Jackie Elliott

Eating problems in adolescents with Type 1 diabetes: a systematic review with meta‐analysis

Diabet. Med. 30, 189–198 (2013)

Antinociceptive and toxic effects of (+)-epibatidine oxalate attributable to nicotinic agonist activity

1 Epibatidine is an analgesic substance, isolated from the skin of the poisonous frog Epipedobates tricolor, for which the mechanism of action was previously unknown. 2 The IC50 of synthetic (+)‐epibatidine oxalate (the naturally occurring isomer) for [3H]‐nicotine binding to rat whole‐brain membranes was 0.1 nm. The (−)−isomer also exhibited high affinity (IC50 = 0.2 nm). 3 (+)‐ and (−)−Epibatidine exhibited much lower affinity for displacement of the muscarinic ligand [3H]‐N‐methylscopolamine binding to rat cortical membranes (Kapp − 6.9μm and 16.0 μm respectively). The (+)‐enantiomer of epibatidine had an antagonist/agonist (NMS/oxo‐M) binding ratio of 4.2 This is consistent with a muscarinic antagonist profile. 4 (+)‐Epibatidine oxalate (10 μm) did not cause significant (>30%) displacement of radioligand binding to opioid, excitatory amino acid, benzodiazepine, 5‐HT, dopamine, adrenaline or peptide receptors. 5 (+)‐ and (−)−Epibatidine (5–20 μg kg−1 s.c.) doubled response latency in the mouse hot‐plate test. Antinociception and behavioural depression induced by (+)‐epibatidine (5 μg kg−1) was fully blocked by the nicotinic antagonists mecamylamine (2 mg kg−1 s.c.) or dihydro‐β‐erythroidine (2 mg kg−1 s.c). The muscarinic antagonist scopolamine (0.4 and 10 mg kg−1 s.c.) caused partial reversal of antinociception induced by (+)‐epibatidine in mice, but not in rats. 6 These findings demonstrate that (+)‐epibatidine oxalate salt is a highly selective and potent nicotinic analgesic agent.

LARGE-FIBER DYSFUNCTION IN DIABETIC PERIPHERAL NEUROPATHY IS PREDICTED BY CARDIOVASCULAR RISK FACTORS

OBJECTIVE Diabetic large–nerve fiber dysfunction, as measured by vibration perception threshold (VPT), predicts foot ulceration, amputation, and mortality. Thus, determination of modifiable risk factors is of great clinical importance. RESEARCH DESIGN AND METHODS We assessed 1,407 patients with type 1 diabetes and a normal VPT participating in the EURODIAB Prospective Complications Study, at baseline mean ± SD age of 32.7 ± 10.2 years with diabetes duration of 14.7 ± 9.3 years and follow-up of 7.3 ± 0.6 years. VPT was measured using biothesiometry on the right big toe and medial malleolus. An abnormal result was defined as >2 SD from the predicted mean for the patient s age. RESULTS An abnormal VPT was associated with an increased incidence of gangrene, amputation, foot ulceration, leg bypass or angioplasty, and mortality (P ≤ 0.02). The incidence of abnormal VPT was 24% over the 7.3-year follow-up. Duration of diabetes and A1C significantly influenced the incidence of abnormal VPT (P < 0.0001). After correction for these, established risk factors for cardiovascular disease (CVD), including male sex (P = 0.0004), hypertension (P < 0.0001), total cholesterol (P = 0.002), LDL cholesterol (P = 0.01), smoking (P < 0.0001), weight (P < 0.0001), and diabetes complications (retinopathy [P = 0.0001], nephropathy [P = 0.01], and autonomic neuropathy [P = 0.001]), were all found to be significant risk factors. A previous history of CVD doubled the incidence of abnormal VPT. CONCLUSIONS This prospective study indicates that cardiovascular risk factors predict development of large-fiber dysfunction, which may account for the high mortality rate in patients with an abnormal VPT, and emphasizes the importance of early determination of VPT to detect subclinical neuropathy and to address cardiovascular risk factors.

Substantial reductions in the number of diabetic ketoacidosis and severe hypoglycaemia episodes requiring emergency treatment lead to reduced costs after structured education in adults with Type 1 diabetes.

To determine the impact of structured education promoting flexible intensive insulin therapy on rates of diabetic ketoacidosis, and the costs associated with emergency treatment for severe hypoglycaemia and ketoacidosis in adults with Type 1 diabetes.

A Psychoeducational Program to Restore Hypoglycemia Awareness: The DAFNE-HART Pilot Study

OBJECTIVE To develop and pilot a novel intervention addressing motivational and cognitive barriers to avoiding hypoglycemia in people with type 1 diabetes and persistent impaired awareness of hypoglycemia (IAH) despite training in flexible insulin therapy. RESEARCH DESIGN AND METHODS A 6-week intervention using motivational interviewing and cognitive behavioral techniques was designed. Diabetes educators were trained and supported in its delivery to 23 people with IAH (Gold score ≥4). RESULTS Twelve months postcourse, hypoglycemia awareness had improved (P < 0.001). Median (range) rates of severe hypoglycemia (SH) fell from 3 (0–104) to 0 (0–3) per person per year (P < 0.0001) and moderate from 14 (0–100) to 0 (0–18) per person per 6 weeks (P < 0.001). Worry and behavior around hyperglycemia improved. HbA1c was unchanged. CONCLUSIONS A pilot intervention targeting motivation and cognitions around hypoglycemia engaged patients with resistant IAH and recurrent SH and was associated with significant improvement, supporting the hypothesis that these factors underpin problematic hypoglycemia.

Tolerance to μ-opioid agonists in human neuroblastoma SH-SY5Y cells as determined by changes in guanosine-5′-O-(3-[35S]-thio)triphosphate binding

The agonist action of morphine on membranes prepared from human neuroblastoma SH‐SY5Y cells was measured by an increase in the binding of the GTP analogue [35S]‐GTPγS. Morphine increased the binding of [35S]‐GTPγS to SH‐SY5Y cell membranes by 30 fmol mg−1 protein with an EC50 value of 76±10 nM. Incubation of SH‐SY5Y cells with 10 μM morphine for 48 h caused a tolerance to morphine manifested by a 2.5 fold shift to the right in the EC50 value with a 31±6% decrease in the maximum stimulation of [35 S]‐GTPγS binding. The response caused by the partial agonist pentazocine was reduced to a greater extent. Chronic treatment of the cells with the more efficacious μ‐ligand [D‐Ala2, MePhe4, Gly‐ol5]enkephalin (DAMGO, 10 μM) for 48 h afforded a greater effect than treatment with morphine. The maximal agonist effect of morphine was reduced to 58.9±6% of that seen in control cells while the maximal effect of DAMGO was reduced to 62.8±4%. There was a complete loss of agonist activity for pentazocine. The development of tolerance was complete within 24 h and was blocked by naloxone and by the nonselective protein kinase inhibitor H7, but not by the putative β‐adrenoceptor kinase (β‐ARK) inhibitor suramin. The observed tolerance effect was accompanied by a down‐regulation of μ‐opioid receptors determined by a decrease in the maximal binding capacity for the opioid antagonist [3H]‐diprenorphine of 66±4%, but with no change in binding affinity. Binding of the agonist [3H]‐DAMGO was similarly reduced. The modulation of [35S]‐GTPγS binding in SH‐SY5Y cell membranes by opioids provides a simple method for the study of opioid tolerance at a site early in the signal transduction cascade.

The value of outpatient hysteroscopy in diagnosing endometrial pathology in postmenopausal women with and without hormone replacement therapy.

Background.  This study examined the endometrial pathology in postmenopausal women who had experienced abnormal uterine bleeding, both with and without hormone replacement therapy (HRT), and who subsequently underwent outpatient hysteroscopy.

Experiences, Views, and Support Needs of Family Members of People With Hypoglycemia Unawareness: Interview Study

OBJECTIVE Hypoglycemia unawareness (HU) affects ∼25% of people with type 1 diabetes. People with HU are often reliant on family to detect hypoglycemia and treat severe episodes. We explored the impact of HU on family members’ lives, their involvement in preventing and managing hypoglycemia, and their information and support needs. RESEARCH DESIGN AND METHODS This study employed an exploratory, qualitative design comprising in-depth interviews with 24 adult family members of persons with type 1 diabetes and HU. RESULTS Family members described restricting their lives so that they could help the person with HU detect and treat hypoglycemia. Some described being very physically afraid of their partner/relative when they had a hypoglycemic episode due to their aggressive and argumentative behavior and personality changes; this could also make treatment administration difficult. Family members also reported feeling anxious and worried about the safety of the person with HU, particularly when they were left unsupervised. These concerns were often precipitated by traumatic events, such as discovering the person with HU in a coma. Family members could neglect their own health and well-being to care for the person with HU and resentment could build up over time. Family members highlighted extensive, unmet needs for information and emotional support; however, some struggled to recognize and accept their own need for help. CONCLUSIONS Our findings reveal a caregiver group currently “in the shadow of the patient” and in urgent need of information and emotional support. Raising awareness among health care professionals is essential, and developing proactive support for family should be considered.

Supporting self-management after attending a structured education programme: a qualitative longitudinal investigation of type 1 diabetes patients' experiences and views

BackgroundStructured education programmes for patients with diabetes and other chronic conditions are being widely adopted. However, follow-up studies suggest that course graduates may struggle to sustain the self-care practices taught on their courses over time. This study explored the support needs of patients with type 1 diabetes after attending a structured education programme promoting an empowerment approach and training in use of flexible intensive insulin therapy, a regimen now widely advocated and used to manage this condition. The objective was to inform future support offered to course graduates.MethodsRepeat, in-depth interviews with 30 type 1 diabetes patients after attending Dose Adjustment for Normal Eating (DAFNE) courses in the UK, and six and 12 months later. Data were analysed using an inductive, thematic approach.ResultsWhile the flexible intensive insulin treatment approach taught on DAFNE courses was seen as a logical and effective way of managing one’s diabetes, it was also considered more technically complex than other insulin regimens. To sustain effective disease self-management using flexible intensive insulin treatment over time, patients often expected, and needed, on-going input and support from health care professionals trained in the approach. This included: help determining insulin dose adjustments; reassurance; and, opportunities to trouble-shoot issues of concern. While some benefits were identified to receiving follow-up support in a group setting, most patients stated a preference or need for tailored and individualised support from appropriately-trained clinicians, accessible on an ‘as and when needed’ basis.ConclusionsOur findings highlight potential limitations to group-based forms of follow-up support for sustaining diabetes self-management. To maintain the clinical benefits of structured education for patients with type 1 diabetes over time, course graduates may benefit from and prefer ongoing, one-to-one support from health care professionals trained in the programme’s practices and principles. This support should be tailored and personalised to reflect patients’ specific and unique experiences of applying their education and training in the context of their everyday lives, and could be the subject of future research.

How and Why do Patients with Type 1 Diabetes Sustain their Use of Flexible Intensive Insulin Therapy?: A Qualitative Longitudinal Investigation of Patients' Self-Management Practices Following Attendance at a Dose Adjustment for Normal Eating (DAFNE) Course

Diabet. Med. 28, 532–538 (2011)