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Call number: LD2668 .T4 1959 D72

Background: Physical activity (PA) poses an additional burden on people living with type 1 diabetes (T1D) as it increases the risk of hypoglycemia, if performed at a moderate intensity. It is hypothesized that adding vigorous PA (VPA) into moderate PA (MPA) may help attenuate exercise-related hypoglycemia. Methods: Seventeen participants with T1D (23.7±6.6 years) completed an observational study of six days with continuous glucose monitoring and accelerometer-derived measures of PA to determine the association between PA intensity and both hypoglycemia risk and glucose variability (GV). Results: Higher evening moderate-to-vigorous PA (MVPA) increased the risk of overnight hypoglycemia (OR 1.03; 95% CI 1.002-1.047, p=0.031). Increased evening VPA was not associated with reduced hypoglycemia, but decreased overnight GV (3.20±0.25 for low vs 2.27±0.29 for high; p=0.022). Conclusions: Performing evening MVPA increases hypoglycemia risk overnight, but incorporating VPA did not prove to be protective. However, VPA reduced GV, which is a predictor of hypoglycemia. / May 2016

Background: Children have historically been fasted for prolonged periods preoperatively to reduce the volume and acidity of their gastric contents and thus the risk of regurgitation and pulmonary aspiration. Evidence shows that this risk is not increased by following the current recommended fasting guidelines, and that prolonged fasting may be detrimental to children, who may present with hunger, thirst, depleted intravascular volume, metabolic acidosis and hypoglycaemia. A recent study at Charlotte Maxeke Johannesburg Academic Hospital showed a 18.5% prevalence of biochemical hypoglycaemia, defined as a blood glucose concentration of less than 3.5 mmol/l, in children from one to five years of age presenting for elective surgery. Aims: The aims of this study were to document the prevalence of biochemical hypoglycaemia in children from the ages of one to five years who were given apple juice to drink at least two hours preoperatively, and to compare these results to a historical control group. Methods: A prospective, contextual comparative study design was used. Approval was obtained from the University of the Witwatersrandʼs Human Ethics Committee and other relevant authorities. The groups were matched for age and weight. Consent was obtained from the guardians of all children who met the inclusion criteria before being enrolled in the study. A standard 200 ml carton of commercially available apple juice was offered to each participant. The volume and time of the juice consumed was documented, along with relevant demographic data. Inhalational induction of anaesthesia proceeded a minimum of two hours later, and a venous glucose concentration was measured. Results: The prevalence of biochemical hypoglycaemia was statistically significantly reduced in the intervention group (p = 0.0163), eliminating the effect of prolonged preoperative fasting. Conclusion: The consumption of clear apple juice on the morning of surgery is a safe, inexpensive, effective way to reduce the prevalence of hypoglycaemia in children presenting for elective surgery.

The combination of bone morphogenetic protein 7 (BMP7) and neurotrophins (e.g. brain-derived neurotrophic factor, BDNF) protects septal neurons during hypoglycemic stress. I investigated the signaling mechanisms underlying this synergistic protection. BMP7 (5 nM) increased phosphorylation and nuclear translocation of BMP-responsive Smads 1/5/8 within 30 min in cultures of rat embryonic septal neurons. BDNF (100 ng/ml) enhanced the BMP7-induced increase in phospho-Smad levels in both nucleus and cytoplasm; this effect was more pronounced after a hypoglycemic stress. BDNF increased both Akt and Erk phosphorylation, but pharmacological blockade of these kinase pathways (with wortmannin and U0126, respectively) did not reduce the Smad phosphorylation produced by the BMP7+BDNF combination. Inhibitors of casein kinase II (CK2) activity reduced the (BMP7 + BDNF)-induced Smad phosphorylation, and this trophic factor combination increased CK2 activity in hypoglycemic cultures. These findings suggest that BDNF can increase BMP-dependent Smad phosphorylation via a mechanism requiring CK2. Preliminary results indicate that a cytoplasmic component robustly inhibits CK2. Protection of septal cholinergic neurons during a hypoglycemic stress is inhibited by a CK2 inhibitor and by a Phosphatidylinositol 3-kinase inhibitor, indicating that increases in CK2 activity and in Smad phosphorylation are only part on the protective mechanisms.

Thesis--Helsinki. / Includes five papers on which the present dissertation is based (p. 61-131). Includes bibliographical references.

We hypothesize that brain glycogen, a stored form of glucose, may provide fuel for the brain conferring both negative and positive effects throughout the brain. The over accumulation of brain glycogen, or supercompensation, is hypothesized to exacerbate hypoglycemia associated autonomic failure (HAAF), promote memory and learning, and reduce neuron cell death during severe episodes of hypoglycemia. It was determined that brain glycogen supercompensation does occur in the mouse 6 hours following single and recurrent hypoglycemic episodes, but it is not likely a significant mechanism behind HAAF due to the supercompensation subsiding at 27 hours following the hypoglycemic episodes. In regard to memory and learning, brain glycogen is not required for motor skill learning while euglycemic, however, it does enhance motor memory while hypoglycemic as determined using a rotarod treadmill in mouse. In regard to associative learning, brain glycogen is important for contextual, but not cued, memories while both euglycemic and hypoglycemic, as assessed by contextual and cued fear conditioning. Two different genetically engineered models of mice lacking brain glycogen yielded opposing results when assessing whether brain glycogen is neuroprotective during severe and prolonged hypoglycemia. In conclusion, brain glycogen does not appear to play a role in HAAF, is important for learning and memory, and its role in neuronal cell survival during hypoglycemia requires further study. / Department of Biology

Hypoglycemia is a severe side effect of insulin overdose in the diabetic population and can result in various neurological sequalae including seizures, coma, and brain death. There is still a limited understanding of the generation and propagation of hypoglycemic seizures, which may exacerbate hypoglycemia-induced neuronal damage. Moreover, glucose reperfusion after a period of transient hypoglycemia has been shown to cause neuronal hyperexcitability which can have further damaging effects. Gap junctional communication can be involved in the spread of hypoglycemic injury in two ways: 1) by providing a cytoplasmic continuity in which seizures can easily propagate and 2) by engaging the astrocytic network in metabolic compensation as well as enhancing astrocytic buffering of K+. This study aims to investigate the role that gap junctions play during brain energy deprivation. Results from these experiments show that gap junction blockade can have a neuroprotective role during hypoglycemia and glucose reperfusion.

Thesis--Helsinki. / Includes five papers on which the present dissertation is based (p. 61-131). Includes bibliographical references.