1. The impact of novel AMP-activated protein kinase (AMPK) activators and glucose variability on pancreatic α-cell function
- Author
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Partridge, Katie, Beall, Craig, Ellacott, Kate, and Rackham, Chloe
- Subjects
alpha cell ,diabetes mellitus ,glucagon ,AMPK - Abstract
The physiological maintenance of normal blood glucose levels (euglycaemia) and prevention of hypoglycaemia is controlled by the intricate process of hormone release from the pancreatic islets of Langerhans, including the secretion of glucose-raising hormone (glucagon) from the islet α-cells. The defective control of glucagon release is commonly associated with both hyperglycaemia and recurrent hypoglycaemia in individuals with diabetes mellitus (DM). There is increasing evidence that α-cells, alongside intra-islet and autonomic control, are directly glucose-sensing to control glucagon secretion, This is includes evidence to suggest the activation of a critical energy sensor, AMP-activated protein kinase (AMPK), is at least partly involved in the stimulation of glucagon release. The mechanisms behind how α-cells intrinsically regulate glucagon secretion, and how these defective regulatory mechanisms could contribute toward the pathophysiology of DM are relatively under-explored. Providing greater understanding of α-cell physiology can therefore aid the development of small molecule compounds to pharmacologically boost α-cell glucose sensing and restore the α-cell functionality observed in DM. Here, the overarching aim of this thesis was to characterise the bioenergetic and secretory effects of pharmacological AMPK activation in pancreatic α-cells by using novel small molecules, including R481, O-304 and BI-9774. By doing so, this will widen the current knowledge on α-cell functional dynamics in both physiological and pathophysiological contexts, including recurrent hypoglycaemia. In addition to this, a literature review was conducted to highlight the putative role of AMPK and potential application of small molecule activators as a therapeutic avenue in cystic fibrosis-related diabetes (CFRD). Evidence suggests that, for the first time, AMPK could be a potent modulator of α-cell metabolic function and substrate utilisation in nutrient-depleted conditions. Here, AMPK activator exposure differentially controlled the glucagon secretory response and total glucagon content in α-cells, suggesting a role of AMPK in regulating glucagon granule dynamics and mechanism-of-action of such small molecules. Similarly, novel findings indicated that α-cells exposed to recurrent hypoglycaemic-like conditions (RLG) had intrinsic glycolytic and mitochondrial adaptations during low glucose and upon recovery, possibly to maintain energy status. The dysregulated intra-islet responses to glycaemia are similarly observed in other DM sub-types, such as CFRD, and contribute to worsened glucose tolerance. The author therefore discussed how the defective glucose-sensing in several tissues could contribute towards worsened glycaemia in CF/CFRD and postulated if the therapeutic application for small molecule AMPK activators could alleviate glucose-related complications, including inflammation, associated with CFRD. Altogether, the themes in this thesis explored the complex and wide-ranging metabolic targets of small molecule AMPK activators in the pancreatic α-cell. Furthermore, evidence suggested α-cells metabolically respond and adapt, respectively, to acute and recurrent nutrient depletion, and thereby pose an important therapeutic avenue in restoring glucose homeostasis in DM.
- Published
- 2023