Morning administration of 0.4U/kg/day insulin glargine 300U/mL provides less fluctuating 24-hour pharmacodynamics and more even pharmacokinetic profiles compared with insulin degludec 100U/mL in type 1 diabetes.

AIM: To compare steady state pharmacodynamic and pharmacokinetic profiles of insulin glargine 300U/mL (Gla-300) with insulin degludec 100U/mL (Deg-100) in people with type 1 diabetes. METHODS: This single-centre, randomized, double-blind crossover euglycaemic clamp study included two parallel cohorts with fixed once-daily morning dose regimens. For both insulins participants received 0.4 (n=24) or 0.6U/kg/day (n=24), before breakfast, for 8 days prior to the clamp. The main endpoint was within-day variability (fluctuation) of the smoothed glucose infusion rate (GIR) over 24 hours (GIR-smFL0-24). RESULTS: Gla-300 provided 20% less fluctuation of steady state glucose infusion rate profiles than Deg-100 over 24 hours at 0.4U/kg/day (GIR-smFL0-24 treatment ratio 0.80 [90% confidence interval: 0.66 to 0.96], P=0.047), while at the dose of 0.6U/kg/day the difference between insulins was not statistically significant (treatment ratio 0.96 [0.83 to 1.11], P=0.603). Serum insulin concentrations appeared more evenly distributed with both dose levels of Gla-300 versus the same doses of Deg-100, as assessed by relative 6-hour fractions of the area under the curve within 24 hours. Both insulins provided exposure and activity until 30 hours (end of clamp). CONCLUSION: Gla-300 provides less fluctuating steady state pharmacodynamic profiles (i.e. lower within-day variability) and more evenly distributed pharmacokinetic profiles, compared with Deg-100 in a once-daily morning dosing regimen of 0.4U/kg/day.

Efficacy and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes (LIRA-SWITCH): a randomized, double-blind, double-dummy, active-controlled 26-week trial.

AIMS: To confirm superiority on glycaemic control by switching from sitagliptin to liraglutide 1.8 mg/d versus continued sitagliptin. MATERIALS AND METHODS: A randomized, multicentre, double-blind, double-dummy, active-controlled trial across 86 office- or hospital-based sites in North America, Europe and Asia. Subjects with type 2 diabetes who had inadequate glycaemic control (glycated haemoglobin [HbA1c] 7.5-9.5% on sitagliptin (100 mg/d) and metformin (≥1500 mg daily) for ≥90 days were randomized to either switch to liraglutide (n = 203) or continue sitagliptin (n = 204), both with metformin. The primary endpoint was change in HbA1c from baseline to week 26. Change in body weight was a confirmatory secondary endpoint. RESULTS: Greater reduction in mean HbA1c was achieved with liraglutide than with continued sitagliptin [-1.14% vs. -0.54%; estimated mean treatment difference (ETD): -0.61% (95% CI -0.82 to -0.40; p < 0.0001)], confirming superiority of switching to liraglutide. Body weight was reduced more with liraglutide [-3.31 kg vs. -1.64 kg; ETD: -1.67 kg (95% CI -2.34 to -0.99; p < 0.0001)]. Nausea was more common with liraglutide [44 subjects (21.8%)] than with continued sitagliptin [16 (7.8%)]. Three subjects (1.5%) taking sitagliptin reported a confirmed hypoglycaemic episode. CONCLUSIONS: Subjects insufficiently controlled with sitagliptin who switch to liraglutide can obtain clinically relevant reductions in glycaemia and body weight, without compromising safety. A switch from sitagliptin to liraglutide provides an option for improved management of type 2 diabetes while still allowing patients to remain on dual therapy.

Basal insulin peglispro versus insulin glargine in insulin-naïve type 2 diabetes: IMAGINE 2 randomized trial.

AIMS: To compare, in a double-blind, randomized, multi-national study, 52- or 78-week treatment with basal insulin peglispro or insulin glargine, added to pre-study oral antihyperglycaemic medications, in insulin-naïve adults with type 2 diabetes. MATERIAL AND METHODS: The primary outcome was non-inferiority of peglispro to glargine with regard to glycated haemoglobin (HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients. RESULTS: Peglispro was non-inferior to glargine in HbA1c reduction [least-squares (LS) mean difference: -0.29%, 95% confidence interval (CI) -0.40, -0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p = .005), more patients achieving HbA1c <7.0% without nocturnal hypoglycaemia [odds ratio (OR) 2.15 (95% CI 1.60, 2.89); p < .001], greater HbA1c reduction (p < .001), and more patients achieving HbA1c<7.0% [OR 1.97 (95% CI 1.57, 2.47); p < .001]. Total hypoglycaemia rate and fasting serum glucose did not achieve statistical superiority. At 52 weeks, peglispro-treated patients had higher triglyceride (1.9 vs 1.7 mmol/L). alanine transaminase (34 vs 27 IU/L), and aspartate transaminase levels (27 vs 24 IU/L). LS mean liver fat content was unchanged with peglispro at 52 weeks but decreased 3.1% with glargine [difference: 2.6% (0.9, 4.2); p = .002]. More peglispro-treated patients experienced adverse injection site reactions (3.5% vs 0.6%, p < .001). CONCLUSIONS: Compared with glargine at 52 weeks, peglispro resulted in a statistically superior reduction in HbA1c, more patients achieving HbA1c targets, less nocturnal hypoglycaemia, no improvement in total hypoglycaemia, higher triglyceride levels, higher aminotransferase levels, and more injection site reactions.

Effect of adding insulin degludec to treatment in patients with type 2 diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized controlled trial (BEGIN: ADD TO GLP-1 Study).

AIM: To evaluate the efficacy and safety of adding insulin degludec (IDeg) to treatment in patients with type 2 diabetes receiving liraglutide and metformin and qualifying for treatment intensification because of inadequate glycaemic control. METHODS: In this 26-week, double-blind trial, patients who still had inadequate glycaemic control after a 15-week run-in period with initiation and dose escalation of liraglutide to 1.8 mg in combination with metformin (≥1500 mg) were randomized to addition of once-daily IDeg ('IDeg add-on to liraglutide' arm; n = 174) or placebo ('placebo add-on to liraglutide' arm; n = 172), with dosing of both IDeg and placebo based on titration guidelines. RESULTS: At 26 weeks, the mean change in glycated haemoglobin level was greater in the IDeg add-on to liraglutide arm (-1.04%) than in the placebo add-on to liraglutide arm (-0.16%; p < 0.0001). Similarly, the mean fasting plasma glucose reduction was greater, and self-measured plasma glucose values were lower at all eight time points, with IDeg add-on versus placebo add-on (both p < 0.0001). At 26 weeks, the IDeg dose was 51 U (0.54 U/kg). During the run-in period with liraglutide, body weight decreased by ∼3 kg in both groups. After 26 weeks, the mean change was +2.0 kg (IDeg add-on to liraglutide) and -1.3 kg (placebo add-on to liraglutide). Confirmed hypoglycaemia rates were low in both groups, although higher with IDeg than with placebo (0.57 vs. 0.12 episodes/patient-years of exposure; p = 0.0002). Nocturnal confirmed hypoglycaemia was infrequent in both groups, with no episodes of severe hypoglycaemia, and no marked differences in adverse events with either treatment approach. CONCLUSION: The addition of liraglutide and IDeg to patients sub-optimally treated with metformin and liraglutide and requiring treatment intensification was found to be effective and well-tolerated.

Automated insulin pump suspension for hypoglycaemia mitigation: development, implementation and implications.

In type 1 diabetes (T1D), insulin replacement therapy should ideally replicate endogenous insulin secretion, but achieving this goal requires frequent adjustments to insulin delivery based on glucose levels and trends, carbohydrate intake and physical activity. An overriding concern for people taking insulin is hypoglycaemia, which remains the most feared consequence of insulin therapy and limits therapy intensification options. Although fully automated systems that achieve consistent euglycaemia in T1D remain an elusive goal, improvements in continuous glucose monitoring (CGM) sensors and control algorithms have enabled semi-automated systems that lower the risk of hypoglycaemia, especially nocturnal hypoglycaemia. The present review focuses on an important advance in insulin delivery systems: the use of CGM data to stop insulin delivery in the presence of hypoglycaemia. Although conceptually simple, this strategy represents a critical step in the journey toward a fully closed-loop artificial pancreas; the next steps in this journey are also discussed.

Outpatient clinic: where is the delay?

In outpatient clinics, consultation times are often eroded by extraneous activities. We measured the components of each outpatient episode in 167 patients attending a general urology follow-up clinic. 41% of time in the clinic was spent away from the patient-administration 17%, disturbances 15%, finding results 9%. The inefficiencies had changed little since a study in the same setting thirteen years earlier. Since then, parallel nurse-practitioner-run clinics have been introduced in the hope of giving consultants longer with the patient; however, time with each patient is now 4.8 min compared with a previous 7.6 min. The most easily addressed inefficiencies are those relating to missing information, such as radiology reports.

Variation in aspects of cysteine proteinase catalytic mechanism deduced by spectroscopic observation of dithioester intermediates, kinetic analysis and molecular dynamics simulations.

The possibility of a slow post-acylation conformational change during catalysis by cysteine proteinases was investigated by using a new chromogenic substrate, N-acetyl-Phe-Gly methyl thionoester, four natural variants (papain, caricain, actinidin and ficin), and stopped-flow spectral analysis to monitor the pre-steady state formation of the dithioacylenzyme intermediates and their steady state hydrolysis. The predicted reversibility of acylation was demonstrated kinetically for actinidin and ficin, but not for papain or caricain. This difference between actinidin and papain was investigated by modelling using QUANTA and CHARMM. The weaker binding of hydrophobic substrates, including the new thionoester, by actinidin than by papain may not be due to the well-known difference in their S2-subsites, whereby that of actinidin in the free enzyme is shorter due to the presence of Met211. Molecular dynamics simulation suggests that during substrate binding the sidechain of Met211 moves to allow full access of a Phe sidechain to the S2-subsite. The highly anionic surface of actinidin may contribute to the specificity difference between papain and actinidin. During subsequent molecular dynamics simulations the P1 product, methanol, diffuses rapidly (over<8 ps) out of papain and caricain but 'lingers' around the active centre of actinidin. Uniquely in actinidin, an Asp142-Lys145 salt bridge allows formation of a cavity which appears to constrain diffusion of the methanol away from the catalytic site. The cavity then undergoes large scale movements (over 4.8 A) in a highly correlated manner, thus controlling the motions of the methanol molecule. The changes in this cavity that release the methanol might be those deduced kinetically.

Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy.

The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti-mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti-4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell-independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti-4-1BB mAb was given within 1 wk after immunization. Anti-4-1BB inhibition was observed in mice lacking functional CD8(+) T cells, indicating that CD8(+) T cells were not required for the induction of anergy. Analysis of the requirements for the anti-4-1BB-mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti-4-1BB-treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti-4-1BB-treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti-4-1BB-treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti-4-1BB mAbs.

Characterization of a CD43/leukosialin-mediated pathway for inducing apoptosis in human T-lymphoblastoid cells.

The monoclonal antibody (mAb) J393 induces apoptosis in Jurkat T-cells. NH2-terminal amino acid sequence analysis identified the 140-kDa surface antigen for mAb J393 as CD43/leukosialin, the major sialoglycoprotein of leukocytes. While Jurkat cells co-expressed two discrete cell-surface isoforms of CD43, recognized by mAb J393 and mAb G10-2, respectively, only J393/CD43 signaled apoptosis. J393/CD43 was found to be hyposialylated, bearing predominantly O-linked monosaccharide glycans, whereas G10-2/CD43 bore complex sialylated tetra- and hexasaccharide chains. Treatment with soluble, bivalent mAb J393 killed 25-50% of the cell population, while concomitant engagement of either the CD3.TcR complex or the integrins CD18 and CD29 significantly potentiated this effect. Treatment of Jurkat cells with mAb J393 induced tyrosine phosphorylation of specific protein substrates that underwent hyperphosphorylation upon antigen receptor costimulation. Tyrosine kinase inhibition by herbimycin A diminished J393/CD43-mediated apoptosis, whereas inhibition of phosphotyrosine phosphatase activity by bis(maltolato)oxovanadium-IV enhanced cell death. Signal transduction through tyrosine kinase activation may lead to altered gene expression, as J393/CD43 ligation prompted decreases in the nuclear localization of the transcriptional regulatory protein NF-kappaB and proteins binding the interferon-inducible regulatory element. Since peripheral blood T-lymphocytes express cryptic epitopes for mAb J393, these findings demonstrate the existence of a tightly regulated CD43-mediated pathway for inducing apoptosis in human T-cell lineages.

Recloning of SV40 early gene transfected human endothelial cells repeatedly recovers subpopulations with low passage characteristics and morphologies.

Cultured human umbilical vein endothelial cells (HUVECs) are a valuable model for investigation of endothelial functions, but they enter senescence at low passage. Transfection of early passage HUVECs with the early genes of SV40 greatly extends the replicative potential of these cells, but eventually results in marked changes in growth, morphology, and biochemistry. Here we report a modified approach that appears to have overcome the problem of late passage decline after transfection. Plasmid pX-8 containing the SV40 early genes was transfected into passage four HUVECs. At passage five, these transfectants were cloned by limiting dilution and selected on the basis of both morphological and biochemical resemblance to their untransfected counterparts. Two clones that expressed factor VIII and in which the basal and the tumor necrosis factor-alpha inducible levels of interleukin 6 and endothelial adhesion molecules were normal were chosen. Vimentin and fibronectin distribution in these clones resembled untransfected cells. At passage 25, growth pattern changes were becoming evident, but recloning these late passage clones recovered numerous subclones of normal, cobblestone appearance. Two of these were further characterized and found to resemble their original parental clone by all of the biochemical criteria listed above. These subclones appeared to transform more rapidly than the parental clone, but repeated subcloning again rescued clones with normal morphologies and normal biochemical characteristics. We conclude that periodic recloning may indefinitely perpetuate lines that are useful equivalents of their original counterparts.

Laparoscopic-assisted vaginal hysterectomy utilising the contact-tip Nd: YAG laser: a review of 67 cases.

The purpose of this study was to determine the efficacy of laparoscopic-assisted vaginal hysterectomy utilising the contact-tip Nd:YAG (Neodymium: Yttrium-Aluminum-Garnet) laser (Surgical Laser Technologies, Oaks, PA). Postoperative activity levels, operative times, blood loss, pain medication use, length of hospital stay, and complications of laparoscopic-assisted vaginal hysterectomy were determined. Sixty-seven women with extensive disease including endometriosis, adenomyosis, adhesions, and multiple fibroids underwent laparoscopic-assisted vaginal hysterectomy (LAVH). The procedures were performed utilising the contact-tip Nd:YAG laser and a laparoscopic linear stapling device. All patients were operated on for a primary diagnosis of pelvic pain and would have required an abdominal approach for surgery due to extensive adhesions, fibroids, or endometriosis. Sixty-eight cases of laparoscopic-assisted vaginal hysterectomy were attempted. In 67 of these cases, the procedure was completed as planned. One case required conversion to abdominal hysterectomy due to extensive adhesions. Average hospital stay after surgery was 2.7 days with a minimum stay of less than one day. The average operating time for the LAVH was 149 minutes with an estimated blood loss of 220 mL and a haemoglobin drop from surgery to day 1 after surgery of 1.9 g. The complication rate was 11.9% with all of the complications occurring in the first 46 cases. By day 14 after surgery, patients reported their activity level at 8.8 on a scale of 1 to 10 with 10 being unlimited activities. By day 21, they reported their activity level at 9.5. The majority of the patients were able to return to work within two weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination therapy for NIDDM with biosynthetic human insulin and glyburide.

OBJECTIVE: TO investigate the effects of the addition of glyburide to the regimen of insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients with regard to their overall insulin requirement and dosage schedule and to assess persistence of these effects. RESEARCH DESIGN AND METHODS: A double-blind randomized parallel-groupo, placebo-controlled, 20-wk outpatient trial at the Clinical Research Unit (CRU) at St. Luke's/Roosevelt Hospital (New York). Subjects were 20 insulin-dependent NIDDM patients previously managed on insulin alone. After a baseline period of satisfactory diabetes control on biosynthetic human insulin alone, insulin dosage was halved, and patients were placed on a combination with either glyburide or placebo. Diabetes control equivalent to baseline was reestablished by adjusting insulin as required on subsequent visits to the CRU. RESULTS: Insulin requirements in the glyburide group decreased by 29 U at 14 wk compared with 9 U in the placebo group (P less than 0.05). At 20 wk, the decreases remained significant (25 vs. 11 U, respectively; P less than 0.05). The mean +/- SD reduction in insulin requirement in the glyburide group was relatively constant (25 +/- 10 U) and was not related to premedication insulin requirement. Successful response to glyburide was inversely correlated with initial serum alkaline phosphatase level. CONCLUSIONS: Glyburide reduces insulin requirements for 20 wk of combination therapy in NIDDM patients. Patients whose initial insulin requirement is less than or equal to 25 U have a 50% chance of achieving equivalent glycemic control on glyburide alone.

Pulmonary coin lesions caused by Dirofilaria immitis.

The dog heartworm Dirofilaria immitis has been diagnosed by thoracotomy as the etiology of neoplastic-appearing nodules in two patients in the Peoria, Illinois area. This brings the total number of reported cases of human pulmonary dirofilariasis to approximately 81 in the United States. The major concern of this benign disease is that in making the diagnosis the patients undergo the risk of surgery because of the presumed preoperative diagnosis of cancer. Greater awareness of this disease is needed as the geographic distribution of human pulmonary dirofilariasis expands in this country.

Combination therapy with insulin and sulfonylureas for type II diabetes.

Combination therapy for type II (non-insulin-dependent) diabetes mellitus with insulin and sulfonylureas has been a topic of interest since the latter were introduced to clinical use. In recent years, improved understanding of potential complications associated with hyperinsulinemia has led to resurgent interest in alternatives to insulin monotherapy for patients who have failed on a regimen of diet and sulfonylureas. A plethora of clinical trials have reported on the efficacy of oral hypoglycemic agents in limiting insulin requirements while achieving glycemic control in this subset of diabetic patients. However, few studies have been appropriate in both design and duration to provide convincing results. The randomized placebo-controlled double-blind trials that have used a parallel design and study periods of up to 1 yr have uniformly investigated second-generation sulfonylureas and yielded the most reliable information. In all instances, the combination regimen achieved reduction in insulin requirement with varying evidence of a pancreatic effect as the responsible mechanism. This treatment modality is becoming more widely accepted in the effort to achieve optimal glycemic control with minimum risk to the patient.

Patterns of foot examination in a diabetes clinic.

Peripheral vascular disease is a well-known source of morbidity and potential mortality in diabetic patients. Sixty-five subjects with diabetes were studied in order to describe the contributions of the patient, the physician, and the health care system to the performance of a preventive foot examination. The incidences of foot examination on the day of study (12.3 percent) and during the previous year (49.2 percent) were similar to those found by other investigators. The feet of patients at higher risk for limb amputation were not examined with greater frequency at the clinic, although such patients were more often referred to a podiatrist. The most significant determinants of physician foot examination were patient recall of foot-related education received at the clinic and inter-physician variability. These data suggest that the patient, physician, and clinic routine all play an important role in the success of a foot screening program for patients with diabetes.