A research team led by scientists at the University of Exeter, working with Rigel Pharmaceuticals, has found a way help to defend against hypoglycemia in diabetes, by boosting hormonal defense systems. The approach, tested in rodents, uses a preclinical test compound, R481, to enter the brain and switch on AMP-activated protein kinase (AMPK). Results from the reported studies suggest that the kinase could represent a promising therapeutic target for the development of antiglycemic drugs.

Senior study author Craig Beall, PhD, at the University of Exeter, said, “Our findings suggest that switching on the brain fuel gauge we’ve identified could be useful for preventing hypoglycemia. In the long term, our aim is to create a pill that could be swallowed before bed, to prevent night time hypos. This is just the first step in a long road, and we hope one day we may be able to give some peace of mind to people with diabetes and parents of children with diabetes that they won’t have a bad night-time hypo.”

Beall and colleagues described their findings in Frontiers in Endocrinology, in a paper titled, “Brain Permeable AMP-Activated Protein Kinase Activator R481 Raises Glycemia by Autonomic Nervous System Activation and Amplifies the Counterregulatory Response to Hypoglycemia in Rats,” in which they concluded, “Taken together, our data suggest that R481 amplifies the counterregulatory response to hypoglycemia by a central rather than a direct effect on the pancreatic alpha-cell. These data provide proof-of-concept that central AMPK could be a target for future drug development for prevention of hypoglycemia and diabetes.”

In all forms of diabetes, blood sugar levels can become too high as the body is either unable to produce insulin, or cannot make enough of it, or the insulin it produces is not effective. This means that people with diabetes have to manage their blood sugar levels themselves, and these levels can commonly become dangerously high (hyperglycemia) or low (hypoglycemia). And as the authors noted, “Achieving more time in the target blood glucose (BG) range is a daily challenge for people with diabetes.” This can become an even greater challenge with tightening glycemic control using insulin treatment, which increases the risk of hypoglycemia. Moreover, the authors noted, “… disease progression and frequent exposure to hypoglycemia can lead to impaired awareness of and defective counterregulatory responses (CRR) to hypoglycemia.”

Episodes of hypoglycemia, also known as “hypos,” often occur at night, disrupting sleep and sometimes causing seizures. Hypoglycemia causes unpleasant symptoms such as anxiety, palpitations, sweating, and hunger. If extreme, they can also cause dizziness, confusion, loss of consciousness and, if untreated, coma and even death. Evidence suggests the 400,000 people with type 1 diabetes in the U.K. experience an average of two episodes of hypoglycemia per week and one severe episode per year.  People with type 2 diabetes experience up to five episodes of hypoglycaemia per year. Although the frequency is lower in type 2 diabetes, the overall rate is higher, because the condition affects well over four million people in the U.K.

Within the last twenty years, scientists have discovered that AMPK acts as a central component of cellular energy sensing, and plays an important role in regulating whole-body energy homeostasis through its actions in the hypothalamus in the brain, and also in the pancreas, the team continued. “Previous studies have shown that direct pharmacological activation of AMPK in the ventromedial nucleus of the hypothalamus (VMH), an important hypoglycemia-sensing brain region, increases the response to hypoglycemia in healthy, recurrently hypoglycemic and diabetic BB rats …”

For their reported studies, the researchers, funded by JDRF and supported by Diabetes UK, conducted laboratory experiments using a preclinical test compound, R481, developed by Rigel Pharmaceuticals, which acts a little like metformin, a widely used treatment for type 2 diabetes, but can directly enter the brain, where it switches on AMPK.

The researchers conducted experiments on specialized brain glucose-sensing neurons (GT1-7 cells) in petri dishes, and found that the compound works by activating this brain fuel gauge. “We assessed the effect of R481 on glucose homeostasis and used this novel compound to test the hypothesis that peripheral delivery of a brain-permeable AMPK activator may improve the CRR to hypoglycemia,” they wrote.

They then found that in healthy rats R481 boosts the hormonal defense against hypoglycemia, by increasing release of glucagon from the pancreas. The results suggested that the drug effectively switched on a brain-pancreas link to defend against hypoglycemia, but without changing fasting blood sugar levels. The authors concluded, “These data demonstrate that peripheral administration of the brain permeable “metformin-like” AMPK activator R481 increases blood glucose by activation of the autonomic nervous system and amplifies the glucagon response to hypoglycemia in rats … We provide proof-of-concept that pharmacological activation of central AMPK may be a suitable therapeutic target for amplifying the defense against hypoglycemia.”

They say that to be clinically useful, any anti-hypoglycemic drug would need to be taken prior to the unpredictable development of hypoglycemia. “A drug with an optimized pharmacodynamic/pharmacokinetic profile permitting dosing, for example, before bedtime, could be taken to prevent the development of nocturnal hypoglycaemia,” they stated. It will also be interesting to find out whether such central AMPK activating drugs could be used to treat severe hypoglycemia and promote rapid recovery of blood glucose levels.

First author Ana Cruz, PhD, at the University of Exeter, commented, “Our work highlights the importance of better understanding the brain-pancreas communication to boost the body’s defenses against hypoglycemia. I see the daily emotional and physical impact hypoglycemia can have and believe that these findings have taken us one step closer to finding targets within this brain-pancreas network to attenuate the impact of hypoglycemia.”

Lucy Chambers, PhD, head of research communications at Diabetes UK, which supported the study, said, “This early-stage research, funded by Diabetes UK has uncovered important links between the brain and the pancreas, that could in future lead to new treatments to help people with diabetes avoid hypos, or bring back their ability to recognize signs of low blood sugars. Hypos and hypo unawareness can be dangerous and debilitating, and can have a huge impact on the daily lives of people living with all types of diabetes. New treatments for treating hypos, or hypo unawareness would make living with diabetes much easier—reducing anxieties and crucially protecting people from the serious consequences that hypos can have.”

Conor McKeever, research communications manager at type 1 diabetes charity JDRF, further commented, “Hypoglycemia is one of the things people with type 1 report fearing most about their condition, so a treatment to prevent hypos would go a long way to relieving some of the burden that comes with living with type 1. It could also help reduce the worry felt by family members, who tell us they regularly lose sleep for fear that their loved one will have a hypo in the night. We’re proud to have funded this research and are keen to see how it develops on the road towards a new treatment for the 400,000 people living with type 1 in the U.K.”

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