Abstract
AimWe evaluated the efficacy of a novel brain permeable “metformin-like” AMP-activated protein kinase activator, R481, in regulating glucose homeostasis.Materials and MethodsWe used glucose sensing hypothalamic GT1-7 neuronal cells and pancreatic αTC1.9 α-cells to examine the effect of R481 on AMPK pathway activation and cellular metabolism. Glucose tolerance tests and hyperinsulinemic-euglycemic and hypoglycemic clamps were used in Sprague-Dawley rats to assess insulin sensitivity and hypoglycemia counterregulation, respectively.Results In vitro, we demonstrate that R481 increased AMPK phosphorylation in GT1-7 and αTC1.9 cells. In Sprague-Dawley rats, R481 increased peak glucose levels during a glucose tolerance test, without altering insulin levels or glucose clearance. The effect of R481 to raise peak glucose levels was attenuated by allosteric brain permeable AMPK inhibitor SBI-0206965. This effect was also completely abolished by blockade of the autonomic nervous system using hexamethonium. During hypoglycemic clamp studies, R481 treated animals had a significantly lower glucose infusion rate compared to vehicle treated controls. Peak plasma glucagon levels were significantly higher in R481 treated rats with no change to plasma adrenaline levels. In vitro, R481 did not alter glucagon release from αTC1.9 cells, but increased glycolysis. Non brain permeable AMPK activator R419 enhanced AMPK activity in vitro in neuronal cells but did not alter glucose excursion in vivo.ConclusionsThese 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. Taken together, our data suggest that R481 amplifies the counterregulatory response to hypoglycemia by a central rather than a direct effect on the pancreatic α-cell. These data provide proof-of-concept that central AMPK could be a target for future drug development for prevention of hypoglycemia in diabetes.
Highlights
Achieving more time in the target blood glucose (BG) range is a daily challenge for people with diabetes
This can become increasingly challenging with tightening glycemic control using insulin treatment, which increases the risk of hypoglycaemia
Previous studies have shown that direct pharmacological activation of AMPK in the ventromedial nucleus of the hypothalamus (VMH), an important hypoglycemia-sensing brain region [9], increases the response to hypoglycemia in healthy [10], recurrently hypoglycemic and diabetic BB rats [11] by increasing hepatic glucose production (HGP) with or without concomitant increases in glucagon and adrenaline levels
Summary
Achieving more time in the target blood glucose (BG) range is a daily challenge for people with diabetes. There are two isoforms of the a-subunit, AMPKa1 and AMPKa2, with the latter isoform having a more prominent role in glucose sensing [3,4,5] This enzyme plays an important role in regulating whole body energy homeostasis through its actions in the hypothalamus [6] and pancreas [7, 8]. Previous studies have shown that direct pharmacological activation of AMPK in the ventromedial nucleus of the hypothalamus (VMH), an important hypoglycemia-sensing brain region [9], increases the response to hypoglycemia in healthy [10], recurrently hypoglycemic and diabetic BB rats [11] by increasing hepatic glucose production (HGP) with or without concomitant increases in glucagon and adrenaline levels. 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
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