AbstractHypoglycaemia and fear of hypoglycaemia is considered one of the greatest barriers to patients optimising their metabolic control in Type 1 Diabetes (T1D). Recurrent hypoglycaemia (RH) leads to diminished symptomatic and hormonal (blunted counterregulatory) responses to further hypoglycaemia, which collectively form a clinical syndrome referred to as Impaired Awareness of Hypoglycaemia (IAH), a condition that affects one in four of all patients with T1D. IAH markedly increases an individual’s risk of severe
hypoglycaemia (defined as the need for active external assistance for recovery), which has a recognised morbidity and mortality.
Despite improvements in insulin formulations and delivery devices, rates of severe hypoglycaemia have remained static in the last two decades, therefore there remains an
urgent clinical need for novel, alternative strategies to prevent severe hypoglycaemia and restore hypoglycaemia awareness.
This thesis contains studies that represent a first attempt to translate basic research in cells and animal models into novel therapies for impaired awareness of hypoglycaemia in human subjects with Type 1 diabetes. The first study was based on the pre-clinical finding that hypothalamic ATP-sensitive K + (KATP) channels are integral to the detection of
hypoglycaemia as well as instrumental to mounting a counter-regulatory response to hypoglycaemia. In a randomised, double-blind hyperinsulinaemic hypoglycaemia clamp
study, I compared the effect of an oral KATP channel activator, Diazoxide, on counterregulatory responses to hypoglycaemia in a cohort of subject with type 1 diabetes and impaired hypoglycaemia awareness. I was able to show that diazoxide magnified the counterregulatory response (particularly adrenaline) in patients with long standing T1D. In addition, a subgroup analysis revealed that participants with E23K polymorphism in the KATP channel had a blunted response to oral diazoxide. This study confirmed for the first time in humans that KATP channels also played an important role in modulating counterregulatory responses to hypoglycaemia and demonstrated the potential utility of KATP channel activators to improve counterregulatory responses to hypoglycemia in subjects with T1D.
The second approach focused on the paradoxical role in Type 1 diabetes of dysregulated glucagon secretion during fasting and in the post-prandial states, contributing to
hyperinsulinaemia, hypoglycaemia and increased glycaemic variability (GV). I postulated that suppression of glucose-induced glucagon secretion in Type 1 diabetes would reduce hyperinsulinaemia, reduce GV and subsequent exposure to hypoglycemia. This in turn, through hypoglycaemia avoidance, would over time lead to improved hypoglycaemia awareness. To test this, we performed a double-blind, 12 week randomized cross over trial, comparing Saxagliptin, a dipeptidyl peptidase 4 inhibitor (DPP4-I) that had been shown to known for its glucagon suppressive action, with placebo in a small cohort of subjects with Type 1 diabetes. However, we found that 12-weeks Saxagliptin therapy failed to have any significant impact on glucose variability indexes in Type 1 diabetes or exposure to hypoglycaemia. Subsequently, I found no differences between Saxagliptin or vehicle on CRR to hypoglycaemia. These findings therefore do not support the use of DPP4-inhibitors as a means of improving hypoglycaemia awareness in T1D.
For the second part of this thesis, we sought to explore the wider impact of recurrent hypoglycaemia on the hypothalamo-pituitary adrenal (HPA) axis. This study arose from the
understanding that hypoglycaemia represents a profound stimulation to the HPA axis, with a rise in peripheral glucocorticoid. Repeated HPA axis stimulation leads to (i) suppression of HPA axis activation in response to recurrent exposure to that stressor - this would have the additional effect of reducing the CRR response to hypoglycaemia, (ii) suppress diurnal variation in cortisol circadian rhythm – associated with increased cardiovascular risk as well as chronic alteration in mood and cognitive state. To examine this I studied T1D subjects with increased glucose variability (GV) (as an index of hypoglycaemia exposure) and measured circadian variation in salivary cortisol levels. In this study, I report that increased GV is associated with a blunted diurnal cortisol diurnal slope, associated with a significant increase in the area under the curve.
As a follow on study to this, I examined the HPA axis in greater detail by conducting a Corticotrophin releasing hormone (CRH) test, to determine the physiological level of the
dysregulation seen in those with T1D and recurrent hypoglycaemia. I found no significant difference to the CRH response between those with recurrent and those with infrequent
In conclusion, this thesis has explored two potential therapeutic strategies, based on current understanding of those mechanisms that underlie the development of impaired
hypoglycaemia awareness in Type 1 diabetes and reported that a strategy based on KATP channel activators, but not DPP4i, may have therapeutic potential. This would need to be explored in longer term intervention studies. In addition, I have shown that increased GV and hypoglycaemia exposure is associated with blunting of normal cortisol circadian patterns. Future studies will aim to assess the impact of this on long-term cardiovascular function and atherosclerosis in Type 1 diabetes.
|Date of Award||2015|
|Supervisor||Rory McCrimmon (Supervisor) & Michael Ashford (Supervisor)|