XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

MicroRNAs (miRNAs) circulate in the bloodstream in a highly stable, extracellular form and are being developed as blood-based biomarkers for cancer and other diseases. However, the mechanism underlying their remarkable stability in the RNase-rich environment of blood is not well understood. The current model in the literature posits that circulating miRNAs are protected by encapsulation in membrane-bound vesicles such as exosomes, but this has not been systematically studied. We used differential centrifugation and size-exclusion chromatography as orthogonal approaches to characterize circulating miRNA complexes in human plasma and serum. We found, surprisingly, that the majority of circulating miRNAs cofractionated with protein complexes rather than with vesicles. miRNAs were also sensitive to protease treatment of plasma, indicating that protein complexes protect circulating miRNAs from plasma RNases. Further characterization revealed that Argonaute2 (Ago2), the key effector protein of miRNA-mediated silencing, was present in human plasma and eluted with plasma miRNAs in size-exclusion chromatography. Furthermore, immunoprecipitation of Ago2 from plasma readily recovered non–vesicle-associated plasma miRNAs. The majority of miRNAs studied copurified with the Ago2 ribonucleoprotein complex, but a minority of specific miRNAs associated predominantly with vesicles. Our results reveal two populations of circulating miRNAs and suggest that circulating Ago2 complexes are a mechanism responsible for the stability of plasma miRNAs. Our study has important implications for the development of biomarker approaches based on capture and analysis of circulating miRNAs. In addition, identification of extracellular Ago2–miRNA complexes in plasma raises the possibility that cells release a functional miRNA-induced silencing complex into the circulation.

https://www.pnas.org/content/pnas/108/12/5003.full.pdf

Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. The majority of miRNAs are transcribed from DNA sequences into primary miRNAs and processed into precursor miRNAs, and finally mature miRNAs. In most cases, miRNAs interact with the 3' untranslated region (3' UTR) of target mRNAs to induce mRNA degradation and translational repression. However, interaction of miRNAs with other regions, including the 5' UTR, coding sequence, and gene promoters, have also been reported. Under certain conditions, miRNAs can also activate translation or regulate transcription. The interaction of miRNAs with their target genes is dynamic and dependent on many factors, such as subcellular location of miRNAs, the abundancy of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. miRNAs can be secreted into extracellular fluids and transported to target cells via vesicles, such as exosomes, or by binding to proteins, including Argonautes. Extracellular miRNAs function as chemical messengers to mediate cell-cell communication. In this review, we provide an update on canonical and non-canonical miRNA biogenesis pathways and various mechanisms underlying miRNA-mediated gene regulations. We also summarize the current knowledge of the dynamics of miRNA action and of the secretion, transfer, and uptake of extracellular miRNAs.

/pdf/overview-of-microrna-biogenesis-mechanisms-of-actions-and-2lluskbdwf.pdf

Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation.

Serum fetuin-A is correlated with metabolic syndrome in middle-aged and elderly Chinese.

Ubiquitin-specific protease 14 (USP14) is one of the major proteasome-associated deubiquitinating enzymes critical for proteome homeostasis. However, substrates of USP14 remain largely unknown, hindering the understanding of its functional roles. Here we conduct a comprehensive proteome, ubiquitinome and interactome analysis for USP14 substrate screening. Bioinformatics analysis reveals broad new potential roles of USP14, especially in lipid and carbohydrate metabolism. Among the potential substrates identified, we show that fatty acid synthase (FASN), a key enzyme involved in hepatic lipogenesis, is a bona fide substrate of USP14. USP14 directly interacts with and increases FASN stability. As a result, overexpression of USP14 promotes liver triglyceride accumulation in C57BL/6 mice, whereas genetic ablation or pharmacological inhibition of USP14 ameliorates hepatosteatosis, hyperglycemia and insulin resistance in obese mice. In conclusion, our findings reveal for the first time an indispensable role of USP14 in hepatosteatosis through FASN stabilization.

/pdf/proteome-wide-analysis-of-usp14-substrates-revealed-its-role-2kbrlibggi.pdf

Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN.

Glucagon-like peptide-1 (7–36) amide (GLP-1) is an insulin secretagogue. Recently, many studies have shown GLP-1 can improve insulin resistance in peripheral tissues. In the present study, we investigated glucose uptake in 3T3-L1 adipocytes in either basal or insulin resistant state and dissected insulin signaling pathway in order to elucidate the molecular mechanisms of GLP-1 mediated improvement of insulin resistance. We found GLP-1 and its long lasting analogue, exendin 4 up-regulated basal IR, IRS-1 and Glut 4 expressions although they did not increase basal glucose uptake alone. However, GLP-1 and exendin-4 increased insulin mediated glucose uptake in intact and TNF-α treated 3T3-L1 adipocytes by up-regulation of phophorylated IRβ, IRS-1, Akt and GSK-3β. These results indicate that GLP-1 and its analogue exendin-4 can amplify insulin signaling in 3T3-L1 adipocytes by up-regulation of some crucial insulin signaling molecules.

GLP-1 amplifies insulin signaling by up-regulation of IRβ, IRS-1 and Glut4 in 3T3-L1 adipocytes

This study is to prospectively investigate the association between serum uric acid and the incidence of type 2 diabetes in middle-aged and elderly Chinese. This study consisted of 924 non-diabetic adults aged 40 years or older at baseline. Subjects who received antidiabetic therapies and those who responded positively to the 75-g oral glucose tolerance test according to the 1999 World Health Organization criteria were diagnosed as having type 2 diabetes. Ninety-eight subjects developed type 2 diabetes during the 3.5-year follow-up. The hazard ratio (HR) for incident diabetes was 1.50 [95% confidence interval (CI) 1.18–1.92] for the highest sex-specific quartile of serum uric acid compared with the lowest after controlling for confounders. Participants with hyperuricemia had an HR of 1.95 (95% CI 1.11–3.44) for incident diabetes compared with those without hyperuricemia. Compared with the lowest quartile, the highest quartile had an HR for incident diabetes of 2.45 (95% CI 1.39–4.33) in men and 1.39 (95% CI 1.04–1.84) in women after fully adjustment. Adding serum uric acid to a model of conventional risk factors for diabetes improved the area under the curve for prediction of type 2 diabetes by 5%. Serum uric acid was an independent predictor of incident type 2 diabetes in middle-aged and elderly Chinese.

Serum uric acid associates with the incidence of type 2 diabetes in a prospective cohort of middle-aged and elderly Chinese

The objective is to evaluate the association of arterial stiffness [brachial-ankle pulse wave velocity (ba-PWV)] with glycemic control and duration of type 2 diabetes in diabetic subjects with or without hypertension. One thousand Chinese diabetic patients (562 with hypertension, 438 without hypertension) were included in this study. All patients underwent ba-PWV and biochemical measurements. Ba-PWV was significantly higher in diabetic subjects with hypertension than those without hypertension (1779 ± 341 vs. 1691 ± 342 cm/s, P 7.0%, respectively, P 10 years, respectively, P all 10 years, respectively, P = 0.0013). Ba-PWV was higher in diabetic subjects with hypertension than in diabetic subjects without hypertension, suggesting the independent effect of hypertension on arterial stiffness in diabetic subjects. Ba-PWV positively correlated with HbA1c and duration of diabetes in subjects with diabetes and hypertension, suggesting the importance of early glycemic control in the prevention of arterial stiffness and vascular complications.

Xiaoying Li

Papers

Serum fetuin-A is correlated with metabolic syndrome in middle-aged and elderly Chinese.

Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN.

GLP-1 amplifies insulin signaling by up-regulation of IRβ, IRS-1 and Glut4 in 3T3-L1 adipocytes

Serum uric acid associates with the incidence of type 2 diabetes in a prospective cohort of middle-aged and elderly Chinese

Association of arterial stiffness with HbA1c in 1,000 type 2 diabetic patients with or without hypertension