikingly, genes with roles in bone matrix formation, mineral ion transport, and bone mineralization were highly expressed in the OOM tumors.

Abstract Transforming growth factor-β (TGF-β) stimulates cellular proliferation and transformation to a myofibroblast phenotype in vivo and in a subset of fibroblast cell lines. As the Smad pathway is activated by TGF-β in essentially all cell types, it is unlikely to be the sole mediator of cell type–specific outcomes to TGF-β stimulation. In the current study, we determined that TGF-β receptor signaling activates phosphatidylinositol 3-kinase (PI3K) in several fibroblast but not epithelial cultures independently of Smad2 and Smad3. PI3K activation occurs in the presence of dominant-negative dynamin and is required for p21-activated kinase-2 kinase activity and the increased proliferation and morphologic change induced by TGF-β in vitro.

Purpose Individuals whose diabetes is being treated in the outpatient setting via an insulin pump often wish to maintain this therapy during hospitalization. The authors propose guidelines for management of patients on insulin pumps who require a hospital admission. Methods A collaborative interinstitutional task force reviewed current available information regarding the use of insulin pumps in the hospital. Results There was little information in the medical literature on how to manage individuals on established insulin pump therapy during a hospital stay. The task force believed that a policy that promotes patient independence through continuation of insulin pump therapy while ensuring patient safety was possible. A set of contraindications for continued use of pump therapy in the hospital are proposed. A sample patient consent form and order set are presented. Finally, measures that can be used to assess effectiveness of an inpatient insulin pump policy are outlined. Conclusions Patients on established insulin pump therapy do not necessarily have to discontinue treatment while hospitalized. However, clear policies and procedures should be established at the institutional level to guide continued use of the technology in the acute care setting.

Purpose The purpose of this study was to determine whether “clinical inertia”—inadequate intensification of therapy by the provider—could contribute to high A1C levels in patients with type 2 diabetes managed in a primary care site. Methods In a prospective observational study, management was compared in the Medical Clinic, a primary care site supervised by general internal medicine faculty, and the Diabetes Clinic, a specialty site supervised by endocrinologists. These municipal hospital clinics serve a common population that is largely African American, poor, and uninsured. Results Four hundred thirty-eight African American patients in the Medical Clinic and 2157 in the Diabetes Clinic were similar in average age, diabetes duration, body mass index, and gender, but A1C averaged 8.6% in the Medical Clinic versus 7.7% in the Diabetes Clinic (P < .0001). Use of pharmacotherapy was less intensive in the Medical Clinic (less use of insulin), and when patients had elevated glucose levels during clinic visits, therapy was less than half as likely to be advanced in the Medical Clinic compared to the Diabetes Clinic (P < .0001). Intensification rates were lower in the Medical Clinic regardless of type of therapy (P < .0001), and intensification of therapy was independently associated with improvement in A1C (P < .001). Conclusions Medical Clinic patients had worse glycemic control, were less likely to be treated with insulin, and were less likely to have their therapy intensified if glucose levels were elevated. To improve diabetes management and glycemic control nationwide, physicians in training and generalists must learn to overcome clinical inertia, to intensify therapy when appropriate, and to use insulin when clinically indicated.

Purpose This study explored patients’ perceptions of barriers to diabetes education among a mostly African American population of adults with diabetes. Methods A survey was conducted among 605 new patients attending an urban outpatient diabetes clinic. The questionnaire gathered information on issues patients believed would adversely affect their ability to learn about diabetes. The type and frequency of education barriers were evaluated, and variables associated with reporting an obstacle were analyzed. Results Average patient age was 50 years, diabetes duration was 5.6 years, body mass index was 32 kg/m2, and hemoglobin A1C was 9.1%. The majority (56%) were women, 89% were African American, and 95% had type 2 diabetes. Most respondents (96%) had received some prior instruction in diabetes care; however, 53% anticipated future difficulties learning about diabetes. The most commonly cited concerns were poor vision (74%) and reading problems (29%). Patients with a perceived barrier to diabetes education were older (P < .001) than were persons without a barrier, and they differed in both employment and educational status (both P < .001). In adjusted analyses, older age, male gender, being disabled, and having an elementary education or less were associated with a significantly increased likelihood of having a barrier to diabetes education, whereas having a college education decreased the odds. Higher hemoglobin A1C levels also tended to be associated with a greater chance of reporting an education barrier (P = .05). Conclusions A substantial number of persons anticipated a barrier to diabetes education. Interventions at multiple levels that address the demographic and socioeconomic obstacles to diabetes education are needed to ensure successful self-management training.

KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo . However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.

ABSTRACT Transforming growth factor‐β (TGF‐β) is the single most important cytokine promoting renal fibrogenesis. p21‐activated kinase‐2 (PAK2) and activa‐ tion of abelson nonreceptor tyrosine kinase (c‐abl) have been shown recently to be smad‐independent, fibro‐ blast‐specific targets downstream of the activated TGF‐β receptor. In the current study we show that in cultured NRK49F‐renal fibroblasts (but not in tubular or mesangial cells) TGF‐β similarly activates PAK2 as well as c‐abl and induces cell proliferation. Inhibition of the c‐abl kinase with imatinib mesylate prevents increased proliferation after TGF‐β addition without affecting PAK2. These in vitro findings were extended to rats with unilateral obstructive nephropathy, a dis‐ ease model of TGF‐β‐driven renal fibrogenesis. In obstructed kidneys, PAK2 and c‐abl activity were in‐ creased but only c‐abl activation was blocked by ima‐ tinib. Treatment with imatinib did not prevent renal interstitial infiltration of macrophages or phosphoryla‐ tion and nuclear translocation of smad2/3 in ob‐ structed kidneys. In contrast, imatinib substantially inhibited an increase in the number of interstitial fibroblasts and myofibroblasts and reduced the expres‐ sion and interstitial accumulation of collagen type III, collagen type IV and fibronectin. These findings indi‐ cate that TGF‐β‐induced activation of the nonreceptor c‐abl tyrosine kinase regulates fibroblast proliferation and, by this means, is a costimulatory signal in TGF‐β‐ dependent renal fibrogenesis. Inhibition of c‐abl activ‐ ity with imatinib mesylate ameliorates experimental renal fibrosis in rats.—Wang, S., Wilkes, M. C., Leof, L. B., Hirschberg, R. Imatinib mesylate blocks a non‐ Smad TGF‐β pathway and reduces renal fibrogenesis in vivo. FASEB J. 19, 1‐11 (2005)