Symbolic Software for the Painleve Test of Nonlinear Ordinary and Partial Differential Equations

The automation of the traditional Painleve test in Mathematica is discussed. The package PainleveTest.m allows for the testing of polynomial systems of ordinary and partial differential equations which may be parameterized by arbitrary functions (or constants). Except where limited by memory, there is no restriction on the number of independent or dependent variables. The package is quite robust in determining all the possible dominant behaviors of the Laurent series solutions of the differential equation. The omission of valid dominant behaviors is a common problem in many implementations of the Painleve test, and these omissions often lead to erroneous results. Finally, our package is compared with the other available implementations of the Painleve test.Comment: Published in the Journal of Nonlinear Mathematical Physics (http://www.sm.luth.se/math/JNMP/), vol. 13(1), pp. 90-110 (Feb. 2006). The software can be downloaded at either http://www.douglasbaldwin.com or http://www.mines.edu/fs_home/wherema

Novel Assay of Metformin Levels in Patients With Type 2 Diabetes and Varying Levels of Renal Function: Clinical recommendations

AbstractObjective: To study trough levels of metformin in serum and its intra individual variation in patients using a newly developed assay. Research Design and Methods: Trough serum levels of metformin was measured once using Liquid Chromatography Tandem Mass Spectrometry (LcMSMS) in 137 type 2 diabetes patients with varying renal function (99 men) and followed repeatedly during two months in 20 patients (16 men) with estimated GFR (eGFR) below 60 ml/min/1.73 m(2) body surface. Results: Patients with eGFR >60, 30-60, and <30 ml/min/1.73 m(2) had a median trough metformin concentration of 4.5 mumol/l (range 0.1-20.7, n=107), 7.71 mumol/l (0.12-15.15, n=21), and 8.88 mumol/l (5.99-18.60, n=9), respectively. The median intraindividual overall coefficient of variation (CV) was 29.4 % (range 9,8-74,2). Conclusions: Determination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values over 20 mumol/L. Metformin measurement is less suitable for dose titration

Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms

YesRecent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors attenuated inflammatory signalling in cultured human endothelial cells. Incubation with clinically-relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin activated AMPK and inhibited IL-1β-stimulated adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated by expression of dominant-negative AMPK and was mimicked by the direct AMPK activator, A769662. Stimulation of cells with either canagliflozin or A769662 had no effect on IL-1β-stimulated cell surface levels of adhesion molecules or nuclear factor-κB signalling. Despite these identical effects of canagliflozin and A769662, IL-1β-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but not A769662, whereas IL-1β-stimulated c-jun N-terminal kinase phosphorylation was inhibited by A769662, but not canagliflozin. These data indicate that clinically-relevant canagliflozin concentrations directly inhibit endothelial pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent mechanisms without affecting early IL-1β signalling.Project Grant (PG/13/82/30483 to IPS and TMP) and PhD studentships (FS/16/55/32731 and FS/14/61/31284 to DB and AS) from the British Heart Foundation and an equipment grant (BDA11/0004309 to IPS and TMP) from Diabetes UK. OJK was supported by a Scholarship from the Iraqi Ministry of Higher Education and Scientific Research. TAA was supported by a Libyan Ministry of Education PhD Studentship

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background Liraglutide 3\ub70 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3\ub70 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2\ub77 times longer with liraglutide than with placebo (95% CI 1\ub79 to 3\ub79, p<0\ub70001), corresponding with a hazard ratio of 0\ub721 (95% CI 0\ub713\u20130\ub734). Liraglutide induced greater weight loss than placebo at week 160 (\u20136\ub71 [SD 7\ub73] vs 121\ub79% [6\ub73]; estimated treatment difference 124\ub73%, 95% CI 124\ub79 to 123\ub77, p<0\ub70001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3\ub70 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark

Pulsatile Stress in Middle-Aged Patients With Type 1 or Type 2 Diabetes Compared With Nondiabetic Control Subjects

AbstractBackground: Arterial pulse pressure (PP) is considered as an independent cardiovascular risk factor. We compared PP during an active orthostatic test in middle-aged patients with type 1 diabetes and with type 2 diabetes, and corresponding nondiabetic controls. Methods: 40 patients with type 1 diabetes (mean age 50 years, diabetes duration 23 years, BMI 23.0 kg/m(2)) were compared to 40 non hypertensive patients with type 2 diabetes (respectively, 50 years, 8 years, 29.7 kg/m(2)). Patients taking antihypertensive agents or with renal insufficiency were excluded. All patients were evaluated with a continuous noninvasive arterial blood pressure monitoring (Finapres(R)) in standing (1 min), squatting (1 min) and again standing position (1 min). Patients with type 1 or type 2 diabetes were compared with two groups of 40 age-, sex- and BMI-matched healthy subjects. Results: Patients with type 1 diabetes and patients with type 2 diabetes showed significantly higher PP, heart rate (HR) and PPxHR double product (type 1 : 5263 vs 4121 mmHg/min, p=0.0004; type 2 : 5359 vs 4321 mmHg, p=0.0023) levels than corresponding controls. There were no significant differences between patients with type 1 diabetes and type 2 diabetes regarding PP (59 vs 58 mmHg), HR (89 vs 88/min), and PPxHR product (5263 vs 5359 mmHg/min). Conclusion: Patients with type 1 diabetes have comparable increased levels of peripheral PP, an indirect marker of arterial stiffness, and PPxHR, an index of pulsatile stress, as non-hypertensive patients with type 2 diabetes at similar mean age of 50 years

TSH-Lowering Effect of Metformin in Type 2 Diabetic Patients: Differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients

OBJECTIVE: To assess the interplay between metformin treatment and thyroid function in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: The acute and long-term effects of metformin on thyroid axis hormones were assessed in diabetic patients with primary hypothyroidism who were either untreated or treated with levothyroxine (L-T4), as well as in diabetic patients with normal thyroid function. RESULTS: No acute changes were found in 11 patients with treated hypothyroidism. After 1 year of metformin administration, a significant thyrotropin (TSH) decrease (P < 0.001) was observed in diabetic subjects with hypothyroidism who were either treated (n = 29; from 2.37 +/- 1.17 to 1.41 +/- 1.21 mIU/l) or untreated (n = 18; 4.5 +/- 0.37 vs. 2.93 +/- 1.48) with L-T4, but not in 54 euthyroid subjects. No significant change in free T4 (FT4) was observed in any group. CONCLUSIONS: Metformin administration influences TSH without change of FT4 in patients with type 2 diabetes and concomitant hypothyroidism. The need for reevaluation of thyroid function in these patients within 6-12 months after starting metformin is indicated

Persistence to Treatment with Novel Antidiabetic Drugs (Dipeptidyl Peptidase-4 Inhibitors, Sodium-Glucose Co-Transporter-2 Inhibitors, and Glucagon-Like Peptide-1 Receptor Agonists) in People with Type 2 Diabetes

INTRODUCTION: Adequate persistence to antidiabetic treatment is highly important to achieve proper glycemic control. In this study we evaluate the persistence to treatment with dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, and glucagon-like peptide-1 receptor agonists in a nationwide cohort of patients with type 2 diabetes. METHODS: Using a central database in Hungary, we analyzed the persistence to the treatment with dipeptidyl peptidase-4 inhibitors (n = 59,900), sodium-glucose co-transporter-2 inhibitors (n = 26,052), and glucagon-like peptide-1 receptor agonists (n = 17,332) at treatment intensification between 2014 and 2016. We also compared the persistence of dipeptidyl peptidase-4 inhibitors (n = 9163) and sodium-glucose co-transporter-2 inhibitors (n = 1257) in initial therapy to that of metformin (n = 79,305) or sulfonylureas (n = 29,057). The rates of persistence to treatment and risk of non-persistence are reported. RESULTS: The persistence rates of dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, and glucagon-like peptide-1 receptor agonists at treatment intensification were 69.6%, 67.8%, and 66.3% at year 1 which decreased to 57.3%, 56.8%, and 52.1% by year 2, respectively. The risk of non-persistence was higher by 6.6% (95% CI 3.6-9.6) for sodium-glucose co-transporter-2 inhibitors and by 8.3% (95% CI 5.0-11.5) for glucagon-like peptide-1 receptor agonists as compared to dipeptidyl peptidase-4 inhibitors. Novel oral antidiabetic drugs in fixed versus free add-on combinations with metformin had higher persistence. The persistence to treatment with novel oral antidiabetic drugs in initial therapy was better (dipeptidyl peptidase-4 inhibitors, 59.6% and 47.6%; sodium-glucose co-transporter-2 inhibitors, 61.9% and 47.0%) than that of initial monotherapy with metformin (47.0% and 39.1%) or sulfonylureas (52.4% and 41.8%) at years 1 and 2, respectively. CONCLUSION: Analysis of persistence of treatment with novel glucose-lowering medications revealed differences between drug classes, favoring dipeptidyl peptidase-4 inhibitors vs. sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. Persistence data of novel antihyperglycemic agents may be useful for guiding the decision at initiation of antidiabetic treatment. FUNDING: Hungarian Diabetes Association. Plain language summary available for this article

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