Gene therapy for diabetes mellitus in rats by hepatic expression of insulin.

Type 1 diabetes mellitus is caused by severe insulin deficiency secondary to the autoimmune destruction of pancreatic beta cells. Patients need to be controlled by periodic insulin injections to prevent the development of ketoacidosis, which can be fatal. Sustained, low-level expression of the rat insulin 1 gene from the liver of severely diabetic rats was achieved by in vivo administration of a recombinant retroviral vector. Ketoacidosis was prevented and the treated animals exhibited normoglycemia during a 24-hr fast, with no evidence of hypoglycemia. Histopathological examination of the liver in the treated animals showed no apparent abnormalities. Thus, the liver is an excellent target organ for ectopic expression of the insulin gene as a potential treatment modality for type 1 diabetes mellitus by gene therapy.

Partial rescue of retinal function in chronically hypoglycemic mice

Purpose. Mice rendered hypoglycemic by a null mutation in the glucagon receptor gene Gcgr display late-onset retinal degeneration and loss of retinal sensitivity. Acute hyperglycemia induced by dextrose ingestion does not restore their retinal function, which is consistent with irreversible loss of vision. The goal of this study was to establish whether long-term administration of high dietary glucose rescues retinal function and circuit connectivity in aged Gcgr−/− mice. Methods. Gcgr−/− mice were administered a carbohydrate-rich diet starting at 12 months of age. After 1 month of treatment, retinal function and structure were evaluated using electroretinographic (ERG) recordings and immunohistochemistry. Results. Treatment with a carbohydrate-rich diet raised blood glucose levels and improved retinal function in Gcgr−/− mice. Blood glucose increased from moderate hypoglycemia to euglycemic levels, whereas ERG b-wave sensitivity improved approximately 10-fold. Because the b-wave reflects the electrical activity of second-order cells, we examined for changes in rod-to-bipolar cell synapses. Gcgr−/− retinas have 20% fewer synaptic pairings than Gcgr+/− retinas. Remarkably, most of the lost synapses were located farthest from the bipolar cell body, near the distal boundary of the outer plexiform layer (OPL), suggesting that apical synapses are most vulnerable to chronic hypoglycemia. Although treatment with the carbohydrate-rich diet restored retinal function, it did not restore these synaptic contacts. Conclusions. Prolonged exposure to diet-induced euglycemia improves retinal function but does not reestablish synaptic contacts lost by chronic hypoglycemia. These results suggest that retinal neurons have a homeostatic mechanism that integrates energetic status over prolonged periods of time and allows them to recover functionality despite synaptic loss.

A propósito de um caso de hipoglicemia...

Introdução: O hipopituitarismo é caracterizado por insuficiência da secreção hormonal hipófisária. A clínica é variável e depende da etiologia, evolução temporal e hormonas envolvi- das. Caso: Criança do sexo masculino com 2 anos, trazida à urgência por alteração súbita da consciência. No período neonatal apresentou quadro de hipoglicemia, trombocitopenia, icterícia e sépsis sem agente identificado. Objetivou-se crescimento regular no P10-25, desenvolvimento psicomotor adequado e estrabismo divergente. Ao exame objectivo apresentava-se subfebril e com Escala de Coma de Glasgow 10. Foi constatada hipoglicemia grave (26mg/dL) sendo realizado de imediato estudo endocrinológico e metabólico que mostrou cortisol baixo e défices de ACTH e GH; posteriormente foi confirmado défice de TSH. Iniciou terapêutica de substituição com hidrocortisona e levotiroxina. A neuroimagem mostrou alterações estruturais com hipoplasia da neuro-hipófise. Conclusão: Este diagnóstico raro exige elevado grau de suspeição. A ocorrência progressiva dos défices hormonais obriga à avaliação clínica e laboratorial regular.

The outcome in Australian children with hyperinsulinism of infancy: early extensive surgery in severe cases lowers risk of diabetes

AIMS Hyperinsulinism of infancy (HI) is characterized by unregulated insulin secretion in the presence of hypoglycaemia, often resulting in brain damage. Pancreatic resection for control of hypoglycaemia is frequently resisted because of the risk of diabetes mellitus (DM). We investigated retrospectively 62 children with HI from nine Australian treatment centres born between 1972 and 1998, comparing endocrine and neurological outcome in 28 patients receiving medical therapy alone with 34 who required pancreatic resection to control their hypoglycaemia. METHODS History, treatment and clinical course were ascertained from file audit and interview. Risk of DM (hazard ratio) attributable to age at surgery (< vs. greater than or equal to 100 days at last pancreatectomy) and extent of resection (< vs. greater than or equal to 95%) were calculated using Cox proportional hazards regression and categorical variables compared by the chi(2) -test. Neurological outcome (normal, mild deficit or severe deficit) was derived from the most authoritative source. RESULTS Surgically treated patients had a greater birthweight, earlier presentation and higher plasma insulin levels. Of 18 infants < 100 days and 16 greater than or equal to 100 days of age at surgery, four (all greater than or equal to 100 days) became diabetic as an immediate consequence of surgery and five (two < 100 days and three greater than or equal to 100 days) became diabetic 7-18 years later. Surgery greater than or equal to 100 days and pancreatectomy greater than or equal to 95% were associated with development of diabetes (HR = 12.61, CI 1.53-104.07 and HR = 7.03, CI 1.43-34.58, respectively). Neurodevelopmental outcome was no different between the surgical and medical groups with 44% overall with neurological deficits. Patients euglycaemic within 35 days of the first symptom of hypoglycaemia (Group A) had a better neurodevelopmental outcome than those still hypoglycaemic > 35 days from first presentation (Group B) (P = 0.007). Prolonged hypoglycaemia in Group B was due either to delayed diagnosis or to need for repeat surgery because of continued hypoglycaemia. Within Group A, medically treated patients (who presented later with apparently milder disease) had a higher incidence of neurodevelopmental deficit (n = 15, four mild, three severe deficit) compared with surgically treated patients (n = 18, two mild, none severe deficit) (P < 0.025). CONCLUSIONS Poor neurodevelopmental outcome remains a major problem in hyperinsulinism of infancy. Risk of diabetes mellitus with pancreatectomy varies according to age at surgery and extent of resection. Patients presenting early with severe disease have a better neurodevelopmental outcome and lower risk of diabetes if they are treated with early extensive surgery.

Strength and endurance training lead to different post exercise glucose profiles in diabetic participants using a continuous subcutaneous glucose monitoring system

Background Although both strength training (ST) and endurance training (ET) seem to be beneficial in type 2 diabetes mellitus (T2D), little is known about post-exercise glucose profiles. The objective of the study was to report changes in blood glucose (BG) values after a 4-month ET and ST programme now that a device for continuous glucose monitoring has become available. Materials and methods Fifteen participants, comprising four men age 56.5 +/- 0.9 years and 11 women age 57.4 +/- 0.9 years with T2D, were monitored with the MiniMed (Northridge, CA, USA) continuous glucose monitoring system (CGMS) for 48 h before and after 4 months of ET or ST. The ST consisted of three sets at the beginning, increasing to six sets per week at the end of the training period, including all major muscle groups and ET performed with an intensity of maximal oxygen uptake of 60% and a volume beginning at 15 min and advancing to a maximum of 30 min three times a week. Results A total of 17 549 single BG measurements pretraining (619.7 +/- 39.8) and post-training (550.3 +/- 30.1) were recorded, correlating to an average of 585 +/- 25.3 potential measurements per participant at the beginning and at the end of the study. The change in BG-value between the beginning (132 mg dL(-1)) and the end (118 mg dL(-1)) for all participants was significant (P = 0.028). The improvement in BG-value for the ST programme was significant (P = 0.02) but for the ET no significant change was measured (P = 0.48). Glycaemic control improved in the ST group and the mean BG was reduced by 15.6% (Cl 3-25%). Conclusion In conclusion, the CGMS may be a useful tool in monitoring improvements in glycaemic control after different exercise programmes. Additionally, the CGMS may help to identify asymptomatic hypoglycaemia or hyperglycaemia after training programmes.

Continuous glucose monitoring in diabetic long distance runners

Marathon running is growing in popularity, and many diabetic patients are participating in various marathon races all over the world each year. This study aimed to investigate the prevalence and extent of glycemic excursions (hypo- and hyperglycemic) during a marathon run in patients with well-controlled diabetes mellitus using a continuous glucose monitoring system (CGMS). Five subjects with type 1 and one patient with type 2 diabetes mellitus were monitored with the Medtronic MiniMed CGMS during the 2002 Vienna City Marathon (n = 3) or the Fernwarme run (n = 3) long distance runs of 42.19/15.8 km. All six patients finished their course. The CGSM system was well tolerated in all patients over an average duration of 34 +/- 4.0 hours and it did not limit the patients' activities. The mean running time for the Vienna city marathon was 257 +/- 8 min (247 to 274 min) and for the Fernwarme run 134 +/- 118 min (113 to 150 min). A total of 1470 blood glucose measurements (mean 245 readings per subject) were performed. During and after the marathons frequent hypo and hyperglycemic episodes with and without clinical symptoms were measured. Our data confirm that the CGMS may help to identify asymptomatic hypoglycemia or hyperglycemia during and after a long distance run. The system may also be helpful to improve our understanding about the individual changes of glucose during and after a marathon and may protect hypoglycemic or hyperglycemic periods in future races.

Insulin sensitivity measures in cats exhibit high inter-day variability

In cats with underlying low insulin sensitivity, obesity is a major risk factor for type 2 diabetes. Strategies to prevent the onset of type 2 diabetes could be implemented if these cats could be identified. Currently, two labour-intensive and complex methods have been used to measure insulin sensitivity in research studies: the hyperinsulinemic euglycemic clamp (Clamp) and the minimal model analysis (MINMOD) of a frequentlysampled intravenous glucose tolerance test. However, simpler measures are required in practice. Validation of simple measures requires a wellestablished method with minimal inter-day variability. The aims of this study were to determine the inter-day variability of the current methods of measuring insulin sensitivity in cats, and to assess the relationship between these tests and simpler measures of insulin sensitivity.

New therapies for diabesity

Many patients with type 2 diabetes are obese (diabesity), and the two conditions together impose a particularly complex therapeutic challenge. Several differently acting agents are often required at the same time, encouraging development of more single-tablet combinations. Longer-acting (once daily and once weekly) injected agonists of glucagon-like peptide-1 are due to provide additional options to stimulate insulin secretion with weight loss and minimal risk of hypoglycemia. Further, dipeptidyl peptidase-4 inhibitors ("weight-neutral" insulinotropic agents) are also expected. Sodium-glucose cotransporter 2 inhibitors offer a new option to reduce hyperglycemia and facilitate weight loss by increasing the elimination of glucose in the urine. Selective peroxisome proliferator-activated receptor modulators are being studied to produce compounds with desired effects. Many other agents with antidiabetic and antiobesity activity are progressing in clinical development.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes

Background - To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. Methods - We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results - A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. Conclusions - Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.)

Inhaled human insulin (Exubera®):clinical profile and patient considerations

Inhaled human insulin (Exubera®) is a rapid-acting regular human insulin administered by oral inhalation before meals. It provides a non-invasive alternative to multiple subcutaneous injections for the treatment of hyperglycemia in adult patients with type 1 and type 2 diabetes. Compared with subcutaneous rapid-acting insulin analogs, Exubera provides equivalent HbA1c control. As a monotherapy or in combination with oral agents, Exubera also provides greater glycemic control than oral agents alone, at least in patients with high levels of HbA1c. Exubera demonstrates improved patient satisfaction compared with subcutaneous insulin or oral agents alone. When offered as a treatment option together with standard treatments in uncontrolled patients naive to insulin, Exubera increases acceptance of insulin therapy three-fold compared with patients offered standard regimens only. Exubera is well tolerated in comparison to subcutaneous insulin, with a similar incidence of mild to moderate hypoglycemia. Although cough is a common adverse effect early in therapy, this leads to treatment discontinuations in less than 1% of patients. Despite an increased incidence of insulin antibodies compared with subcutaneous administration, and a consistent but minor impact on pulmonary function, long-term safety data of up to 4 years continue to support the safety profile of Exubera.

Insulin therapy in people with type 2 diabetes:opportunities and challenges?

Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes. © 2014 by the American Diabetes Association.

Thiazolidinediones

Thiazolidinediones (TZDs), also termed "glitazones", are used as antidiabetic agents for the treatment of type 2 (non-insulin dependent) diabetes mellitus. They activate the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma). This increases the transcription of various insulin-sensitive genes, improving insulin action and lowering blood glucose concentrations. TZDs currently in clinical use for the treatment of type 2 diabetes are rosiglitazone and pioglitazone. Troglitazone was withdrawn due to hepatotoxicity. Other TZDs (e.g. ciglitazone) have been studied preclinically, but not introduced into clinical use. TZDs do not cause severe hypoglycemia, hence they are regarded as antihyperglycemic (rather than hypoglycemic) agents .... © 2007 Elsevier Inc. All rights reserved..

Segurança do paciente em terapia intensiva neonatal: identificação e análise de eventos adversos

The patient safety is a major concern in health services for its global dimension, as evidenced by the fragility of care processes that predispose an occurrence of adverse events. These events in a neonatal intensive care unit are considered serious and hazardous to lives of newborns. The present study aimed to identify and analyze adverse events in a neonatal intensive care unit based in Trigger Tool. It is an epidemiological, cross-sectional , exploratory, retrospective study with quantitative, descriptive and analytical approach, performed in 2015 at a school hospital. The sample was not probabilistic, involving 116 newborns who met the eligibility criteria. Data collection was performed by retrospective review of medical records, using a specific kind of "trigger" instrument, composed of sentinel events in neonatology, adapted from the American model used by the Vermont-Oxford Network. Data were analyzed using descriptive and inferential statistics. The chi-square test for linear trend was used to assess the associations between the variables of interest. The research received a favorable agreement from Ethics Committee of the Federal University of Rio Grande do Norte, under number 1055533, and Presentation Certificate for Ethics Assessment 43894515.6.0000.5537. The results show among investigated newborns, 110 experienced at least one adverse event during their stay, with a total of 391 medical records analyzed and rate of 3.37 events per patient. Prevailed the preterm newborns with low birth weight, from mother who had hypertensive diseases during pregnancy and urinary tract infection. The average hospitalization time was 25 days, associated with hospital-acquired infections events (p = 0.01). Among the identified adverse events stood out the events related to thermoregulation disorders (39.0%), with prevalence of hypothermia (26.0%), followed by health care-related infections (16.4%) and blood glucose disorders, hypoglycemia (9.00%) and hyperglycemia (6.64%). Most of these incidents were classified in categories E and F, which represents that there was damage small proportion. Due to these damages come from the care practice with newborn, 78% were classified as avoidable. There was statistically significant association between the variable birth weight with infections (p = 0.006) as well as peri/intraventricular bleeding (p = 0.02), hypoglycemia (p = 0.021), hyperglycemia (p = 0.001), hyperthermia (p = 0.39) and death (p=0,02). Gestational age was associated with seizures (p = 0.002), hyperglycemia (p=0.017) e hyperthermia (p=0.027). The security institution culture was reported by the health workers as intermediate, even though the number of adverse events found in only one unit of service indicates that there is much to be done. Thus the high rate of adverse events identified in the neonatal intensive care unit reinforces the necessity to elaborate specific preventive strategies for this risk environment.

Segurança do paciente em terapia intensiva neonatal: identificação e análise de eventos adversos

The patient safety is a major concern in health services for its global dimension, as evidenced by the fragility of care processes that predispose an occurrence of adverse events. These events in a neonatal intensive care unit are considered serious and hazardous to lives of newborns. The present study aimed to identify and analyze adverse events in a neonatal intensive care unit based in Trigger Tool. It is an epidemiological, cross-sectional , exploratory, retrospective study with quantitative, descriptive and analytical approach, performed in 2015 at a school hospital. The sample was not probabilistic, involving 116 newborns who met the eligibility criteria. Data collection was performed by retrospective review of medical records, using a specific kind of "trigger" instrument, composed of sentinel events in neonatology, adapted from the American model used by the Vermont-Oxford Network. Data were analyzed using descriptive and inferential statistics. The chi-square test for linear trend was used to assess the associations between the variables of interest. The research received a favorable agreement from Ethics Committee of the Federal University of Rio Grande do Norte, under number 1055533, and Presentation Certificate for Ethics Assessment 43894515.6.0000.5537. The results show among investigated newborns, 110 experienced at least one adverse event during their stay, with a total of 391 medical records analyzed and rate of 3.37 events per patient. Prevailed the preterm newborns with low birth weight, from mother who had hypertensive diseases during pregnancy and urinary tract infection. The average hospitalization time was 25 days, associated with hospital-acquired infections events (p = 0.01). Among the identified adverse events stood out the events related to thermoregulation disorders (39.0%), with prevalence of hypothermia (26.0%), followed by health care-related infections (16.4%) and blood glucose disorders, hypoglycemia (9.00%) and hyperglycemia (6.64%). Most of these incidents were classified in categories E and F, which represents that there was damage small proportion. Due to these damages come from the care practice with newborn, 78% were classified as avoidable. There was statistically significant association between the variable birth weight with infections (p = 0.006) as well as peri/intraventricular bleeding (p = 0.02), hypoglycemia (p = 0.021), hyperglycemia (p = 0.001), hyperthermia (p = 0.39) and death (p=0,02). Gestational age was associated with seizures (p = 0.002), hyperglycemia (p=0.017) e hyperthermia (p=0.027). The security institution culture was reported by the health workers as intermediate, even though the number of adverse events found in only one unit of service indicates that there is much to be done. Thus the high rate of adverse events identified in the neonatal intensive care unit reinforces the necessity to elaborate specific preventive strategies for this risk environment.

Profil d’activité physique des enfants et adolescents diabétiques de type 1

Les patients diabétiques de type 1 (DT1) ont avantage à avoir un bon contrôle glycémique pour réduire les effets négatifs à court et long terme d’un mauvais contrôle glycémique sur leur santé. Pour contrôler leur glycémie, ils doivent prendre de l’insuline, mais il est aussi recommandé qu’ils aient de bonnes habitudes de vie comme une nutrition appropriée et une pratique adéquate d’activité physique. Par contre, les patients DT1 ne suivent généralement pas les recommandations en activité physique et une partie du problème vient de leurs barrières personnelles à un style de vie actif, telle la peur des hypoglycémies. L’utilisation de la pompe comme traitement à l’insuline aide à mieux contrôler la glycémie, plus précisément l’hémoglobine glyquée, que les injections d’insuline, et le dispositif est de plus en plus prescrit chez les enfants et adolescents. Par contre, son impact sur la pratique des activités sédentaire et physique n’est pas encore bien connu. L’objectif de la présente étude est donc de révéler le profil d’activité physique complet, incluant les barrières à l’exercice et les habitudes de vie des parents, des enfants et adolescents DT1, selon leur type de traitement à l’insuline (pompe ou injections). L’étude a été conduite à la clinique d’endocrinologie du Centre hospitalier universitaire de Sainte-Justine (Montréal, Canada). Un questionnaire auto-administré a été complété par 188 patients DT1 âgés de 6 à 17 ans et un de leurs parents. Soixante pourcent des patients étaient des utilisateurs de la pompe à insuline. Il n’y avait pas de différence significative pour aucune des composantes du profil d’activité physique, des habitudes sédentaires et des barrières à l’exercice entre les patients DT1 utilisant les injections et ceux utilisant la pompe. La peur de faire des hypoglycémies était la barrière à l’activité physique principale pour les deux groupes de traitement. Les adolescents dont les parents pratiquaient une plus grande variété d’activités physiques faisaient plus d’activité physique d’intensité moyenne à élevée et passaient moins de temps devant les écrans. En conclusion, le type de traitement n’était pas associé à un style de vie plus sain chez les patients pédiatriques DT1, mais un profil d’activité physique parental varié était le facteur principal d’intérêt pour des habitudes de vie plus saines chez les adolescents DT1.