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Hypoglycaemia is a serious condition often associated with diabetes treatment, and has significant comorbidities. When repeated, as is often the case, it can lead to impaired awareness of hypoglycaemia in the body, and defective counterregulatory responses. Avoiding hypoglycaemia by maintaining a euglycaemic blood glucose level is a constant challenge for those with diabetes. AMP-activated protein kinase (AMPK) has an important role in cellular energy sensing, and has emerged as a regulator of whole body energy homeostasis via the hypothalamus and pancreas. Modulating the activation of AMPK may help to improve the hypoglycaemia response in diabetes patients. The Beall team has used AMPK activators to test changes in the counterregulatory response to hypoglycaemia, with the aim to identify future targets for drug development for hypoglycaemia prevention in diabetes.
Working with Rigel Pharmaceuticals, Inc. (USA), we tested novel AMP-activated protein kinase (AMPK) activating drugs, to find out if they can improve the hormonal response to insulin-induced hypoglycaemia.
This research is now published in Frontiers in Endocrinology: Brain Permeable AMP-Activated Protein Kinase Activator R481 Raises Glycaemia by Autonomic Nervous System Activation and Amplifies the Counterregulatory Response to Hypoglycaemia in Rats
A summary is also provided below:
R481 is a small molecule indirect AMPK activator (it stimulates the kinase by mild mitochondrial inhibition)
The drug has a similar mechanism of action to metformin but it is much more potent
If given to mice, the drug rapidly enters the brain (and may accumulate there)
Giving the drug to rats with a glucose load produced significantly higher blood glucose levels
This effect was completely prevented by blockers of the autonomic nervous system
The drug did not alter insulin sensitivity measured using a euglycaemic clamp
During insulin-induced hypoglycaemic clamps, R481 treated animals had a lower glucose infusion rate and an amplified glucagon response to hypoglycaemia.
The effect of the drug was not particularly long lasting but suggests that AMPK activation could be useful for prevention of hypoglycaemia
Whether the drug has effects of the pancreatic glucagon response more directly is not known but this is currently under investigation
Summary schematic from Ana Cruz's PhD thesis
Publications:
Publications:
Cruz AM, Partridge KM, Malekizadeh Y, Vlachaki Walker JM, Weightman Potter PG, Pye KR, Shaw SJ, Ellacott KLJ, Beall C. Brain Permeable AMP-Activated Protein Kinase Activator R481 Raises Glycaemia by Autonomic Nervous System Activation and Amplifies the Counterregulatory Response to Hypoglycaemia in Rats. Frontiers in Endocrinology. (2021) Dec 17;12:697445
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