Recovery of hypoglycemia awareness in long-standing type 1 diabetes: a multicenter 2 × 2 factorial randomized controlled trial comparing insulin pump with multiple daily injections and continuous with conventional glucose self-monitoring (HypoCOMPaSS)

To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin infusion [CSII]) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG).

Insulin analog preparations and their use in children and adolescents with type 1 diabetes mellitus.

Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.

Novas Insulinas

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Hypoglycémie nocturne et habitudes alimentaires en soirée chez l'adulte atteint de diabète de type 1

L’hypoglycémie est une barrière au traitement du diabète de type 1 (DbT1). La collation au coucher est recommandée pour prévenir l’hypoglycémie nocturne (HN), mais son efficacité n’est pas démontrée. Objectif : Déterminer si une prise alimentaire en soirée est associée à la survenue d’HN. Étude observationnelle : 100 DbT1 ont porté un lecteur de glucose en continu et complété un journal alimentaire pendant 72 heures. L’HN est survenue durant 28 % des nuits. Une prise alimentaire en soirée n’était pas associée à l’HN. Toutefois, dans un modèle ajusté, l’apport en glucides en soirée était positivement associé aux HN (avec injection d’insuline rapide) et l’apport en protéines inversement associé aux HN (sans injection d’insuline rapide). Manger en soirée ne semble pas associé à moins d’HN. Des études contrôlées sont nécessaires pour comprendre l’effet de la collation au coucher sur le contrôle glycémique et le rôle de l’insuline rapide injectée en soirée.

Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies for successful prevention

Hypoglycaemia remains an over-riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long-duration diabetes and is one of the most feared diabetes-related complications. In this review, we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter-regulation, hypoglycaemia-associated autonomic failure, psychosocial and behavioural factors and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta-cell replacement therapies have been employed, yet there is little randomized controlled trial evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, as well as frequency and severity of all hypoglycaemic episodes.

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.

Fear and danger in nocturnal urban environments

At the centre of this research is an ethnographic study that saw the researcher embedded within the fabric of inner city life to better understand what characteristics of user activity and interaction could be enhanced by technology. The initial research indicated that the experience of traversing the city after dark unified an otherwise divergent user group through a shared concern for personal safety. Managing this fear and danger represented an important user need. We found that mobile social networking systems are not only integral for bringing people together, they can help in the process of users safely dispersing as well. We conclude, however, that at a time when the average iPhone staggers under the weight of a plethora of apps that do everything from acting as a carpenter’s level to a pregnancy predictor, we consider the potential for the functionality of a personal safety device to be embodied within a stand alone artifact.

Retinal anatomy of the New Zealand kiwi: Structural traits consistent with their nocturnal behavior

Kiwi (Apteryx spp.) have a visual system unlike that of other nocturnal birds, and have specializations to their auditory, olfactory and tactile systems. Eye size, binocular visual fields and visual brain centers in kiwi are proportionally the smallest yet recorded among birds. Given the many unique features of the kiwi visual system, we examined the laminar organization of the kiwi retina to determine if they evolved increased light sensitivity with a shift to a nocturnal niche or if they retained features of their diurnal ancestor. The laminar organization of the kiwi retina was consistent with an ability to detect low light levels similar to that of other nocturnal species. In particular, the retina appeared to have a high proportion of rod photoreceptors compared to diurnal species, as evidenced by a thick outer nuclear layer, and also numerous thin photoreceptor segments intercalated among the conical shaped cone photoreceptor inner segments. Therefore, the retinal structure of kiwi was consistent with increased light sensitivity, although other features of the visual system, such as eye size, suggest a reduced reliance on vision. The unique combination of a nocturnal retina and smaller than expected eye size, binocular visual fields and brain regions make the kiwi visual system unlike that of any bird examined to date. Whether these features of their visual system are an evolutionary design that meets their specific visual needs or are a remnant of a kiwi ancestor that relied more heavily on vision is yet to be determined.

Kiwi Forego Vision in the Guidance of Their Nocturnal Activities

Background In vision, there is a trade-off between sensitivity and resolution, and any eye which maximises information gain at low light levels needs to be large. This imposes exacting constraints upon vision in nocturnal flying birds. Eyes are essentially heavy, fluid-filled chambers, and in flying birds their increased size is countered by selection for both reduced body mass and the distribution of mass towards the body core. Freed from these mass constraints, it would be predicted that in flightless birds nocturnality should favour the evolution of large eyes and reliance upon visual cues for the guidance of activity. Methodology/Principal Findings We show that in Kiwi (Apterygidae), flightlessness and nocturnality have, in fact, resulted in the opposite outcome. Kiwi show minimal reliance upon vision indicated by eye structure, visual field topography, and brain structures, and increased reliance upon tactile and olfactory information. Conclusions/Significance This lack of reliance upon vision and increased reliance upon tactile and olfactory information in Kiwi is markedly similar to the situation in nocturnal mammals that exploit the forest floor. That Kiwi and mammals evolved to exploit these habitats quite independently provides evidence for convergent evolution in their sensory capacities that are tuned to a common set of perceptual challenges found in forest floor habitats at night and which cannot be met by the vertebrate visual system. We propose that the Kiwi visual system has undergone adaptive regressive evolution driven by the trade-off between the relatively low rate of gain of visual information that is possible at low light levels, and the metabolic costs of extracting that information.

Temporal and environmental influences on the vocal behaviour of a nocturnal bird

Temporal and environmental variation in vocal activity can provide information on avian behaviour and call function not available to short-term experimental studies. Intersexual differences in this variation can provide insight into selection effects. Yet factors influencing vocal behaviour have not been assessed in many birds, even those monitored by acoustic methods. This applies to the New Zealand kiwi (Apterygidae), for which call censuses are used extensively in conservation monitoring, yet which have poorly understood acoustic ecology. We investigated little spotted kiwi Apteryx owenii vocal behaviour over 3 yr, measuring influences on vocal activity in both sexes from time of night, season, weather conditions and lunar cycle. We tested hypotheses that call rate variation reflects call function, foraging efficiency, historic predation risk and variability in sound transmission, and that there are inter-sexual differences in call function. Significant seasonal variation showed that vocalisations were important in kiwi reproduction, and inter-sexual synchronisation of call rates indicated that contact, pair-bonding or resource defence were key functions. All weather variables significantly affected call rates, with elevated calling during increased humidity and ground moisture indicating a relation between vocal activity and foraging conditions. A significant decrease in calling activity on cloudy nights, combined with no moonlight effect, suggests an impact of light pollution in this species. These influences on vocal activity provide insight into kiwi call function, have direct consequences for conservation monitoring of kiwi, and have wider implications in understanding vocal behaviour in a range of nocturnal birds

A role for nocturnal serum testosterone surge in regulating spermatogenesis in the adult non-human primate

Adult male bonnet monkeys exhibit nychthemeral rhythms in testosterone (T) secretion but the precise role of this heightened level of T secretion in regulating spermatogenesis is not known. Intranasal administration of microdoses (500 mu g or 250 mu g/day) of Norethisterone (IN-NET) to adult monkeys (n = 6) at 1600 h each day selectively and completely suppressed the nocturnal surge levels of serum T. Concomitant with this was a significant reduction (P<0.01) in serum LH but not FSH levels. DNA flow cytometric analysis of testicular biopsy tissue showed by week 10 of IN-NET treatment an arrest in meiotic transformation of primary spermatocytes (4C) to round/elongate (1C/HC) spermatids and by week 20 there was a complete absence of 4C, 1C and HC cells (with a relative accumulation in 2C cells). The accumulated meiotic (4C) cells at week 10 showed an increase (>80%, P<0.01) in coefficient of variation and a decrease in intensity of DNA-bound ethidium bromide fluorescence, parameters characteristic of degenerating 'apoptotic' subpopulation of germ cells. While two monkeys exhibited acute oligozoospermia 4 became azoospermic by 20 weeks of IN-NET treatment. A complete, qualitative reversal in the regressive changes in spermatogenesis and near-normal sperm output were apparent at the end of a 20-week recovery phase. These data demonstrate that prolonged, selective suppression of nocturnal surge levels of serum T secretion exerts a primary effect on meiosis in spermatogenesis leading to oligo/azoospermic status in adult bonnet monkeys.

Nocturnal Perching of Scarabaeine Dung Beetles (Coleoptera, Scarabaeidae) in an Australian Tropical Rain Forest

Wongabel, a northeastern Queensland tropical, wet, evergreen forest, contains 22 species of Scarabaeinae dung beetles. Five of these species were observed to perch commonly on leaves at night. Length of the beetle and the height of its perch were recorded for each of 56 1 specimens. Unlike the New World tropical dung beetle perchers, no clear evidence was found that small species perched closer to the ground than larger species. The evidence gathered, at least for the four most common perchers, supports the hypothesis that perching is one type of foraging strategy. The similarities and differences between the Australian and New World perchers are discussed.

Visual ecology of Indian carpenter bees II: adaptations of eyes and ocelli to nocturnal and diurnal lifestyles

Most bees are diurnal, with behaviour that is largely visually mediated, but several groups have made evolutionary shifts to nocturnality, despite having apposition compound eyes unsuited to vision in dim light. We compared the anatomy and optics of the apposition eyes and the ocelli of the nocturnal carpenter bee, Xylocopa tranquebarica, with two sympatric species, the strictly diurnal X. leucothorax and the occasionally crepuscular X. tenuiscapa. The ocelli of the nocturnal X. tranquebarica are unusually large (diameter ca. 1 mm) and poorly focussed. Moreover, their apposition eyes show specific visual adaptations for vision in dim light, including large size, large facets and very wide rhabdoms, which together make these eyes 9 times more sensitive than those of X. tenuiscapa and 27 times more sensitive than those of X. leucothorax. These differences in optical sensitivity are surprisingly small considering that X. tranquebarica can fly on moonless nights when background luminance is as low as 10(-5) cd m(-2), implying that this bee must employ additional visual strategies to forage and find its way back to the nest. These strategies may include photoreceptors with longer integration times and higher contrast gains as well as higher neural summation mechanisms for increasing visual reliability in dim light.

Role of prolactin(prl) in regulation of the nocturnal surge of testosterone (t) in the bonnet monkey (macaca radiata)

Earlier studies from this lebordory have shown thet adult male bonnet monkeys exhibit nychthemrel rhythmicity la the secretion of serum 'T' the levele reehlng peek by 22OOhr. Of the gonedotropine cnelyeed only serum PRL showed a concommitent increme with T(Biol.of Reprod. 24,814, 1981). In the present study mMinietretion of l rgobromocryptin (EBC) either by i.v.route(2mg)or by naeel l pr~(100~)reeulted in blockade of nocturnal increase of both PRL end T(Controle T-18.6ng/ml: PRL 130=29ng/ml: EBC treated T-2.2&1.2ng/ml; PRL n.d.to 15nng/ml). Adminietretion of N oPRL could not reverse the effect of EBC. Although, increaeed serum PRL induced by injection of Chlorprommine did not result in increase in serum 'T' during the dey time, the nocturnel 'T' surge could not be obeeerved. EBC treeted monkeys, however, showed normal testosterone response to exogenous hCG. These IeSUlte a0 SwgeStive of high levels of PRL me&in6 reeponeiveneee of testes to tonic levels of serum IX. (Aided by grant8 from ICMR, Kew Delhi, WHO, Geneva eld FPF, India).