M.R. Graham1*, B. Davies2, Pates J3, P.J. Evans4 and J.S. Baker5 1MBChB, PhD, Llantarnam Research Academy, Newport Road, Llantarnam, Cwmbran, UK 2FACSM, Health and Exercise Science Department, University of South Wales, UK 3Bournville College, Birmingham, UK 4Royal Gwent Hospital, Newport, Wales, UK 5FRSM, FHBA, FSB, FICR, C.Biol, C.Sci Director of Research, Institute of Clinical Exercise and Health Science, Applied Physiology Research Laboratory, School of Science and Sport, University of the West of Scotland, Hamilton, Lanarkshire, Scotland

Short reportFree Access The role of diabetic alert dogs in the management of impaired hypoglycaemia awareness Dr Jason Seewoodhary BSc(Hons), MBBCh(Hons), MRCP(UK), MSc(Dist), Corresponding Author Dr Jason Seewoodhary BSc(Hons), MBBCh(Hons), MRCP(UK), MSc(Dist) Specialist Registrar in Diabetes Mellitus Endocrinology/General Internal Medicine Wrexham Maelor Hospital, Wrexham, UKCorrespondence to: Dr Jason Seewoodhary, Department of Diabetes Mellitus & Endocrinology, Wrexham Maelor Hospital, Croesnewydd Road, Wrexham LL13 7TD, UK; email: seewoodharyj@hotmail.comSearch for more papers by this authorDr Thomas Dacruz MBBS, MRCP(UK), Dr Thomas Dacruz MBBS, MRCP(UK) Specialist Registrar in Diabetes Mellitus Endocrinology/ General Internal Medicine Royal Gwent Hospital, Newport, Gwent, UKSearch for more papers by this authorDr Erin Lloyd MBBCh(Wales), Dr Erin Lloyd MBBCh(Wales) Foundation Year 1 Doctor in Diabetes Mellitus Endocrinology/General Internal Medicine Wrexham Maelor Hospital, Wrexham, UKSearch for more papers by this authorProfessor Peter J Evans MD, FRCP, Professor Peter J Evans MD, FRCP Consultant Physician, Diabetes Mellitus Endocrinology/General Internal Medicine Royal Gwent Hospital, Newport, Gwent, UKSearch for more papers by this author Dr Jason Seewoodhary BSc(Hons), MBBCh(Hons), MRCP(UK), MSc(Dist), Corresponding Author Dr Jason Seewoodhary BSc(Hons), MBBCh(Hons), MRCP(UK), MSc(Dist) Specialist Registrar in Diabetes Mellitus Endocrinology/General Internal Medicine Wrexham Maelor Hospital, Wrexham, UKCorrespondence to: Dr Jason Seewoodhary, Department of Diabetes Mellitus & Endocrinology, Wrexham Maelor Hospital, Croesnewydd Road, Wrexham LL13 7TD, UK; email: seewoodharyj@hotmail.comSearch for more papers by this authorDr Thomas Dacruz MBBS, MRCP(UK), Dr Thomas Dacruz MBBS, MRCP(UK) Specialist Registrar in Diabetes Mellitus Endocrinology/ General Internal Medicine Royal Gwent Hospital, Newport, Gwent, UKSearch for more papers by this authorDr Erin Lloyd MBBCh(Wales), Dr Erin Lloyd MBBCh(Wales) Foundation Year 1 Doctor in Diabetes Mellitus Endocrinology/General Internal Medicine Wrexham Maelor Hospital, Wrexham, UKSearch for more papers by this authorProfessor Peter J Evans MD, FRCP, Professor Peter J Evans MD, FRCP Consultant Physician, Diabetes Mellitus Endocrinology/General Internal Medicine Royal Gwent Hospital, Newport, Gwent, UKSearch for more papers by this author First published: 16 October 2014 https://doi.org/10.1002/pdi.1895Citations: 5AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat The challenges of hypoglycaemia Most healthy adults maintain a fasting glucose concentration >4mmol/L and develop symptoms of hypoglycaemia when the glucose concentration is <4mmol/L. Criteria referred to as Whipple's triad are used to determine a diagnosis of hypoglycaemia and consist of: symptoms known to be caused by hypoglycaemia; low glucose at the time the symptoms occur; and reversal of symptoms when the glucose is restored to normal.1 Accordingly, a pragmatic approach to clinically defining hypoglycaemia is dependent upon: the clinical context of the definition; patient age and comorbidities; the measurement method; and the presence or absence of symptoms. Hypoglycaemia is a serious and common complication of the treatment for diabetes. An estimated 2–4% of deaths in patients with type 1 diabetes mellitus (T1DM) have been attributed to hypoglycaemia.2 The Diabetes Control and Complications Trial (DCCT) reported a significantly higher prevalence in severe hypoglycaemia and coma in intensively-treated patients relative to those treated conventionally.3 The DCCT also reported that patients with T1DM on intensive treatment encountered ~10 episodes of symptomatic hypoglycaemia weekly and severe temporarily disabling hypoglycaemia at least once a year.4 The United Kingdom Prospective Diabetes Study Group (UKPDS) reported prevalence rates of hypoglycaemia in patients with type 2 diabetes mellitus (T2DM) using insulin of 70–80%.5 Predictors of hypoglycaemia in patients with diabetes include a history of previous hypoglycaemia and the duration of insulin treatment. Self-reported hypoglycaemia is lower in T2DM relative to T1DM.6 Recurrent episodes of hypoglycaemia can lead to impaired hypoglycaemia awareness, characterised by attenuation of the warning symptoms associated with the protective autonomic and neuroglycopaenic responses. This leads to the development of three clinical phenomena as a dangerous iatrogenic sequel of hypoglycaemia, namely unawareness, defective glucose counter-regulation and a lowered hypoglycaemic threshold for symptoms. Two to three weeks of careful avoidance of hypoglycaemia can reverse hypoglycaemia unawareness. Leading on from this, recent evidence suggests that restoration of impaired hypoglycaemia awareness and defective counter-regulation can be achieved using an interventional treatment strategy comprising the HypoCOMPaSS education tool. This study reported that glucose concentrations, at which patients first felt hypoglycaemic, significantly increased from 2.6 ± 0.1mmol/L to 3.1 ± 0.2mmol/L and symptom and plasma metanephrine responses to hypoglycaemia were significantly higher.7 However, if prolonged avoidance of hypoglycaemia fails to restore warning symptoms, then treatment is limited in its application. Accordingly, recent evidence suggests diabetes alert dogs (DADs) may have a therapeutic role in this regard. This review will critically consider the evidence underlying this. Canine olfactory system The olfactory acuity of the dog can detect odorant concentration levels at 1–2 parts per trillion (10 000–100 000 times that of the human). The gross anatomical structure of the nasal cavity is an indicator of olfactory acuity. Macrosmats (canines) possess a highly developed 'olfactory recess' at the rear of the nasal cavity, off the main respiratory passage that contains scroll-like ethmoturbinates, which are lined with olfactory epithelium. This is largely absent in microsmats, such as humans where the olfactory mucosa is characteristically located in the superior part of the nasal cavity. The nasal airway architecture in dogs enables airflow to be forced in a unidirectional flow to the olfactory recess and remain stagnant for a period of expiration. Olfactory discrimination occurs through the unique spatio-temporal odorant deposition pattern in the olfactory epithelium for different chemicals.8 Training DAD breeds are predominantly Labrador, Golden Retriever and German Shepherd. There are no national standards, protocols nor government regulations for training, assessing and monitoring DADs. Training takes 18–24 months, starting soon after birth with scent-imprinting using odour samples collected from clients during hypoglycaemic episodes. Training also includes scent work, house training, work in public, leash training, and formal training about alerts and other DAD tasks such as retrieving phones or glucose monitoring kits. Once trained, the owner receives two weeks of training with the dog. Some dogs are already owned by the patient while others are shaped by trainers and placed with selected patients. As changes in glucose concentrations appear in body secretions 15–30 minutes before showing up in the blood, values from continuous glucose meters or home blood glucose meters lag behind what a well-trained DAD can sense. In addition to sensing hypoglycaemia, DADs can also be trained to detect the scent of ketosis, thereby potentially preventing diabetic ketoacidosis. DADs are trained to recognise this through associative learning similar to that of any sniffer dog training. DADs can be particularly helpful in detecting nocturnal hypoglycaemia. When DADs smell changes in the patient's blood glucose, they rouse them from sleep. The patient is alerted to hypoglycaemic events through barking, whining, licking a hand or using another signalling method that ultimately depends on the patient's needs, age, health and lifestyle. This reduces the risk of seizures, brain damage and death.9 Evidence A limited number of case studies have suggested that some dogs can detect and alert their owners to hypoglycaemic episodes before they become symptomatic by exhibiting specific behaviours. A survey of 212 owners of dogs kept as pets found that 65% of these dogs showed behavioural reactions to at least one hypoglycaemia episode; 33.6% of owners believed their dog's reactions occurred before they were personally aware of the episode.10 Furthermore, a recent preliminary survey completed by 36 DAD owners found that, over a one-month period, 36.1% of all occurrences of hypoglycaemia were alerted by the dog and 27.8% reported less than one event per week. In all, 91.7% reported that DAD alerts occurred at blood glucose levels between 3.3–3.9mmol/L. Interestingly, 61.1% of respondents reported a decreased anxiety about hypoglycaemia, suggesting a beneficial psychological outcome for the patient.11 There have been cases of dogs alerting their owners to glycaemic episodes at critical points in time such as while driving/sleeping. A recent observational study was performed by researchers from the University of Dundee in collaboration with a charity called Medical Detection Dogs. All 17 participants reported reduced paramedic call-outs and episodes of unconsciousness and overall improved independence. Eight out of 10 dogs responded consistently to glucose levels out of the target range and the HbA1c showed a small but non-significant reduction after the introduction of a medical alert dog.9 Current position in the UK In the UK, Medical Detection Dogs is an organisation that trains and supplies DADs. Due to limited resources, there is a waiting list and strict eligibility criteria, which includes: being aged between 5–70 years and diagnosed with diabetes for at least 12 months associated with impaired hypoglycaemia awareness that has significantly affected the patient's quality of life, e.g. multiple hospital admissions; the extent that impaired hypoglycaemia awareness has negatively impacted upon education and employment; the patient's ability to bond with the DAD, coupled with their commitment to the ongoing training of the dog inclusive of attending the training centre and public access training days; and the need for a successor dog. Medical Detection Dogs has an appeals procedure for patients wishing to appeal against a decision not to place a Medical Alert Assistance Dog following application.12 Case study – Gemma and Polo the Labrador13 'Gemma was diagnosed with type 1 diabetes aged three years. Although Gemma was lucky enough to receive an insulin pump, she battled with poor hypoglycaemia awareness. 'To try and catch these hypos we used to test up to 15 times throughout the day and night. As her parents, we often set the alarm clock up to three times throughout the early hours to measure and prevent night-time hypoglycaemia, as Gemma never wakes when she is having night-time hypos. 'When Gemma first read about Medical Alert Assistance Dogs she was very excited to think how this would make such a difference to her daily life and how a dog with this training could keep her safe and healthy. 'We soon completed an application. We explained to Gemma to try and not get her hopes up too high; we knew the charity was in its infancy and we could only imagine the demand that was being put on them. A year or so on, we were really excited to get a call from the charity; we were invited up for an interview. When Gemma learned that she had been accepted onto the waiting list, we were all over the moon. A few weeks passed and then we received an email to say that they had a possible dog for Gemma: a black Labrador called Polo. 'Polo is one of the family. Not only does he alert to Gemma's blood glucose levels, but he is great fun to be around. 'A really important date was when Polo alerted during the night to Gemma having a hypo. He came into our bedroom and came up to me; I knew he was telling me there was a problem – we tested Gemma's blood and she was 3.6! 'There have been times when it has been hard to manage her condition. She has been admitted to hospital on several occasions, when complications have occurred and we haven't been able to manage the diabetes at home. 'Gemma said to us that having Polo her Medical Detection Dog is the best thing that has happened to her! He has such a lovely nature, placid and funny at the same time. He has made a difference to all our lives. Not only does Gemma feel safer and more confident, at night we can sleep easier, knowing that Polo will come and wake us if there is something wrong with Gemma's blood glucose levels.' Future/long-term role Medical alert dogs have been shown to be beneficial in augmenting patient independence and glycaemic control that could ultimately reduce the costs of long-term health care, although further longitudinal research studies are needed. Current research is limited in its application and utility by the pitfalls of case-series data – namely small sample sizes, non-randomisation, recall bias, subjectivity and no control group for comparison. Furthermore, most reports rely on owner accuracy in recalling events, thus potentially over-reporting success rates. Conclusions Trained dogs are worth approximately US $25–30 000 when taking into consideration other costs such as breeding, veterinary bills and training, and follow-up services once the dog has been placed with the owner. Health insurance companies rarely cover the costs of dogs due to the lack of proven effectiveness from scientific studies. In terms of practicality, there are difficulties in training the dog to recognise the scent emitted via a human as opposed to a static sample in the training room and to respond to a hypoglycaemic event even when the owner is not attentive. Variability in location when the hypoglycaemic event occurs may affect the dog's learned behaviours and helping the owner to sustain a consistent alert process are all factors that need to be taken into account. Declaration of interests There are no conflicts of interest declared. Funding: none declared. References 1Cryer PE, et al. Evaluation and management of adult hypoglycaemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009; 94: 709– 28. 2Cryer PE. Current concepts: Diverse causes of hypoglycaemia-associated autonomic failure in diabetes. N Eng J Med 2004; 350: 2272– 9. 3 The Diabetes Control and Complications Trial Research Group. Hypoglycaemia in the Diabetes Control and Complications Trial. Diabetes 1997; 46: 271– 86. 4 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J Med 1993; 329: 977– 86. 5Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837– 53. 6Donnelly LA, et al. Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study. Diabet Med 2005; 22: 749– 55. 7Leelarathna L, et al. Restoration of self-awareness of hypoglycaemia in adults with long-standing type 1 diabetes. Diabetes Care 2013; 36: 4063– 70. 8Craven BA, et al. The fluid dynamics of canine olfaction: unique nasal airflow patterns as an explanation of macrosmia. J R Soc Interface 2010; 7: 933– 43. 9Rooney NJ, et al. Investigation into the value of trained glycaemic alert dogs to clients with type 1 diabetes. PLoS ONE 2013; 8: e69921. 10Wells DL, et al. Canine responses to hypoglycemia in patients with type 1 diabetes. J Altern Complement Med 2008; 14: 1235– 41. 11Gonder-Frederick L, et al. Diabetic alert dogs: a preliminary survey of current users. Diabetes Care 2013; 36: e47. 12www.medicaldetectiondogs.org.uk/criteria.html. 13http://medicaldetectiondogs.org.uk/gemma_polo.html. Citing Literature Volume31, Issue8October 2014Pages 323-325 ReferencesRelatedInformation

Stem cells offer a novel approach to diabetes care based on regeneration, which can potentially shift treatment paradigms towards curation; therapeutic approaches have honed in on generating functional stem cell-derived islet cells for transplantation. Other approaches include stimulating endogenous stem cell replication followed by differentiation into functional islet cells in situ. This review critically considers the impact of diabetes on endogenous stem cells and discusses the potential utility of stem cell therapies for the treatment of diabetes.

Abstract Anabolic-androgenic steroids (AASs) can be used to increase muscle mass and strength in adult males. Despite successful detection and convictions by sporting anti-doping agencies, they are still being used to increase physical performance and improve appearance. The adverse side effects and potential dangers of AAS use are well documented. Recent epidemiological research has identified that the designer drugs growth hormone (GH) and insulin are also being used because of the belief that they improve sporting performance. This chapter summarizes the classification of AASs, GH, and insulin as well as their prevalence and patterns of use. The physiology of GH and its pathophysiology in the disease states of deficiency and excess and in catabolic states are discussed and a distinction is made on the different effects between therapeutic use in replacement and abuse in a sporting context. The history, physiology, and pathophysiology of insulin in therapeutic replacement and its abuse in a sporting context are also described. A suggestion is made on potential mechanisms of the effects of GH and insulin.

Arterial endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and predisposes individuals to the deposition of unstable atherosclerotic plaques. It can also lead to increased arterial stiffness, which is an accepted cause of increased arterial pulse wave velocity (APWV). Endothelial dysfunction is reversed by recombinant human growth hormone (rhGH) therapy in patients with growth hormone (GH) deficiency (GHD), favorably influencing the risk for atherogenesis. Endogenous human growth hormone (hGH), secreted by the anterior pituitary, and levels of insulin-like growth factor-I (IGF-I), produced in response to hGH stimulation of the liver, peak during early adulthood, but decline throughout adulthood. It is suspected that low-grade inflammatory cardiovascular pathophysiologic markers such as homocysteine, nitric oxide, C-reactive protein (CRP), and fibrinogen and plasminogen activator inhibitor along with changes in lipid and glucose metabolism may all contribute to GHD-associated metabolic and cardiovascular complications. These effects are associated with increased APWV, but are attenuated by rhGH therapy in GHD. GH replacement increases IGF-I levels and reduces CRP and large-artery stiffness. Reviews of rhGH in the somatopause have not been overtly favorable. Whereas reviews of rhGH/rhIGF-I combinations in GH resistance are more positive than those for rhGH alone, their combined use in the somatopause is limited. Senescent individuals may benefit from such a combination.

The current drastic escalation in obesity may be contributing to the exponential rise in drugs used for image enhancement. Drugs such as anabolic-androgenic steroids (AAS) are perceived as a viable method of achieving a perfect physique. They are also the most widely abused drugs in sport. The Internet has encouraged the abuse of expensive drugs, particularly human growth hormone (hGH), resulting in increased importation for personal use. The substantial increase in this market has opened up avenues for counterfeiting, estimated as a multi-million pound business. The acute adverse effects from contaminated vials may result in a variety of pathologies including communicable diseases. In 2007, in the UK, a series of intramuscular abscesses, requiring surgical treatment, led us to study samples obtained from the underground market. The analysis of 38 parenteral samples and 19 oral samples of tablets was performed by a World Anti-Doping Agency (WADA) accredited laboratory, in an attempt to establish the extent of available counterfeit products. Fifty-three per cent (20) of the injectable AAS esters and 21% (4) of the oral tablets were counterfeit. Culture and sensitivity revealed the presence of skin commensal organisms, which may have contributed to the development of the abscesses. Users of AAS and hGH for sport, including bodybuilding, are currently risking their health because of counterfeit and poorly controlled products.

Athletes have enjoyed almost a thirty year amnesty of rhGH abuse, which they consider has contributed to the winning of medals and the breaking of world records. Such a reprieve is almost at an end, since WADA have identified a method to detect rhGH abuse. Or have they? The anecdotal word "on the street" is that rhGH is still undetectable and athletes believe that the benefits, at the dosages they administer, far outweigh the risks! Scientists are aware that in a hormone deficiency condition, replacement can halt and in certain situations reverse some of the adverse effects. Growth hormone deficiency can lead to a loss of skeletal muscle mass and an increase in abdomino-visceral obesity, which is reversed on replacement with rhGH. Since the availability of GH, athletes have been trying to extrapolate these effects from the deficiency state to the healthy corpus and increase their sporting prowess. Past confessions from athletes, such as Ben Johnson, Kelly White, Tim Montgomery, Marion Jones and currently Dwain Chambers have demonstrated that they are prepared to tread the very fine lines that separate the "men from the boys". Rewards are so great, that anonymous surveys have identified that athletes will risk ill health, if they believe they can cheat, win and not get caught. The question that still needs to be answered is, "does growth hormone enhance performance"? Recent research suggests that it could. There is also a suspicion that in "cycled" low supraphysiological doses, it is no where near as harmful as WADA claim it to be.

BACKGROUND/AIMS:Recombinant human growth hormone (rhGH) as opposed to cadaver pituitary GH is misused for physical improvement. Six days' rhGH administration, in abstinent anabolic-androgenic steroid dependents, was compared with controls. METHOD:Male subjects (n = 48) were randomly divided into two groups: (1): control group (C), n = 24, mean +/- SD, age 32 +/- 11 years, height 1.8 +/- 0.06 m; (2): rhGH-using group (0.058 IU.kg(-1).day(-1)) (GH), n = 24, mean +/- SD, age 32 +/- 9 years, height 1.8 +/- 0.07 m. Physiological measurements included anthropometry, strength, power and peak oxygen uptake (VO(2) peak). Biochemical measurements included haemoglobin, packed cell volume, glucose, sodium, potassium, urea, creatinine, total protein, albumin, thyroid function, testosterone, prolactin, cortisol, GH and insulin-like growth factor-I (IGF-I). RESULTS:Strength, peak power output and IGF-I significantly increased and total protein, albumin and free tetra-iodothyronine significantly decreased compared to controls (p < 0.05) and within the GH group (p < 0.017). Fat-free mass index and VO(2) peak significantly increased, while body fat and thyroid-stimulating hormone significantly decreased within the GH group (p < 0.017). CONCLUSIONS:Short-term rhGH increased strength and power. Of therapeutic value is the possibility that muscle bulk and strength could be increased in patients with muscle-wasting conditions.

Blood pressure (BP) measurements provide information regarding risk factors associated with cardiovascular disease, but only in a specific artery. Arterial stiffness (AS) can be determined by measurement of arterial pulse wave velocity (APWV). Separate from any role as a surrogate marker, AS is an important determinant of pulse pressure, left ventricular function and coronary artery perfusion pressure. Proximal elastic arteries and peripheral muscular arteries respond differently to aging and to medication. Endogenous human growth hormone (hGH), secreted by the anterior pituitary, peaks during early adulthood, declining at 14% per decade. Levels of insulin-like growth factor-I (IGF-I) are at their peak during late adolescence and decline throughout adulthood, mirror imaging GH. Arterial endothelial dysfunction, an accepted cause of increased APWV in GH deficiency (GHD) is reversed by recombinant human (rh) GH therapy, favorably influencing the risk for atherogenesis. APWV is a noninvasive method for measuring atherosclerotic and hypertensive vascular changes increases with age and atherosclerosis leading to increased systolic blood pressure and increased left ventricular hypertrophy. Aerobic exercise training increases arterial compliance and reduces systolic blood pressure. Whole body arterial compliance is lowered in strength-trained individuals. Homocysteine and C-reactive protein are two inflammatory markers directly linked with arterial endothelial dysfunction. Reviews of GH in the somatopause have not been favorable and side effects of treatment have marred its use except in classical GHD. Is it possible that we should be assessing the combined effects of therapy with rhGH and rhIGF-I? Only multiple intervention studies will provide the answer.

The nontherapeutic use of prescription medicines by individuals involved in sport is increasing. Anabolic-androgenic steroids (AAS) are the most widely abused drug. Much of our knowledge of the psychological and physiological effects of human growth hormone (hGH) and insulin has been learned from deficiency states. As a consequence of the Internet revolution, previously unobtainable and expensive designer drugs, particularly recombinant human growth hormone (rhGH) and insulin, have become freely available at ridiculously discounted prices from countries such as China and are being abused. These drugs have various physiological and psychological effects and medical personnel must become aware that such prescription medicine abuse appears to be used not only for performance and cosmetic reasons, but as a consequence of psychological pre-morbidity.