Glucagon-like peptide 1 improved glycemic control in type 1 diabetes

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. METHODS: Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis. RESULTS: In 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 ± 0.9, mean ± se, vs 5.4 ± 0.8 mmol/l, p < .05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 ± 3.1 vs 37 ± 9.6 pmol/l, p < .05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 ± 2.5 vs 3.1 ± 1.9 ng/l, p < .04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 ± 0.33 vs 0.34 ± 0.26 mmol/l, p < .05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1. CONCLUSION: We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs

Evidence-Based Research Series-Paper 2 : Using an Evidence-Based Research approach before a new study is conducted to ensure value

Background and Objectives There is considerable actual and potential waste in research. The aim of this article is to describe how using an evidence-based research approach before conducting a study helps to ensure that the new study truly adds value. Study Design and Setting Evidence-based research is the use of prior research in a systematic and transparent way to inform a new study so that it is answering questions that matter in a valid, efficient, and accessible manner. In this second article of the evidence-based research series, we describe how to apply an evidence-based research approach before starting a new study. Results Before a new study is performed, researchers need to provide a solid justification for it using the available scientific knowledge as well as the perspectives of end users. The key method for both is to conduct a systematic review of earlier relevant studies. Conclusion Describing the ideal process illuminates the challenges and opportunities offered through the suggested evidence-based research approach. A systematic and transparent approach is needed to provide justification for and to optimally design a relevant and necessary new study

Evidence-Based Research Series-Paper 3: Using an Evidence-Based Research approach to place your results into context after the study is performed to ensure usefulness of the conclusion

Background and Objective There is considerable actual and potential waste in research. Using evidence-based research (EBR) can ensure the value of a new study. The aim of this article, the third in a series, is to describe an EBR approach to putting research results into context. Study Design and Setting EBR is the use of prior research in a systematic and transparent way to inform a new study so that it is answering questions that matter in a valid, efficient, and accessible manner. In this third and final article of a series, we describe how to use the context of existing evidence to reach and present a trustworthy and useful conclusion when reporting results from a new clinical study. Results We describe a method, the EBR approach, that by using a systematic and transparent consideration of earlier similar studies when interpreting and presenting results from a new original study will ensure usefulness of the conclusion. Conclusion Using an EBR approach will improve the usefulness of a clinical study by providing the context to draw more valid conclusions and explicit information about new research needs

Change in physical activity level and clinical outcomes in older adults with knee pain: a secondary analysis from a randomised controlled trial

BACKGROUND: Exercise interventions improve clinical outcomes of pain and function in adults with knee pain due to osteoarthritis and higher levels of physical activity are associated with lower severity of pain and higher levels of physical functioning in older adults with knee osteoarthritis in cross-sectional studies. However, to date no studies have investigated if change in physical activity level during exercise interventions can explain clinical outcomes of pain and function. This study aimed to investigate if change in physical activity during exercise interventions is associated with future pain and physical function in older adults with knee pain. METHODS: Secondary longitudinal data analyses of a three armed exercise intervention randomised controlled trial. Participants were adults with knee pain attributed to osteoarthritis, over the age of 45 years old (n = 514) from Primary Care Services in the Midlands and Northwest regions of England. Crude and adjusted associations between absolute change in physical activity from baseline to 3 months (measured by the self-report Physical Activity Scale for the Elderly (PASE)) and i) pain ii) physical function (Western Ontario and McMaster Universities Osteoarthritis Index) and iii) treatment response (OMERACT-OARSI responder criteria) at 3 and 6 months follow-up were investigated using linear and logistic regression. RESULTS: Change in physical activity level was not associated with future pain, function or treatment response outcomes in crude or adjusted models at 3 or 6 months (P > 0.05). A 10 point increase in PASE was not associated with pain β = - 0.01 (- 0.05, 0.02), physical function β = - 0.09 (- 0.19, 0.02) or likelihood (odds ratio) of treatment response 1.02 (0.99, 1.04) at 3 months adjusting for sociodemographics, clinical covariates and the trial intervention arm. Findings were similar for 6 month outcome models. CONCLUSIONS: Change in physical activity did not explain future clinical outcomes of pain and function in this study. Other factors may be responsible for clinical improvements following exercise interventions. However, the PASE may not be sufficiently responsive to measure change in physical activity level. We also recommend further investigation into the responsiveness of commonly used physical activity measures. TRIAL REGISTRATION: ( ISRCTN93634563 ). Registered 29th September 2011

Amyloid in the islets of Langerhans: Thoughts and some historical aspects

Deposition of amyloid, derived from the polypeptide hormone islet amyloid polypeptide (IAPP; ‘amylin’) is the single most typical islet alteration in type 2 diabetes. Islet amyloid was described as hyalinization already in 1901, but not until 1986 was it understood that it is a polymerization product of a novel β-cell regulatory product. The subject of this focused review deals with the pathogenesis and importance of the islet amyloid itself, not with the biological effect of the polypeptide. Similar to the situation in Alzheimer's disease, it has been argued that the amyloid may not be of importance since there is no strict correlation between the degree of islet amyloid infiltration and the disease. However, it is hardly discussable that the amyloid is important in subjects where islets have been destroyed by pronounced islet amyloid deposits. Even when there is less islet amyloid the deposits are widely spread, and β-cells show ultrastructural signs of cell membrane destruction. It is suggested that type 2 diabetes is heterogeneous and that in one major subtype aggregation of IAPP into amyloid fibrils is determining the progressive loss of β-cells. Interestingly, development of islet amyloid may be an important event in the loss of β-cell function after islet transplantation into type 1 diabetic subjects

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe