Submitted on July 15, 2008
Revised on March 10, 2009
Accepted on March 27, 2009
Hypothalamic AMP-activated Protein Kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of Type 1 diabetes
Xiaoning Fan1, Yuyan Ding1, Stacey Brown1, Ligang Zhou, Margaret Shaw1, Monica C. Vella1, Haiying Cheng1, Ewan C McNay2, Robert S. Sherwin1, and Rory J McCrimmon1*
1 Yale University
2 U. Albany (SUNY)
* To whom correspondence should be addressed. E-mail: rory.mccrimmon{at}yale.edu.
In non-diabetic rodents, AMPK-activated protein kinase (AMPK) plays a role in the glucose-sensing mechanism used by the ventromedial hypothalamus (VMH), a key brain region involved in the detection of hypoglycemia. However, AMPK is regulated by both hyper- and hypoglycemia, and so whether AMPK plays a similar role in type 1 diabetes (T1DM) is unknown. Initially, we sought to establish the utility of AICAR (5- aminoimidazole-4-carboxamide) as a pharmacological activator of AMPK and demonstrate in non-diabetic rats that the stimulatory effect of local VMH AICAR delivery is blocked following the selective-down regulation of AMPK in the VMH using RNA interference. Subsequently, in vivo hyperinsulinemic hypoglycemic clamp studies were performed in insulin-dependent diabetic BB rats exposed to either recurrent hypoglycemia (RH), of chronic hyperglycemia (CH). VMH AICAR was shown to amplify both the glucagon (~180%) and epinephrine (~300%) response to subsequent hypoglycemia in RH-BB rats, and to amplify the glucagon (~80%) to hypoglycemia in CH-BB rats. We conclude that VMH AMPK also plays a role in glucose-sensing during hypoglycemia in a rodent model of T1DM. Moreover, our data suggest that it may be possible to partially restore the hypoglycemia-specific glucagon secretory defect characteristic of T1DM through manipulation of VMH AMPK.
